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Sign up cialis safe online for our newsletter Full page map Updated 6:11 a.m. Eastern, 10/20/20 Covid-19 spread in rural America at a record-breaking pace again last week, adding 160 counties to the red-zone list and bringing the total number of rural Americans who have tested positive for the coronavirus to more than 1 million. Nearly 70% of the nation’s 1,976 rural (nonmetropolitan) counties are now in the red zone, a term used by the White House Coronavirus Task Force to designate localities cialis safe online where the spread of the virus is out of control. Red-zone counties have a rate of at least 100 new infections per 100,000 in population.

Rural America had 82,188 new infections last week, a 16% increase and the fourth consecutive week of record-breaking levels of new cases. With last week’s cases, the cialis safe online total number of rural residents who have tested positive for the coronavirus broke 1 million (1,068,949), according to data compiled by the nonprofit USA Facts. The rate of new infections in rural counties now exceeds the urban rate by 63%, according to this week’s Daily Yonder analysis, which covers Sunday, October 11, through Saturday, October 17. Daily Yonder cialis safe online analysis/Data.

USA Facts Here are other highlights from this week’s analysis. The number of rural counties on the red-zone list grew to 1,358, last week, breaking the record of 1,198 set just the week before.Metropolitan areas also broke a record for red-zone counties last week. The metro red-zone list grew to 630, or 54% of cialis safe online the nation’s metropolitan counties. New metropolitan cases surpassed 300,000 last week.

That was an increase of 17% from the previous week but still cialis safe online falls short of the 400,000 new cases that metro counties added at the height of the July wave.Rural counties’ share of new cases continues to outpace the new caseload being experienced in metro counties. Last week, 21.3% or new cases originated in rural counties. Only 14% of the U.S. Population lives in nonmetropolitan counties.Deaths in rural counties totaled 1,277 for last week, an increase in the death toll by 94 cialis safe online.

In all, the deaths of 22,556 residents of rural America are attributed to Covid-19.Ninety percent of rural America’s new cases originated in red-zone counties last week. About two-thirds of metropolitan cases originated in red-zone counties.UPDATE. Wisconsin became the first state since Florida earlier this year to have all its rural counties in the red cialis safe online zone (46 of 46). It surpassed South Dakota, which has had 98% of its rural counties in the red zone the previous two weeks (57 of 58 counties).Twenty-three states have more than half of their rural counties in the red zone.

The table below lists states by cialis safe online the number of rural counties in the red zone. You Might Also LikeIHS Consultation and ConferOn October 14, 2020, IHS initiated tribal consultation and urban confer on the IHS COVID-19 Pandemic Vaccination Draft Plan [PDF – 694 KB] This document is currently in a draft status and may not be fully accessible to persons using assistive technology. For assistance with the information in this file, contact the IHS Office of Public Health Support at 301-443-0222. Tribal programs may cialis safe online submit written comments on the Draft Plan to consultation@ihs.gov and urban programs may submit comments to urbanconfer@ihs.gov.

Please include the following - SUBJECT LINE. IHS COVID-19 Pandemic Vaccine Draft cialis safe online Plan. The deadline for written comments is Wednesday, October 21, 2020. IHS developed and will continue to tailor the IHS COVID 19 Pandemic Vaccine Draft Plan based on available information and your input.

Additional Resources The Food &. Drug Administration will also hold a Vaccines and Related Biological Products Advisory Committee on October 22, 2020. Any members of the public wishing to make an oral presentation at the meeting should submit a request to the FDA by October 7, 2020..

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NCHS Data free cialis trial samples Brief buy cialis usa No. 286, September 2017PDF Versionpdf icon (374 KB)Anjel Vahratian, Ph.D.Key findingsData from the National Health Interview Survey, 2015Among those aged 40–59, perimenopausal women (56.0%) were more likely than postmenopausal (40.5%) and premenopausal (32.5%) women to sleep less than 7 hours, on average, in a 24-hour period.Postmenopausal women aged 40–59 were more likely than premenopausal women aged 40–59 to have trouble falling asleep (27.1% compared with 16.8%, respectively), and staying asleep (35.9% compared with 23.7%), four times or more in the past week.Postmenopausal women aged 40–59 (55.1%) were more likely than premenopausal women aged 40–59 (47.0%) to not wake up feeling well rested 4 days or more in the past week.Sleep duration and quality are important contributors to health and wellness. Insufficient sleep is associated with an increased risk for chronic buy cialis usa conditions such as cardiovascular disease (1) and diabetes (2). Women may be particularly vulnerable to sleep problems during times of reproductive hormonal change, such as after the menopausal transition.

Menopause is “the permanent cessation of menstruation that occurs after the loss of ovarian buy cialis usa activity” (3). This data brief describes sleep duration and sleep quality among nonpregnant women aged 40–59 by menopausal status. The age range selected for this analysis reflects the focus on midlife sleep health. In this analysis, 74.2% of women are premenopausal, 3.7% are perimenopausal, and 22.1% are postmenopausal buy cialis usa.

Keywords. Insufficient sleep, menopause, National Health Interview Survey Perimenopausal women were more likely than premenopausal and postmenopausal women to sleep less than 7 hours, on average, in a 24-hour period.More than one in three nonpregnant women aged 40–59 slept less than 7 hours, on average, in a 24-hour period (35.1%) buy cialis usa (Figure 1). Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period (56.0%), compared with 32.5% of premenopausal and 40.5% of postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to sleep less than 7 hours, on average, in a 24-hour period.

Figure 1 buy cialis usa. Percentage of nonpregnant women aged 40–59 who slept less than 7 hours, on average, in a 24-hour period, by menopausal status. United States, 2015image icon1Significant quadratic trend by menopausal buy cialis usa status (p <. 0.05).NOTES.

Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago buy cialis usa or less. Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 1pdf buy cialis usa icon.SOURCE.

NCHS, National Health Interview Survey, 2015. The percentage of women aged 40–59 who buy cialis usa had trouble falling asleep four times or more in the past week varied by menopausal status.Nearly one in five nonpregnant women aged 40–59 had trouble falling asleep four times or more in the past week (19.4%) (Figure 2). The percentage of women in this age group who had trouble falling asleep four times or more in the past week increased from 16.8% among premenopausal women to 24.7% among perimenopausal and 27.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble falling asleep four times or more in the past week.

Figure 2 buy cialis usa. Percentage of nonpregnant women aged 40–59 who had trouble falling asleep four times or more in the past week, by menopausal status. United States, 2015image icon1Significant linear trend buy cialis usa by menopausal status (p <. 0.05).NOTES.

Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and buy cialis usa their last menstrual cycle was 1 year ago or less. Women were premenopausal if they still had a menstrual cycle. Access data buy cialis usa table for Figure 2pdf icon.SOURCE.

NCHS, National Health Interview Survey, 2015. The percentage of women aged 40–59 who had trouble staying asleep four times or more in the past week varied buy cialis usa by menopausal status.More than one in four nonpregnant women aged 40–59 had trouble staying asleep four times or more in the past week (26.7%) (Figure 3). The percentage of women aged 40–59 who had trouble staying asleep four times or more in the past week increased from 23.7% among premenopausal, to 30.8% among perimenopausal, and to 35.9% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble staying asleep four times or more in the past week.

Figure 3 buy cialis usa. Percentage of nonpregnant women aged 40–59 who had trouble staying asleep four times or more in the past week, by menopausal status. United States, 2015image buy cialis usa icon1Significant linear trend by menopausal status (p <. 0.05).NOTES.

Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 buy cialis usa year ago or less. Women were premenopausal if they still had a menstrual cycle. Access data table buy cialis usa for Figure 3pdf icon.SOURCE.

NCHS, National Health Interview Survey, 2015. The percentage of women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week varied by menopausal status.Nearly one in two nonpregnant women aged 40–59 did not wake up feeling well rested 4 days or more in the past week (48.9%) (Figure 4). The percentage of buy cialis usa women in this age group who did not wake up feeling well rested 4 days or more in the past week increased from 47.0% among premenopausal women to 49.9% among perimenopausal and 55.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to not wake up feeling well rested 4 days or more in the past week.

Figure 4 buy cialis usa. Percentage of nonpregnant women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week, by menopausal status. United States, 2015image icon1Significant linear trend by menopausal status (p <. 0.05).NOTES.

Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less. Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 4pdf icon.SOURCE.

NCHS, National Health Interview Survey, 2015. SummaryThis report describes sleep duration and sleep quality among U.S. Nonpregnant women aged 40–59 by menopausal status. Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period compared with premenopausal and postmenopausal women.

In contrast, postmenopausal women were most likely to have poor-quality sleep. A greater percentage of postmenopausal women had frequent trouble falling asleep, staying asleep, and not waking well rested compared with premenopausal women. The percentage of perimenopausal women with poor-quality sleep was between the percentages for the other two groups in all three categories. Sleep duration changes with advancing age (4), but sleep duration and quality are also influenced by concurrent changes in women’s reproductive hormone levels (5).

Because sleep is critical for optimal health and well-being (6), the findings in this report highlight areas for further research and targeted health promotion. DefinitionsMenopausal status. A three-level categorical variable was created from a series of questions that asked women. 1) “How old were you when your periods or menstrual cycles started?.

€. 2) “Do you still have periods or menstrual cycles?. €. 3) “When did you have your last period or menstrual cycle?.

€. And 4) “Have you ever had both ovaries removed, either as part of a hysterectomy or as one or more separate surgeries?. € Women were postmenopausal if they a) had gone without a menstrual cycle for more than 1 year or b) were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they a) no longer had a menstrual cycle and b) their last menstrual cycle was 1 year ago or less.

Premenopausal women still had a menstrual cycle.Not waking feeling well rested. Determined by respondents who answered 3 days or less on the questionnaire item asking, “In the past week, on how many days did you wake up feeling well rested?. €Short sleep duration. Determined by respondents who answered 6 hours or less on the questionnaire item asking, “On average, how many hours of sleep do you get in a 24-hour period?.

€Trouble falling asleep. Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble falling asleep?. €Trouble staying asleep. Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble staying asleep?.

€ Data source and methodsData from the 2015 National Health Interview Survey (NHIS) were used for this analysis. NHIS is a multipurpose health survey conducted continuously throughout the year by the National Center for Health Statistics. Interviews are conducted in person in respondents’ homes, but follow-ups to complete interviews may be conducted over the telephone. Data for this analysis came from the Sample Adult core and cancer supplement sections of the 2015 NHIS.

For more information about NHIS, including the questionnaire, visit the NHIS website.All analyses used weights to produce national estimates. Estimates on sleep duration and quality in this report are nationally representative of the civilian, noninstitutionalized nonpregnant female population aged 40–59 living in households across the United States. The sample design is described in more detail elsewhere (7). Point estimates and their estimated variances were calculated using SUDAAN software (8) to account for the complex sample design of NHIS.

Linear and quadratic trend tests of the estimated proportions across menopausal status were tested in SUDAAN via PROC DESCRIPT using the POLY option. Differences between percentages were evaluated using two-sided significance tests at the 0.05 level. About the authorAnjel Vahratian is with the National Center for Health Statistics, Division of Health Interview Statistics. The author gratefully acknowledges the assistance of Lindsey Black in the preparation of this report.

ReferencesFord ES. Habitual sleep duration and predicted 10-year cardiovascular risk using the pooled cohort risk equations among US adults. J Am Heart Assoc 3(6):e001454. 2014.Ford ES, Wheaton AG, Chapman DP, Li C, Perry GS, Croft JB.

Associations between self-reported sleep duration and sleeping disorder with concentrations of fasting and 2-h glucose, insulin, and glycosylated hemoglobin among adults without diagnosed diabetes. J Diabetes 6(4):338–50. 2014.American College of Obstetrics and Gynecology. ACOG Practice Bulletin No.

141. Management of menopausal symptoms. Obstet Gynecol 123(1):202–16. 2014.Black LI, Nugent CN, Adams PF.

Tables of adult health behaviors, sleep. National Health Interview Survey, 2011–2014pdf icon. 2016.Santoro N. Perimenopause.

From research to practice. J Women’s Health (Larchmt) 25(4):332–9. 2016.Watson NF, Badr MS, Belenky G, Bliwise DL, Buxton OM, Buysse D, et al. Recommended amount of sleep for a healthy adult.

A joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. J Clin Sleep Med 11(6):591–2. 2015.Parsons VL, Moriarity C, Jonas K, et al. Design and estimation for the National Health Interview Survey, 2006–2015.

National Center for Health Statistics. Vital Health Stat 2(165). 2014.RTI International. SUDAAN (Release 11.0.0) [computer software].

2012. Suggested citationVahratian A. Sleep duration and quality among women aged 40–59, by menopausal status. NCHS data brief, no 286.

Hyattsville, MD. National Center for Health Statistics. 2017.Copyright informationAll material appearing in this report is in the public domain and may be reproduced or copied without permission. Citation as to source, however, is appreciated.National Center for Health StatisticsCharles J.

Rothwell, M.S., M.B.A., DirectorJennifer H. Madans, Ph.D., Associate Director for ScienceDivision of Health Interview StatisticsMarcie L. Cynamon, DirectorStephen J. Blumberg, Ph.D., Associate Director for Science.

NCHS Data http://cz.keimfarben.de/how-much-does-generic-cialis-cost/ Brief cialis safe online No. 286, September 2017PDF Versionpdf icon (374 KB)Anjel Vahratian, Ph.D.Key findingsData from the National Health Interview Survey, 2015Among those aged 40–59, perimenopausal women (56.0%) were more likely than postmenopausal (40.5%) and premenopausal (32.5%) women to sleep less than 7 hours, on average, in a 24-hour period.Postmenopausal women aged 40–59 were more likely than premenopausal women aged 40–59 to have trouble falling asleep (27.1% compared with 16.8%, respectively), and staying asleep (35.9% compared with 23.7%), four times or more in the past week.Postmenopausal women aged 40–59 (55.1%) were more likely than premenopausal women aged 40–59 (47.0%) to not wake up feeling well rested 4 days or more in the past week.Sleep duration and quality are important contributors to health and wellness. Insufficient sleep cialis safe online is associated with an increased risk for chronic conditions such as cardiovascular disease (1) and diabetes (2).

Women may be particularly vulnerable to sleep problems during times of reproductive hormonal change, such as after the menopausal transition. Menopause is cialis safe online “the permanent cessation of menstruation that occurs after the loss of ovarian activity” (3). This data brief describes sleep duration and sleep quality among nonpregnant women aged 40–59 by menopausal status.

The age range selected for this analysis reflects the focus on midlife sleep health. In this cialis safe online analysis, 74.2% of women are premenopausal, 3.7% are perimenopausal, and 22.1% are postmenopausal. Keywords.

Insufficient sleep, menopause, National Health Interview Survey Perimenopausal women were more likely than premenopausal and postmenopausal women to sleep less cialis safe online than 7 hours, on average, in a 24-hour period.More than one in three nonpregnant women aged 40–59 slept less than 7 hours, on average, in a 24-hour period (35.1%) (Figure 1). Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period (56.0%), compared with 32.5% of premenopausal and 40.5% of postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to sleep less than 7 hours, on average, in a 24-hour period.

Figure 1 cialis safe online. Percentage of nonpregnant women aged 40–59 who slept less than 7 hours, on average, in a 24-hour period, by menopausal status. United States, 2015image icon1Significant quadratic trend cialis safe online by menopausal status (p <.

0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last cialis safe online menstrual cycle was 1 year ago or less.

Women were premenopausal if they still had a menstrual cycle. Access data cialis safe online table for Figure 1pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

The percentage of women aged 40–59 who had trouble falling asleep four times cialis safe online or more in the past week varied by menopausal status.Nearly one in five nonpregnant women aged 40–59 had trouble falling asleep four times or more in the past week (19.4%) (Figure 2). The percentage of women in this age group who had trouble falling asleep four times or more in the past week increased from 16.8% among premenopausal women to 24.7% among perimenopausal and 27.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble falling asleep four times or more in the past week.

Figure 2 cialis safe online. Percentage of nonpregnant women aged 40–59 who had trouble falling asleep four times or more in the past week, by menopausal status. United States, cialis safe online 2015image icon1Significant linear trend by menopausal status (p <.

0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago cialis safe online or less.

Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 2pdf icon.SOURCE cialis safe online. NCHS, National Health Interview Survey, 2015.

The percentage of women aged 40–59 who had trouble staying asleep four times or more in the cialis safe online past week varied by menopausal status.More than one in four nonpregnant women aged 40–59 had trouble staying asleep four times or more in the past week (26.7%) (Figure 3). The percentage of women aged 40–59 who had trouble staying asleep four times or more in the past week increased from 23.7% among premenopausal, to 30.8% among perimenopausal, and to 35.9% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble staying asleep four times or more in the past week.

Figure 3 cialis safe online. Percentage of nonpregnant women aged 40–59 who had trouble staying asleep four times or more in the past week, by menopausal status. United States, cialis safe online 2015image icon1Significant linear trend by menopausal status (p <.

0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle cialis safe online and their last menstrual cycle was 1 year ago or less.

Women were premenopausal if they still had a menstrual cycle. Access data table for Figure cialis safe online 3pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

The percentage of women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week varied by menopausal status.Nearly one in two nonpregnant women aged 40–59 did not wake up feeling well rested 4 days or more in the past week (48.9%) (Figure 4). The percentage of women in cialis safe online this age group who did not wake up feeling well rested 4 days or more in the past week increased from 47.0% among premenopausal women to 49.9% among perimenopausal and 55.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to not wake up feeling well rested 4 days or more in the past week.

Figure 4 cialis safe online. Percentage of nonpregnant women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week, by menopausal status. United States, 2015image icon1Significant linear trend by menopausal status (p <.

0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less.

Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 4pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

SummaryThis report describes sleep duration and sleep quality among U.S. Nonpregnant women aged 40–59 by menopausal status. Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period compared with premenopausal and postmenopausal women.

In contrast, postmenopausal women were most likely to have poor-quality sleep. A greater percentage of postmenopausal women had frequent trouble falling asleep, staying asleep, and not waking well rested compared with premenopausal women. The percentage of perimenopausal women with poor-quality sleep was between the percentages for the other two groups in all three categories.

Sleep duration changes with advancing age (4), but sleep duration and quality are also influenced by concurrent changes in women’s reproductive hormone levels (5). Because sleep is critical for optimal health and well-being (6), the findings in this report highlight areas for further research and targeted health promotion. DefinitionsMenopausal status.

A three-level categorical variable was created from a series of questions that asked women. 1) “How old were you when your periods or menstrual cycles started?. €.

2) “Do you still have periods or menstrual cycles?. €. 3) “When did you have your last period or menstrual cycle?.

€. And 4) “Have you ever had both ovaries removed, either as part of a hysterectomy or as one or more separate surgeries?. € Women were postmenopausal if they a) had gone without a menstrual cycle for more than 1 year or b) were in surgical menopause after the removal of their ovaries.

Women were perimenopausal if they a) no longer had a menstrual cycle and b) their last menstrual cycle was 1 year ago or less. Premenopausal women still had a menstrual cycle.Not waking feeling well rested. Determined by respondents who answered 3 days or less on the questionnaire item asking, “In the past week, on how many days did you wake up feeling well rested?.

€Short sleep duration. Determined by respondents who answered 6 hours or less on the questionnaire item asking, “On average, how many hours of sleep do you get in a 24-hour period?. €Trouble falling asleep.

Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble falling asleep?. €Trouble staying asleep. Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble staying asleep?.

€ Data source and methodsData from the 2015 National Health Interview Survey (NHIS) were used for this analysis. NHIS is a multipurpose health survey conducted continuously throughout the year by the National Center for Health Statistics. Interviews are conducted in person in respondents’ homes, but follow-ups to complete interviews may be conducted over the telephone.

Data for this analysis came from the Sample Adult core and cancer supplement sections of the 2015 NHIS. For more information about NHIS, including the questionnaire, visit the NHIS website.All analyses used weights to produce national estimates. Estimates on sleep duration and quality in this report are nationally representative of the civilian, noninstitutionalized nonpregnant female population aged 40–59 living in households across the United States.

The sample design is described in more detail elsewhere (7). Point estimates and their estimated variances were calculated using SUDAAN software (8) to account for the complex sample design of NHIS. Linear and quadratic trend tests of the estimated proportions across menopausal status were tested in SUDAAN via PROC DESCRIPT using the POLY option.

Differences between percentages were evaluated using two-sided significance tests at the 0.05 level. About the authorAnjel Vahratian is with the National Center for Health Statistics, Division of Health Interview Statistics. The author gratefully acknowledges the assistance of Lindsey Black in the preparation of this report.

ReferencesFord ES. Habitual sleep duration and predicted 10-year cardiovascular risk using the pooled cohort risk equations among US adults. J Am Heart Assoc 3(6):e001454.

2014.Ford ES, Wheaton AG, Chapman DP, Li C, Perry GS, Croft JB. Associations between self-reported sleep duration and sleeping disorder with concentrations of fasting and 2-h glucose, insulin, and glycosylated hemoglobin among adults without diagnosed diabetes. J Diabetes 6(4):338–50.

2014.American College of Obstetrics and Gynecology. ACOG Practice Bulletin No. 141.

Management of menopausal symptoms. Obstet Gynecol 123(1):202–16. 2014.Black LI, Nugent CN, Adams PF.

Tables of adult health behaviors, sleep. National Health Interview Survey, 2011–2014pdf icon. 2016.Santoro N.

Perimenopause. From research to practice. J Women’s Health (Larchmt) 25(4):332–9.

2016.Watson NF, Badr MS, Belenky G, Bliwise DL, Buxton OM, Buysse D, et al. Recommended amount of sleep for a healthy adult. A joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society.

J Clin Sleep Med 11(6):591–2. 2015.Parsons VL, Moriarity C, Jonas K, et al. Design and estimation for the National Health Interview Survey, 2006–2015.

National Center for Health Statistics. Vital Health Stat 2(165). 2014.RTI International.

SUDAAN (Release 11.0.0) [computer software]. 2012. Suggested citationVahratian A.

Sleep duration and quality among women aged 40–59, by menopausal status. NCHS data brief, no 286. Hyattsville, MD.

National Center for Health Statistics. 2017.Copyright informationAll material appearing in this report is in the public domain and may be reproduced or copied without permission. Citation as to source, however, is appreciated.National Center for Health StatisticsCharles J.

Rothwell, M.S., M.B.A., DirectorJennifer H. Madans, Ph.D., Associate Director for ScienceDivision of Health Interview StatisticsMarcie L. Cynamon, DirectorStephen J.

Blumberg, Ph.D., Associate Director for Science.

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In good news, Premier Daniel Andrews has announced the easing of some coronavirus restrictions in cialis savings card Melbourne and regional Victoria after days cialis usa buy of intense lockdown. Here's a full rundown of all the changes.After more than 100 cialis savings card days in one of the world’s toughest coronavirus lockdowns, Victoria’s COVID restrictions are slowly easing. Premier Daniel Andrews expressed his gratitude towards the community, saying Victorians had done “an amazing cialis savings card job” during months of intense lockdown.“What it means is that as so many cities across the world head into what is going to be a deadly winter, we in Melbourne and across Victoria are well-placed to have a Covid-safe summer and a Covid-normal 2021,” he said on Sunday.However, it doesn’t mean life is completely back to ‘normal’.

Here are all the latest changes you need to know about so you can avoid being fined.Like what you see?. Sign up to our bodyandsoul.com.au newsletter for more stories like this.Everything you need to know about Victoria’s easing COVID restrictionsTravel radius expands to 25km Melbourne’s 5km travel radius has expanded to 25km from midnight on Sunday.Mr Andrews said the new 25km travel limit will be in place for “at least” the next fortnight and “may well be a feature” beyond November 1 – the scheduled date for the second stage of easing restrictions - as a means to stop large groups congregating in popular attractions.There are no travel distance restrictions in regional Victoria.Two-hour time limit lifted The city’s two-hour time limit for outdoor exercise and socialising has also been lifted and up to 10 people from two different households are now be able to gather outdoors.This means people will be able to gather outdoors for as long as they like, provided they are social distancing, wearing masks and are not more than 25km from home.Hairdressers reopenHairdressers will now be able to reopen their doors for business cialis savings card as of Monday.However, other beauty services such as nail salons, facials, tanning and waxing will remain closed until the next stage of easing restrictions.Golf, tennis, fishing and swimming permitted Certain sports that don’t require close contact will now be permitted as long as they take place within the city’s new 25km travel radius.Skate parks, tennis courts, golf courses and swimming pools are now allowed to reopen. Outdoor pools are now able to host up to 30 cialis savings card swimmers, but indoor pools are limited to one-on-one hydrotherapy sessions with a health professional.Real estate auctions are now able to recommence, too.Regional Victorians allowed to have family or people over Regional Victorians are now allowed to host up to two adults and any dependents in their homes.However, this doesn’t apply to Melburnians who are still not allowed to have visitors over for the next fortnight.Restaurants, cafes and pubs remain closed Restaurants, cafes, pubs and clubs will remain closed until November 1, with hopes venues will be allowed to seat up to 20 patrons indoors or 50 outdoors.As for regional Victoria, pubs, clubs and restaurants are now allowed to set up to 40 people inside and 70 outdoors.Reasons for leaving the house Unfortunately, the four permitted reasons for Melburnians leaving their home are still enforced – that is for work, shopping, socialising or exercising, and caregiving.Gyms remain closed Melbourne and regional Victorian gyms will remain closed for the foreseeable future.

Premier Daniel Andrews described gyms as a “high-risk environment” and said “it would not be safe” to reopen them.From juggling motherhood with running KORA Organics, to maintaining a friendship with ex-husband Orlando Bloom and fiancée Katy Perry, here's how Miranda Kerr manages to harmoniously balance it all. Miranda Kerr has been awake and in motion since 5.30am – juggling her three boys, taking work calls and even posing for a photo shoot in the pool room at the end of cialis savings card her garden at home near the California coast. Just before settling in for her chat cialis savings card with Body+Soul, she squeezed in a quick breastfeed for her one-year-old son Myles.

And thus, she admits, she’s worked up an appetite herself.A banana will have to do the trick, the model and skincare-and-wellness mogul decides, surmising that she should most definitely eat a snack lest she keel over from exhaustion mid-sentence.Kerr may look like a woman who glides seamlessly through life but, as she soon reveals, a lot of planning goes on beneath the surface in order to ensure her business and family lives run smoothly.Like what you see?. Sign up to our bodyandsoul.com.au newsletter for more stories like this.While cialis savings card she and her husband, Snap Inc. CEO and billionaire Evan Spiegel, are now one of Los Angeles’ premier power couples – The Wall Street Journal recently described their cialis savings card union as “a marriage of mindfulness” – they present a new paradigm of success.In essence, they both work hard – she on her skincare range Kora Organics, he on his company and its flagship social media platform Snapchat, which he co-founded in 2011.

But their days remain punctuated with healthy routines and behaviours aimed at providing balance and contentment.As Kerr tells Body+Soul, “[When I was] growing up, my mum was always busy and working a lot and that’s encouraged a great work ethic… but I also made a promise to cialis savings card myself that I’d have more balance in my life because I knew how much it affected my mum not to be there. I was lucky my grandparents were, and that I spent a lot of time with them.”A pandemic has disrupted everybody’s lives, but it’s enhanced them, too. Kerr, for instance, points out the benefits that come from being able to work from home alongside her husband.While Spiegel has set up a home office, she works from the children’s playroom so that Flynn, 9 – her son with ex-husband Orlando Bloom – can do his schooling online from her usual workspace.The family, which also includes two-year-old son Hart, gathers for breakfast, at which they all drink celery juice before getting on with their days.Then the former Victoria’s Secret model works on her skincare business, which she started in Australia in 2009 and launched internationally three years ago.Kerr spearheaded the “clean beauty” movement and is understandably proud that her award-winning products launch nationally in Myer cialis savings card stores this month.“Kora is, literally, my baby girl,” she says.

€œWhen I launched the brand I was busy modelling and it was more like a hobby and passion, but when I took it international, I really had to step up my game and be involved every day.”She says Spiegel, who at 30 is cialis savings card seven years her junior, encouraged her to take more risks. €œEvan started using my Noni Glow Face Oil every day and said, ‘Wow, this really works.’ I said to him, ‘What did you think... That I cialis savings card was just playing around?.

€™ He said I had an incredible product so why wasn’t I investing more in cialis savings card it. He had confidence in me and he was right about that.”She’s similarly supportive of his endeavours. €œHe’s such an intelligent man and I’ll do whatever I can to support him because he’s built his business with such integrity and creativity.” As to whether they Snapchat each cialis savings card other, she laughingly admits they do.

€œOh my god, all day, cialis savings card even when we’re in the same house!. I’ll Snap him when I’m doing a photo shoot or looking after the kids, or breastfeeding.”While Kerr has a full-time nanny who lives in a guest-house on their property, she makes a point of sitting down to dinner with her sons before bathing them, reading stories and putting them to bed.Sometimes she has what she calls a “half and half” dinner, eating a little with her sons, then more later with her husband. On the evening of our chat, the pair have a special dinner planned, one of a series of monthly meals cooked by cialis savings card a chef from Kerr’s favourite restaurant.

€œEvan bought it as a gift for our anniversary,” she says.The fact they both embrace cialis savings card a healthy lifestyle gives a synchronicity to their home and working lives, says Kerr, who’s a brand ambassador for infant probiotic brand Biostime. As she says, proper nutrition gives children a great start in life.With such an enviable life, Kerr stays focused on being grateful for all that she has, including her cialis savings card warm relationship with Bloom and his fiancée Katy Perry.“I have this incredible family and we all have a lot of respect for each other. We’re great friends and all enjoy each other’s company, although we haven’t seen each other much because of COVID and because they have a new baby.

But I adore cialis savings card Katy, and I’m so grateful that she and Orlando found each other. It all worked out in cialis savings card the end.”How Miranda Kerr lives her best life1. €œI put my phone on airplane mode at night and leave it on until after the kids have eaten their breakfast.

Sleep is cialis savings card important and it’s great to start the mornings without thinking about work. I’ve also learnt to cialis savings card go to bed early and wake up early.”2. €œIt’s good to keep a schedule but be flexible with it.

I have a colour-coordinated diary with everything I need to do, from breastfeeding to calling cialis savings card my mum. But I say to my team that cialis savings card we have to be flexible like a willow tree, not rigid like an oak tree. Because in a storm, the oak tree falls down.

I’m a big cialis savings card believer in going with the flow. I like things mapped out but that cialis savings card embrace flexibility.”3.“I take an hour of just-me time in the morning to do yoga or meditate. Make sure you have a minimum of 20 minutes to yourself each cialis savings card day, whether it’s spent reading or meditating or doing yoga.

Focusing on filling up your cup makes you a better partner, parent and friend.”4. €œExercise is cialis savings card super important. I’ve always liked cialis savings card yoga but nowadays I try to include exercise in the everyday, even if it’s just walking with the kids in a pram.

Or I put music on and dance with them or jump on a trampoline. I get more cialis savings card out of exercise as I get older. You need to book it in and not cialis savings card feel guilty about it.”5.

€œEvery thought we think affects our reality. The way we talk to ourselves has an impact cialis savings card on us on a cellular level. The way cialis savings card we self-talk matters.

We can look outside and think, ‘It’s so gloomy, I can’t believe it’s raining again.’ Or we can say, ‘Oh, wow, we really need this rain.’ There’s always a positive and a negative, and if you can’t choose a more positive approach then at least be neutral about it.”.

In good news, Premier Daniel Andrews has announced the easing of some coronavirus restrictions roman cialis in Melbourne and regional Victoria after days of cialis safe online intense lockdown. Here's a full rundown of all the changes.After more than cialis safe online 100 days in one of the world’s toughest coronavirus lockdowns, Victoria’s COVID restrictions are slowly easing. Premier Daniel Andrews expressed his gratitude towards the community, saying Victorians had done “an amazing job” during months of intense lockdown.“What it means is that as so many cities across the world head into what is cialis safe online going to be a deadly winter, we in Melbourne and across Victoria are well-placed to have a Covid-safe summer and a Covid-normal 2021,” he said on Sunday.However, it doesn’t mean life is completely back to ‘normal’.

Here are all the latest changes you need to know about so you can avoid being fined.Like what you see?. Sign up to our bodyandsoul.com.au newsletter for more stories like this.Everything you need to know about Victoria’s easing COVID restrictionsTravel radius expands to 25km Melbourne’s 5km travel radius has expanded to 25km from midnight on Sunday.Mr Andrews said the new 25km travel limit will be in place for “at least” the next fortnight and “may well be a feature” beyond November 1 – the scheduled date for the second stage cialis safe online of easing restrictions - as a means to stop large groups congregating in popular attractions.There are no travel distance restrictions in regional Victoria.Two-hour time limit lifted The city’s two-hour time limit for outdoor exercise and socialising has also been lifted and up to 10 people from two different households are now be able to gather outdoors.This means people will be able to gather outdoors for as long as they like, provided they are social distancing, wearing masks and are not more than 25km from home.Hairdressers reopenHairdressers will now be able to reopen their doors for business as of Monday.However, other beauty services such as nail salons, facials, tanning and waxing will remain closed until the next stage of easing restrictions.Golf, tennis, fishing and swimming permitted Certain sports that don’t require close contact will now be permitted as long as they take place within the city’s new 25km travel radius.Skate parks, tennis courts, golf courses and swimming pools are now allowed to reopen. Outdoor pools are now able to host up to 30 swimmers, but indoor pools are limited to one-on-one hydrotherapy sessions with a health professional.Real estate auctions cialis safe online are now able to recommence, too.Regional Victorians allowed to have family or people over Regional Victorians are now allowed to host up to two adults and any dependents in their homes.However, this doesn’t apply to Melburnians who are still not allowed to have visitors over for the next fortnight.Restaurants, cafes and pubs remain closed Restaurants, cafes, pubs and clubs will remain closed until November 1, with hopes venues will be allowed to seat up to 20 patrons indoors or 50 outdoors.As for regional Victoria, pubs, clubs and restaurants are now allowed to set up to 40 people inside and 70 outdoors.Reasons for leaving the house Unfortunately, the four permitted reasons for Melburnians leaving their home are still enforced – that is for work, shopping, socialising or exercising, and caregiving.Gyms remain closed Melbourne and regional Victorian gyms will remain closed for the foreseeable future.

Premier Daniel Andrews described gyms as a “high-risk environment” and said “it would not be safe” to reopen them.From juggling motherhood with running KORA Organics, to maintaining a friendship with ex-husband Orlando Bloom and fiancée Katy Perry, here's how Miranda Kerr manages to harmoniously balance it all. Miranda Kerr has been awake and in motion since 5.30am – juggling her three boys, taking work calls and even posing for a photo shoot in the pool room at the end of cialis safe online her garden at home near the California coast. Just before settling in for her cialis safe online chat with Body+Soul, she squeezed in a quick breastfeed for her one-year-old son Myles.

And thus, she admits, she’s worked up an appetite herself.A banana will have to do the trick, the model and skincare-and-wellness mogul decides, surmising that she should most definitely eat a snack lest she keel over from exhaustion mid-sentence.Kerr may look like a woman who glides seamlessly through life but, as she soon reveals, a lot of planning goes on beneath the surface in order to ensure her business and family lives run smoothly.Like what you see?. Sign up to our bodyandsoul.com.au newsletter for more stories like cialis safe online this.While she and her husband, Snap Inc. CEO and billionaire Evan Spiegel, are now one of Los Angeles’ premier power couples – The Wall Street Journal recently described their union as “a marriage of mindfulness” – they present a new paradigm of success.In essence, they both work hard – she on her skincare range Kora Organics, cialis safe online he on his company and its flagship social media platform Snapchat, which he co-founded in 2011.

But their days remain punctuated with healthy routines and behaviours aimed at providing balance and contentment.As Kerr tells Body+Soul, “[When I cialis safe online was] growing up, my mum was always busy and working a lot and that’s encouraged a great work ethic… but I also made a promise to myself that I’d have more balance in my life because I knew how much it affected my mum not to be there. I was lucky my grandparents were, and that I spent a lot of time with them.”A pandemic has disrupted everybody’s lives, but it’s enhanced them, too. Kerr, for instance, points out the benefits that come from being able to work from home alongside her husband.While Spiegel has set up a home office, she works from the children’s playroom so that Flynn, 9 – her son with ex-husband Orlando Bloom – cialis safe online can do his schooling online from her usual workspace.The family, which also includes two-year-old son Hart, gathers for breakfast, at which they all drink celery juice before getting on with their days.Then the former Victoria’s Secret model works on her skincare business, which she started in Australia in 2009 and launched internationally three years ago.Kerr spearheaded the “clean beauty” movement and is understandably proud that her award-winning products launch nationally in Myer stores this month.“Kora is, literally, my baby girl,” she says.

€œWhen I launched the brand I was busy modelling and it was more like a hobby and passion, but when I took it international, I really had to step up my game and be involved every day.”She says Spiegel, who at 30 is seven years her junior, encouraged her to take more cialis safe online risks. €œEvan started using my Noni Glow Face Oil every day and said, ‘Wow, this really works.’ I said to him, ‘What did you think... That I was just playing cialis safe online around?.

€™ He said I cialis safe online had an incredible product so why wasn’t I investing more in it. He had confidence in me and he was right about that.”She’s similarly supportive of his endeavours. €œHe’s such an intelligent man and I’ll do whatever I can to support him because he’s built his business cialis safe online with such integrity and creativity.” As to whether they Snapchat each other, she laughingly admits they do.

€œOh my god, all day, even when cialis safe online we’re in the same house!. I’ll Snap him when I’m doing a photo shoot or looking after the kids, or breastfeeding.”While Kerr has a full-time nanny who lives in a guest-house on their property, she makes a point of sitting down to dinner with her sons before bathing them, reading stories and putting them to bed.Sometimes she has what she calls a “half and half” dinner, eating a little with her sons, then more later with her husband. On the evening of our chat, the pair have a special dinner planned, one of a series of monthly meals cooked cialis safe online by a chef from Kerr’s favourite restaurant.

€œEvan bought it as a gift for our cialis 5mg reviews anniversary,” she cialis safe online says.The fact they both embrace a healthy lifestyle gives a synchronicity to their home and working lives, says Kerr, who’s a brand ambassador for infant probiotic brand Biostime. As she says, proper nutrition gives children a great start in life.With such an enviable life, Kerr stays focused on being grateful for all that she has, cialis safe online including her warm relationship with Bloom and his fiancée Katy Perry.“I have this incredible family and we all have a lot of respect for each other. We’re great friends and all enjoy each other’s company, although we haven’t seen each other much because of COVID and because they have a new baby.

But I adore Katy, and I’m so grateful that she cialis safe online and Orlando found each other. It all worked out in cialis safe online the end.”How Miranda Kerr lives her best life1. €œI put my phone on airplane mode at night and leave it on until after the kids have eaten their breakfast.

Sleep is important and it’s great to start the cialis safe online mornings without thinking about work. I’ve also learnt to go to bed early and wake up early.”2 cialis safe online. €œIt’s good to keep a schedule but be flexible with it.

I have a colour-coordinated diary with everything I need to do, from breastfeeding to calling cialis safe online my mum. But I say to my team that we have to be flexible like a willow tree, not rigid like an oak tree cialis safe online. Because in a storm, the oak tree falls down.

I’m a big believer in going with cialis safe online the flow. I like things mapped cialis safe online out but that embrace flexibility.”3.“I take an hour of just-me time in the morning to do yoga or meditate. Make sure you cialis safe online have a minimum of 20 minutes to yourself each day, whether it’s spent reading or meditating or doing yoga.

Focusing on filling up your cup makes you a better partner, parent and friend.”4. €œExercise is cialis safe online super important. I’ve always liked yoga but nowadays cialis safe online I try to include exercise in the everyday, even if it’s just walking with the kids in a pram.

Or I put music on and dance with them or jump on a trampoline. I get more out of exercise as I get older cialis safe online. You need to book it in cialis safe online and not feel guilty about it.”5.

€œEvery thought we think affects our reality. The way we talk to ourselves has an impact on us cialis safe online on a cellular level. The way cialis safe online we self-talk matters.

We can look outside and think, ‘It’s so gloomy, I can’t believe it’s raining again.’ Or we can say, ‘Oh, wow, we really need this rain.’ There’s always a positive and a negative, and if you can’t choose a more positive approach then at least be neutral about it.”.

What is the maximum amount of cialis i can take

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This document does not apply to clinical information submitted to support the go to this site market authorization of a medical device under the Medical Device Regulations or of a new drug submission under the Food and Drug Regulations what is the maximum amount of cialis i can take (FDR). The exception are new drug submissions for COVID-19 indications submitted under the FDR. For more information on the public release of this information, see the Public Release of Clinical Information. Guidance document.Also not applicable what is the maximum amount of cialis i can take under this document is the CBI disclosure authority under section 21.1(3)(c) of the Food and Drugs Act.

This section permits the Minister of Health to disclose CBI to certain persons for the purpose of protection or promotion of human health or the safety of the public. For information on this authority, see the guidance document Disclosure of Confidential Business Information under Paragraph 21.1(3)(c) of the Food and Drugs Act.Proactive release of drug application informationWe will proactively publish safety and efficacy information used to support interim order drug applications upon authorization. This includes clinical information in applications submitted under sections 3, 6 and 14 of the interim order.How to request clinical information in medical device applicationsWe will publish safety and effectiveness information used to support interim order medical device applications when we receive a request from the public and within the limits of what is the maximum amount of cialis i can take our administrative capacity. Requests made for multiple applications will be processed in sequence and subject to prioritization.

Further prioritization may be given to products that have a greater impact on the health system, such as. Products that are used a lot products that have a higher public interestRequests received for information in applications under the interim order will be prioritized over requests for clinical information in non-COVID19-related drugs submissions and device applications.To request clinical information on medical device applications, use our special portal to submit an what is the maximum amount of cialis i can take electronic request form. Be sure to identify the product name listed on the following sites. Publication process Publication of safety and efficacy information used to support drug interim order applications The publication of information follows the process described in section 4 and Appendix C of the Public Release of Clinical Information guidance document.In accordance with PRCI timelines, we aim to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from starting the process.

The process starts automatically on the day an what is the maximum amount of cialis i can take authorization is issued.Step 1. Notice to the company and request for proposed CBI redactions and anonymizationFollowing the authorization of a drug under the interim order, Health Canada will give the manufacturer an opportunity to take part in a process initiation meeting. The first 60 days of the 120-day publication process is allocated for the company to review the clinical information. The company uses the Proposed Redaction Control Sheet (Appendix E, Public Release what is the maximum amount of cialis i can take of Clinical Information (PRCI) guidance document) to propose any redaction of CBI.

Proposed CBI redactions should pertain to information that meets the definition of confidential business information. This is defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the definition. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to what is the maximum amount of cialis i can take the person or a material financial gain to their competitorsFollowing an assessment of the proposals, text within an in-scope document found to meet the above definition will be protected. Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business information.

Exceptions to the PRCI regulations described in C.08.009.2(2)(a) and (b) of the Food and Drug Regulations or section 43.12(2)(a) and (b) of the Medical Device Regulations will be considered when applying redactions to confidential business information. Further information on what is the maximum amount of cialis i can take the application of these exceptions can be found in the Health Canada PRCI guidance document.All personal information should be anonymized in accordance with section 6 of the Public Release of Clinical Information guidance document. The proposal package from the manufacturer should include. The proposed redaction control sheet the draft anonymization report annotated documentsManufacturers submit for Health Canada assessment using either CanadaPost ePost Connect or a suitable secure file transfer site of the manufacturer’s choosing.Step 2.

Health Canada assessment of company representationsWithin 30 days of receiving the proposal package, Health Canada will what is the maximum amount of cialis i can take complete and return our assessment of the proposed CBI redactions and anonymization methodology. Proposed redactions that meet the definition of confidential business information will be protected. We will review the anonymization methodology to ensure all personal information is protected while maximizing the disclosure of useful clinical information. Step 3 what is the maximum amount of cialis i can take.

Revision of proposed CBI redactions and anonymizationIf proposed CBI redactions are rejected or revision is required to the anonymization methodology, in accordance with the Public Release of Clinical Information. Guidance document, the manufacturer will be given 15 days to make the revisions and resubmit. We will send our final assessment to the manufacturer within what is the maximum amount of cialis i can take 5 days of receiving the revised package. Step 4.

Finalization and publicationWithin 5 days of receiving our final assessment, the manufacturer must format and submit the final redacted and anonymization clinical documents within 5 days of receiving our final assessment. The final what is the maximum amount of cialis i can take documents must comply with the Guidance Document. Preparation of Regulatory Activities using the Electronic Common Technical Document (eCTD) Format. These documents are to be submitted using the Common Electronic Submission Gateway.

We will publish the final redacted documents within 5 days of receiving the final sequence.Publication of safety and effectiveness information used to support medical device interim order applicationsThe publication of information within an interim order application will proceed through the abbreviated process what is the maximum amount of cialis i can take described below. Our goal is to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from initiation of the process.Step 1. Health Canada screening of requestsAfter we receive a request for information, we will retrieve the interim order application from docubridge (or other location). Information related to safety and effectiveness will be considered what is the maximum amount of cialis i can take in-scope of publication.

Other information will not be released publicly. Only information available at the time the request is made will be considered for disclosure. Information submitted after the original request for disclosure will be considered for public release upon what is the maximum amount of cialis i can take receipt of a subsequent request.Examples of in scope information include. Clinical testing information validation testing that supports the effectiveness of the product, including testing performed in vitro or in silico summaries or overviews on safety or efficacy pre- or post-market, including literature reviewsExamples of out of scope information include.

Manufacturing details not related to safety or efficacy engineering and design details general documents, such as user manuals, package inserts and instructions for use individual patient information, such as patient listings and case report forms, that require extensive anonymization interim clinical study data (see the PRCI guidance)Step 2a. Health Canada assessment of confidential business information To reduce administrative burden on the manufacturer, we will review in-scope records for confidential business information, as defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that what is the maximum amount of cialis i can take meets each of the following 3 elements of the definition will be protected. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitorsText in an in-scope document found to meet this definition will be redacted using a PDF redaction tool. Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business information.

Exceptions to the PRCI regulations what is the maximum amount of cialis i can take are outlined section 43.12(2)(a) and (b) of the Medical Device Regulations. These exceptions will be considered when applying redactions to confidential business information. Further information on the application of these exceptions can be found in the PRCI guidance document.Step 2b. Assessing personal what is the maximum amount of cialis i can take informationIn general, in-scope records do not contain a large volume of personal identification information.

Any personal information, as defined in the Privacy Act and in accordance with PRCI guidance, information that could help to identify an individual will be protected. For example, this can include the names of authors and investigators as well as subject identification numbers.A large volume of indirectly identifying information is not expected in the medical device records that are in-scope of publication. Consequently, limited protection what is the maximum amount of cialis i can take of personal information is anticipated.Personal information will be redacted using a PDF redaction tool. Step 3.

Notice to the company and request for redaction proposalFollowing the review and redaction of in scope documents, we will send the manufacturer a written notice indicating our intent to publish the identified documents. A copy of what is the maximum amount of cialis i can take the release package will be sent for the manufacturer’s review. Any further proposed redactions by the manufacturer must be received within 14 calendar days.Manufacturer are asked to use the Proposed Redaction Control Sheet (see Appendix E of the PRCI guidance document) to suggest further redactions.Step 4. Health Canada assessment of company representationsAny further redactions proposed by the manufacturer will be assessed in accordance with the process outlined in step 2, above.

Those that meet the what is the maximum amount of cialis i can take definition of personal or confidential business information will be accepted.Step 5. PublicationIn-scope documents will be published within 120 days following receipt of the request. The redacted information will be uploaded to the Clinical Information Portal, indexed by application number. Published documents will carry a watermark and be subject to terms of use, as described in the PRCI guidance.Mailing addressInformation Science and Openness DivisionResource Management and Operations DirectorateHealth Products and Food BranchHealth Canada Graham Spry Building 250 Lanark what is the maximum amount of cialis i can take Ave Ottawa ON K1A 0K9 Telephone.

613-960-4687Email. Hc.clinicaldata-donneescliniques.sc@canada.ca Terminology and definitions Anonymization. Means the what is the maximum amount of cialis i can take process through which personal information is modified by. removing direct identifiers and any related code that would enable linkage with identifying information and ensuring that the remaining indirect identifiers no longer present a serious possibility of re-identifying an individual CBI.

Confidential business information, as meant in common law and as defined in Section 2 of the Food and Drugs Act. in respect what is the maximum amount of cialis i can take of a person to whose business or affairs the information relates, means (subject to the regulations) business information that. Is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitors Clinical information. Means information in respect of a clinical trial, clinical studies or investigational testing, such as.

clinical overviews, clinical summaries and clinical study reports for drugs summaries and detailed what is the maximum amount of cialis i can take information of all clinical studies and investigational testing that provided evidence of safety and effectiveness for medical devices Clinical study report. Means an "integrated" full report of an individual study of any therapeutic, prophylactic or diagnostic agent (drug or treatment) conducted in patients, in which. the clinical and statistical description, presentations and analyses are integrated into a single report incorporating tables and figures into the main text of the report or at the end of the text appendices contain the protocol, sample case report forms, investigator-related information, information related to the test drugs/investigational products, including active control/comparators, technical statistical documentation, related publications, patient data listings and technical statistical details such as derivations, computations, analyses and computer output FDA. Food and what is the maximum amount of cialis i can take Drugs Act FDR.

Food and Drug Regulations IMDRF ToC. International Medical Device Regulators Forum Table of Contents Medical device. Has the same meaning as insee the what is the maximum amount of cialis i can take Medical Devices Regulations. For information on the classification of medical devices, please see the guidance documents on the.

risk-based classification system for in vitro diagnostic devices (IVDDs) risk-based classification system for non-in vitro diagnostic devices (non-IVDDs) Non-commercial purpose. Means the what is the maximum amount of cialis i can take information will not be used to support a marketing authorization application anywhere in the world or sold or traded to another person Personal information. Has the same meaning as in Section 3 of the Privacy Act Related linksOn this page About the guidance document This guidance document supports the Interim Order Respecting Drugs, Medical Devices and Foods for a Special Dietary Purpose in Relation to COVID-19. The Minister of Health approved the Interim Order on March 30, 2020, to address the unprecedented demand and urgent need for medical devices to treat, diagnose and protect Canadians against COVID-19.

The guidance covers what is the maximum amount of cialis i can take sections 15 to 19 of the Interim Order. It remains in effect as long as the Interim Order is in effect. Under the Interim Order, manufacturers and importers must report medical device shortages related to COVID-19 to Health Canada. The devices to which what is the maximum amount of cialis i can take the shortages apply are on the List of Medical Devices — Notification of Shortages (specified medical devices).

A specified medical device is a device that is either. set out in the list of medical devices or part of a category of medical devices that is set out in that list The guidance is intended to help manufacturers and importers meet their regulatory obligations. It outlines their responsibilities concerning the mandatory reporting of medical device shortages what is the maximum amount of cialis i can take. About medical device shortages and reporting A medical device shortage occurs when a manufacturer is unable to meet Canadian market demand for the device or for its components, accessories, parts or consumable materials.

This does not apply when a substitute device, component, accessory, part or consumable material is available in Canada. There are 2 what is the maximum amount of cialis i can take types of shortages. actual, when the current supply can’t meet current demand anticipated, when the future supply can’t meet projected demand Manufacturers and importers must. report a medical device shortage provide a shortage status update if there is a change in the shortage information submitted provide additional information related to a shortage when requested by Health Canada report an end of a medical device shortage This guidance document also provides some guidance on how to voluntarily report a medical device shortage that does not fall under the Interim Order.

Everyone has a role to play Manufacturers and importers Manufacturers and importers have a key role to play in preventing and reducing the impact what is the maximum amount of cialis i can take of medical device shortages. They can control the volume of medical devices in the supply chain and can take steps to resolve a medical device shortage when one occurs. They are also in the best position to communicate to customers about the availability of their devices. When a manufacturer experiences a shortage of a what is the maximum amount of cialis i can take critical medical device it sells, we expect that the manufacturer will take all necessary measures to resolve the shortage as quickly as possible.

Provincial/territorial governments and health care authorities Provincial and territorial governments and health care authorities also have an important role to play in preventing and mitigating critical medical device shortages. They can. conserve and reallocate stock within regions or provinces to where it is most needed and collaborate to share supply identify and secure additional supplies of medical devices from other vendors or another provincial or territorial government identify and secure other compatible substitute medical devices Government of Canada The federal government administers the Food and Drugs Act, Radiation Emitting Devices Act and Medical Devices Regulations. We do not provide or control the supply of medical devices in Canada or have the authority to compel a manufacturer to supply a device.

We work with stakeholders across the medical device supply chain to help determine the details and status of a shortage. We also coordinate and facilitate information sharing.

For more information on the public release of this information, see the Public cialis safe online Release of Clinical Information. Guidance document.Also not applicable under this document is the CBI disclosure authority under section 21.1(3)(c) of the Food and Drugs Act. This section permits the Minister of Health to disclose CBI to certain persons for the purpose of protection or promotion of human health or the safety of the public. For information on this authority, see the guidance document Disclosure of Confidential Business Information under Paragraph 21.1(3)(c) of the Food and cialis safe online Drugs Act.Proactive release of drug application informationWe will proactively publish safety and efficacy information used to support interim order drug applications upon authorization. This includes clinical information in applications submitted under sections 3, 6 and 14 of the interim order.How to request clinical information in medical device applicationsWe will publish safety and effectiveness information used to support interim order medical device applications when we receive a request from the public and within the limits of our administrative capacity.

Requests made for multiple applications will be processed in sequence and subject to prioritization. Further prioritization may be given to products that have cialis safe online a greater impact on the health system, such as. Products that are used a lot products that have a higher public interestRequests received for information in applications under the interim order will be prioritized over requests for clinical information in non-COVID19-related drugs submissions and device applications.To request clinical information on medical device applications, use our special portal to submit an electronic request form. Be sure to identify the product name listed on the following sites. Publication process cialis safe online Publication of safety and efficacy information used to support drug interim order applications The publication of information follows the process described in section 4 and Appendix C of the Public Release of Clinical Information guidance document.In accordance with PRCI timelines, we aim to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from starting the process.

The process starts automatically on the day an authorization is issued.Step 1. Notice to the company and request for proposed CBI redactions and anonymizationFollowing the authorization of a drug under the interim order, Health Canada will give the manufacturer an opportunity to take part in a process initiation meeting. The first 60 days of the 120-day cialis safe online publication process is allocated for the company to review the clinical information. The company uses the Proposed Redaction Control Sheet (Appendix E, Public Release of Clinical Information (PRCI) guidance document) to propose any redaction of CBI. Proposed CBI redactions should pertain to information that meets the definition of confidential business information.

This is defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the cialis safe online following 3 elements of the definition. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitorsFollowing an assessment of the proposals, text within an in-scope document found to meet the above definition will be protected. Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business information. Exceptions to the PRCI regulations described in C.08.009.2(2)(a) and (b) of the Food and Drug Regulations or section 43.12(2)(a) cialis safe online and (b) of the Medical Device Regulations will be considered when applying redactions to confidential business information. Further information on the application of these exceptions can be found in the Health Canada PRCI guidance document.All personal information should be anonymized in accordance with section 6 of the Public Release of Clinical Information guidance document.

The proposal package from the manufacturer should include. The proposed redaction control sheet the draft anonymization report annotated documentsManufacturers submit for Health cialis safe online Canada assessment using either CanadaPost ePost Connect or a suitable secure file transfer site of the manufacturer’s choosing.Step 2. Health Canada assessment of company representationsWithin 30 days of receiving the proposal package, Health Canada will complete and return our assessment of the proposed CBI redactions and anonymization methodology. Proposed redactions that meet the definition of confidential business information will be protected. We will cialis safe online review the anonymization methodology to ensure all personal information is protected while maximizing the disclosure of useful clinical information.

Step 3. Revision of proposed CBI redactions and anonymizationIf proposed CBI redactions are rejected or revision is required to the anonymization methodology, in accordance with the Public Release of Clinical Information. Guidance document, the manufacturer will be cialis safe online given 15 days to make the revisions and resubmit. We will send our final assessment to the manufacturer within 5 days of receiving the revised package. Step 4.

Finalization and publicationWithin cialis safe online 5 days of receiving our final assessment, the manufacturer must format and submit the final redacted and anonymization clinical documents within 5 days of receiving our final assessment. The final documents must comply with the Guidance Document. Preparation of Regulatory Activities using the Electronic Common Technical Document (eCTD) Format. These documents are to be submitted using the Common Electronic cialis safe online Submission Gateway. We will publish the final redacted documents within 5 days of receiving the final sequence.Publication of safety and effectiveness information used to support medical device interim order applicationsThe publication of information within an interim order application will proceed through the abbreviated process described below.

Our goal is to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from initiation of the process.Step 1. Health Canada screening of requestsAfter we receive a request for information, we will retrieve the interim order application from docubridge (or other location) cialis safe online. Information related to safety and effectiveness will be considered in-scope of publication. Other information will not be released publicly. Only information cialis safe online available at the time the request is made will be considered for disclosure.

Information submitted after the original request for disclosure will be considered for public release upon receipt of a subsequent request.Examples of in scope information include. Clinical testing information validation testing that supports the effectiveness of the product, including testing performed in vitro or in silico summaries or overviews on safety or efficacy pre- or post-market, including literature reviewsExamples of out of scope information include. Manufacturing details not related to safety or efficacy engineering and design details general documents, such as user manuals, package inserts and instructions for use individual patient cialis safe online information, such as patient listings and case report forms, that require extensive anonymization interim clinical study data (see the PRCI guidance)Step 2a. Health Canada assessment of confidential business information To reduce administrative burden on the manufacturer, we will review in-scope records for confidential business information, as defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the definition will be protected. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitorsText in an in-scope document found to meet this definition will be redacted using a PDF redaction tool.

Similar to Public Release of Clinical Information cialis safe online policies, any information that meets the definition of “clinical information” will not be considered confidential business information. Exceptions to the PRCI regulations are outlined section 43.12(2)(a) and (b) of the Medical Device Regulations. These exceptions will be considered when applying redactions to confidential business information. Further information on the application cialis safe online of these exceptions can be found in the PRCI guidance document.Step 2b. Assessing personal informationIn general, in-scope records do not contain a large volume of personal identification information.

Any personal information, as defined in the Privacy Act and in accordance with PRCI guidance, information that could help to identify an individual will be protected. For example, this can include the names of authors and investigators as cialis safe online well as subject identification numbers.A large volume of indirectly identifying information is not expected in the medical device records that are in-scope of publication. Consequently, limited protection of personal information is anticipated.Personal information will be redacted using a PDF redaction tool. Step 3. Notice to the company and request for redaction proposalFollowing the review and redaction cialis safe online of in scope documents, we will send the manufacturer a written notice indicating our intent to publish the identified documents.

A copy of the release package will be sent for the manufacturer’s review. Any further proposed redactions by the manufacturer must be received within 14 calendar days.Manufacturer are asked to use the Proposed Redaction Control Sheet (see Appendix E of the PRCI guidance document) to suggest further redactions.Step 4. Health Canada assessment of company representationsAny further redactions proposed by the manufacturer will be cialis safe online assessed in accordance with the process outlined in step 2, above. Those that meet the definition of personal or confidential business information will be accepted.Step 5. PublicationIn-scope documents will be published within 120 days following receipt of the request.

The redacted cialis safe online information will be uploaded to the Clinical Information Portal, indexed by application number. Published documents will carry a watermark and be subject to terms of use, as described in the PRCI guidance.Mailing addressInformation Science and Openness DivisionResource Management and Operations DirectorateHealth Products and Food BranchHealth Canada Graham Spry Building 250 Lanark Ave Ottawa ON K1A 0K9 Telephone. 613-960-4687Email. Hc.clinicaldata-donneescliniques.sc@canada.ca Terminology and cialis safe online definitions Anonymization. Means the process through which personal information is modified by.

removing direct identifiers and any related code that would enable linkage with identifying information and ensuring that the remaining indirect identifiers no longer present a serious possibility of re-identifying an individual CBI. Confidential business cialis safe online information, as meant in common law and as defined in Section 2 of the Food and Drugs Act. in respect of a person to whose business or affairs the information relates, means (subject to the regulations) business information that. Is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitors Clinical information. Means information in respect of a clinical trial, clinical studies or investigational testing, cialis safe online such as.

clinical overviews, clinical summaries and clinical study reports for drugs summaries and detailed information of all clinical studies and investigational testing that provided evidence of safety and effectiveness for medical devices Clinical study report. Means an "integrated" full report of an individual study of any therapeutic, prophylactic or diagnostic agent (drug or treatment) conducted in patients, in which. the clinical and statistical description, presentations and analyses are integrated into a single report incorporating tables and figures into the main text of the report or at the end of the text appendices contain the protocol, sample case report forms, investigator-related information, information related to the test drugs/investigational products, including active control/comparators, technical statistical documentation, related publications, patient data listings and technical statistical details such as derivations, cialis safe online computations, analyses and computer output FDA. Food and Drugs Act FDR. Food and Drug Regulations IMDRF ToC.

International Medical Device Regulators Forum Table of Contents Medical device cialis safe online. Has the same meaning as insee the Medical Devices Regulations. For information on the classification of medical devices, please see the guidance documents on the. risk-based classification system cialis safe online for in vitro diagnostic devices (IVDDs) risk-based classification system for non-in vitro diagnostic devices (non-IVDDs) Non-commercial purpose. Means the information will not be used to support a marketing authorization application anywhere in the world or sold or traded to another person Personal information.

Has the same meaning as in Section 3 of the Privacy Act Related linksOn this page About the guidance document This guidance document supports the Interim Order Respecting Drugs, Medical Devices and Foods for a Special Dietary Purpose in Relation to COVID-19. The Minister of Health approved the Interim Order on March 30, 2020, cialis safe online to address the unprecedented demand and urgent need for medical devices to treat, diagnose and protect Canadians against COVID-19. The guidance covers sections 15 to 19 of the Interim Order. It remains in effect as long as the Interim Order is in effect. Under the Interim Order, manufacturers and importers must report medical device shortages cialis safe online related to COVID-19 to Health Canada.

The devices to which the shortages apply are on the List of Medical Devices — Notification of Shortages (specified medical devices). A specified medical device is a device that is either. set out in the list of medical devices or part of a category of medical devices that is set out in that list The guidance is intended to help manufacturers cialis safe online and importers meet their regulatory obligations. It outlines their responsibilities concerning the mandatory reporting of medical device shortages. About medical device shortages and reporting A medical device shortage occurs when a manufacturer is unable to meet Canadian market demand for the device or for its components, accessories, parts or consumable materials.

This does not apply when a substitute cialis safe online device, component, accessory, part or consumable material is available in Canada. There are 2 types of shortages. actual, when the current supply can’t meet current demand anticipated, when the future supply can’t meet projected demand Manufacturers and importers must. report a medical device shortage provide a shortage status update if there is a change in the shortage information submitted provide additional information related to a shortage when requested by Health Canada report an end of a medical device shortage This guidance document also provides some guidance on how to voluntarily report a medical device shortage that does not fall under cialis safe online the Interim Order. Everyone has a role to play Manufacturers and importers Manufacturers and importers have a key role to play in preventing and reducing the impact of medical device shortages.

They can control the volume of medical devices in the supply chain and can take steps to resolve a medical device shortage when one occurs. They are also in the best position to communicate to cialis safe online customers about the availability of their devices. When a manufacturer experiences a shortage of a critical medical device it sells, we expect that the manufacturer will take all necessary measures to resolve the shortage as quickly as possible. Provincial/territorial governments and health care authorities Provincial and territorial governments and health care authorities also have an important role to play in preventing and mitigating critical medical device shortages. They can cialis safe online.

conserve and reallocate stock within regions or provinces to where it is most needed and collaborate to share supply identify and secure additional supplies of medical devices from other vendors or another provincial or territorial government identify and secure other compatible substitute medical devices Government of Canada The federal government administers the Food and Drugs Act, Radiation Emitting Devices Act and Medical Devices Regulations. We do not provide or control the supply of medical devices in Canada or have the authority to compel a manufacturer to supply a device. We work with stakeholders across the medical device supply chain to help determine the details and cialis safe online status of a shortage. We also coordinate and facilitate information sharing. When it comes to medical device shortages, Health Canada depends on early reporting of anticipated or actual shortages to help us.

prevent or manage impacts related to medical device shortages work with industry to identify mitigation strategies inform the procurement of medical devices for Canada Depending on the situation, our options include.

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Trial Population Table 1 generic cialis cvs cialis 5mg daily how long before it works. Table 1. Characteristics of the Participants in the mRNA-1273 generic cialis cvs Trial at Enrollment.

The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020 (Fig. S1). Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second vaccination window owing to isolation for suspected Covid-19 while the test results, ultimately negative, were pending.

All continued to attend scheduled trial visits. The demographic characteristics of participants at enrollment are provided in Table 1. Vaccine Safety No serious adverse events were noted, and no prespecified trial halting rules were met.

As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination. Figure 1. Figure 1.

Systemic and Local Adverse Events. The severity of solicited adverse events was graded as mild, moderate, or severe (see Table S1).After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group. All were mild or moderate in severity (Figure 1 and Table S2).

Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events. None of the participants had fever after the first vaccination. After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever.

One of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. (Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.) Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common. Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site.

Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3). SARS-CoV-2 Binding Antibody Responses Table 2. Table 2.

Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 in Participants and in Convalescent Serum Specimens. Figure 2. Figure 2.

SARS-CoV-2 Antibody and Neutralization Responses. Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live virus PRNT80 responses (Panel D). In Panel A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and median area under the curve (AUC), respectively.

Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The convalescent serum panel includes specimens from 41 participants. Red dots indicate the 3 specimens that were also tested in the PRNT assay.

The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent serum panel. In Panel C, boxes and horizontal bars denote IQR and median ID50, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR.

In the convalescent serum panel, red dots indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent panel. In Panel D, boxes and horizontal bars denote IQR and median PRNT80, respectively.

Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The three convalescent serum specimens were also tested in ELISA and PsVNA assays. Because of the time-intensive nature of the PRNT assay, for this preliminary report, PRNT results were available only for the 25-μg and 100-μg dose groups.Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A).

Dose-dependent responses to the first and second vaccinations were evident. Receptor-binding domain–specific antibody responses were similar in pattern and magnitude (Figure 2B). For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens.

The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]). SARS-CoV-2 Neutralization Responses No participant had detectable PsVNA responses before vaccination. After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50].

Figure 2C, Fig. S8, and Table 2. 80% inhibitory dilution [ID80].

Fig. S2 and Table S6). However, after the second vaccination, PsVNA responses were identified in serum samples from all participants.

The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43. The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43). These responses were similar to values in the upper half of the distribution of values for convalescent serum specimens.

Before vaccination, no participant had detectable 80% live-virus neutralization at the highest serum concentration tested (1:8 dilution) in the PRNT assay. At day 43, wild-type virus–neutralizing activity capable of reducing SARS-CoV-2 infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D). Neutralizing PRNT80 average responses were generally at or above the values of the three convalescent serum specimens tested in this assay.

Good agreement was noted within and between the values from binding assays for S-2P and receptor-binding domain and neutralizing activity measured by PsVNA and PRNT (Figs. S3 through S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273. SARS-CoV-2 T-Cell Responses The 25-μg and 100-μg doses elicited CD4 T-cell responses (Figs.

S9 and S10) that on stimulation by S-specific peptide pools were strongly biased toward expression of Th1 cytokines (tumor necrosis factor α >. Interleukin 2 >. Interferon γ), with minimal type 2 helper T-cell (Th2) cytokine expression (interleukin 4 and interleukin 13).

CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100-μg dose group (Fig. S11).Patients Figure 1. Figure 1.

Enrollment and Randomization. Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization. 541 were assigned to the remdesivir group and 522 to the placebo group (Figure 1).

Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Forty-nine patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death (36 patients) or because the patient withdrew consent (13). Of those assigned to receive placebo, 518 patients (99.2%) received placebo as assigned.

Fifty-three patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death (36 patients), because the patient withdrew consent (15), or because the patient was found to be ineligible for trial enrollment (2). As of April 28, 2020, a total of 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day 29, recovered, or died. Eight patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29.

There were 132 patients in the remdesivir group and 169 in the placebo group who had not recovered and had not completed the day 29 follow-up visit. The analysis population included 1059 patients for whom we have at least some postbaseline data available (538 in the remdesivir group and 521 in the placebo group). Four of the 1063 patients were not included in the primary analysis because no postbaseline data were available at the time of the database freeze.

Table 1. Table 1. Demographic and Clinical Characteristics at Baseline.

The mean age of patients was 58.9 years, and 64.3% were male (Table 1). On the basis of the evolving epidemiology of Covid-19 during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1). Overall, 53.2% of the patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were designated as other or not reported.

249 (23.4%) were Hispanic or Latino. Most patients had either one (27.0%) or two or more (52.1%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12).

Nine hundred forty-three (88.7%) patients had severe disease at enrollment as defined in the Supplementary Appendix. 272 (25.6%) patients met category 7 criteria on the ordinal scale, 197 (18.5%) category 6, 421 (39.6%) category 5, and 127 (11.9%) category 4. There were 46 (4.3%) patients who had missing ordinal scale data at enrollment.

No substantial imbalances in baseline characteristics were observed between the remdesivir group and the placebo group. Primary Outcome Figure 2. Figure 2.

Kaplan–Meier Estimates of Cumulative Recoveries. Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen. Panel B), in those with a baseline score of 5 (receiving oxygen.

Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in those with a baseline score of 7 (receiving mechanical ventilation or ECMO. Panel E).

Table 2. Table 2. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population.

Figure 3. Figure 3. Time to Recovery According to Subgroup.

The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and ethnic group were reported by the patients. Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 11 days, as compared with 15 days.

Rate ratio for recovery, 1.32. 95% confidence interval [CI], 1.12 to 1.55. P<0.001.

1059 patients (Figure 2 and Table 2). Among patients with a baseline ordinal score of 5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84). Among patients with a baseline score of 4 (127 patients) and those with a baseline score of 6 (197 patients), the rate ratio estimates for recovery were 1.38 (95% CI, 0.94 to 2.03) and 1.20 (95% CI, 0.79 to 1.81), respectively.

For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7. 272 patients), the rate ratio for recovery was 0.95 (95% CI, 0.64 to 1.42). A test of interaction of treatment with baseline score on the ordinal scale was not significant.

An analysis adjusting for baseline ordinal score as a stratification variable was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome. This adjusted analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.31. 95% CI, 1.12 to 1.54.

1017 patients). Table S2 in the Supplementary Appendix shows results according to the baseline severity stratum of mild-to-moderate as compared with severe. Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.28 (95% CI, 1.05 to 1.57.

664 patients), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.38 (95% CI, 1.05 to 1.81. 380 patients) (Figure 3). Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.50.

95% CI, 1.18 to 1.91. P=0.001. 844 patients) (Table 2 and Fig.

S5). Mortality was numerically lower in the remdesivir group than in the placebo group, but the difference was not significant (hazard ratio for death, 0.70. 95% CI, 0.47 to 1.04.

1059 patients). The Kaplan–Meier estimates of mortality by 14 days were 7.1% and 11.9% in the remdesivir and placebo groups, respectively (Table 2). The Kaplan–Meier estimates of mortality by 28 days are not reported in this preliminary analysis, given the large number of patients that had yet to complete day 29 visits.

An analysis with adjustment for baseline ordinal score as a stratification variable showed a hazard ratio for death of 0.74 (95% CI, 0.50 to 1.10). Safety Outcomes Serious adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141 patients (27.0%) in the placebo group (Table S3). 4 events (2 in each group) were judged by site investigators to be related to remdesivir or placebo.

There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients). Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group. No deaths were considered to be related to treatment assignment, as judged by the site investigators.

Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4). The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group). Acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]).

Pyrexia (27 events [5.0%], as compared with 17 [3.3%]). Hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]). And increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]).

Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.Announced on May 15, Operation Warp Speed (OWS) — a partnership of the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector — aims to accelerate control of the Covid-19 pandemic by advancing development, manufacturing, and distribution of vaccines, therapeutics, and diagnostics. OWS is providing support to promising candidates and enabling the expeditious, parallel execution of the necessary steps toward approval or authorization of safe products by the Food and Drug Administration (FDA).The partnership grew out of an acknowledged need to fundamentally restructure the way the U.S. Government typically supports viagra cialis product development and vaccine distribution.

The initiative was premised on setting a “stretch goal” — one that initially seemed impossible but that is becoming increasingly achievable.The concept of an integrated structure for Covid-19 countermeasure research and development across the U.S. Government was based on experience with Zika and the Zika Leadership Group led by the National Institutes of Health (NIH) and the assistant secretary for preparedness and response (ASPR). One of us (M.S.) serves as OWS chief advisor.

We are drawing on expertise from the NIH, ASPR, the Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority (BARDA), and the DOD, including the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and the Defense Advanced Research Projects Agency. OWS has engaged experts in all critical aspects of medical countermeasure research, development, manufacturing, and distribution to work in close coordination.The initiative set ambitious objectives. To deliver tens of millions of doses of a SARS-CoV-2 vaccine — with demonstrated safety and efficacy, and approved or authorized by the FDA for use in the U.S.

Population — beginning at the end of 2020 and to have as many as 300 million doses of such vaccines available and deployed by mid-2021. The pace and scope of such a vaccine effort are unprecedented. The 2014 West African Ebola virus epidemic spurred rapid vaccine development, but though preclinical data existed before the outbreak, a period of 12 months was required to progress from phase 1 first-in-human trials to phase 3 efficacy trials.

OWS aims to compress this time frame even further. SARS-CoV-2 vaccine development began in January, phase 1 clinical studies in March, and the first phase 3 trials in July. Our objectives are based on advances in vaccine platform technology, improved understanding of safe and efficacious vaccine design, and similarities between the SARS-CoV-1 and SARS-CoV-2 disease mechanisms.OWS’s role is to enable, accelerate, harmonize, and advise the companies developing the selected vaccines.

The companies will execute the clinical or process development and manufacturing plans, while OWS leverages the full capacity of the U.S. Government to ensure that no technical, logistic, or financial hurdles hinder vaccine development or deployment.OWS selected vaccine candidates on the basis of four criteria. We required candidates to have robust preclinical data or early-stage clinical trial data supporting their potential for clinical safety and efficacy.

Candidates had to have the potential, with our acceleration support, to enter large phase 3 field efficacy trials this summer or fall (July to November 2020) and, assuming continued active transmission of the virus, to deliver efficacy outcomes by the end of 2020 or the first half of 2021. Candidates had to be based on vaccine-platform technologies permitting fast and effective manufacturing, and their developers had to demonstrate the industrial process scalability, yields, and consistency necessary to reliably produce more than 100 million doses by mid-2021. Finally, candidates had to use one of four vaccine-platform technologies that we believe are the most likely to yield a safe and effective vaccine against Covid-19.

The mRNA platform, the replication-defective live-vector platform, the recombinant-subunit-adjuvanted protein platform, or the attenuated replicating live-vector platform.OWS’s strategy relies on a few key principles. First, we sought to build a diverse project portfolio that includes two vaccine candidates based on each of the four platform technologies. Such diversification mitigates the risk of failure due to safety, efficacy, industrial manufacturability, or scheduling factors and may permit selection of the best vaccine platform for each subpopulation at risk for contracting or transmitting Covid-19, including older adults, frontline and essential workers, young adults, and pediatric populations.

In addition, advancing eight vaccines in parallel will increase the chances of delivering 300 million doses in the first half of 2021.Second, we must accelerate vaccine program development without compromising safety, efficacy, or product quality. Clinical development, process development, and manufacturing scale-up can be substantially accelerated by running all streams, fully resourced, in parallel. Doing so requires taking on substantial financial risk, as compared with the conventional sequential development approach.

OWS will maximize the size of phase 3 trials (30,000 to 50,000 participants each) and optimize trial-site location by consulting daily epidemiologic and disease-forecasting models to ensure the fastest path to an efficacy readout. Such large trials also increase the safety data set for each candidate vaccine.With heavy up-front investment, companies can conduct clinical operations and site preparation for these phase 3 efficacy trials even as they file their Investigational New Drug application (IND) for their phase 1 studies, thereby ensuring immediate initiation of phase 3 when they get a green light from the FDA. To permit appropriate comparisons among the vaccine candidates and to optimize vaccine utilization after approval by the FDA, the phase 3 trial end points and assay readouts have been harmonized through a collaborative effort involving the National Institute of Allergy and Infectious Diseases (NIAID), the Coronavirus Prevention Network, OWS, and the sponsor companies.Finally, OWS is supporting the companies financially and technically to commence process development and scale up manufacturing while their vaccines are in preclinical or very early clinical stages.

To ensure that industrial processes are set, running, and validated for FDA inspection when phase 3 trials end, OWS is also supporting facility building or refurbishing, equipment fitting, staff hiring and training, raw-material sourcing, technology transfer and validation, bulk product processing into vials, and acquisition of ample vials, syringes, and needles for each vaccine candidate. We aim to have stockpiled, at OWS’s expense, a few tens of millions of vaccine doses that could be swiftly deployed once FDA approval is obtained.This strategy aims to accelerate vaccine development without curtailing the critical steps required by sound science and regulatory standards. The FDA recently reissued guidance and standards that will be used to assess each vaccine for a Biologics License Application (BLA).

Alternatively, the agency could decide to issue an Emergency Use Authorization to permit vaccine administration before all BLA procedures are completed.Of the eight vaccines in OWS’s portfolio, six have been announced and partnerships executed with the companies. Moderna and Pfizer/BioNTech (both mRNA), AstraZeneca and Janssen (both replication-defective live-vector), and Novavax and Sanofi/GSK (both recombinant-subunit-adjuvanted protein). These candidates cover three of the four platform technologies and are currently in clinical trials.

The remaining two candidates will enter trials soon.Moderna developed its RNA vaccine in collaboration with the NIAID, began its phase 1 trial in March, recently published encouraging safety and immunogenicity data,1 and entered phase 3 on July 27. Pfizer and BioNTech’s RNA vaccine also produced encouraging phase 1 results2 and started its phase 3 trial on July 27. The ChAdOx replication-defective live-vector vaccine developed by AstraZeneca and Oxford University is in phase 3 trials in the United Kingdom, Brazil, and South Africa, and it should enter U.S.

Phase 3 trials in August.3 The Janssen Ad26 Covid-19 replication-defective live-vector vaccine has demonstrated excellent protection in nonhuman primate models and began its U.S. Phase 1 trial on July 27. It should be in phase 3 trials in mid-September.

Novavax completed a phase 1 trial of its recombinant-subunit-adjuvanted protein vaccine in Australia and should enter phase 3 trials in the United States by the end of September.4 Sanofi/GSK is completing preclinical development steps and plans to commence a phase 1 trial in early September and to be well into phase 3 by year’s end.5On the process-development front, the RNA vaccines are already being manufactured at scale. The other candidates are well advanced in their scale-up development, and manufacturing sites are being refurbished.While development and manufacturing proceed, the HHS–DOD partnership is laying the groundwork for vaccine distribution, subpopulation prioritization, financing, and logistic support. We are working with bioethicists and experts from the NIH, the CDC, BARDA, and the Centers for Medicare and Medicaid Services to address these critical issues.

We will receive recommendations from the CDC Advisory Committee on Immunization Practices, and we are working to ensure that the most vulnerable and at-risk persons will receive vaccine doses once they are ready. Prioritization will also depend on the relative performance of each vaccine and its suitability for particular populations. Because some technologies have limited previous data on safety in humans, the long-term safety of these vaccines will be carefully assessed using pharmacovigilance surveillance strategies.No scientific enterprise could guarantee success by January 2021, but the strategic decisions and choices we’ve made, the support the government has provided, and the accomplishments to date make us optimistic that we will succeed in this unprecedented endeavor.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial to evaluate postexposure prophylaxis with hydroxychloroquine after exposure to Covid-19.12 We randomly assigned participants in a 1:1 ratio to receive either hydroxychloroquine or placebo.

Participants had known exposure (by participant report) to a person with laboratory-confirmed Covid-19, whether as a household contact, a health care worker, or a person with other occupational exposures. Trial enrollment began on March 17, 2020, with an eligibility threshold to enroll within 3 days after exposure. The objective was to intervene before the median incubation period of 5 to 6 days.

Because of limited access to prompt testing, health care workers could initially be enrolled on the basis of presumptive high-risk exposure to patients with pending tests. However, on March 23, eligibility was changed to exposure to a person with a positive polymerase-chain-reaction (PCR) assay for SARS-CoV-2, with the eligibility window extended to within 4 days after exposure. This trial was approved by the institutional review board at the University of Minnesota and conducted under a Food and Drug Administration Investigational New Drug application.

In Canada, the trial was approved by Health Canada. Ethics approvals were obtained from the Research Institute of the McGill University Health Centre, the University of Manitoba, and the University of Alberta. Participants We included participants who had household or occupational exposure to a person with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure).

Participants were excluded if they were younger than 18 years of age, were hospitalized, or met other exclusion criteria (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Persons with symptoms of Covid-19 or with PCR-proven SARS-CoV-2 infection were excluded from this prevention trial but were separately enrolled in a companion clinical trial to treat early infection. Setting Recruitment was performed primarily with the use of social media outreach as well as traditional media platforms.

Participants were enrolled nationwide in the United States and in the Canadian provinces of Quebec, Manitoba, and Alberta. Participants enrolled themselves through a secure Internet-based survey using the Research Electronic Data Capture (REDCap) system.13 After participants read the consent form, their comprehension of its contents was assessed. Participants provided a digitally captured signature to indicate informed consent.

We sent follow-up e-mail surveys on days 1, 5, 10, and 14. A survey at 4 to 6 weeks asked about any follow-up testing, illness, or hospitalizations. Participants who did not respond to follow-up surveys received text messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes.

When these methods were unsuccessful, the emergency contact provided by the enrollee was contacted to determine the participant’s illness and vital status. When all communication methods were exhausted, Internet searches for obituaries were performed to ascertain vital status. Interventions Randomization occurred at research pharmacies in Minneapolis and Montreal.

The trial statisticians generated a permuted-block randomization sequence using variably sized blocks of 2, 4, or 8, with stratification according to country. A research pharmacist sequentially assigned participants. The assignments were concealed from investigators and participants.

Only pharmacies had access to the randomization sequence. Hydroxychloroquine sulfate or placebo was dispensed and shipped overnight to participants by commercial courier. The dosing regimen for hydroxychloroquine was 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for 4 more days for a total course of 5 days (19 tablets total).

If participants had gastrointestinal upset, they were advised to divide the daily dose into two or three doses. We chose this hydroxychloroquine dosing regimen on the basis of pharmacokinetic simulations to achieve plasma concentrations above the SARS-CoV-2 in vitro half maximal effective concentration for 14 days.14 Placebo folate tablets, which were similar in appearance to the hydroxychloroquine tablets, were prescribed as an identical regimen for the control group. Rising Pharmaceuticals provided a donation of hydroxychloroquine, and some hydroxychloroquine was purchased.

Outcomes The primary outcome was prespecified as symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable, Covid-19–related symptoms. We assumed that health care workers would have access to Covid-19 testing if symptomatic. However, access to testing was limited throughout the trial period.

Covid-19–related symptoms were based on U.S. Council for State and Territorial Epidemiologists criteria for confirmed cases (positivity for SARS-Cov-2 on PCR assay), probable cases (the presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea).15 All the participants had epidemiologic linkage,15 per trial eligibility criteria. Four infectious disease physicians who were unaware of the trial-group assignments reviewed symptomatic participants to generate a consensus with respect to whether their condition met the case definition.15 Secondary outcomes included the incidence of hospitalization for Covid-19 or death, the incidence of PCR-confirmed SARS-CoV-2 infection, the incidence of Covid-19 symptoms, the incidence of discontinuation of the trial intervention owing to any cause, and the severity of symptoms (if any) at days 5 and 14 according to a visual analogue scale (scores ranged from 0 [no symptoms] to 10 [severe symptoms]).

Data on adverse events were also collected with directed questioning for common side effects along with open-ended free text. Outcome data were measured within 14 days after trial enrollment. Outcome data including PCR testing results, possible Covid-19–related symptoms, adherence to the trial intervention, side effects, and hospitalizations were all collected through participant report.

Details of trial conduct are provided in the protocol and statistical analysis plan, available at NEJM.org. Sample Size We anticipated that illness compatible with Covid-19 would develop in 10% of close contacts exposed to Covid-19.9 Using Fisher’s exact method with a 50% relative effect size to reduce new symptomatic infections, a two-sided alpha of 0.05, and 90% power, we estimated that 621 persons would need to be enrolled in each group. With a pragmatic, Internet-based, self-referral recruitment strategy, we planned for a 20% incidence of attrition by increasing the sample size to 750 participants per group.

We specified a priori that participants who were already symptomatic on day 1 before receiving hydroxychloroquine or placebo would be excluded from the prophylaxis trial and would instead be separately enrolled in the companion symptomatic treatment trial. Because the estimates for both incident symptomatic Covid-19 after an exposure and loss to follow-up were relatively unknown in early March 2020,9 the protocol prespecified a sample-size reestimation at the second interim analysis. This reestimation, which used the incidence of new infections in the placebo group and the observed percentage of participants lost to follow-up, was aimed at maintaining the ability to detect an effect size of a 50% relative reduction in new symptomatic infections.

Interim Analyses An independent data and safety monitoring board externally reviewed the data after 25% and 50% of the participants had completed 14 days of follow-up. Stopping guidelines were provided to the data and safety monitoring board with the use of a Lan–DeMets spending function analogue of the O’Brien–Fleming boundaries for the primary outcome. A conditional power analysis was performed at the second and third interim analysis with the option of early stopping for futility.

At the second interim analysis on April 22, 2020, the sample size was reduced to 956 participants who could be evaluated with 90% power on the basis of the higher-than-expected event rate of infections in the control group. At the third interim analysis on May 6, the trial was halted on the basis of a conditional power of less than 1%, since it was deemed futile to continue. Statistical Analysis We assessed the incidence of Covid-19 disease by day 14 with Fisher’s exact test.

Secondary outcomes with respect to percentage of patients were also compared with Fisher’s exact test. Among participants in whom incident illness compatible with Covid-19 developed, we summarized the symptom severity score at day 14 with the median and interquartile range and assessed the distributions with a Kruskal–Wallis test. We conducted all analyses with SAS software, version 9.4 (SAS Institute), according to the intention-to-treat principle, with two-sided type I error with an alpha of 0.05.

For participants with missing outcome data, we conducted a sensitivity analysis with their outcomes excluded or included as an event. Subgroups that were specified a priori included type of contact (household vs. Health care), days from exposure to enrollment, age, and sex.Trial Design and Oversight The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.

(Details regarding this trial are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The trial is being coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, or lopinavir–ritonavir has now been stopped, the trial continues randomization to groups receiving azithromycin, tocilizumab, or convalescent plasma. Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial.

Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020. Pregnant or breast-feeding women were eligible. Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent.

The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee. The protocol with its statistical analysis plan is available at NEJM.org and on the trial website at www.recoverytrial.net.

The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan.

Randomization We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.

For some patients, dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from entry in the randomized comparison between dexamethasone and usual care and hence were not included in this report. The randomly assigned treatment was prescribed by the treating clinician.

Patients and local members of the trial staff were aware of the assigned treatments. Procedures A single online follow-up form was to be completed when the patients were discharged or had died or at 28 days after randomization, whichever occurred first. Information was recorded regarding the patients’ adherence to the assigned treatment, receipt of other trial treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal support, and vital status (including the cause of death).

In addition, we obtained routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy. Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization. Further analyses were specified at 6 months.

Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespecified clinical outcomes included cause-specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation. Statistical Analysis As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the Covid-19 pandemic.

As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that if 28-day mortality was 20%, then the enrollment of at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of at least 90% at a two-sided P value of 0.01 to detect a clinically relevant proportional reduction of 20% (an absolute difference of 4 percentage points) between the two groups. Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients. For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio.

Among the few patients (0.1%) who had not been followed for 28 days by the time of the data cutoff on July 6, 2020, data were censored either on that date or on day 29 if the patient had already been discharged. That is, in the absence of any information to the contrary, these patients were assumed to have survived for 28 days. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period.

Cox regression was used to analyze the secondary outcome of hospital discharge within 28 days, with censoring of data on day 29 for patients who had died during hospitalization. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who were not receiving invasive mechanical ventilation at randomization), the precise date of invasive mechanical ventilation was not available, so a log-binomial regression model was used to estimate the risk ratio. Table 1.

Table 1. Characteristics of the Patients at Baseline, According to Treatment Assignment and Level of Respiratory Support. Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group (Table 1).

To account for this imbalance in an important prognostic factor, estimates of rate ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years). This adjustment was not specified in the first version of the statistical analysis plan but was added once the imbalance in age became apparent. Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix.

Prespecified analyses of the primary outcome were performed in five subgroups, as defined by characteristics at randomization. Age, sex, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk. (One further prespecified subgroup analysis regarding race will be conducted once the data collection has been completed.) In prespecified subgroups, we estimated rate ratios (or risk ratios in some analyses) and their confidence intervals using regression models that included an interaction term between the treatment assignment and the subgroup of interest.

Chi-square tests for linear trend across the subgroup-specific log estimates were then performed in accordance with the prespecified plan. All P values are two-sided and are shown without adjustment for multiple testing. All analyses were performed according to the intention-to-treat principle.

The full database is held by the trial team, which collected the data from trial sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford..

Trial Population cialis safe online http://cz.keimfarben.de/cialis-for-sale/ Table 1. Table 1. Characteristics of the Participants in the mRNA-1273 Trial at Enrollment cialis safe online.

The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020 (Fig. S1). Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second vaccination window owing to isolation for suspected Covid-19 while the test results, ultimately negative, were pending.

All continued to attend scheduled trial visits. The demographic characteristics of participants at enrollment are provided in Table 1. Vaccine Safety No serious adverse events were noted, and no prespecified trial halting rules were met.

As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination. Figure 1. Figure 1.

Systemic and Local Adverse Events. The severity of solicited adverse events was graded as mild, moderate, or severe (see Table S1).After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group. All were mild or moderate in severity (Figure 1 and Table S2).

Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events. None of the participants had fever after the first vaccination. After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever.

One of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. (Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.) Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common. Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site.

Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3). SARS-CoV-2 Binding Antibody Responses Table 2. Table 2.

Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 in Participants and in Convalescent Serum Specimens. Figure 2. Figure 2.

SARS-CoV-2 Antibody and Neutralization Responses. Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live virus PRNT80 responses (Panel D). In Panel A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and median area under the curve (AUC), respectively.

Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The convalescent serum panel includes specimens from 41 participants. Red dots indicate the 3 specimens that were also tested in the PRNT assay.

The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent serum panel. In Panel C, boxes and horizontal bars denote IQR and median ID50, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR.

In the convalescent serum panel, red dots indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent panel. In Panel D, boxes and horizontal bars denote IQR and median PRNT80, respectively.

Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The three convalescent serum specimens were also tested in ELISA and PsVNA assays. Because of the time-intensive nature of the PRNT assay, for this preliminary report, PRNT results were available only for the 25-μg and 100-μg dose groups.Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A).

Dose-dependent responses to the first and second vaccinations were evident. Receptor-binding domain–specific antibody responses were similar in pattern and magnitude (Figure 2B). For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens.

The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]). SARS-CoV-2 Neutralization Responses No participant had detectable PsVNA responses before vaccination. After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50].

Figure 2C, Fig. S8, and Table 2. 80% inhibitory dilution [ID80].

Fig. S2 and Table S6). However, after the second vaccination, PsVNA responses were identified in serum samples from all participants.

The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43. The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43). These responses were similar to values in the upper half of the distribution of values for convalescent serum specimens.

Before vaccination, no participant had detectable 80% live-virus neutralization at the highest serum concentration tested (1:8 dilution) in the PRNT assay. At day 43, wild-type virus–neutralizing activity capable of reducing SARS-CoV-2 infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D). Neutralizing PRNT80 average responses were generally at or above the values of the three convalescent serum specimens tested in this assay.

Good agreement was noted within and between the values from binding assays for S-2P and receptor-binding domain and neutralizing activity measured by PsVNA and PRNT (Figs. S3 through S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273. SARS-CoV-2 T-Cell Responses The 25-μg and 100-μg doses elicited CD4 T-cell responses (Figs.

S9 and S10) that on stimulation by S-specific peptide pools were strongly biased toward expression of Th1 cytokines (tumor necrosis factor α >. Interleukin 2 >. Interferon γ), with minimal type 2 helper T-cell (Th2) cytokine expression (interleukin 4 and interleukin 13).

CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100-μg dose group (Fig. S11).Patients Figure 1. Figure 1.

Enrollment and Randomization. Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization. 541 were assigned to the remdesivir group and 522 to the placebo group (Figure 1).

Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Forty-nine patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death (36 patients) or because the patient withdrew consent (13). Of those assigned to receive placebo, 518 patients (99.2%) received placebo as assigned.

Fifty-three patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death (36 patients), because the patient withdrew consent (15), or because the patient was found to be ineligible for trial enrollment (2). As of April 28, 2020, a total of 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day 29, recovered, or died. Eight patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29.

There were 132 patients in the remdesivir group and 169 in the placebo group who had not recovered and had not completed the day 29 follow-up visit. The analysis population included 1059 patients for whom we have at least some postbaseline data available (538 in the remdesivir group and 521 in the placebo group). Four of the 1063 patients were not included in the primary analysis because no postbaseline data were available at the time of the database freeze.

Table 1. Table 1. Demographic and Clinical Characteristics at Baseline.

The mean age of patients was 58.9 years, and 64.3% were male (Table 1). On the basis of the evolving epidemiology of Covid-19 during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1). Overall, 53.2% of the patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were designated as other or not reported.

249 (23.4%) were Hispanic or Latino. Most patients had either one (27.0%) or two or more (52.1%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12).

Nine hundred forty-three (88.7%) patients had severe disease at enrollment as defined in the Supplementary Appendix. 272 (25.6%) patients met category 7 criteria on the ordinal scale, 197 (18.5%) category 6, 421 (39.6%) category 5, and 127 (11.9%) category 4. There were 46 (4.3%) patients who had missing ordinal scale data at enrollment.

No substantial imbalances in baseline characteristics were observed between the remdesivir group and the placebo group. Primary Outcome Figure 2. Figure 2.

Kaplan–Meier Estimates of Cumulative Recoveries. Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen. Panel B), in those with a baseline score of 5 (receiving oxygen.

Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in those with a baseline score of 7 (receiving mechanical ventilation or ECMO. Panel E).

Table 2. Table 2. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population.

Figure 3. Figure 3. Time to Recovery According to Subgroup.

The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and ethnic group were reported by the patients. Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 11 days, as compared with 15 days.

Rate ratio for recovery, 1.32. 95% confidence interval [CI], 1.12 to 1.55. P<0.001.

1059 patients (Figure 2 and Table 2). Among patients with a baseline ordinal score of 5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84). Among patients with a baseline score of 4 (127 patients) and those with a baseline score of 6 (197 patients), the rate ratio estimates for recovery were 1.38 (95% CI, 0.94 to 2.03) and 1.20 (95% CI, 0.79 to 1.81), respectively.

For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7. 272 patients), the rate ratio for recovery was 0.95 (95% CI, 0.64 to 1.42). A test of interaction of treatment with baseline score on the ordinal scale was not significant.

An analysis adjusting for baseline ordinal score as a stratification variable was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome. This adjusted analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.31. 95% CI, 1.12 to 1.54.

1017 patients). Table S2 in the Supplementary Appendix shows results according to the baseline severity stratum of mild-to-moderate as compared with severe. Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.28 (95% CI, 1.05 to 1.57.

664 patients), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.38 (95% CI, 1.05 to 1.81. 380 patients) (Figure 3). Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.50.

95% CI, 1.18 to 1.91. P=0.001. 844 patients) (Table 2 and Fig.

S5). Mortality was numerically lower in the remdesivir group than in the placebo group, but the difference was not significant (hazard ratio for death, 0.70. 95% CI, 0.47 to 1.04.

1059 patients). The Kaplan–Meier estimates of mortality by 14 days were 7.1% and 11.9% in the remdesivir and placebo groups, respectively (Table 2). The Kaplan–Meier estimates of mortality by 28 days are not reported in this preliminary analysis, given the large number of patients that had yet to complete day 29 visits.

An analysis with adjustment for baseline ordinal score as a stratification variable showed a hazard ratio for death of 0.74 (95% CI, 0.50 to 1.10). Safety Outcomes Serious adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141 patients (27.0%) in the placebo group (Table S3). 4 events (2 in each group) were judged by site investigators to be related to remdesivir or placebo.

There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients). Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group. No deaths were considered to be related to treatment assignment, as judged by the site investigators.

Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4). The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group). Acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]).

Pyrexia (27 events [5.0%], as compared with 17 [3.3%]). Hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]). And increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]).

Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.Announced on May 15, Operation Warp Speed (OWS) — a partnership of the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector — aims to accelerate control of the Covid-19 pandemic by advancing development, manufacturing, and distribution of vaccines, therapeutics, and diagnostics. OWS is providing support to promising candidates and enabling the expeditious, parallel execution of the necessary steps toward approval or authorization of safe products by the Food and Drug Administration (FDA).The partnership grew out of an acknowledged need to fundamentally restructure the way the U.S. Government typically supports cialis efficacy product development and vaccine distribution.

The initiative was premised on setting a “stretch goal” — one that initially seemed impossible but that is becoming increasingly achievable.The concept of an integrated structure for Covid-19 countermeasure research and development across the U.S. Government was based on experience with Zika and the Zika Leadership Group led by the National Institutes of Health (NIH) and the assistant secretary for preparedness and response (ASPR). One of us (M.S.) serves as OWS chief advisor.

We are drawing on expertise from the NIH, ASPR, the Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority (BARDA), and the DOD, including the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and the Defense Advanced Research Projects Agency. OWS has engaged experts in all critical aspects of medical countermeasure research, development, manufacturing, and distribution to work in close coordination.The initiative set ambitious objectives. To deliver tens of millions of doses of a SARS-CoV-2 vaccine — with demonstrated safety and efficacy, and approved or authorized by the FDA for use in the U.S.

Population — beginning at the end of 2020 and to have as many as 300 million doses of such vaccines available and deployed by mid-2021. The pace and scope of such a vaccine effort are unprecedented. The 2014 West African Ebola virus epidemic spurred rapid vaccine development, but though preclinical data existed before the outbreak, a period of 12 months was required to progress from phase 1 first-in-human trials to phase 3 efficacy trials.

OWS aims to compress this time frame even further. SARS-CoV-2 vaccine development began in January, phase 1 clinical studies in March, and the first phase 3 trials in July. Our objectives are based on advances in vaccine platform technology, improved understanding of safe and efficacious vaccine design, and similarities between the SARS-CoV-1 and SARS-CoV-2 disease mechanisms.OWS’s role is to enable, accelerate, harmonize, and advise the companies developing the selected vaccines.

The companies will execute the clinical or process development and manufacturing plans, while OWS leverages the full capacity of the U.S. Government to ensure that no technical, logistic, or financial hurdles hinder vaccine development or deployment.OWS selected vaccine candidates on the basis of four criteria. We required candidates to have robust preclinical data or early-stage clinical trial data supporting their potential for clinical safety and efficacy.

Candidates had to have the potential, with our acceleration support, to enter large phase 3 field efficacy trials this summer or fall (July to November 2020) and, assuming continued active transmission of the virus, to deliver efficacy outcomes by the end of 2020 or the first half of 2021. Candidates had to be based on vaccine-platform technologies permitting fast and effective manufacturing, and their developers had to demonstrate the industrial process scalability, yields, and consistency necessary to reliably produce more than 100 million doses by mid-2021. Finally, candidates had to use one of four vaccine-platform technologies that we believe are the most likely to yield a safe and effective vaccine against Covid-19.

The mRNA platform, the replication-defective live-vector platform, the recombinant-subunit-adjuvanted protein platform, or the attenuated replicating live-vector platform.OWS’s strategy relies on a few key principles. First, we sought to build a diverse project portfolio that includes two vaccine candidates based on each of the four platform technologies. Such diversification mitigates the risk of failure due to safety, efficacy, industrial manufacturability, or scheduling factors and may permit selection of the best vaccine platform for each subpopulation at risk for contracting or transmitting Covid-19, including older adults, frontline and essential workers, young adults, and pediatric populations.

In addition, advancing eight vaccines in parallel will increase the chances of delivering 300 million doses in the first half of 2021.Second, we must accelerate vaccine program development without compromising safety, efficacy, or product quality. Clinical development, process development, and manufacturing scale-up can be substantially accelerated by running all streams, fully resourced, in parallel. Doing so requires taking on substantial financial risk, as compared with the conventional sequential development approach.

OWS will maximize the size of phase 3 trials (30,000 to 50,000 participants each) and optimize trial-site location by consulting daily epidemiologic and disease-forecasting models to ensure the fastest path to an efficacy readout. Such large trials also increase the safety data set for each candidate vaccine.With heavy up-front investment, companies can conduct clinical operations and site preparation for these phase 3 efficacy trials even as they file their Investigational New Drug application (IND) for their phase 1 studies, thereby ensuring immediate initiation of phase 3 when they get a green light from the FDA. To permit appropriate comparisons among the vaccine candidates and to optimize vaccine utilization after approval by the FDA, the phase 3 trial end points and assay readouts have been harmonized through a collaborative effort involving the National Institute of Allergy and Infectious Diseases (NIAID), the Coronavirus Prevention Network, OWS, and the sponsor companies.Finally, OWS is supporting the companies financially and technically to commence process development and scale up manufacturing while their vaccines are in preclinical or very early clinical stages.

To ensure that industrial processes are set, running, and validated for FDA inspection when phase 3 trials end, OWS is also supporting facility building or refurbishing, equipment fitting, staff hiring and training, raw-material sourcing, technology transfer and validation, bulk product processing into vials, and acquisition of ample vials, syringes, and needles for each vaccine candidate. We aim to have stockpiled, at OWS’s expense, a few tens of millions of vaccine doses that could be swiftly deployed once FDA approval is obtained.This strategy aims to accelerate vaccine development without curtailing the critical steps required by sound science and regulatory standards. The FDA recently reissued guidance and standards that will be used to assess each vaccine for a Biologics License Application (BLA).

Alternatively, the agency could decide to issue an Emergency Use Authorization to permit vaccine administration before all BLA procedures are completed.Of the eight vaccines in OWS’s portfolio, six have been announced and partnerships executed with the companies. Moderna and Pfizer/BioNTech (both mRNA), AstraZeneca and Janssen (both replication-defective live-vector), and Novavax and Sanofi/GSK (both recombinant-subunit-adjuvanted protein). These candidates cover three of the four platform technologies and are currently in clinical trials.

The remaining two candidates will enter trials soon.Moderna developed its RNA vaccine in collaboration with the NIAID, began its phase 1 trial in March, recently published encouraging safety and immunogenicity data,1 and entered phase 3 on July 27. Pfizer and BioNTech’s RNA vaccine also produced encouraging phase 1 results2 and started its phase 3 trial on July 27. The ChAdOx replication-defective live-vector vaccine developed by AstraZeneca and Oxford University is in phase 3 trials in the United Kingdom, Brazil, and South Africa, and it should enter U.S.

Phase 3 trials in August.3 The Janssen Ad26 Covid-19 replication-defective live-vector vaccine has demonstrated excellent protection in nonhuman primate models and began its U.S. Phase 1 trial on July 27. It should be in phase 3 trials in mid-September.

Novavax completed a phase 1 trial of its recombinant-subunit-adjuvanted protein vaccine in Australia and should enter phase 3 trials in the United States by the end of September.4 Sanofi/GSK is completing preclinical development steps and plans to commence a phase 1 trial in early September and to be well into phase 3 by year’s end.5On the process-development front, the RNA vaccines are already being manufactured at scale. The other candidates are well advanced in their scale-up development, and manufacturing sites are being refurbished.While development and manufacturing proceed, the HHS–DOD partnership is laying the groundwork for vaccine distribution, subpopulation prioritization, financing, and logistic support. We are working with bioethicists and experts from the NIH, the CDC, BARDA, and the Centers for Medicare and Medicaid Services to address these critical issues.

We will receive recommendations from the CDC Advisory Committee on Immunization Practices, and we are working to ensure that the most vulnerable and at-risk persons will receive vaccine doses once they are ready. Prioritization will also depend on the relative performance of each vaccine and its suitability for particular populations. Because some technologies have limited previous data on safety in humans, the long-term safety of these vaccines will be carefully assessed using pharmacovigilance surveillance strategies.No scientific enterprise could guarantee success by January 2021, but the strategic decisions and choices we’ve made, the support the government has provided, and the accomplishments to date make us optimistic that we will succeed in this unprecedented endeavor.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial to evaluate postexposure prophylaxis with hydroxychloroquine after exposure to Covid-19.12 We randomly assigned participants in a 1:1 ratio to receive either hydroxychloroquine or placebo.

Participants had known exposure (by participant report) to a person with laboratory-confirmed Covid-19, whether as a household contact, a health care worker, or a person with other occupational exposures. Trial enrollment began on March 17, 2020, with an eligibility threshold to enroll within 3 days after exposure. The objective was to intervene before the median incubation period of 5 to 6 days.

Because of limited access to prompt testing, health care workers could initially be enrolled on the basis of presumptive high-risk exposure to patients with pending tests. However, on March 23, eligibility was changed to exposure to a person with a positive polymerase-chain-reaction (PCR) assay for SARS-CoV-2, with the eligibility window extended to within 4 days after exposure. This trial was approved by the institutional review board at the University of Minnesota and conducted under a Food and Drug Administration Investigational New Drug application.

In Canada, the trial was approved by Health Canada. Ethics approvals were obtained from the Research Institute of the McGill University Health Centre, the University of Manitoba, and the University of Alberta. Participants We included participants who had household or occupational exposure to a person with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure).

Participants were excluded if they were younger than 18 years of age, were hospitalized, or met other exclusion criteria (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Persons with symptoms of Covid-19 or with PCR-proven SARS-CoV-2 infection were excluded from this prevention trial but were separately enrolled in a companion clinical trial to treat early infection. Setting Recruitment was performed primarily with the use of social media outreach as well as traditional media platforms.

Participants were enrolled nationwide in the United States and in the Canadian provinces of Quebec, Manitoba, and Alberta. Participants enrolled themselves through a secure Internet-based survey using the Research Electronic Data Capture (REDCap) system.13 After participants read the consent form, their comprehension of its contents was assessed. Participants provided a digitally captured signature to indicate informed consent.

We sent follow-up e-mail surveys on days 1, 5, 10, and 14. A survey at 4 to 6 weeks asked about any follow-up testing, illness, or hospitalizations. Participants who did not respond to follow-up surveys received text messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes.

When these methods were unsuccessful, the emergency contact provided by the enrollee was contacted to determine the participant’s illness and vital status. When all communication methods were exhausted, Internet searches for obituaries were performed to ascertain vital status. Interventions Randomization occurred at research pharmacies in Minneapolis and Montreal.

The trial statisticians generated a permuted-block randomization sequence using variably sized blocks of 2, 4, or 8, with stratification according to country. A research pharmacist sequentially assigned participants. The assignments were concealed from investigators and participants.

Only pharmacies had access to the randomization sequence. Hydroxychloroquine sulfate or placebo was dispensed and shipped overnight to participants by commercial courier. The dosing regimen for hydroxychloroquine was 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for 4 more days for a total course of 5 days (19 tablets total).

If participants had gastrointestinal upset, they were advised to divide the daily dose into two or three doses. We chose this hydroxychloroquine dosing regimen on the basis of pharmacokinetic simulations to achieve plasma concentrations above the SARS-CoV-2 in vitro half maximal effective concentration for 14 days.14 Placebo folate tablets, which were similar in appearance to the hydroxychloroquine tablets, were prescribed as an identical regimen for the control group. Rising Pharmaceuticals provided a donation of hydroxychloroquine, and some hydroxychloroquine was purchased.

Outcomes The primary outcome was prespecified as symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable, Covid-19–related symptoms. We assumed that health care workers would have access to Covid-19 testing if symptomatic. However, access to testing was limited throughout the trial period.

Covid-19–related symptoms were based on U.S. Council for State and Territorial Epidemiologists criteria for confirmed cases (positivity for SARS-Cov-2 on PCR assay), probable cases (the presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea).15 All the participants had epidemiologic linkage,15 per trial eligibility criteria. Four infectious disease physicians who were unaware of the trial-group assignments reviewed symptomatic participants to generate a consensus with respect to whether their condition met the case definition.15 Secondary outcomes included the incidence of hospitalization for Covid-19 or death, the incidence of PCR-confirmed SARS-CoV-2 infection, the incidence of Covid-19 symptoms, the incidence of discontinuation of the trial intervention owing to any cause, and the severity of symptoms (if any) at days 5 and 14 according to a visual analogue scale (scores ranged from 0 [no symptoms] to 10 [severe symptoms]).

Data on adverse events were also collected with directed questioning for common side effects along with open-ended free text. Outcome data were measured within 14 days after trial enrollment. Outcome data including PCR testing results, possible Covid-19–related symptoms, adherence to the trial intervention, side effects, and hospitalizations were all collected through participant report.

Details of trial conduct are provided in the protocol and statistical analysis plan, available at NEJM.org. Sample Size We anticipated that illness compatible with Covid-19 would develop in 10% of close contacts exposed to Covid-19.9 Using Fisher’s exact method with a 50% relative effect size to reduce new symptomatic infections, a two-sided alpha of 0.05, and 90% power, we estimated that 621 persons would need to be enrolled in each group. With a pragmatic, Internet-based, self-referral recruitment strategy, we planned for a 20% incidence of attrition by increasing the sample size to 750 participants per group.

We specified a priori that participants who were already symptomatic on day 1 before receiving hydroxychloroquine or placebo would be excluded from the prophylaxis trial and would instead be separately enrolled in the companion symptomatic treatment trial. Because the estimates for both incident symptomatic Covid-19 after an exposure and loss to follow-up were relatively unknown in early March 2020,9 the protocol prespecified a sample-size reestimation at the second interim analysis. This reestimation, which used the incidence of new infections in the placebo group and the observed percentage of participants lost to follow-up, was aimed at maintaining the ability to detect an effect size of a 50% relative reduction in new symptomatic infections.

Interim Analyses An independent data and safety monitoring board externally reviewed the data after 25% and 50% of the participants had completed 14 days of follow-up. Stopping guidelines were provided to the data and safety monitoring board with the use of a Lan–DeMets spending function analogue of the O’Brien–Fleming boundaries for the primary outcome. A conditional power analysis was performed at the second and third interim analysis with the option of early stopping for futility.

At the second interim analysis on April 22, 2020, the sample size was reduced to 956 participants who could be evaluated with 90% power on the basis of the higher-than-expected event rate of infections in the control group. At the third interim analysis on May 6, the trial was halted on the basis of a conditional power of less than 1%, since it was deemed futile to continue. Statistical Analysis We assessed the incidence of Covid-19 disease by day 14 with Fisher’s exact test.

Secondary outcomes with respect to percentage of patients were also compared with Fisher’s exact test. Among participants in whom incident illness compatible with Covid-19 developed, we summarized the symptom severity score at day 14 with the median and interquartile range and assessed the distributions with a Kruskal–Wallis test. We conducted all analyses with SAS software, version 9.4 (SAS Institute), according to the intention-to-treat principle, with two-sided type I error with an alpha of 0.05.

For participants with missing outcome data, we conducted a sensitivity analysis with their outcomes excluded or included as an event. Subgroups that were specified a priori included type of contact (household vs. Health care), days from exposure to enrollment, age, and sex.Trial Design and Oversight The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.

(Details regarding this trial are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.) The trial is being coordinated by the Nuffield Department of Population Health at the University of Oxford, the trial sponsor. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, or lopinavir–ritonavir has now been stopped, the trial continues randomization to groups receiving azithromycin, tocilizumab, or convalescent plasma. Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put patients at substantial risk if they were to participate in the trial.

Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was removed starting on May 9, 2020. Pregnant or breast-feeding women were eligible. Written informed consent was obtained from all the patients or from a legal representative if they were unable to provide consent.

The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and was approved by the U.K. Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee. The protocol with its statistical analysis plan is available at NEJM.org and on the trial website at www.recoverytrial.net.

The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication. The first and last members of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan.

Randomization We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.

For some patients, dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from entry in the randomized comparison between dexamethasone and usual care and hence were not included in this report. The randomly assigned treatment was prescribed by the treating clinician.

Patients and local members of the trial staff were aware of the assigned treatments. Procedures A single online follow-up form was to be completed when the patients were discharged or had died or at 28 days after randomization, whichever occurred first. Information was recorded regarding the patients’ adherence to the assigned treatment, receipt of other trial treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal support, and vital status (including the cause of death).

In addition, we obtained routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy. Outcome Measures The primary outcome was all-cause mortality within 28 days after randomization. Further analyses were specified at 6 months.

Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespecified clinical outcomes included cause-specific mortality, receipt of renal hemodialysis or hemofiltration, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventilation. Statistical Analysis As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the Covid-19 pandemic.

As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that if 28-day mortality was 20%, then the enrollment of at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of at least 90% at a two-sided P value of 0.01 to detect a clinically relevant proportional reduction of 20% (an absolute difference of 4 percentage points) between the two groups. Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients. For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio.

Among the few patients (0.1%) who had not been followed for 28 days by the time of the data cutoff on July 6, 2020, data were censored either on that date or on day 29 if the patient had already been discharged. That is, in the absence of any information to the contrary, these patients were assumed to have survived for 28 days. Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period.

Cox regression was used to analyze the secondary outcome of hospital discharge within 28 days, with censoring of data on day 29 for patients who had died during hospitalization. For the prespecified composite secondary outcome of invasive mechanical ventilation or death within 28 days (among patients who were not receiving invasive mechanical ventilation at randomization), the precise date of invasive mechanical ventilation was not available, so a log-binomial regression model was used to estimate the risk ratio. Table 1.

Table 1. Characteristics of the Patients at Baseline, According to Treatment Assignment and Level of Respiratory Support. Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group (Table 1).

To account for this imbalance in an important prognostic factor, estimates of rate ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years). This adjustment was not specified in the first version of the statistical analysis plan but was added once the imbalance in age became apparent. Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix.

Prespecified analyses of the primary outcome were performed in five subgroups, as defined by characteristics at randomization. Age, sex, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk. (One further prespecified subgroup analysis regarding race will be conducted once the data collection has been completed.) In prespecified subgroups, we estimated rate ratios (or risk ratios in some analyses) and their confidence intervals using regression models that included an interaction term between the treatment assignment and the subgroup of interest.

Chi-square tests for linear trend across the subgroup-specific log estimates were then performed in accordance with the prespecified plan. All P values are two-sided and are shown without adjustment for multiple testing. All analyses were performed according to the intention-to-treat principle.

The full database is held by the trial team, which collected the data from trial sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford..