Can you get ventolin without a prescription

Masks slow the spread of asthma by reducing how much infected people spray the ventolin into the can you get ventolin without a prescription environment around them when they cough or talk. Evidence from can you get ventolin without a prescription laboratory experiments, hospitals and whole countries show that masks work, and the Centers for Disease Control and Prevention recommends face coverings for the U.S. Public.

With all this evidence, mask wearing has become the norm in many places.I can you get ventolin without a prescription am an infectious disease doctor and a professor of medicine at the University of California, San Francisco. As governments and workplaces began to recommend or mandate mask wearing, my colleagues and I noticed an interesting trend. In places where most people wore masks, those who did get infected seemed dramatically less likely to get severely ill compared to places with less mask-wearing.It seems people get less sick if they wear a mask.When you wear a mask – even a cloth can you get ventolin without a prescription mask – you typically are exposed to a lower dose of the asthma than if you didn’t.

Both recent experiments in animal models using asthma and nearly a hundred years of viral research show that lower viral doses usually means less severe disease.No mask is perfect, and wearing one might not prevent you from getting infected. But it might be the difference between a case of can you get ventolin without a prescription asthma treatment that sends you to the hospital and a case so mild you don’t even realize you’re infected.Exposure Dose Determines Severity of DiseaseWhen you breathe in a respiratory ventolin, it immediately begins hijacking any cells it lands near to turn them into ventolin production machines. The immune system tries to stop this process to halt the spread of the ventolin.The amount of ventolin that you’re exposed to – called the viral inoculum, or dose – has a lot to do with how sick you get.

If the exposure dose is very can you get ventolin without a prescription high, the immune response can become overwhelmed. Between the ventolin taking over huge numbers of cells and the immune system’s drastic efforts to contain the , a lot of damage is done to the body and a person can become very sick.On the other hand, if the initial dose of the ventolin is small, the immune system is able to contain the ventolin with less drastic measures. If this happens, the person experiences fewer symptoms, if any.This concept of viral dose being related to disease can you get ventolin without a prescription severity has been around for almost a century.

Many animal studies have shown that the higher the dose of a ventolin you give an animal, the more sick it becomes. In 2015, researchers tested this concept in human volunteers using a can you get ventolin without a prescription nonlethal flu ventolin and found the same result. The higher the flu ventolin dose given to the volunteers, the sicker they became.In July, researchers published a paper showing that viral dose was related to disease severity in hamsters exposed to the asthma.

Hamsters who were given a higher viral dose got more sick than hamsters given a lower dose.Based on this body of research, it seems very likely that if you are exposed to asthma, the lower the dose, the less can you get ventolin without a prescription sick you will get.So what can a person do to lower the exposure dose?. Masks Reduce Viral DoseMost infectious disease researchers and epidemiologists believe that the asthma is mostly spread by can you get ventolin without a prescription airborne droplets and, to a lesser extent, tiny aerosols. Research shows that both cloth and surgical masks can block the majority of particles that could contain asthma.

While no mask is perfect, the goal is not can you get ventolin without a prescription to block all of the ventolin, but simply reduce the amount that you might inhale. Almost any mask will successfully block some amount.Laboratory experiments have shown that good cloth masks and surgical masks could block at least 80% of viral particles from entering your nose and mouth. Those particles and other contaminants will get trapped in the fibers of the mask, so the CDC recommends washing your cloth mask after each use if possible.The final piece of experimental evidence showing that masks reduce viral dose comes from another hamster experiment can you get ventolin without a prescription.

Hamsters were divided into an unmasked group and a masked group by placing surgical mask material over the pipes that brought air into the cages of the masked group. Hamsters infected with the asthma were placed in cages next to the masked and unmasked hamsters, and air was pumped from the infected cages into the cages with uninfected hamsters.As expected, the can you get ventolin without a prescription masked hamsters were less likely to get infected with asthma treatment. But when some of the masked hamsters did get infected, they had more mild disease than the unmasked hamsters.Masks Increase Rate of Asymptomatic CasesIn July, the CDC estimated that around 40% of people infected with asthma are asymptomatic, and a number of other studies have confirmed this number.However, in places where everyone wears masks, the rate of asymptomatic seems to be much higher.

In an outbreak on an Australian cruise ship called the Greg Mortimer in late March, the passengers were all given surgical masks and the staff were given N95 can you get ventolin without a prescription masks after the first case of asthma treatment was identified. Mask usage was apparently very high, and even though 128 of the 217 passengers and staff eventually tested positive for the asthma, 81% of the infected people remained asymptomatic.Further evidence has come from two more recent outbreaks, the first at a seafood processing plant in Oregon and the second at a chicken processing plant in Arkansas. In both places, can you get ventolin without a prescription the workers were provided masks and required to wear them at all times.

In the outbreaks from both plants, nearly 95% of infected people were asymptomatic.There is no doubt that universal mask wearing slows the spread of the asthma. My colleagues and I believe that evidence from laboratory experiments, case studies like the cruise ship and food processing plant outbreaks and long-known biological principles make a strong case that masks protect the wearer too.The goal of any tool to fight this ventolin is to slow the spread of can you get ventolin without a prescription the ventolin and save lives. Universal masking will do both.Monica Gandhi is a Professor of Medicine with the Division of HIV, Infectious Diseases and Global Medicine at the University of California, San Francisco.

This article originally appeared on The Conversation and is republished can you get ventolin without a prescription under a Creative Commons license. Read the original here..

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First-of-its-kind study, based on a mouse model, finds living in a polluted environment ventolin expectorant dosage could be comparable to eating a high-fat diet, leading to a pre-diabetic state CLEVELAND—Air pollution is the world’s leading environmental risk factor, and causes more than nine million deaths per year. New research published in the Journal of Clinical Investigation shows air pollution may play a role in the development of cardiometabolic diseases, such as diabetes. Importantly, the effects were ventolin expectorant dosage reversible with cessation of exposure. Researchers found that air pollution was a “risk factor for a risk factor” that contributed to the common soil of other fatal problems like heart attack and stroke.

Similar to how an unhealthy diet and lack of exercise can lead to disease, exposure to air pollution could be added to this risk factor list as well ventolin expectorant dosage. “In this study, we created an environment that mimicked a polluted day in New Delhi or Beijing,” said Sanjay Rajagopalan, MD, first author on the study, Chief of Cardiovascular Medicine at University Hospitals Harrington Heart and Vascular Institute, and Director of the Case Western Reserve University Cardiovascular Research Institute. €œWe concentrated fine particles of air pollution, called ventolin expectorant dosage PM2.5 (particulate matter component <. 2.5 microns).

Concentrated particles like this develop from human impact on the environment, such as automobile exhaust, power generation and other fossil fuels.” These particles have been strongly connected to risk factors for disease. For example, cardiovascular effects of air pollution can lead to heart attack and ventolin expectorant dosage stroke. The research team has shown exposure to air pollution can increase the likelihood of the same risk factors that lead to heart disease, such as insulin resistance and type 2 diabetes. In the ventolin expectorant dosage mouse model study, three groups were observed.

A control group receiving clean filtered air, a group exposed to polluted air for 24 weeks, and a group fed a high-fat diet. Interestingly, the researchers found that being exposed to air pollution was comparable to eating ventolin expectorant dosage a high-fat diet. Both the air pollution and high-fat diet groups showed insulin resistance and abnormal metabolism – just like one would see in a pre-diabetic state. These changes were associated with changes in the epigenome, a layer of control that can masterfully turn on and turn off thousands of genes, representing a critical buffer in response to environmental factors.

This study is the first-of-its-kind to compare genome-wide epigenetic changes in response to air pollution, compare and contrast these changes ventolin expectorant dosage with that of eating an unhealthy diet, and examine the impact of air pollution cessation on these changes.“The good news is that these effects were reversible, at least in our experiments” added Dr. Rajagopalan. €œOnce the air pollution was removed from the environment, the mice appeared ventolin expectorant dosage healthier and the pre-diabetic state seemed to reverse.” Dr. Rajagopalan explains that if you live in a densely polluted environment, taking actions such as wearing an N95 mask, using portable indoor air cleaners, utilizing air conditioning, closing car windows while commuting, and changing car air filters frequently could all be helpful in staying healthy and limiting air pollution exposure.Next steps in this research involve meeting with a panel of experts, as well as the National Institutes of Health, to discuss conducting clinical trials that compare heart health and the level of air pollution in the environment.

For example, ventolin expectorant dosage if someone has a heart attack, should they be wearing an N95 mask or using a portable air filter at home during recovery?. Dr. Rajagopalan and his team believe that it is important to address the environment as a population health risk factor and continue to diligently research these issues. The authors also note that these findings should encourage policymakers to enact measures aimed at reducing air pollution.Shyam Biswal, PhD, ventolin expectorant dosage Professor in the Department of Environmental Health and Engineering at Johns Hopkins University School of Public Health, is the joint senior author on the study.

Drs. Rajagopalan and Biswal are co-PIs on the NIH grant that ventolin expectorant dosage supported this work.###Rajagopalan, S., Biswal, S., et al. €œMetabolic effects of air pollution exposure and reversibility.” Journal of Clinical Investigation. DOI.

10.1172/JCI137315. This work was supported by the National Institute of Environmental Health Sciences TaRGET II Consortium grant U01ES026721, as well as grants R01ES015146 and R01ES019616..

First-of-its-kind study, based on a mouse model, finds living in a polluted environment could be comparable to eating a high-fat diet, leading to a pre-diabetic state CLEVELAND—Air pollution is can you get ventolin without a prescription the world’s leading environmental risk factor, and causes more than nine million deaths per year. New research published in the Journal of Clinical Investigation shows air pollution may play a role in the development of cardiometabolic diseases, such as diabetes. Importantly, the can you get ventolin without a prescription effects were reversible with cessation of exposure. Researchers found that air pollution was a “risk factor for a risk factor” that contributed to the common soil of other fatal problems like heart attack and stroke. Similar to how an can you get ventolin without a prescription unhealthy diet and lack of exercise can lead to disease, exposure to air pollution could be added to this risk factor list as well.

“In this study, we created an environment that mimicked a polluted day in New Delhi or Beijing,” said Sanjay Rajagopalan, MD, first author on the study, Chief of Cardiovascular Medicine at University Hospitals Harrington Heart and Vascular Institute, and Director of the Case Western Reserve University Cardiovascular Research Institute. €œWe concentrated can you get ventolin without a prescription fine particles of air pollution, called PM2.5 (particulate matter component <. 2.5 microns). Concentrated particles like this develop from human impact on the environment, such as automobile exhaust, power generation and other fossil fuels.” These particles have been strongly connected to risk factors for disease. For example, cardiovascular effects of air pollution can lead to heart attack and can you get ventolin without a prescription stroke.

The research team has shown exposure to air pollution can increase the likelihood of the same risk factors that lead to heart disease, such as insulin resistance and type 2 diabetes. In the mouse model study, three groups were observed can you get ventolin without a prescription. A control group receiving clean filtered air, a group exposed to polluted air for 24 weeks, and a group fed a high-fat diet. Interestingly, the researchers found that being exposed to air pollution can you get ventolin without a prescription was comparable to eating a high-fat diet. Both the air pollution and high-fat diet groups showed insulin resistance and abnormal metabolism – just like one would see in a pre-diabetic state.

These changes were associated with changes in the epigenome, a layer of control that can masterfully turn on and turn off thousands of genes, representing a critical buffer in response to environmental factors. This study is the first-of-its-kind to compare genome-wide epigenetic changes in response to can you get ventolin without a prescription air pollution, compare and contrast these changes with that of eating an unhealthy diet, and examine the impact of air pollution cessation on these changes.“The good news is that these effects were reversible, at least in our experiments” added Dr. Rajagopalan. €œOnce the air pollution was removed from the environment, the mice appeared healthier and can you get ventolin without a prescription the pre-diabetic state seemed to reverse.” Dr. Rajagopalan explains that if you live in a densely polluted environment, taking actions such as wearing an N95 mask, using portable indoor air cleaners, utilizing air conditioning, closing car windows while commuting, and changing car air filters frequently could all be helpful in staying healthy and limiting air pollution exposure.Next steps in this research involve meeting with a panel of experts, as well as the National Institutes of Health, to discuss conducting clinical trials that compare heart health and the level of air pollution in the environment.

For example, if someone has a heart attack, should they be wearing an N95 mask can you get ventolin without a prescription or using a portable air filter at home during recovery?. Dr. Rajagopalan and his team believe that it is important to address the environment as a population health risk factor and continue to diligently research these issues. The authors also note that these findings should encourage policymakers to enact measures aimed at reducing air pollution.Shyam Biswal, PhD, Professor in the Department of Environmental Health and Engineering at Johns Hopkins University can you get ventolin without a prescription School of Public Health, is the joint senior author on the study. Drs.

Rajagopalan and Biswal are co-PIs on the NIH grant that supported this work.###Rajagopalan, S., Biswal, S., can you get ventolin without a prescription et al. €œMetabolic effects of air pollution exposure and reversibility.” Journal of Clinical Investigation. DOI. 10.1172/JCI137315. This work was supported by the National Institute of Environmental Health Sciences TaRGET II Consortium grant U01ES026721, as well as grants R01ES015146 and R01ES019616..

What side effects may I notice from Ventolin?

Side effects that you should report to your doctor or health care professional as soon as possible:

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):

This list may not describe all possible side effects. Call your doctor for medical advice about side effects.

Ventolin h

A free pilot program to help new and expectant fathers navigate the physical, mental and emotional challenges of becoming a dad buy ventolin hfa will be rolled out in ventolin h four regions in NSW from today.Health Minister Brad Hazzard said the ‘Focus on New Fathers’ program will be trialled with men in Northern NSW, Northern and Western Sydney and the Murrumbidgee area. €œAsk any father and they will tell you, becoming a parent is an equally joyous and terrifying experience because your entire routine is turned on its head,” Mr Hazzard said. €œIt is a considerable adjustment which can put tremendous stress on you and on your relationship, so it’s important to know you are not ventolin h alone and help is at hand – literally.

€œThis pilot will see texts sent to dads, offering valuable health advice and links into pathways to ensure support options are available, particularly in these uncertain asthma treatment times.” Research has shown men are often reluctant to engage with the health system to get support, despite around one in 10 dads experiencing depression and anxiety in the postnatal period. The pilot, which is being delivered by the University of Newcastle in partnership with NSW ventolin h Health, will run over the next year with results helping to improve the program. Men living in the trial site areas will be eligible for the program if they are over the age of 18, their partner is at least 16 weeks pregnant or their baby is up to 24 weeks of age.

They must have a mobile phone capable of receiving and sending text messages. Associate Professor Elisabeth Murphy, Senior Clinical Advisor, Child and Family Health, said self-care for new fathers is extremely important as the mental and physical wellbeing of both parents has a direct effect on their ventolin h children. €œReceiving help with health issues early on ensures dads are in the best possible position to care for their new baby and partner,” Associate Professor Murphy said.

€œWe also understand expecting and new parents may experience more ventolin h worries about their health and wellbeing in relation to asthma treatment. We encourage expectant and new parents, particularly at this time, to reach out for support to their healthcare provider or GP.” ​​​​​​Regional and rural patients now have access to 24-hour critical care under a $21.7 million telestroke service being rolled out across NSW.Patients at Port Macquarie and Coffs Harbour hospitals are the first to benefit from the NSW Telestroke Service, based at Sydney’s http://becomingtheiceman.com/faq Prince of Wales Hospital. Health Minister Brad Hazzard said the revolutionary service will expand ventolin h to up to 23 sites over the next three years.

€œThe NSW Telestroke Service will remove geographical barriers and improve outcomes for thousands of regional and rural stroke patients every year, giving them a much greater chance of surviving and leading a normal life,” Mr Hazzard said. €œPeople in regional and rural areas have a far greater risk of hospitalisation from stroke and this vital service will provide them with immediate, life-saving diagnosis and treatment from the state’s leading clinicians.” In 2018-19, 13,651 people were hospitalised for a stroke in NSW. Of those, 32 per cent were from ventolin h regional, rural or remote areas.

A successful pilot project in the Hunter New England, Central Coast and Mid North Coast local health districts since 2017 has already helped 1200 patients. The Stroke Foundation’s Chief ventolin h Executive Officer Sharon McGowan welcomed the launch of the statewide service, jointly funded by the State and Federal governments. €œWhen a stroke strikes, it kills up to 1.9 million brain cells per minute.

This service will have an enormous impact by providing time-critical, best-practice ventolin h treatment that saves lives and reduces lifelong disability,” Ms McGowan said. Prince of Wales Hospital’s Director of Clinical Neuroscience Professor Ken Butcher said. €œThe service links expert stroke clinicians with local emergency physicians to quickly determine the best possible treatment plan for a patient.” ​.

A free pilot program to help new and expectant fathers navigate the physical, mental and emotional challenges of becoming a dad can you get ventolin without a prescription will be rolled out in four regions in NSW from today.Health Minister Brad Hazzard said the ‘Focus on New Fathers’ program will be trialled with men in Northern NSW, Northern and Western Sydney and the Murrumbidgee area. €œAsk any father and they will tell you, becoming a parent is an equally joyous and terrifying experience because your entire routine is turned on its head,” Mr Hazzard said. €œIt is a considerable adjustment which can put tremendous stress on you and on your relationship, so it’s can you get ventolin without a prescription important to know you are not alone and help is at hand – literally.

€œThis pilot will see texts sent to dads, offering valuable health advice and links into pathways to ensure support options are available, particularly in these uncertain asthma treatment times.” Research has shown men are often reluctant to engage with the health system to get support, despite around one in 10 dads experiencing depression and anxiety in the postnatal period. The pilot, can you get ventolin without a prescription which is being delivered by the University of Newcastle in partnership with NSW Health, will run over the next year with results helping to improve the program. Men living in the trial site areas will be eligible for the program if they are over the age of 18, their partner is at least 16 weeks pregnant or their baby is up to 24 weeks of age.

They must have a mobile phone capable of receiving and sending text messages. Associate Professor Elisabeth can you get ventolin without a prescription Murphy, Senior Clinical Advisor, Child and Family Health, said self-care for new fathers is extremely important as the mental and physical wellbeing of both parents has a direct effect on their children. €œReceiving help with health issues early on ensures dads are in the best possible position to care for their new baby and partner,” Associate Professor Murphy said.

€œWe also understand expecting and new parents may experience can you get ventolin without a prescription more worries about their health and wellbeing in relation to asthma treatment. We encourage expectant and new parents, particularly at this time, to reach out for support to their healthcare provider or GP.” ​​​​​​Regional and rural patients now have access to 24-hour critical care under a $21.7 million telestroke service being rolled out across NSW.Patients at Port Macquarie and Coffs Harbour hospitals are the first to benefit from the NSW Telestroke Service, based at Sydney’s Prince of Wales Hospital. Health Minister Brad Hazzard said the revolutionary service will expand to can you get ventolin without a prescription up to 23 sites over the next three years.

€œThe NSW Telestroke Service will remove geographical barriers and improve outcomes for thousands of regional and rural stroke patients every year, giving them a much greater chance of surviving and leading a normal life,” Mr Hazzard said. €œPeople in regional and rural areas have a far greater risk of hospitalisation from stroke and this vital service will provide them with immediate, life-saving diagnosis and treatment from the state’s leading clinicians.” In 2018-19, 13,651 people were hospitalised for a stroke in NSW. Of those, 32 can you get ventolin without a prescription per cent were from regional, rural or remote areas.

A successful pilot project in the Hunter New England, Central Coast and Mid North Coast local health districts since 2017 has already helped 1200 patients. The Stroke Foundation’s Chief Executive Officer Sharon McGowan welcomed the launch of the statewide service, jointly funded by the State and can you get ventolin without a prescription Federal governments. €œWhen a stroke strikes, it kills up to 1.9 million brain cells per minute.

This service will have an enormous impact by providing time-critical, best-practice treatment can you get ventolin without a prescription that saves lives and reduces lifelong disability,” Ms McGowan said. Prince of Wales Hospital’s Director of Clinical Neuroscience Professor Ken Butcher said. €œThe service links expert stroke clinicians with local emergency physicians to quickly determine the best possible treatment plan for a patient.” ​.

Is there a generic for ventolin hfa

The items below are highlights from the free newsletter, “Smart, useful, science stuff about asthma treatment.” To is there a generic for ventolin hfa receive newsletter issues daily in your inbox, sign up here. Please consider a monthly contribution to support this newsletter. For some asthma treatment makers, a treatment "could meet the companies' benchmarks for success if it lowered the risk of mild asthma treatment, but was never shown to reduce moderate or severe" asthma treatment, is there a generic for ventolin hfa nor the risk of hospitalization, intensive care admission or death, according to an essay published 9/22/20 in The New York Times. This statement pertains to treatments being developed by Moderna, by Pfizer, and by AstraZeneca, the essay states.

The benchmarks should be higher, the authors contend. Evidence should instead show that a treatment reduces the risk of moderate or is there a generic for ventolin hfa severe cases, write Dr. Peter Doshi of the University of Maryland School of Pharmacy and Dr. Eric Topol at Scripps Research.

The essay states that reducing the is there a generic for ventolin hfa risk of mild asthma treatment does not guarantee a similar reduction for moderate or severe cases. In both the Moderna treatment experiments and the Pfizer treatment experiments, some people report feeling “side effects that are similar to the symptoms of mild asthma treatment,” the essay states. London could be the site of the first experiments in which quarantined volunteers would be deliberately exposed to asthma after being inoculated is there a generic for ventolin hfa with a candidate treatment to protect against the new asthma, according to various reports. Such experiments are called human challenge trials.

The London experiments are expected to start in January, Reuters reported 9/23/20, picking up an initial report by The Financial Times (paywalled). So far, is there a generic for ventolin hfa about 2,000 participants have volunteered with the group 1Day Sooner for asthma challenge trials, the Reuters story states. Tanya Lewis at Scientific American has reported a feature story on some of the more than 100 U.S. Universities and colleges that have contracted rapid, frequent asthma testing for their campus to a program offered by the Broad Institute of the Massachusetts Institute of Technology and Harvard University (9/23/20).

Institutions’ reports on the program so far are positive, and such an approach to testing “could be a model for reopening is there a generic for ventolin hfa colleges and institutions nationwide,” Lewis writes. The program enables testing once or twice a week throughout the semester for students, faculty and staff, the story states. The story includes comments from users of the Broad program, including representatives from Tufts University, Bowdoin College, and is there a generic for ventolin hfa University of Massachusetts Amherst, where the basketball arena reportedly has been converted into a asthma testing center. Plans for early access to highly anticipated asthma treatments are “taking shape,” reports Nidhi Subbaraman at Nature (9/17/20).

Organizations that have issued preliminary plans or guidance so far include an advisory group at the World Health Organization and a panel convened by the U.S. National Academies of Sciences, Engineering, and Medicine (NASEM), is there a generic for ventolin hfa the story states. The NASEM panel gives top priority for vaccination to health-care workers and first responders, and then to “medically vulnerable groups,” such as people with preexisting conditions such as heart disease or diabetes as well as “older people living in crowded conditions,” Subbaraman reports. The NASEM panel's third priority group includes high-risk-of-exposure essential workers such as those working in public transit and schools, as well as people living in homeless shelters and prisons, the story states.

Fourth priority goes to young adults, children and essential workers “at increased risk of exposure,” and the fifth priority is everyone remaining is there a generic for ventolin hfa. NASEM is set to release a final plan in October, the story states. In a feature story for The Scientist, Katarina Zimmer explores the latest theories for why some is there a generic for ventolin hfa people develop severe asthma treatment and others do not (9/16/20). More details are coming into focus on why the immune system “goes haywire” in some people infected with the ventolin.

One study she mentions found that the blood of patients with severe asthma treatment showed an initial diminished response of interferons, which she defines as "cytokines [small signaling compounds/proteins] that, in general, act to curtail viral replication.” And that can lead to damage that leads to inflammation, the story states. €œThe higher the damage, the more the immune system is there a generic for ventolin hfa is trying to get rid of the damage,” says the director of the Precision Medicine Institute at Mount Sinai. €œSo it gets activated and at some point…it goes completely crazy.” That leads to the phenomenon called a cytokine storm — the immune system over-reaction. The piece also details new insights into function problems and creation problems in various immune cells (e.g.

Myeloid cells, T cells, is there a generic for ventolin hfa and antibodies). Near the end of the piece, the same researcher is attributed as saying that the myeloid defects could be at the root of the runaway cytokine responses. But an immunologist at Emory University is quoted saying that it’s hard to tease apart the chicken and the egg. Parts of is there a generic for ventolin hfa the U.S.

€œmay be witnessing the first days of an autumn surge,” according a daily asthma data page updated 9/24/20 at National Geographic. Lower on the page, graphs indicate that asthma case-counts have increased in is there a generic for ventolin hfa the past week in Utah, Wisconsin, South Dakota, Montana, and Texas. And decreases appear to have taken place in the same period in Delaware, Louisiana, Indiana, Georgia, and Kentucky. Early evidence suggests that asthma appears so far not to be spreading inside U.S.

Schools, report Laura Meckler and Valerie Strauss at The Washington is there a generic for ventolin hfa Post (9/23/20). Thousands of teachers and students have been reported as infected, the story suggests, but these “rates of are far below what is found in the surrounding communities,” the reporters write. The evidence hints that re-opening schools “may not be as risky as many have feared,” the story states. The story notes that testing and reporting for asthma is weak in many parts of the U.S., so it’s hard to say if this is an accurate picture of in-school is there a generic for ventolin hfa transmission.

The story also quotes epidemiologist Michael Osterholm of the Center for Infectious Disease Research and Policy at the University of Minnesota as saying. €œEveryone had a fear there would be explosive outbreaks of transmission in the is there a generic for ventolin hfa schools. In colleges, there have been. We have to say that, to date, we have not seen those in the younger kids.” Several indoor-air quality researchers and other scientists have collaborated on a highly accessible 53-page google-document, “FAQs on protecting yourself from asthma treatment aerosol transmission,” designed to inform the general public (9/15/20).

The information represents “our best understanding at this time and should always be is there a generic for ventolin hfa similar or more stringent than information provided by [the U.S. Centers for Disease Control], [World Health Organization], and most regional &. Local health authorities.” The document’s authors include Linsey Marr of Virginia Tech. Shelly Miller and Jose-Luis Jimenez both of is there a generic for ventolin hfa University of Colorado, Boulder.

Kimberly Prather at University of California, San Diego. Charles Haas is there a generic for ventolin hfa at Drexel University. And Richard Corsi of Portland State University. I haven’t read the whole document, but a primary point regarding reducing asthma transmission is that “you should pay at least as much attention to the air you breathe as you do to sanitizing surfaces and your hands.” This 9/22/20 Bloomberg piece by opinion columnists Max Nisen and Elaine He features an easy-to-read graphic that illustrates the risks to long-term health posed by with asthma.

The data came from is there a generic for ventolin hfa a survey of more than 1,500 asthma treatment survivors who reported to an Indiana University Medical School researcher nearly 100 different long-term health problems. €œResearchers have yet to ascertain what share of people infected with asthma treatment suffer from long-term symptoms. But the potential for harm is vast,” based on the number of people infected with asthma, the story states. There’s also a powerful graphic lower on the is there a generic for ventolin hfa page showing a data scientist's estimate of the actual number of U.S.

s through November compared with the confirmed figures. You might enjoy, “Where the sidewalk ends, outdoor dining begins,” by Jeremy Hooper for McSweeney’s (9/23/20)..

The items below are highlights from the free newsletter, “Smart, useful, science stuff about asthma treatment.” To receive newsletter issues visit the site daily in your inbox, sign can you get ventolin without a prescription up here. Please consider a monthly contribution to support this newsletter. For some asthma treatment makers, a treatment "could meet the companies' benchmarks for success if it lowered the risk of mild can you get ventolin without a prescription asthma treatment, but was never shown to reduce moderate or severe" asthma treatment, nor the risk of hospitalization, intensive care admission or death, according to an essay published 9/22/20 in The New York Times. This statement pertains to treatments being developed by Moderna, by Pfizer, and by AstraZeneca, the essay states. The benchmarks should be higher, the authors contend.

Evidence should can you get ventolin without a prescription instead show that a treatment reduces the risk of moderate or severe cases, write Dr. Peter Doshi of the University of Maryland School of Pharmacy and Dr. Eric Topol at Scripps Research. The essay states that reducing the risk of mild asthma treatment does not can you get ventolin without a prescription guarantee a similar reduction for moderate or severe cases. In both the Moderna treatment experiments and the Pfizer treatment experiments, some people report feeling “side effects that are similar to the symptoms of mild asthma treatment,” the essay states.

London could be the site of the first experiments in which quarantined volunteers would be deliberately exposed to asthma after being inoculated with a candidate treatment to protect against the can you get ventolin without a prescription new asthma, according to various reports. Such experiments are called human challenge trials. The London experiments are expected to start in January, Reuters reported 9/23/20, picking up an initial report by The Financial Times (paywalled). So far, about 2,000 participants can you get ventolin without a prescription have volunteered with the group 1Day Sooner for asthma challenge trials, the Reuters story states. Tanya Lewis at Scientific American has reported a feature story on some of the more than 100 U.S.

Universities and colleges that have contracted rapid, frequent asthma testing for their campus to a program offered by the Broad Institute of the Massachusetts Institute of Technology and Harvard University (9/23/20). Institutions’ reports can you get ventolin without a prescription on the program so far are positive, and such an approach to testing “could be a model for reopening colleges and institutions nationwide,” Lewis writes. The program enables testing once or twice a week throughout the semester for students, faculty and staff, the story states. The story includes comments from users of the Broad program, including representatives from Tufts University, Bowdoin College, and University of Massachusetts Amherst, where the basketball arena reportedly has been converted into can you get ventolin without a prescription a asthma testing center. Plans for early access to highly anticipated asthma treatments are “taking shape,” reports Nidhi Subbaraman at Nature (9/17/20).

Organizations that have issued preliminary plans or guidance so far include an advisory group at the World Health Organization and a panel convened by the U.S. National Academies of Sciences, Engineering, and Medicine (NASEM), the story states can you get ventolin without a prescription. The NASEM panel gives top priority for vaccination to health-care workers and first responders, and then to “medically vulnerable groups,” such as people with preexisting conditions such as heart disease or diabetes as well as “older people living in crowded conditions,” Subbaraman reports. The NASEM panel's third priority group includes high-risk-of-exposure essential workers such as those working in public transit and schools, as well as people living in homeless shelters and prisons, the story states. Fourth priority goes to young adults, children and essential workers “at increased risk of exposure,” and the fifth priority is can you get ventolin without a prescription everyone remaining.

NASEM is set to release a final plan in October, the story states. In a feature story for The Scientist, Katarina Zimmer explores the latest theories for why some can you get ventolin without a prescription people develop severe asthma treatment and others do not (9/16/20). More details are coming into focus on why the immune system “goes haywire” in some people infected with the ventolin. One study she mentions found that the blood of patients with severe asthma treatment showed an initial diminished response of interferons, which she defines as "cytokines [small signaling compounds/proteins] that, in general, act to curtail viral replication.” And that can lead to damage that leads to inflammation, the story states. €œThe higher the damage, the more the immune system is trying to get rid of the damage,” says the director of the Precision Medicine can you get ventolin without a prescription Institute at Mount Sinai.

€œSo it gets activated and at some point…it goes completely crazy.” That leads to the phenomenon called a cytokine storm — the immune system over-reaction. The piece also details new insights into function problems and creation problems in various immune cells (e.g. Myeloid cells, T cells, can you get ventolin without a prescription and antibodies). Near the end of the piece, the same researcher is attributed as saying that the myeloid defects could be at the root of the runaway cytokine responses. But an immunologist at Emory University is quoted saying that it’s hard to tease apart the chicken and the egg.

Parts of can you get ventolin without a prescription the U.S. €œmay be witnessing the first days of an autumn surge,” according a daily asthma data page updated 9/24/20 at National Geographic. Lower on the page, graphs indicate that asthma case-counts have increased in the can you get ventolin without a prescription past week in Utah, Wisconsin, South Dakota, Montana, and Texas. And decreases appear to have taken place in the same period in Delaware, Louisiana, Indiana, Georgia, and Kentucky. Early evidence suggests that asthma appears so far not to be spreading inside U.S.

Schools, report can you get ventolin without a prescription Laura Meckler and Valerie Strauss at The Washington Post (9/23/20). Thousands of teachers and students have been reported as infected, the story suggests, but these “rates of are far below what is found in the surrounding communities,” the reporters write. The evidence hints that re-opening schools “may not be as risky as many have feared,” the story states. The story notes that testing and reporting for asthma is weak in many parts of the U.S., so it’s can you get ventolin without a prescription hard to say if this is an accurate picture of in-school transmission. The story also quotes epidemiologist Michael Osterholm of the Center for Infectious Disease Research and Policy at the University of Minnesota as saying.

€œEveryone had a fear can you get ventolin without a prescription there would be explosive outbreaks of transmission in the schools. In colleges, there have been. We have to say that, to date, we have not seen those in the younger kids.” Several indoor-air quality researchers and other scientists have collaborated on a highly accessible 53-page google-document, “FAQs on protecting yourself from asthma treatment aerosol transmission,” designed to inform the general public (9/15/20). The information represents can you get ventolin without a prescription “our best understanding at this time and should always be similar or more stringent than information provided by [the U.S. Centers for Disease Control], [World Health Organization], and most regional &.

Local health authorities.” The document’s authors include Linsey Marr of Virginia Tech. Shelly Miller can you get ventolin without a prescription and Jose-Luis Jimenez both of University of Colorado, Boulder. Kimberly Prather at University of California, San Diego. Charles Haas at Drexel can you get ventolin without a prescription University. And Richard Corsi of Portland State University.

I haven’t read the whole document, but a primary point regarding reducing asthma transmission is that “you should pay at least as much attention to the air you breathe as you do to sanitizing surfaces and your hands.” This 9/22/20 Bloomberg piece by opinion columnists Max Nisen and Elaine He features an easy-to-read graphic that illustrates the risks to long-term health posed by with asthma. The data came from a survey of more than 1,500 asthma treatment survivors who reported to an Indiana University Medical School researcher nearly 100 different long-term health problems can you get ventolin without a prescription. €œResearchers have yet to ascertain what share of people infected with asthma treatment suffer from long-term symptoms. But the potential for harm is vast,” based on the number of people infected with asthma, the story states. There’s also can you get ventolin without a prescription a powerful graphic lower on the page showing a data scientist's estimate of the actual number of U.S.

s through November compared with the confirmed figures. You might enjoy, “Where the sidewalk ends, outdoor dining begins,” by Jeremy Hooper for McSweeney’s (9/23/20)..

Can you take symbicort and ventolin at the same time

Participants Figure can you take symbicort and ventolin at the same time 1 click here to read. Figure 1. Enrollment and Randomization can you take symbicort and ventolin at the same time.

The diagram represents all enrolled participants through November 14, 2020. The safety subset (those with a median of 2 months of follow-up, in accordance with application requirements for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date. The further procedures that one participant in the placebo group declined after dose 2 (lower right corner of the diagram) were those can you take symbicort and ventolin at the same time involving collection of blood and nasal swab samples.Table 1.

Table 1. Demographic Characteristics of the can you take symbicort and ventolin at the same time Participants in the Main Safety Population. Between July 27, 2020, and November 14, 2020, a total of 44,820 persons were screened, and 43,548 persons 16 years of age or older underwent randomization at 152 sites worldwide (United States, 130 sites.

Argentina, 1. Brazil, 2 can you take symbicort and ventolin at the same time. South Africa, 4.

Germany, 6 can you take symbicort and ventolin at the same time. And Turkey, 9) in the phase 2/3 portion of the trial. A total of 43,448 participants received injections.

21,720 received BNT162b2 and 21,728 received placebo (Figure 1) can you take symbicort and ventolin at the same time. At the data cut-off date of October 9, a total of 37,706 participants had a median of at least 2 months of safety data available after the second dose and contributed to the main safety data set. Among these 37,706 participants, 49% were female, 83% were White, 9% were Black or African can you take symbicort and ventolin at the same time American, 28% were Hispanic or Latinx, 35% were obese (body mass index [the weight in kilograms divided by the square of the height in meters] of at least 30.0), and 21% had at least one coexisting condition.

The median age was 52 years, and 42% of participants were older than 55 years of age (Table 1 and Table S2). Safety Local Reactogenicity Figure 2. Figure 2 can you take symbicort and ventolin at the same time.

Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group. Data on local and systemic reactions and use of can you take symbicort and ventolin at the same time medication were collected with electronic diaries from participants in the reactogenicity subset (8,183 participants) for 7 days after each vaccination. Solicited injection-site (local) reactions are shown in Panel A.

Pain at the injection site was assessed according to the following scale. Mild, does can you take symbicort and ventolin at the same time not interfere with activity. Moderate, interferes with activity.

Severe, prevents daily activity. And grade 4, emergency department visit can you take symbicort and ventolin at the same time or hospitalization. Redness and swelling were measured according to the following scale.

Mild, 2.0 to 5.0 can you take symbicort and ventolin at the same time cm in diameter. Moderate, >5.0 to 10.0 cm in diameter. Severe, >10.0 cm in diameter.

And grade 4, necrosis or exfoliative dermatitis (for redness) and can you take symbicort and ventolin at the same time necrosis (for swelling). Systemic events and medication use are shown in Panel B. Fever categories are designated in the can you take symbicort and ventolin at the same time key.

Medication use was not graded. Additional scales were as follows. Fatigue, headache, chills, new or worsened muscle pain, can you take symbicort and ventolin at the same time new or worsened joint pain (mild.

Does not interfere with activity. Moderate. Some interference with activity.

Or severe. Prevents daily activity), vomiting (mild. 1 to 2 times in 24 hours.

Moderate. >2 times in 24 hours. Or severe.

Requires intravenous hydration), and diarrhea (mild. 2 to 3 loose stools in 24 hours. Moderate.

4 to 5 loose stools in 24 hours. Or severe. 6 or more loose stools in 24 hours).

Grade 4 for all events indicated an emergency department visit or hospitalization. Н™¸ bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.The reactogenicity subset included 8183 participants. Overall, BNT162b2 recipients reported more local reactions than placebo recipients.

Among BNT162b2 recipients, mild-to-moderate pain at the injection site within 7 days after an injection was the most commonly reported local reaction, with less than 1% of participants across all age groups reporting severe pain (Figure 2). Pain was reported less frequently among participants older than 55 years of age (71% reported pain after the first dose. 66% after the second dose) than among younger participants (83% after the first dose.

78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), and no participant reported a grade 4 local reaction.

In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days. Systemic Reactogenicity Systemic events were reported more often by younger treatment recipients (16 to 55 years of age) than by older treatment recipients (more than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B). The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger treatment recipients.

51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger treatment recipients. 17% and 14% among older recipients). The frequency of any severe systemic event after the first dose was 0.9% or less.

Severe systemic events were reported in less than 2% of treatment recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after the second dose. Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger treatment recipients and by 11% of older recipients. Only 0.2% of treatment recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose.

Two participants each in the treatment and placebo groups reported temperatures above 40.0°C. Younger treatment recipients were more likely to use antipyretic or pain medication (28% after dose 1. 45% after dose 2) than older treatment recipients (20% after dose 1.

38% after dose 2), and placebo recipients were less likely (10 to 14%) than treatment recipients to use the medications, regardless of age or dose. Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter. Daily use of the electronic diary ranged from 90 to 93% for each day after the first dose and from 75 to 83% for each day after the second dose.

No difference was noted between the BNT162b2 group and the placebo group. Adverse Events Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3). More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related adverse event (21% and 5%).

This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by treatment recipients than by placebo recipients. Sixty-four treatment recipients (0.3%) and 6 placebo recipients (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial.

Four related serious adverse events were reported among BNT162b2 recipients (shoulder injury related to treatment administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia). Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). No deaths were considered by the investigators to be related to the treatment or placebo.

No asthma treatment–associated deaths were observed. No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of treatment.

Efficacy Table 2. Table 2. treatment Efficacy against asthma treatment at Least 7 days after the Second Dose.

Table 3. Table 3. treatment Efficacy Overall and by Subgroup in Participants without Evidence of before 7 Days after Dose 2.

Figure 3. Figure 3. Efficacy of BNT162b2 against asthma treatment after the First Dose.

Shown is the cumulative incidence of asthma treatment after the first dose (modified intention-to-treat population). Each symbol represents asthma treatment cases starting on a given day. Filled symbols represent severe asthma treatment cases.

Some symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged y axis, through 21 days. Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point.

The time period for asthma treatment case accrual is from the first dose to the end of the surveillance period. The confidence interval (CI) for treatment efficacy (VE) is derived according to the Clopper–Pearson method.Among 36,523 participants who had no evidence of existing or prior asthma , 8 cases of asthma treatment with onset at least 7 days after the second dose were observed among treatment recipients and 162 among placebo recipients. This case split corresponds to 95.0% treatment efficacy (95% confidence interval [CI], 90.3 to 97.6.

Table 2). Among participants with and those without evidence of prior SARS CoV-2 , 9 cases of asthma treatment at least 7 days after the second dose were observed among treatment recipients and 169 among placebo recipients, corresponding to 94.6% treatment efficacy (95% CI, 89.9 to 97.3). Supplemental analyses indicated that treatment efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population (Table 3 and Table S4).

treatment efficacy among participants with hypertension was analyzed separately but was consistent with the other subgroup analyses (treatment efficacy, 94.6%. 95% CI, 68.7 to 99.9. Case split.

BNT162b2, 2 cases. Placebo, 44 cases). Figure 3 shows cases of asthma treatment or severe asthma treatment with onset at any time after the first dose (mITT population) (additional data on severe asthma treatment are available in Table S5).

Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a treatment efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the treatment, starting as soon as 12 days after the first dose.Trial Oversight This phase 3 randomized, stratified, observer-blinded, placebo-controlled trial enrolled adults in medically stable condition at 99 U.S. Sites. Participants received the first trial injection between July 27 and October 23, 2020.

The trial is being conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Good Clinical Practice guidelines, and applicable government regulations. The central institutional review board approved the protocol and the consent forms. All participants provided written informed consent before enrollment.

Safety is reviewed by a protocol safety review team weekly and by an independent data and safety monitoring board on a continual basis. The trial Investigational New Drug sponsor, Moderna, was responsible for the overall trial design (with input from the Biomedical Advanced Research and Development Authority, the NIAID, the asthma treatment Prevention Network, and the trial cochairs), site selection and monitoring, and data analysis. Investigators are responsible for data collection.

A medical writer funded by Moderna assisted in drafting the manuscript for submission. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The trial is ongoing, and the investigators remain unaware of participant-level data.

Designated team members within Moderna have unblinded access to the data, to facilitate interface with the regulatory agencies and the data and safety monitoring board. All other trial staff and participants remain unaware of the treatment assignments. Participants, Randomization, and Data Blinding Eligible participants were persons 18 years of age or older with no known history of asthma and with locations or circumstances that put them at an appreciable risk of asthma , a high risk of severe asthma treatment, or both.

Inclusion and exclusion criteria are provided in the protocol (available with the full text of this article at NEJM.org). To enhance the diversity of the trial population in accordance with Food and Drug Administration Draft Guidance, site-selection and enrollment processes were adjusted to increase the number of persons from racial and ethnic minorities in the trial, in addition to the persons at risk for asthma in the local population. The upper limit for stratification of enrolled participants considered to be “at risk for severe illness” at screening was increased from 40% to 50%.17 Participants were randomly assigned in a 1:1 ratio, through the use of a centralized interactive response technology system, to receive treatment or placebo.

Assignment was stratified, on the basis of age and asthma treatment complications risk criteria, into the following risk groups. Persons 65 years of age or older, persons younger than 65 years of age who were at heightened risk (at risk) for severe asthma treatment, and persons younger than 65 years of age without heightened risk (not at risk). Participants younger than 65 years of age were categorized as having risk for severe asthma treatment if they had at least one of the following risk factors, based on the Centers for Disease Control and Prevention (CDC) criteria available at the time of trial design.

Chronic lung disease (e.g., emphysema, chronic bronchitis, idiopathic pulmonary fibrosis, cystic fibrosis, or moderate-to-severe asthma). Cardiac disease (e.g., heart failure, congenital coronary artery disease, cardiomyopathies, or pulmonary hypertension). Severe obesity (body mass index [the weight in kilograms divided by the square of the height in meters] ≥40).

Diabetes (type 1, type 2, or gestational). Liver disease. Or with the human immunodeficiency ventolin.18 treatment dose preparation and administration were performed by pharmacists and treatment administrators who were aware of treatment assignments but had no other role in the conduct of the trial.

Once the injection was completed, only trial staff who were unaware of treatment assignments performed assessments and interacted with the participants. Access to the randomization code was strictly controlled at the pharmacy. The data and safety monitoring board reviewed efficacy data at the group level and unblinded safety data at the participant level.

Trial treatment The mRNA-1273 treatment, provided as a sterile liquid at a concentration of 0.2 mg per milliliter, was administered by injection into the deltoid muscle according to a two-dose regimen. Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 μg of mRNA-1273 or saline placebo.1 treatment mRNA-1273 was stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and vaccination. No dilution was required.

Doses could be held in syringes for up to 8 hours at room temperature before administration. Safety Assessments Safety assessments included monitoring of solicited local and systemic adverse events for 7 days after each injection. Unsolicited adverse reactions for 28 days after each injection.

Adverse events leading to discontinuation from a dose, from participation in the trial, or both. And medically attended adverse events and serious adverse events from day 1 through day 759. Adverse event grading criteria and toxicity tables are described in the protocol.

Cases of asthma treatment and severe asthma treatment were continuously monitored by the data and safety monitoring board from randomization onward. Efficacy Assessments The primary end point was the efficacy of the mRNA-1273 treatment in preventing a first occurrence of symptomatic asthma treatment with onset at least 14 days after the second injection in the per-protocol population, among participants who were seronegative at baseline. End points were judged by an independent adjudication committee that was unaware of group assignment.

asthma treatment cases were defined as occurring in participants who had at least two of the following symptoms. Fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for asthma by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test. Participants were assessed for the presence of asthma–binding antibodies specific to the asthma nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for asthma RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection.

asthma–infected volunteers were followed daily, to assess symptom severity, for 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab for RT-PCR testing and a blood sample for identifying serologic evidence of asthma were collected from participants with symptoms of asthma treatment. The consistency of treatment efficacy at the primary end point was evaluated across various subgroups, including age groups (18 to <65 years of age and ≥65 years), age and health risk for severe disease (18 to <65 years and not at risk.

18 to <65 years and at risk. And ≥65 years), sex (female or male), race and ethnic group, and risk for severe asthma treatment illness. If the number of participants in a subgroup was too small, it was combined with other subgroups for the subgroup analyses.

A secondary end point was the efficacy of mRNA-1273 in the prevention of severe asthma treatment as defined by one of the following criteria. Respiratory rate of 30 or more breaths per minute. Heart rate at or exceeding 125 beats per minute.

Oxygen saturation at 93% or less while the participant was breathing ambient air at sea level or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen below 300 mm Hg. Respiratory failure. Acute respiratory distress syndrome.

Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or a need for vasopressors). Clinically significant acute renal, hepatic, or neurologic dysfunction. Admission to an intensive care unit.

Or death. Additional secondary end points included the efficacy of the treatment at preventing asthma treatment after a single dose or at preventing asthma treatment according to a secondary (CDC), less restrictive case definition. Having any symptom of asthma treatment and a positive asthma test by RT-PCR (see Table S1 in the Supplementary Appendix, available at NEJM.org).

Statistical Analysis For analysis of the primary end point, the trial was designed for the null hypothesis that the efficacy of the mRNA-1273 treatment is 30% or less. A total of 151 cases of asthma treatment would provide 90% power to detect a 60% reduction in the hazard rate (i.e., 60% treatment efficacy), with two planned interim analyses at approximately 35% and 70% of the target total number of cases (151) and with a one-sided O’Brien–Fleming boundary for efficacy and an overall one-sided error rate of 0.025. The efficacy of the mRNA-1273 treatment could be demonstrated at either the interim or the primary analysis, performed when the target total number of cases had been observed.

The Lan–DeMets alpha-spending function was used for calculating efficacy boundaries at each analysis. At the first interim analysis on November 15, 2020, treatment efficacy had been demonstrated in accordance with the prespecified statistical criteria. The treatment efficacy estimate, based on a total of 95 adjudicated cases (63% of the target total), was 94.5%, with a one-sided P value of less than 0.001 to reject the null hypothesis that treatment efficacy would be 30% or less.

The data and safety monitoring board recommendation to the oversight group and the trial sponsor was that the efficacy findings should be shared with the participants and the community (full details are available in the protocol and statistical analysis plan). treatment efficacy was assessed in the full analysis population (randomized participants who received at least one dose of mRNA-1273 or placebo), the modified intention-to-treat population (participants in the full analysis population who had no immunologic or virologic evidence of asthma treatment on day 1, before the first dose), and the per-protocol population (participants in the modified intention-to-treat population who received two doses, with no major protocol deviations). The primary efficacy end point in the interim and primary analyses was assessed in the per-protocol population.

Participants were evaluated in the treatment groups to which they were assigned. treatment efficacy was defined as the percentage reduction in the hazard ratio for the primary end point (mRNA-1273 vs. Placebo).

A stratified Cox proportional hazards model was used to assess the treatment efficacy of mRNA-1273 as compared with placebo in terms of the percentage hazard reduction. (Details regarding the analysis of treatment efficacy are provided in the Methods section of the Supplementary Appendix.) Safety was assessed in all participants in the solicited safety population (i.e., those who received at least one injection and reported a solicited adverse event). Descriptive summary data (numbers and percentages) for participants with any solicited adverse events, unsolicited adverse events, unsolicited severe adverse events, serious adverse events, medically attended adverse events, and adverse events leading to discontinuation of the injections or withdrawal from the trial are provided by group.

Two-sided 95% exact confidence intervals (Clopper–Pearson method) are provided for the percentages of participants with solicited adverse events. Unsolicited adverse events are presented according to the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0, preferred terms and system organ class categories. To meet the regulatory agencies’ requirement of a median follow-up duration of at least 2 months after completion of the two-dose regimen, a second analysis was performed, with an efficacy data cutoff date of November 21, 2020.

This second analysis is considered the primary analysis of efficacy, with a total of 196 adjudicated asthma treatment cases in the per-protocol population, which exceeds the target total number of cases (151) specified in the protocol. This was an increase from the 95 cases observed at the first interim analysis data cutoff on November 11, 2020. Results from the primary analysis are presented in this report.

Subsequent analyses are considered supplementary.Participants From July 22 to August 7, 2020, a total of 593 persons underwent screening for enrollment in cohort 1 (including 1a and 1b combined) (Fig. S1). Of these persons, 405 were enrolled and 402 received the first dose of Ad26.COV2.S.

These participants had received the second dose by November 7, 2020. From August 3 to August 24, 2020, a total of 660 persons underwent screening for cohort 3. Of these participants, 405 were enrolled and 403 received the first dose of Ad26.COV2.S.

(Details regarding age distribution are provided in Table S2.) Analyses of data obtained from participants in cohort 3 after the administration of the second dose, as well as durability and longer-term safety data, are ongoing. Table 1. Table 1.

Characteristics of the Participants at Baseline. At baseline, the percentage of participants who were seropositive for asthma S-specific antibodies was 2% in cohort 1a and 1% in cohort 3. The baseline characteristics of the participants were broadly similar across the groups (Table 1).

treatment Safety and Reactogenicity Figure 1. Figure 1. Solicited Adverse Events in Cohorts 1 and 3 after the First treatment Dose.

Shown are solicited adverse events in participants who received the Ad26.COV2.S treatment at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo. Healthy adults between the ages of 18 and 55 years were included in cohort 1 (Panel A), and those 65 years of age or older were included in cohort 3 (Panel B). The younger group was divided into cohorts 1a and 1b, with the latter designated as an exploratory cohort for in-depth analysis of immunogenicity.

As shown here, data for cohorts 1a and 1b have been pooled. Data for patients in cohort 1a who received a second dose of treatment are provided in Figure S2 in the Supplementary Appendix.Data regarding both solicited and unsolicited adverse events and serious adverse events were available for more than 99% of the participants who returned diary cards. The investigator’s assessment of reactogenicity after the administration of the first dose of treatment was available for 402 participants in cohort 1 and for 403 participants in cohort 3.

In the two cohorts, solicited local adverse events were mostly of grade 1 or 2. The most frequent event was injection-site pain. In cohort 1, solicited local adverse events were reported in 103 of 162 low-dose recipients (64%), in 123 of 158 high-dose recipients (78%), and in 7 of 82 placebo recipients (9%) (Figure 1A and Table S3).

In cohort 3, solicited local adverse events were reported in 66 of 161 low-dose recipients (41%), in 68 of 161 high-dose recipients (42%), and in 11 of 81 placebo recipients (14%) (Figure 1B). In the two cohorts, most solicited systemic adverse events were of grade 1 or 2. The most frequent events were fatigue, headache, and myalgia.

In cohort 1, solicited systemic adverse events were reported in 105 low-dose recipients (65%), in 133 high-dose recipients (84%), and in 21 placebo recipients (26%). In cohort 3, solicited systemic adverse events were reported in 74 low-dose recipients (46%), in 88 high-dose recipients (55%), and in 19 placebo recipients (23%). In cohort 1, solicited grade 3 systemic adverse events were reported in 15 low-dose recipients (9%) and in 32 high-dose recipients (20%).

No placebo recipients reported such events. In cohort 1a, among the participants between the ages of 18 and 30 years who had one or more solicited grade 3 adverse events, 24% had received the low dose and 26% had received the high dose. In those between the ages of 31 and 45 years, the corresponding percentages were 43% and 14%.

And in those between the ages of 46 and 55 years, the corresponding percentages were 3% and 11%. In cohort 3, grade 3 solicited systemic adverse events were reported in 1 low-dose recipient (1%) and in 4 high-dose recipients (2%). No placebo recipients reported having such events.

In cohort 1, fever was reported in 25 low-dose recipients (15%) and in 62 high-dose recipients (39%). Grade 3 fever (temperature range, 39.0 to 40.0°C) was reported in 8 low-dose recipients (5%) and in 15 high-dose recipients (9%). In cohort 3, fever was reported in 7 low-dose recipients (4%) and in 14 high-dose recipients (9%).

Grade 3 fever was reported in no low-dose recipients and in 2 high-dose recipients (1%). No participants in the placebo group in either cohort reported having fever. All cases of fever occurred within 2 days after immunization and resolved within 1 or 2 days.

More than 80% of the participants with fever received an antipyretic drug at the onset of symptoms. In cohort 1, unsolicited adverse events were reported in 34 low-dose recipients (21%), in 56 high-dose recipients (35%), and in 14 placebo recipients (17%). In cohort 3, unsolicited adverse events were reported in 27 low-dose recipients (17%), in 38 high-dose recipients (24%), and in 13 placebo recipients (16%) (Table S4).

No grade 4 adverse events (solicited or unsolicited) were reported in any cohort. In cohort 1a, safety data after the administration of the second dose of treatment were available for 363 participants (Fig. S2).

One or more solicited adverse events were noted in 77% and 80% of the participants in the low-dose and high-dose groups, respectively, as compared with 34% and 31% of those who received placebo as a second dose after a first dose of treatment and in 22% of those who received placebo for both doses. Solicited adverse events of grade 3 or higher were noted in 1% of low-dose recipients and in 7% of high-dose recipients. The corresponding percentages were 1% and 2% among participants in the placebo group who received a first dose of treatment and in no participants who received placebo for both doses.

No grade 3 fevers were reported in any group after a second dose of treatment. No participant discontinued the trial because of an adverse event. Five serious adverse events occurred.

One case of hypotension that was deemed by the investigator to be unrelated to the treatment because of a history of recurrent hypotension. One case of bilateral nephrolithiasis in a participant with a history of kidney stones (not related). One case of legionella pneumonia (not related).

One worsening of multiple sclerosis, which had remained undiagnosed for approximately 8 to 10 years on the basis of findings on magnetic resonance imaging (not related). And one case of fever that resulted in hospitalization because of suspicion of asthma treatment. In the last case, the participant recovered within 12 hours, and the fever was subsequently deemed by the investigator to be related to the treatment.

Details regarding all safety data are provided in the Supplementary Appendix. Immunogenicity and Seroconversion Figure 2. Figure 2.

Humoral Immunogenicity. Shown are measures of humoral immunogenicity in serum samples obtained from the participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. In cohort 1a, the participants received two injections of high-dose or low-dose treatment or placebo, as indicated with slashes (e.g., placebo/placebo if they received two injections of placebo).

The samples were measured on enzyme-linked immunosorbent assay (ELISA) in ELISA units (EU) per milliliter (Panel A) and on wild-type ventolin neutralization assay, with seropositivity defined as a half maximal inhibitory concentration (IC50) titer of more than 58 at the lower limit of quantitation (Panel B). Logarithmic values are reported as the geometric mean concentration (GMC) in the ELISA analyses and as the geometric mean titer (GMT) in the neutralizing-antibody analyses. The values were measured at baseline and at day 29 after vaccination in all the participants and on days 57 and 71 in those in cohort 1a.

The two horizontal dotted lines in each panel indicate the lower and upper limits of quantitation of the respective assay. Values below the lower line have been imputed to half the lower limit of quantitation. Н™¸ bars indicate 95% confidence intervals.

HCS denotes human convalescent serum.Immunogenicity data for this interim analysis were unblinded according to dose level. In all five groups in cohort 1a, the binding-antibody geometric mean concentration (GMC), as reported in ELISA units per milliliter, was measured against a stabilized asthma full-length spike protein. At baseline, the GMC values in all the participants were lower than the lower limit of quantitation.

By day 29 after vaccination, the values had increased to 478 (95% confidence interval [CI], 379 to 603) in the low-dose/placebo group, 586 (95% CI, 445 to 771) in the low-dose/low-dose group, 625 (95% CI, 505 to 773) in the high-dose/placebo group, and 788 (95% CI, 628 to 988) in the high-dose/high-dose group, with an incidence of seroconversion of 99% or more in all the groups (Figure 2A and Fig. S3A). By day 57, the corresponding GMC values had further increased to 660 (95% CI, 513 to 849), 754 (95% CI, 592 to 961), 873 (95% CI, 701 to 1087), and 1100 (95% CI, 908 to 1332).

After the first dose, the incidence of seroconversion was 100% in all but the high-dose/placebo group (97%). Fourteen days after the second dose, the GMC was 1677 (95% CI, 1334 to 2109) in the low-dose/low-dose group and 2292 (95% CI, 1846 to 2845) in the high-dose/high-dose group, with 100% seroconversion in each group. On day 71, in the low-dose/placebo and high-dose/placebo groups, the GMC was 600 (95% CI, 443 to 814) and 951 (95% CI, 696 to 1,300), respectively, values that were similar to those on day 57.

In cohort 3, the GMCs in all the participants were also below the lower limit of quantitation at baseline. By day 15 after vaccination, the GMC had increased to 122 (95% CI, 97 to 152) in the low-dose group and to 141 (95% CI, 114 to 175) in the high-dose group, with a seroconversion incidence of 75% and 77%, respectively. By day 29, the GMC was 312 (95% CI, 246 to 396) in the low-dose group and 350 (95% CI, 281 to 429) in the high-dose group, with 96% seroconversion.

The asthma neutralizing-antibody titer (IC50) was measured in a random subgroup of participants in cohorts 1a and 3. In cohort 1a, the geometric mean titer (GMT) was below the lower limit of quantitation at baseline and by day 29 after vaccination had increased to 224 (95% CI, 158 to 318) in the low-dose/placebo group, 224 (95% CI, 168 to 298) in the low-dose/low-dose group, 215 (95% CI, 169 to 273) in the high-dose/placebo group, and 354 (95% CI, 220 to 571) in the high-dose/high-dose group, with an incidence of seroconversion of 96%, 88%, 96%, and 92%, respectively (Figure 2B and Fig. S3B).

By day 57, the GMT had further increased to 310 (95% CI, 228 to 422), 288 (95% CI, 221 to 376), 370 (95% CI, 268 to 511), and 488 (95% CI, 334 to 714), respectively, with a 100% incidence of seroconversion in the low-dose/placebo group and 96% seroconversion in the other groups. In cohort 1a, 14 days after the second dose, the GMT was 827 (95% CI, 508 to 1183) in the low-dose/low-dose group and 1266 (95% CI, 746 to 2169) in the high-dose/high-dose group, with 100% seroconversion in the two dose groups. On day 71, the GMT was 321 (95% CI, 227 to 438) in the low-dose/placebo group and 388 (95% CI, 290 to 509) in the high-dose/placebo group, values that were similar to those on day 57.

The incidence of seroconversion was 100% in both groups. In cohort 3, the GMTs in all the participants were below the lower limit of quantitation at baseline and had increased to 212 (95% CI, 137 to 284) in the low-dose group and 172 (95% CI, 119 to 269) in the high-dose group on day 15 and to 277 (95% CI, 193 to 307) and 212 (95% CI, 163 to 266), respectively, on day 29. The incidence of seroconversion was 91% and 84%, respectively, on day 15 and 96% and 88%, respectively, on day 29.

These data were confirmed on IC80 analysis (Fig. S4). Antibody levels as measured on wild-type ventolin neutralization assay and ELISA were strongly correlated in the two cohorts (Fig.

S5). However, the correlation had a wider elliptical shape in cohort 3, which suggested more variability in the relationship between the neutralizing-antibody titer and the binding-antibody titer in the older adults. Antibody levels in the different human convalescent serum panels that were included in assays for humoral-immunity assessment that were performed in different laboratories and in serum samples that were obtained from treatment recipients were in the same range.

Details regarding differences in values according to demographic characteristics are provided in Tables S5 and S6 in the Supplementary Appendix. Levels of Ad26 neutralizing antibodies at baseline or after the first dose of treatment did not correlate with the levels of asthma neutralizing antibodies on either day 29 or day 71 (Fig. S6).

S-Specific T-Cell Responses Figure 3. Figure 3. Cellular Immunogenicity of Ad26.COV2.S.

In CD4+ T cells, the response to low-dose or high-dose treatment or placebo in type 1 helper T (Th1) cells was characterized by the expression of interferon-γ, interleukin-2, or both, without cytokines expressed by type 2 helper T (Th2) cells (Panel A). The response in CD4+ Th2 cells was characterized by the expression of interleukin-4, interleukin-5, or interleukin-13 (or all three cytokines) plus CD40L (Panel B). In CD8+ T cells, the response was measured by the expression of interferon-γ, interleukin-2, or both (Panel C).

In all three panels, the horizontal bars indicate median values on intracellular cytokine staining for individual responses to a asthma S protein peptide pool in peripheral-blood mononuclear cells at baseline and 15 days after vaccination in a subgroup of participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. The horizontal dotted line in each panel indicates the lower limit of quantitation (LLOQ). Values below the line have been imputed to half the LLOQ.The treatment-elicited responses in S-specific CD4+ Th1 and Th2 cells and in CD8+ T cells were assessed in a subgroup of participants at baseline and 15 days after the first dose.

In cohort 1a, a Th1 response to S peptides was detected in 76% (95% CI, 65 to 86) of low-dose recipients and in 83% (95% CI, 73 to 91) of high-dose recipients. The corresponding values in cohort 3 were 60% (95% CI, 46 to 74) and 67% (95% CI, 53 to 79), respectively (Figure 3A). In cohort 1a, the median CD4+ Th1 response to S peptides increased from an undetectable level at baseline to a median of 0.08% (interquartile range [IQR], 0.05 to 0.16) in low-dose recipients and 0.11% (IQR, 0.07 to 0.16) in high-dose recipients on day 15.

In cohort 3, the corresponding values were 0.09% (IQR, 0.04 to 0.17) and 0.11% (IQR, 0.04 to 0.15), respectively. A low-dose recipient in cohort 1a and a high-dose recipient in cohort 3 had a measurable Th2 response (Figure 3B). However, all the participants who had a measurable Th1 or Th2 response had a Th1:Th2 ratio that was well above 1, which indicated a treatment-induced Th1-skewed response.

S-specific CD8+ T-cell responses, as identified by the expression of interferon-γ or interleukin-2 cytokines on S-peptide stimulation, were absent at baseline in the two cohorts (Figure 3C). On day 15 in cohort 1a, a CD8+ T-cell response was detected in 51% of participants (95% CI, 39 to 63) in the low-dose group and in 64% (95% CI, 52 to 75) in the high-dose group, with a median S-specific CD8+ T-cell response of 0.07% (IQR, 0.03 to 0.19) and 0.09% (IQR, 0.05 to 0.19), respectively. In cohort 3, CD8+ T-cell responses were lower, with an incidence of 36% (95% CI, 23 to 51) in the low-dose group and 24% (95% CI, 13 to 37) in the high-dose group, with a median response of 0.06% (IQR, 0.02 to 0.12) and 0.02% (IQR, 0.01 to 0.08), respectively.

The correlation between CD4+ Th1 and CD8+ T-cell response was poor in the two cohorts (Fig. S7).Patients Figure 1. Figure 1.

Enrollment and Randomization. Of the 1114 patients who were assessed for eligibility, 1062 underwent randomization. 541 were assigned to the remdesivir group and 521 to the placebo group (intention-to-treat population) (Figure 1).

159 (15.0%) were categorized as having mild-to-moderate disease, and 903 (85.0%) were in the severe disease stratum. Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Fifty-two patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death and 10 withdrew consent.

Of those assigned to receive placebo, 517 patients (99.2%) received placebo as assigned. Seventy patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death and 14 withdrew consent. A total of 517 patients in the remdesivir group and 508 in the placebo group completed the trial through day 29, recovered, or died.

Fourteen patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29. A total of 54 of the patients who were in the mild-to-moderate stratum at randomization were subsequently determined to meet the criteria for severe disease, resulting in 105 patients in the mild-to-moderate disease stratum and 957 in the severe stratum. The as-treated population included 1048 patients who received the assigned treatment (532 in the remdesivir group, including one patient who had been randomly assigned to placebo and received remdesivir, and 516 in the placebo group).

Table 1. Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.

The mean age of the patients was 58.9 years, and 64.4% were male (Table 1). On the basis of the evolving epidemiology of asthma treatment 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 in the Supplementary Appendix). Overall, 53.3% of the patients were White, 21.3% were Black, 12.7% were Asian, and 12.7% were designated as other or not reported.

250 (23.5%) were Hispanic or Latino. Most patients had either one (25.9%) or two or more (54.5%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (50.2%), obesity (44.8%), and type 2 diabetes mellitus (30.3%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12) (Table S2).

A total of 957 patients (90.1%) had severe disease at enrollment. 285 patients (26.8%) met category 7 criteria on the ordinal scale, 193 (18.2%) category 6, 435 (41.0%) category 5, and 138 (13.0%) category 4. Eleven patients (1.0%) had missing ordinal scale data at enrollment.

All these patients discontinued the study before treatment. During the study, 373 patients (35.6% of the 1048 patients in the as-treated population) received hydroxychloroquine and 241 (23.0%) received a glucocorticoid (Table S3). 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 extracorporeal membrane oxygenation [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, 10 days, as compared with 15 days. Rate ratio for recovery, 1.29.

95% confidence interval [CI], 1.12 to 1.49. P<0.001) (Figure 2 and Table 2). In the severe disease stratum (957 patients) the median time to recovery was 11 days, as compared with 18 days (rate ratio for recovery, 1.31.

95% CI, 1.12 to 1.52) (Table S4). The rate ratio for recovery was largest among patients with a baseline ordinal score of 5 (rate ratio for recovery, 1.45. 95% CI, 1.18 to 1.79).

Among patients with a baseline score of 4 and those with a baseline score of 6, the rate ratio estimates for recovery were 1.29 (95% CI, 0.91 to 1.83) and 1.09 (95% CI, 0.76 to 1.57), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 0.98 (95% CI, 0.70 to 1.36). Information on interactions of treatment with baseline ordinal score as a continuous variable is provided in Table S11.

An analysis adjusting for baseline ordinal score as a covariate 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, 1.26. 95% CI, 1.09 to 1.46).

Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.37 (95% CI, 1.14 to 1.64), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.20 (95% CI, 0.94 to 1.52) (Figure 3). The benefit of remdesivir was larger when given earlier in the illness, though the benefit persisted in most analyses of duration of symptoms (Table S6). Sensitivity analyses in which data were censored at earliest reported use of glucocorticoids or hydroxychloroquine still showed efficacy of remdesivir (9.0 days to recovery with remdesivir vs.

14.0 days to recovery with placebo. Rate ratio, 1.28. 95% CI, 1.09 to 1.50, and 10.0 vs.

16.0 days to recovery. Rate ratio, 1.32. 95% CI, 1.11 to 1.58, respectively) (Table S8).

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, 1.5. 95% CI, 1.2 to 1.9, adjusted for disease severity) (Table 2 and Fig. S7).

Mortality Kaplan–Meier estimates of mortality by day 15 were 6.7% in the remdesivir group and 11.9% in the placebo group (hazard ratio, 0.55. 95% CI, 0.36 to 0.83). The estimates by day 29 were 11.4% and 15.2% in two groups, respectively (hazard ratio, 0.73.

95% CI, 0.52 to 1.03). The between-group differences in mortality varied considerably according to baseline severity (Table 2), with the largest difference seen among patients with a baseline ordinal score of 5 (hazard ratio, 0.30. 95% CI, 0.14 to 0.64).

Information on interactions of treatment with baseline ordinal score with respect to mortality is provided in Table S11. Additional Secondary Outcomes Table 3. Table 3.

Additional Secondary Outcomes. Patients in the remdesivir group had a shorter time to improvement of one or of two categories on the ordinal scale from baseline than patients in the placebo group (one-category improvement. Median, 7 vs.

9 days. Rate ratio for recovery, 1.23. 95% CI, 1.08 to 1.41.

Two-category improvement. Median, 11 vs. 14 days.

Rate ratio, 1.29. 95% CI, 1.12 to 1.48) (Table 3). Patients in the remdesivir group had a shorter time to discharge or to a National Early Warning Score of 2 or lower than those in the placebo group (median, 8 days vs.

12 days. Hazard ratio, 1.27. 95% CI, 1.10 to 1.46).

The initial length of hospital stay was shorter in the remdesivir group than in the placebo group (median, 12 days vs. 17 days). 5% of patients in the remdesivir group were readmitted to the hospital, as compared with 3% in the placebo group.

Among the 913 patients receiving oxygen at enrollment, those in the remdesivir group continued to receive oxygen for fewer days than patients in the placebo group (median, 13 days vs. 21 days), and the incidence of new oxygen use among patients who were not receiving oxygen at enrollment was lower in the remdesivir group than in the placebo group (incidence, 36% [95% CI, 26 to 47] vs. 44% [95% CI, 33 to 57]).

For the 193 patients receiving noninvasive ventilation or high-flow oxygen at enrollment, the median duration of use of these interventions was 6 days in both the remdesivir and placebo groups. Among the 573 patients who were not receiving noninvasive ventilation, high-flow oxygen, invasive ventilation, or ECMO at baseline, the incidence of new noninvasive ventilation or high-flow oxygen use was lower in the remdesivir group than in the placebo group (17% [95% CI, 13 to 22] vs. 24% [95% CI, 19 to 30]).

Among the 285 patients who were receiving mechanical ventilation or ECMO at enrollment, patients in the remdesivir group received these interventions for fewer subsequent days than those in the placebo group (median, 17 days vs. 20 days), and the incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was lower in the remdesivir group than in the placebo group (13% [95% CI, 10 to 17] vs. 23% [95% CI, 19 to 27]) (Table 3).

Safety Outcomes In the as-treated population, serious adverse events occurred in 131 of 532 patients (24.6%) in the remdesivir group and in 163 of 516 patients (31.6%) in the placebo group (Table S17). There were 47 serious respiratory failure adverse events in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for endotracheal intubation, and 80 in the placebo group (15.5% of patients) (Table S19). No deaths were considered by the investigators to be related to treatment assignment.

Grade 3 or 4 adverse events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 (57.2%) in the placebo group (Table S18). 41 events were judged by the investigators to be related to remdesivir and 47 events to placebo (Table S17). The most common nonserious adverse events occurring in at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, increased blood creatinine level, and increased blood glucose level (Table S20).

The incidence of these adverse events was generally similar in the remdesivir and placebo groups. Crossover After the data and safety monitoring board recommended that the preliminary primary analysis report be provided to the sponsor, data on a total of 51 patients (4.8% of the total study enrollment) — 16 (3.0%) in the remdesivir group and 35 (6.7%) in the placebo group — were unblinded. 26 (74.3%) of those in the placebo group whose data were unblinded were given remdesivir.

Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9)..

Participants Figure Best place to buy amoxil online 1 can you get ventolin without a prescription. Figure 1. Enrollment and can you get ventolin without a prescription Randomization. The diagram represents all enrolled participants through November 14, 2020. The safety subset (those with a median of 2 months of follow-up, in accordance with application requirements for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date.

The further procedures that one participant in the placebo group declined can you get ventolin without a prescription after dose 2 (lower right corner of the diagram) were those involving collection of blood and nasal swab samples.Table 1. Table 1. Demographic Characteristics of the Participants can you get ventolin without a prescription in the Main Safety Population. Between July 27, 2020, and November 14, 2020, a total of 44,820 persons were screened, and 43,548 persons 16 years of age or older underwent randomization at 152 sites worldwide (United States, 130 sites. Argentina, 1.

Brazil, 2 can you get ventolin without a prescription. South Africa, 4. Germany, 6 can you get ventolin without a prescription. And Turkey, 9) in the phase 2/3 portion of the trial. A total of 43,448 participants received injections.

21,720 received BNT162b2 and can you get ventolin without a prescription 21,728 received placebo (Figure 1). At the data cut-off date of October 9, a total of 37,706 participants had a median of at least 2 months of safety data available after the second dose and contributed to the main safety data set. Among these 37,706 participants, 49% can you get ventolin without a prescription were female, 83% were White, 9% were Black or African American, 28% were Hispanic or Latinx, 35% were obese (body mass index [the weight in kilograms divided by the square of the height in meters] of at least 30.0), and 21% had at least one coexisting condition. The median age was 52 years, and 42% of participants were older than 55 years of age (Table 1 and Table S2). Safety Local Reactogenicity Figure 2.

Figure 2 can you get ventolin without a prescription. Local and Systemic Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group. Data on local can you get ventolin without a prescription and systemic reactions and use of medication were collected with electronic diaries from participants in the reactogenicity subset (8,183 participants) for 7 days after each vaccination. Solicited injection-site (local) reactions are shown in Panel A. Pain at the injection site was assessed according to the following scale.

Mild, does not interfere can you get ventolin without a prescription with activity. Moderate, interferes with activity. Severe, prevents daily activity. And grade can you get ventolin without a prescription 4, emergency department visit or hospitalization. Redness and swelling were measured according to the following scale.

Mild, 2.0 to 5.0 cm in diameter can you get ventolin without a prescription. Moderate, >5.0 to 10.0 cm in diameter. Severe, >10.0 cm in diameter. And grade 4, necrosis or exfoliative dermatitis (for redness) and necrosis (for can you get ventolin without a prescription swelling). Systemic events and medication use are shown in Panel B.

Fever categories are designated can you get ventolin without a prescription in the key. Medication use was not graded. Additional scales were as follows. Fatigue, headache, chills, new or worsened muscle pain, new or worsened joint can you get ventolin without a prescription pain (mild. Does not interfere with activity.

Moderate. Some interference with activity. Or severe. Prevents daily activity), vomiting (mild. 1 to 2 times in 24 hours.

Moderate. >2 times in 24 hours. Or severe. Requires intravenous hydration), and diarrhea (mild. 2 to 3 loose stools in 24 hours.

Moderate. 4 to 5 loose stools in 24 hours. Or severe. 6 or more loose stools in 24 hours). Grade 4 for all events indicated an emergency department visit or hospitalization.

Н™¸ bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.The reactogenicity subset included 8183 participants. Overall, BNT162b2 recipients reported more local reactions than placebo recipients. Among BNT162b2 recipients, mild-to-moderate pain at the injection site within 7 days after an injection was the most commonly reported local reaction, with less than 1% of participants across all age groups reporting severe pain (Figure 2). Pain was reported less frequently among participants older than 55 years of age (71% reported pain after the first dose. 66% after the second dose) than among younger participants (83% after the first dose.

78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), and no participant reported a grade 4 local reaction. In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days. Systemic Reactogenicity Systemic events were reported more often by younger treatment recipients (16 to 55 years of age) than by older treatment recipients (more than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B).

The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger treatment recipients. 51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger treatment recipients. 17% and 14% among older recipients). The frequency of any severe systemic event after the first dose was 0.9% or less. Severe systemic events were reported in less than 2% of treatment recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after the second dose.

Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger treatment recipients and by 11% of older recipients. Only 0.2% of treatment recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose. Two participants each in the treatment and placebo groups reported temperatures above 40.0°C. Younger treatment recipients were more likely to use antipyretic or pain medication (28% after dose 1. 45% after dose 2) than older treatment recipients (20% after dose 1.

38% after dose 2), and placebo recipients were less likely (10 to 14%) than treatment recipients to use the medications, regardless of age or dose. Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter. Daily use of the electronic diary ranged from 90 to 93% for each day after the first dose and from 75 to 83% for each day after the second dose. No difference was noted between the BNT162b2 group and the placebo group. Adverse Events Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3).

More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related adverse event (21% and 5%). This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by treatment recipients than by placebo recipients. Sixty-four treatment recipients (0.3%) and 6 placebo recipients (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial. Four related serious adverse events were reported among BNT162b2 recipients (shoulder injury related to treatment administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia).

Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). No deaths were considered by the investigators to be related to the treatment or placebo. No asthma treatment–associated deaths were observed. No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of treatment.

Efficacy Table 2. Table 2. treatment Efficacy against asthma treatment at Least 7 days after the Second Dose. Table 3. Table 3.

treatment Efficacy Overall and by Subgroup in Participants without Evidence of before 7 Days after Dose 2. Figure 3. Figure 3. Efficacy of BNT162b2 against asthma treatment after the First Dose. Shown is the cumulative incidence of asthma treatment after the first dose (modified intention-to-treat population).

Each symbol represents asthma treatment cases starting on a given day. Filled symbols represent severe asthma treatment cases. Some symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged y axis, through 21 days. Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point.

The time period for asthma treatment case accrual is from the first dose to the end of the surveillance period. The confidence interval (CI) for treatment efficacy (VE) is derived according to the Clopper–Pearson method.Among 36,523 participants who had no evidence of existing or prior asthma , 8 cases of asthma treatment with onset at least 7 days after the second dose were observed among treatment recipients and 162 among placebo recipients. This case split corresponds to 95.0% treatment efficacy (95% confidence interval [CI], 90.3 to 97.6. Table 2). Among participants with and those without evidence of prior SARS CoV-2 , 9 cases of asthma treatment at least 7 days after the second dose were observed among treatment recipients and 169 among placebo recipients, corresponding to 94.6% treatment efficacy (95% CI, 89.9 to 97.3).

Supplemental analyses indicated that treatment efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population (Table 3 and Table S4). treatment efficacy among participants with hypertension was analyzed separately but was consistent with the other subgroup analyses (treatment efficacy, 94.6%. 95% CI, 68.7 to 99.9. Case split. BNT162b2, 2 cases.

Placebo, 44 cases). Figure 3 shows cases of asthma treatment or severe asthma treatment with onset at any time after the first dose (mITT population) (additional data on severe asthma treatment are available in Table S5). Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a treatment efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the treatment, starting as soon as 12 days after the first dose.Trial Oversight This phase 3 randomized, stratified, observer-blinded, placebo-controlled trial enrolled adults in medically stable condition at 99 U.S. Sites. Participants received the first trial injection between July 27 and October 23, 2020.

The trial is being conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Good Clinical Practice guidelines, and applicable government regulations. The central institutional review board approved the protocol and the consent forms. All participants provided written informed consent before enrollment. Safety is reviewed by a protocol safety review team weekly and by an independent data and safety monitoring board on a continual basis. The trial Investigational New Drug sponsor, Moderna, was responsible for the overall trial design (with input from the Biomedical Advanced Research and Development Authority, the NIAID, the asthma treatment Prevention Network, and the trial cochairs), site selection and monitoring, and data analysis.

Investigators are responsible for data collection. A medical writer funded by Moderna assisted in drafting the manuscript for submission. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The trial is ongoing, and the investigators remain unaware of participant-level data. Designated team members within Moderna have unblinded access to the data, to facilitate interface with the regulatory agencies and the data and safety monitoring board.

All other trial staff and participants remain unaware of the treatment assignments. Participants, Randomization, and Data Blinding Eligible participants were persons 18 years of age or older with no known history of asthma and with locations or circumstances that put them at an appreciable risk of asthma , a high risk of severe asthma treatment, or both. Inclusion and exclusion criteria are provided in the protocol (available with the full text of this article at NEJM.org). To enhance the diversity of the trial population in accordance with Food and Drug Administration Draft Guidance, site-selection and enrollment processes were adjusted to increase the number of persons from racial and ethnic minorities in the trial, in addition to the persons at risk for asthma in the local population. The upper limit for stratification of enrolled participants considered to be “at risk for severe illness” at screening was increased from 40% to 50%.17 Participants were randomly assigned in a 1:1 ratio, through the use of a centralized interactive response technology system, to receive treatment or placebo.

Assignment was stratified, on the basis of age and asthma treatment complications risk criteria, into the following risk groups. Persons 65 years of age or older, persons younger than 65 years of age who were at heightened risk (at risk) for severe asthma treatment, and persons younger than 65 years of age without heightened risk (not at risk). Participants younger than 65 years of age were categorized as having risk for severe asthma treatment if they had at least one of the following risk factors, based on the Centers for Disease Control and Prevention (CDC) criteria available at the time of trial design. Chronic lung disease (e.g., emphysema, chronic bronchitis, idiopathic pulmonary fibrosis, cystic fibrosis, or moderate-to-severe asthma). Cardiac disease (e.g., heart failure, congenital coronary artery disease, cardiomyopathies, or pulmonary hypertension).

Severe obesity (body mass index [the weight in kilograms divided by the square of the height in meters] ≥40). Diabetes (type 1, type 2, or gestational). Liver disease. Or with the human immunodeficiency ventolin.18 treatment dose preparation and administration were performed by pharmacists and treatment administrators who were aware of treatment assignments but had no other role in the conduct of the trial. Once the injection was completed, only trial staff who were unaware of treatment assignments performed assessments and interacted with the participants.

Access to the randomization code was strictly controlled at the pharmacy. The data and safety monitoring board reviewed efficacy data at the group level and unblinded safety data at the participant level. Trial treatment The mRNA-1273 treatment, provided as a sterile liquid at a concentration of 0.2 mg per milliliter, was administered by injection into the deltoid muscle according to a two-dose regimen. Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 μg of mRNA-1273 or saline placebo.1 treatment mRNA-1273 was stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and vaccination. No dilution was required.

Doses could be held in syringes for up to 8 hours at room temperature before administration. Safety Assessments Safety assessments included monitoring of solicited local and systemic adverse events for 7 days after each injection. Unsolicited adverse reactions for 28 days after each injection. Adverse events leading to discontinuation from a dose, from participation in the trial, or both. And medically attended adverse events and serious adverse events from day 1 through day 759.

Adverse event grading criteria and toxicity tables are described in the protocol. Cases of asthma treatment and severe asthma treatment were continuously monitored by the data and safety monitoring board from randomization onward. Efficacy Assessments The primary end point was the efficacy of the mRNA-1273 treatment in preventing a first occurrence of symptomatic asthma treatment with onset at least 14 days after the second injection in the per-protocol population, among participants who were seronegative at baseline. End points were judged by an independent adjudication committee that was unaware of group assignment. asthma treatment cases were defined as occurring in participants who had at least two of the following symptoms.

Fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for asthma by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) test. Participants were assessed for the presence of asthma–binding antibodies specific to the asthma nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for asthma RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection. asthma–infected volunteers were followed daily, to assess symptom severity, for 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab for RT-PCR testing and a blood sample for identifying serologic evidence of asthma were collected from participants with symptoms of asthma treatment. The consistency of treatment efficacy at the primary end point was evaluated across various subgroups, including age groups (18 to <65 years of age and ≥65 years), age and health risk for severe disease (18 to <65 years and not at risk.

18 to <65 years and at risk. And ≥65 years), sex (female or male), race and ethnic group, and risk for severe asthma treatment illness. If the number of participants in a subgroup was too small, it was combined with other subgroups for the subgroup analyses. A secondary end point was the efficacy of mRNA-1273 in the prevention of severe asthma treatment as defined by one of the following criteria. Respiratory rate of 30 or more breaths per minute.

Heart rate at or exceeding 125 beats per minute. Oxygen saturation at 93% or less while the participant was breathing ambient air at sea level or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen below 300 mm Hg. Respiratory failure. Acute respiratory distress syndrome. Evidence of shock (systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, or a need for vasopressors).

Clinically significant acute renal, hepatic, or neurologic dysfunction. Admission to an intensive care unit. Or death. Additional secondary end points included the efficacy of the treatment at preventing asthma treatment after a single dose or at preventing asthma treatment according to a secondary (CDC), less restrictive case definition. Having any symptom of asthma treatment and a positive asthma test by RT-PCR (see Table S1 in the Supplementary Appendix, available at NEJM.org).

Statistical Analysis For analysis of the primary end point, the trial was designed for the null hypothesis that the efficacy of the mRNA-1273 treatment is 30% or less. A total of 151 cases of asthma treatment would provide 90% power to detect a 60% reduction in the hazard rate (i.e., 60% treatment efficacy), with two planned interim analyses at approximately 35% and 70% of the target total number of cases (151) and with a one-sided O’Brien–Fleming boundary for efficacy and an overall one-sided error rate of 0.025. The efficacy of the mRNA-1273 treatment could be demonstrated at either the interim or the primary analysis, performed when the target total number of cases had been observed. The Lan–DeMets alpha-spending function was used for calculating efficacy boundaries at each analysis. At the first interim analysis on November 15, 2020, treatment efficacy had been demonstrated in accordance with the prespecified statistical criteria.

The treatment efficacy estimate, based on a total of 95 adjudicated cases (63% of the target total), was 94.5%, with a one-sided P value of less than 0.001 to reject the null hypothesis that treatment efficacy would be 30% or less. The data and safety monitoring board recommendation to the oversight group and the trial sponsor was that the efficacy findings should be shared with the participants and the community (full details are available in the protocol and statistical analysis plan). treatment efficacy was assessed in the full analysis population (randomized participants who received at least one dose of mRNA-1273 or placebo), the modified intention-to-treat population (participants in the full analysis population who had no immunologic or virologic evidence of asthma treatment on day 1, before the first dose), and the per-protocol population (participants in the modified intention-to-treat population who received two doses, with no major protocol deviations). The primary efficacy end point in the interim and primary analyses was assessed in the per-protocol population. Participants were evaluated in the treatment groups to which they were assigned.

treatment efficacy was defined as the percentage reduction in the hazard ratio for the primary end point (mRNA-1273 vs. Placebo). A stratified Cox proportional hazards model was used to assess the treatment efficacy of mRNA-1273 as compared with placebo in terms of the percentage hazard reduction. (Details regarding the analysis of treatment efficacy are provided in the Methods section of the Supplementary Appendix.) Safety was assessed in all participants in the solicited safety population (i.e., those who received at least one injection and reported a solicited adverse event). Descriptive summary data (numbers and percentages) for participants with any solicited adverse events, unsolicited adverse events, unsolicited severe adverse events, serious adverse events, medically attended adverse events, and adverse events leading to discontinuation of the injections or withdrawal from the trial are provided by group.

Two-sided 95% exact confidence intervals (Clopper–Pearson method) are provided for the percentages of participants with solicited adverse events. Unsolicited adverse events are presented according to the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0, preferred terms and system organ class categories. To meet the regulatory agencies’ requirement of a median follow-up duration of at least 2 months after completion of the two-dose regimen, a second analysis was performed, with an efficacy data cutoff date of November 21, 2020. This second analysis is considered the primary analysis of efficacy, with a total of 196 adjudicated asthma treatment cases in the per-protocol population, which exceeds the target total number of cases (151) specified in the protocol. This was an increase from the 95 cases observed at the first interim analysis data cutoff on November 11, 2020.

Results from the primary analysis are presented in this report. Subsequent analyses are considered supplementary.Participants From July 22 to August 7, 2020, a total of 593 persons underwent screening for enrollment in cohort 1 (including 1a and 1b combined) (Fig. S1). Of these persons, 405 were enrolled and 402 received the first dose of Ad26.COV2.S. These participants had received the second dose by November 7, 2020.

From August 3 to August 24, 2020, a total of 660 persons underwent screening for cohort 3. Of these participants, 405 were enrolled and 403 received the first dose of Ad26.COV2.S. (Details regarding age distribution are provided in Table S2.) Analyses of data obtained from participants in cohort 3 after the administration of the second dose, as well as durability and longer-term safety data, are ongoing. Table 1. Table 1.

Characteristics of the Participants at Baseline. At baseline, the percentage of participants who were seropositive for asthma S-specific antibodies was 2% in cohort 1a and 1% in cohort 3. The baseline characteristics of the participants were broadly similar across the groups (Table 1). treatment Safety and Reactogenicity Figure 1. Figure 1.

Solicited Adverse Events in Cohorts 1 and 3 after the First treatment Dose. Shown are solicited adverse events in participants who received the Ad26.COV2.S treatment at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo. Healthy adults between the ages of 18 and 55 years were included in cohort 1 (Panel A), and those 65 years of age or older were included in cohort 3 (Panel B). The younger group was divided into cohorts 1a and 1b, with the latter designated as an exploratory cohort for in-depth analysis of immunogenicity. As shown here, data for cohorts 1a and 1b have been pooled.

Data for patients in cohort 1a who received a second dose of treatment are provided in Figure S2 in the Supplementary Appendix.Data regarding both solicited and unsolicited adverse events and serious adverse events were available for more than 99% of the participants who returned diary cards. The investigator’s assessment of reactogenicity after the administration of the first dose of treatment was available for 402 participants in cohort 1 and for 403 participants in cohort 3. In the two cohorts, solicited local adverse events were mostly of grade 1 or 2. The most frequent event was injection-site pain. In cohort 1, solicited local adverse events were reported in 103 of 162 low-dose recipients (64%), in 123 of 158 high-dose recipients (78%), and in 7 of 82 placebo recipients (9%) (Figure 1A and Table S3).

In cohort 3, solicited local adverse events were reported in 66 of 161 low-dose recipients (41%), in 68 of 161 high-dose recipients (42%), and in 11 of 81 placebo recipients (14%) (Figure 1B). In the two cohorts, most solicited systemic adverse events were of grade 1 or 2. The most frequent events were fatigue, headache, and myalgia. In cohort 1, solicited systemic adverse events were reported in 105 low-dose recipients (65%), in 133 high-dose recipients (84%), and in 21 placebo recipients (26%). In cohort 3, solicited systemic adverse events were reported in 74 low-dose recipients (46%), in 88 high-dose recipients (55%), and in 19 placebo recipients (23%).

In cohort 1, solicited grade 3 systemic adverse events were reported in 15 low-dose recipients (9%) and in 32 high-dose recipients (20%). No placebo recipients reported such events. In cohort 1a, among the participants between the ages of 18 and 30 years who had one or more solicited grade 3 adverse events, 24% had received the low dose and 26% had received the high dose. In those between the ages of 31 and 45 years, the corresponding percentages were 43% and 14%. And in those between the ages of 46 and 55 years, the corresponding percentages were 3% and 11%.

In cohort 3, grade 3 solicited systemic adverse events were reported in 1 low-dose recipient (1%) and in 4 high-dose recipients (2%). No placebo recipients reported having such events. In cohort 1, fever was reported in 25 low-dose recipients (15%) and in 62 high-dose recipients (39%). Grade 3 fever (temperature range, 39.0 to 40.0°C) was reported in 8 low-dose recipients (5%) and in 15 high-dose recipients (9%). In cohort 3, fever was reported in 7 low-dose recipients (4%) and in 14 high-dose recipients (9%).

Grade 3 fever was reported in no low-dose recipients and in 2 high-dose recipients (1%). No participants in the placebo group in either cohort reported having fever. All cases of fever occurred within 2 days after immunization and resolved within 1 or 2 days. More than 80% of the participants with fever received an antipyretic drug at the onset of symptoms. In cohort 1, unsolicited adverse events were reported in 34 low-dose recipients (21%), in 56 high-dose recipients (35%), and in 14 placebo recipients (17%).

In cohort 3, unsolicited adverse events were reported in 27 low-dose recipients (17%), in 38 high-dose recipients (24%), and in 13 placebo recipients (16%) (Table S4). No grade 4 adverse events (solicited or unsolicited) were reported in any cohort. In cohort 1a, safety data after the administration of the second dose of treatment were available for 363 participants (Fig. S2). One or more solicited adverse events were noted in 77% and 80% of the participants in the low-dose and high-dose groups, respectively, as compared with 34% and 31% of those who received placebo as a second dose after a first dose of treatment and in 22% of those who received placebo for both doses.

Solicited adverse events of grade 3 or higher were noted in 1% of low-dose recipients and in 7% of high-dose recipients. The corresponding percentages were 1% and 2% among participants in the placebo group who received a first dose of treatment and in no participants who received placebo for both doses. No grade 3 fevers were reported in any group after a second dose of treatment. No participant discontinued the trial because of an adverse event. Five serious adverse events occurred.

One case of hypotension that was deemed by the investigator to be unrelated to the treatment because of a history of recurrent hypotension. One case of bilateral nephrolithiasis in a participant with a history of kidney stones (not related). One case of legionella pneumonia (not related). One worsening of multiple sclerosis, which had remained undiagnosed for approximately 8 to 10 years on the basis of findings on magnetic resonance imaging (not related). And one case of fever that resulted in hospitalization because of suspicion of asthma treatment.

In the last case, the participant recovered within 12 hours, and the fever was subsequently deemed by the investigator to be related to the treatment. Details regarding all safety data are provided in the Supplementary Appendix. Immunogenicity and Seroconversion Figure 2. Figure 2. Humoral Immunogenicity.

Shown are measures of humoral immunogenicity in serum samples obtained from the participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo. In cohort 1a, the participants received two injections of high-dose or low-dose treatment or placebo, as indicated with slashes (e.g., placebo/placebo if they received two injections of placebo). The samples were measured on enzyme-linked immunosorbent assay (ELISA) in ELISA units (EU) per milliliter (Panel A) and on wild-type ventolin neutralization assay, with seropositivity defined as a half maximal inhibitory concentration (IC50) titer of more than 58 at the lower limit of quantitation (Panel B). Logarithmic values are reported as the geometric mean concentration (GMC) in the ELISA analyses and as the geometric mean titer (GMT) in the neutralizing-antibody analyses. The values were measured at baseline and at day 29 after vaccination in all the participants and on days 57 and 71 in those in cohort 1a.

The two horizontal dotted lines in each panel indicate the lower and upper limits of quantitation of the respective assay. Values below the lower line have been imputed to half the lower limit of quantitation. Н™¸ bars indicate 95% confidence intervals. HCS denotes human convalescent serum.Immunogenicity data for this interim analysis were unblinded according to dose level. In all five groups in cohort 1a, the binding-antibody geometric mean concentration (GMC), as reported in ELISA units per milliliter, was measured against a stabilized asthma full-length spike protein.

At baseline, the GMC values in all the participants were lower than the lower limit of quantitation. By day 29 after vaccination, the values had increased to 478 (95% confidence interval [CI], 379 to 603) in the low-dose/placebo group, 586 (95% CI, 445 to 771) in the low-dose/low-dose group, 625 (95% CI, 505 to 773) in the high-dose/placebo group, and 788 (95% CI, 628 to 988) in the high-dose/high-dose group, with an incidence of seroconversion of 99% or more in all the groups (Figure 2A and Fig. S3A). By day 57, the corresponding GMC values had further increased to 660 (95% CI, 513 to 849), 754 (95% CI, 592 to 961), 873 (95% CI, 701 to 1087), and 1100 (95% CI, 908 to 1332). After the first dose, the incidence of seroconversion was 100% in all but the high-dose/placebo group (97%).

Fourteen days after the second dose, the GMC was 1677 (95% CI, 1334 to 2109) in the low-dose/low-dose group and 2292 (95% CI, 1846 to 2845) in the high-dose/high-dose group, with 100% seroconversion in each group. On day 71, in the low-dose/placebo and high-dose/placebo groups, the GMC was 600 (95% CI, 443 to 814) and 951 (95% CI, 696 to 1,300), respectively, values that were similar to those on day 57. In cohort 3, the GMCs in all the participants were also below the lower limit of quantitation at baseline. By day 15 after vaccination, the GMC had increased to 122 (95% CI, 97 to 152) in the low-dose group and to 141 (95% CI, 114 to 175) in the high-dose group, with a seroconversion incidence of 75% and 77%, respectively. By day 29, the GMC was 312 (95% CI, 246 to 396) in the low-dose group and 350 (95% CI, 281 to 429) in the high-dose group, with 96% seroconversion.

The asthma neutralizing-antibody titer (IC50) was measured in a random subgroup of participants in cohorts 1a and 3. In cohort 1a, the geometric mean titer (GMT) was below the lower limit of quantitation at baseline and by day 29 after vaccination had increased to 224 (95% CI, 158 to 318) in the low-dose/placebo group, 224 (95% CI, 168 to 298) in the low-dose/low-dose group, 215 (95% CI, 169 to 273) in the high-dose/placebo group, and 354 (95% CI, 220 to 571) in the high-dose/high-dose group, with an incidence of seroconversion of 96%, 88%, 96%, and 92%, respectively (Figure 2B and Fig. S3B). By day 57, the GMT had further increased to 310 (95% CI, 228 to 422), 288 (95% CI, 221 to 376), 370 (95% CI, 268 to 511), and 488 (95% CI, 334 to 714), respectively, with a 100% incidence of seroconversion in the low-dose/placebo group and 96% seroconversion in the other groups. In cohort 1a, 14 days after the second dose, the GMT was 827 (95% CI, 508 to 1183) in the low-dose/low-dose group and 1266 (95% CI, 746 to 2169) in the high-dose/high-dose group, with 100% seroconversion in the two dose groups.

On day 71, the GMT was 321 (95% CI, 227 to 438) in the low-dose/placebo group and 388 (95% CI, 290 to 509) in the high-dose/placebo group, values that were similar to those on day 57. The incidence of seroconversion was 100% in both groups. In cohort 3, the GMTs in all the participants were below the lower limit of quantitation at baseline and had increased to 212 (95% CI, 137 to 284) in the low-dose group and 172 (95% CI, 119 to 269) in the high-dose group on day 15 and to 277 (95% CI, 193 to 307) and 212 (95% CI, 163 to 266), respectively, on day 29. The incidence of seroconversion was 91% and 84%, respectively, on day 15 and 96% and 88%, respectively, on day 29. These data were confirmed on IC80 analysis (Fig.

S4). Antibody levels as measured on wild-type ventolin neutralization assay and ELISA were strongly correlated in the two cohorts (Fig. S5). However, the correlation had a wider elliptical shape in cohort 3, which suggested more variability in the relationship between the neutralizing-antibody titer and the binding-antibody titer in the older adults. Antibody levels in the different human convalescent serum panels that were included in assays for humoral-immunity assessment that were performed in different laboratories and in serum samples that were obtained from treatment recipients were in the same range.

Details regarding differences in values according to demographic characteristics are provided in Tables S5 and S6 in the Supplementary Appendix. Levels of Ad26 neutralizing antibodies at baseline or after the first dose of treatment did not correlate with the levels of asthma neutralizing antibodies on either day 29 or day 71 (Fig. S6). S-Specific T-Cell Responses Figure 3. Figure 3.

Cellular Immunogenicity of Ad26.COV2.S. In CD4+ T cells, the response to low-dose or high-dose treatment or placebo in type 1 helper T (Th1) cells was characterized by the expression of interferon-γ, interleukin-2, or both, without cytokines expressed by type 2 helper T (Th2) cells (Panel A). The response in CD4+ Th2 cells was characterized by the expression of interleukin-4, interleukin-5, or interleukin-13 (or all three cytokines) plus CD40L (Panel B). In CD8+ T cells, the response was measured by the expression of interferon-γ, interleukin-2, or both (Panel C). In all three panels, the horizontal bars indicate median values on intracellular cytokine staining for individual responses to a asthma S protein peptide pool in peripheral-blood mononuclear cells at baseline and 15 days after vaccination in a subgroup of participants in cohort 1a (left side) and cohort 3 (right side), according to the receipt of the low or high dose of Ad26.COV2.S or placebo.

The horizontal dotted line in each panel indicates the lower limit of quantitation (LLOQ). Values below the line have been imputed to half the LLOQ.The treatment-elicited responses in S-specific CD4+ Th1 and Th2 cells and in CD8+ T cells were assessed in a subgroup of participants at baseline and 15 days after the first dose. In cohort 1a, a Th1 response to S peptides was detected in 76% (95% CI, 65 to 86) of low-dose recipients and in 83% (95% CI, 73 to 91) of high-dose recipients. The corresponding values in cohort 3 were 60% (95% CI, 46 to 74) and 67% (95% CI, 53 to 79), respectively (Figure 3A). In cohort 1a, the median CD4+ Th1 response to S peptides increased from an undetectable level at baseline to a median of 0.08% (interquartile range [IQR], 0.05 to 0.16) in low-dose recipients and 0.11% (IQR, 0.07 to 0.16) in high-dose recipients on day 15.

In cohort 3, the corresponding values were 0.09% (IQR, 0.04 to 0.17) and 0.11% (IQR, 0.04 to 0.15), respectively. A low-dose recipient in cohort 1a and a high-dose recipient in cohort 3 had a measurable Th2 response (Figure 3B). However, all the participants who had a measurable Th1 or Th2 response had a Th1:Th2 ratio that was well above 1, which indicated a treatment-induced Th1-skewed response. S-specific CD8+ T-cell responses, as identified by the expression of interferon-γ or interleukin-2 cytokines on S-peptide stimulation, were absent at baseline in the two cohorts (Figure 3C). On day 15 in cohort 1a, a CD8+ T-cell response was detected in 51% of participants (95% CI, 39 to 63) in the low-dose group and in 64% (95% CI, 52 to 75) in the high-dose group, with a median S-specific CD8+ T-cell response of 0.07% (IQR, 0.03 to 0.19) and 0.09% (IQR, 0.05 to 0.19), respectively.

In cohort 3, CD8+ T-cell responses were lower, with an incidence of 36% (95% CI, 23 to 51) in the low-dose group and 24% (95% CI, 13 to 37) in the high-dose group, with a median response of 0.06% (IQR, 0.02 to 0.12) and 0.02% (IQR, 0.01 to 0.08), respectively. The correlation between CD4+ Th1 and CD8+ T-cell response was poor in the two cohorts (Fig. S7).Patients Figure 1. Figure 1. Enrollment and Randomization.

Of the 1114 patients who were assessed for eligibility, 1062 underwent randomization. 541 were assigned to the remdesivir group and 521 to the placebo group (intention-to-treat population) (Figure 1). 159 (15.0%) were categorized as having mild-to-moderate disease, and 903 (85.0%) were in the severe disease stratum. Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Fifty-two patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death and 10 withdrew consent.

Of those assigned to receive placebo, 517 patients (99.2%) received placebo as assigned. Seventy patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death and 14 withdrew consent. A total of 517 patients in the remdesivir group and 508 in the placebo group completed the trial through day 29, recovered, or died. Fourteen patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29. A total of 54 of the patients who were in the mild-to-moderate stratum at randomization were subsequently determined to meet the criteria for severe disease, resulting in 105 patients in the mild-to-moderate disease stratum and 957 in the severe stratum.

The as-treated population included 1048 patients who received the assigned treatment (532 in the remdesivir group, including one patient who had been randomly assigned to placebo and received remdesivir, and 516 in the placebo group). Table 1. Table 1. Demographic and Clinical Characteristics of the Patients at Baseline. The mean age of the patients was 58.9 years, and 64.4% were male (Table 1).

On the basis of the evolving epidemiology of asthma treatment 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 in the Supplementary Appendix). Overall, 53.3% of the patients were White, 21.3% were Black, 12.7% were Asian, and 12.7% were designated as other or not reported. 250 (23.5%) were Hispanic or Latino. Most patients had either one (25.9%) or two or more (54.5%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (50.2%), obesity (44.8%), and type 2 diabetes mellitus (30.3%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12) (Table S2).

A total of 957 patients (90.1%) had severe disease at enrollment. 285 patients (26.8%) met category 7 criteria on the ordinal scale, 193 (18.2%) category 6, 435 (41.0%) category 5, and 138 (13.0%) category 4. Eleven patients (1.0%) had missing ordinal scale data at enrollment. All these patients discontinued the study before treatment. During the study, 373 patients (35.6% of the 1048 patients in the as-treated population) received hydroxychloroquine and 241 (23.0%) received a glucocorticoid (Table S3).

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 extracorporeal membrane oxygenation [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, 10 days, as compared with 15 days.

Rate ratio for recovery, 1.29. 95% confidence interval [CI], 1.12 to 1.49. P<0.001) (Figure 2 and Table 2). In the severe disease stratum (957 patients) the median time to recovery was 11 days, as compared with 18 days (rate ratio for recovery, 1.31. 95% CI, 1.12 to 1.52) (Table S4).

The rate ratio for recovery was largest among patients with a baseline ordinal score of 5 (rate ratio for recovery, 1.45. 95% CI, 1.18 to 1.79). Among patients with a baseline score of 4 and those with a baseline score of 6, the rate ratio estimates for recovery were 1.29 (95% CI, 0.91 to 1.83) and 1.09 (95% CI, 0.76 to 1.57), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 0.98 (95% CI, 0.70 to 1.36). Information on interactions of treatment with baseline ordinal score as a continuous variable is provided in Table S11.

An analysis adjusting for baseline ordinal score as a covariate 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, 1.26. 95% CI, 1.09 to 1.46). Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.37 (95% CI, 1.14 to 1.64), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.20 (95% CI, 0.94 to 1.52) (Figure 3). The benefit of remdesivir was larger when given earlier in the illness, though the benefit persisted in most analyses of duration of symptoms (Table S6).

Sensitivity analyses in which data were censored at earliest reported use of glucocorticoids or hydroxychloroquine still showed efficacy of remdesivir (9.0 days to recovery with remdesivir vs. 14.0 days to recovery with placebo. Rate ratio, 1.28. 95% CI, 1.09 to 1.50, and 10.0 vs. 16.0 days to recovery.

Rate ratio, 1.32. 95% CI, 1.11 to 1.58, respectively) (Table S8). 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, 1.5. 95% CI, 1.2 to 1.9, adjusted for disease severity) (Table 2 and Fig. S7).

Mortality Kaplan–Meier estimates of mortality by day 15 were 6.7% in the remdesivir group and 11.9% in the placebo group (hazard ratio, 0.55. 95% CI, 0.36 to 0.83). The estimates by day 29 were 11.4% and 15.2% in two groups, respectively (hazard ratio, 0.73. 95% CI, 0.52 to 1.03). The between-group differences in mortality varied considerably according to baseline severity (Table 2), with the largest difference seen among patients with a baseline ordinal score of 5 (hazard ratio, 0.30.

95% CI, 0.14 to 0.64). Information on interactions of treatment with baseline ordinal score with respect to mortality is provided in Table S11. Additional Secondary Outcomes Table 3. Table 3. Additional Secondary Outcomes.

Patients in the remdesivir group had a shorter time to improvement of one or of two categories on the ordinal scale from baseline than patients in the placebo group (one-category improvement. Median, 7 vs. 9 days. Rate ratio for recovery, 1.23. 95% CI, 1.08 to 1.41.

Two-category improvement. Median, 11 vs. 14 days. Rate ratio, 1.29. 95% CI, 1.12 to 1.48) (Table 3).

Patients in the remdesivir group had a shorter time to discharge or to a National Early Warning Score of 2 or lower than those in the placebo group (median, 8 days vs. 12 days. Hazard ratio, 1.27. 95% CI, 1.10 to 1.46). The initial length of hospital stay was shorter in the remdesivir group than in the placebo group (median, 12 days vs.

17 days). 5% of patients in the remdesivir group were readmitted to the hospital, as compared with 3% in the placebo group. Among the 913 patients receiving oxygen at enrollment, those in the remdesivir group continued to receive oxygen for fewer days than patients in the placebo group (median, 13 days vs. 21 days), and the incidence of new oxygen use among patients who were not receiving oxygen at enrollment was lower in the remdesivir group than in the placebo group (incidence, 36% [95% CI, 26 to 47] vs. 44% [95% CI, 33 to 57]).

For the 193 patients receiving noninvasive ventilation or high-flow oxygen at enrollment, the median duration of use of these interventions was 6 days in both the remdesivir and placebo groups. Among the 573 patients who were not receiving noninvasive ventilation, high-flow oxygen, invasive ventilation, or ECMO at baseline, the incidence of new noninvasive ventilation or high-flow oxygen use was lower in the remdesivir group than in the placebo group (17% [95% CI, 13 to 22] vs. 24% [95% CI, 19 to 30]). Among the 285 patients who were receiving mechanical ventilation or ECMO at enrollment, patients in the remdesivir group received these interventions for fewer subsequent days than those in the placebo group (median, 17 days vs. 20 days), and the incidence of new mechanical ventilation or ECMO use among the 766 patients who were not receiving these interventions at enrollment was lower in the remdesivir group than in the placebo group (13% [95% CI, 10 to 17] vs.

23% [95% CI, 19 to 27]) (Table 3). Safety Outcomes In the as-treated population, serious adverse events occurred in 131 of 532 patients (24.6%) in the remdesivir group and in 163 of 516 patients (31.6%) in the placebo group (Table S17). There were 47 serious respiratory failure adverse events in the remdesivir group (8.8% of patients), including acute respiratory failure and the need for endotracheal intubation, and 80 in the placebo group (15.5% of patients) (Table S19). No deaths were considered by the investigators to be related to treatment assignment. Grade 3 or 4 adverse events occurred on or before day 29 in 273 patients (51.3%) in the remdesivir group and in 295 (57.2%) in the placebo group (Table S18).

41 events were judged by the investigators to be related to remdesivir and 47 events to placebo (Table S17). The most common nonserious adverse events occurring in at least 5% of all patients included decreased glomerular filtration rate, decreased hemoglobin level, decreased lymphocyte count, respiratory failure, anemia, pyrexia, hyperglycemia, increased blood creatinine level, and increased blood glucose level (Table S20). The incidence of these adverse events was generally similar in the remdesivir and placebo groups. Crossover After the data and safety monitoring board recommended that the preliminary primary analysis report be provided to the sponsor, data on a total of 51 patients (4.8% of the total study enrollment) — 16 (3.0%) in the remdesivir group and 35 (6.7%) in the placebo group — were unblinded. 26 (74.3%) of those in the placebo group whose data were unblinded were given remdesivir.

Sensitivity analyses evaluating the unblinding (patients whose treatment assignments were unblinded had their data censored at the time of unblinding) and crossover (patients in the placebo group treated with remdesivir had their data censored at the initiation of remdesivir treatment) produced results similar to those of the primary analysis (Table S9)..

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