April 29, 2020

expert reaction to trial of remdesivir in adults

A study, as published in The Lancet,  looked at the use of the drug remdesivir for the treatment of COVID-19 in adults and found no significant clinical benefits, and recommended that more research is needed.

Prof Duncan Richards, clinical pharmacologist and CLIMAX Professor of Clinical Therapeutics, University of Oxford, said:

“This is the first randomised study of remdesivir to treat COVID-19 patients: it does not show a dramatic effect. When a study is randomised and controlled, we can be more confident of the results – in marked contrast to data from uncontrolled ‘compassionate use’ studies, such as the paper in the New England Journal of Medicine the other week. This, therefore, emphasises the vital importance of proper randomised studies.

“However, this current study is mainly in people with relatively advanced disease. Remdesivir is an antiviral drug that stops viral replication. There is an increasing view that the most serious consequences of the disease result from the immune response as opposed to viral replication per se. Therefore, a bigger effect with these drugs might be expected earlier in the disease rather than later phases. More randomised controlled studies looking at the safety and effectiveness of anti-virals during the earlier stages of COVID-19 are needed.

“In emergency situations, there may be a tendency to use study designs that are less robust than would be expected in ‘normal times’. While the urgent public health need is recognised, if we do studies in the wrong population we are not doing our best by patients. It is critical to get the patient population right. This emphasises the importance of not abandoning the principles of good design even in an emergency situation.”

Prof Stephen Evans, Professor of Pharmacoepidemiology in the Dept of Medical Statistics, London School of Hygiene & Tropical Medicine, said:

“I previously commented on the inadvertent leak of results from this trial on April 23^rd. These comments are an edited version of those comments. There are no fundamental changes in the views expressed previously.

“These data are the data from a randomised trial with confirmed severe Covid-19 disease who had been admitted to ten hospitals in Wuhan, China and give the first reliable evidence on the benefits and an outline of possible harms of remdesivir.  Most other released data did not have a proper comparison group, while this trial has a group given standard treatment but no remdesivir, allocated at random. The description of the methods makes it clear that this was a well-conducted trial, but it had to terminate early because of recruitment issues – “No patients were enrolled after March 12, because of the control of the outbreak in Wuhan”.

“The trial was registered appropriately at the US National Institutes of Health supported registry clinicaltrials.gov-

https://clinicaltrials.gov/ct2/show/NCT04257656?term=remdesivir&cond=COVID-19&draw=2&rank=4

“The trial had 237 participants (as in the leaked WHO entry) but was intended to recruit 453 patients. One patient who did not receive treatment was not included in the analysis.

“Those on remdesivir and on placebo had similar outcomes. The trial was designed with a primary outcome of time to a defined clinical improvement. This required improvement of 2 points on a 6 point scale with death as the worst category and recovery or discharge from hospital as the best. The analysis is slightly idiosyncratic since “improvement” is the outcome studied and both death and no improvement count the same. The time to clinical improvement was marginally better (shorter) on remdesivir (21 vs 23 days), but this was far from a statistically significant difference. The mortality rate on remdesivir was 22/158 (13.9%) while on placebo was 10/78 (12.8%). The paper reports this in the same way as I had calculated on the leaked data – a 1% difference in the death rate (13.9-12.8%), which is compatible with a reduction of 8% and an increase of 10%. They note that those who received remdesivir within 10 days of symptom onset may have fared better, but there was no statistical evidence to support this as a conclusion.

“They do not report it as a relative risk of 1.09 with a confidence interval from 0.54 to 2.18, based on my calculation. This indicates the numbers are too small to exclude a halving or a doubling of the death rate. It was also noted that a larger number stopped their treatment because of adverse events while on remdesivir. The numbers (again those calculated from the leaked data were correct) were 18/158 vs 4/78. The risk ratio is 2.2, compatible with a range from 0.78 to 6.34. The numbers in the trial are too small to draw strong conclusions, but certainly are not any indication of benefit for remdesivir and are slightly more compatible with possible harm.

“The trial was too small in numbers recruited to detect what could be a clinically important benefit or an important increase in risk. It does not show that remdesivir has a really dramatic improvement in mortality, but could nevertheless be compatible with a small improvement in spite of the results apparently showing remdesivir does slightly worse in mortality than placebo.

“The trial protocol required patients to be entered into the trial within 12 days of the onset of symptoms. It has been suggested that these drugs need to be started early in the course of disease, but it would seem that there are a number of days after infection before symptoms appear. If the drug only works well when given very early after infection, it may be much less useful in practice. We need appropriate randomised trials to test this hypothesis.

“What is incontrovertible is that randomised controlled trials with a proper comparison group (the best standard of care, ideally with a placebo) are the only ones from which reliable conclusions can be drawn. There are larger trials of that type being carried out now and results will be available later in the year.

“The accompanying editorial makes most of these points but does not comment that the large trial (NCT04292899) Gilead intending to recruit 6000 patients gives remdesivir with two durations of treatment- all groups get remdesivir. I’m pleased to note there are non-Gilead-sponsored trials that have large numbers and a valid comparison group.”

Dr Penny Ward, Visiting Professor in pharmaceutical medicine at Kings College London and the Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:

“This publication provides more detail concerning the outcomes of the remdesivir trial conducted early in the COVID-19 outbreak in China.

“The trial was terminated early due to incomplete recruitment. Remdesivir is a specific antiviral with activity in vitro and in vivo vs a range of viruses including SARS CoV2; as viral load peaks at or within 2 days following first onset of symptoms of SARS CoV2 infection, this trial regrettably started treatment late, and for the most part at a time when the individuals will have been developing neutralising antibody. Additionally, the results are confounded by the sizeable proportion of patients receiving a range of other treatments, particularly corticosteroids and interferon 2alpha, which may have confounded the comparisons the trial was seeking to make.

“Nonetheless it appears that some patients receiving remdesivir may have had more favourable outcomes than those receiving SOC alone. These signals merit further investigation in additional studies in treatment starts earlier than was possible in this study and from which confounding medications are eliminated. One area of potential concern is the report of a patient in the remdesivir arm with ‘recurrent COVID-19’. It will be important to study potential emergence of resistant virus following treatment, as has been described in vitro.”

Prof Saad Shakir, Director of the Drug Safety Research Unit, near Southampton, said:

“This is the first randomised double-blind placebo controlled multi-centre trial for the use of Remdesivir in adults with Covid-19 infection. The study did not show that Remdesivir was associated with clinical benefits in patients with Covid-19. However, the study was terminated early with only 237 patients enrolled out of the 453 patients according to the protocol.  Therefore, the study was underpowered to identify the planned 1.4 relative benefit. The termination was because further recruitment was not possible because of an improvement in the epidemic in Hubei in China.  

“This is not the end of the story of Remdesivir in this indication because other studies examining the efficacy of the drug in Covid-19 are underway. Given the unmet medical need, we will wait to see the results of these studies, which hopefully will achieve recruitment according to the planned sample sizes. We also need to wait for the inevitable metanalysis and structured benefit-risk evaluation for the totality of the randomised controlled trials for the product in this indication and other information about the safety and tolerability of Remdesivir in the treatment of Covid-19 infection.”

Professor Trudie Lang, Director of The Global Health Network, Nuffield Department of Medicine, University of Oxford, said:

“It is very useful to see the rapid analysis and reporting of this randomised, controlled clinical trial of one of the antivirals that is being considered globally as a potential treatment for COVID-19.

“Although this trial had to stop early it did have enough data to allow the researchers to conclude that remdesivir was not associated with improving outcomes in this group of severely ill patients in Wuhan.

“This is important, but it raises more questions. It could be that late stage disease is not the optimum setting to evaluate antiviral potential of drugs for the treatment of COVID-19. It might be better to ask this question in much earlier stages of infection. This is supported by the evidence we are seeing from the disease characterisation studies and our existing knowledge of how viruses behave in early infection; where the therapeutic goal is to stop replication. Therefore, we should be making a global effort to undertake trials of drugs with potential anti-viral activity in community settings, or certainly earlier in infection, such as when patients present with the first onset of symptoms and have a positive test. However, this would not have been an ideal patient group for this specific drug because remdesivir is given by injection and is likely to be expensive.

“These two factors would have also limited the usefulness of this drug globally for widespread use, especially in early stage disease. More randomised controlled trials are needed with potential anti-viral trials in early stages of infection; furthermore, these trials are needed across the globe to ensure there is equity in who benefits from the data and interventions that are being developed. 

“This trial had to stop early because it was running as the patient numbers began to come down in Wuhan, and the cases numbers dropped so low that they stopped the trial.  This highlights another important challenge in undertaking research during disease outbreaks. There is a limited window within which clinical research can be undertaken as enough patients are needed to answer the questions. It is critical therefore to plan research as early as possible in these situations, and embed research within the public health response. Currently we are seeing disparity across the globe in where research is being implemented and so there should be a strong push to support research across all nations, especially in coordination and support within countries with lower levels of experience.

“Many questions remain about our understanding of COVID-19, and we still need to evaluate drugs and vaccines. The whole world will benefit from answering these questions across all populations and different settings. It is a global pandemic and we need to ensure global equity in who benefits from the evidence and treatments that are developed.”

‘Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial’ by Yeming Wang et al was published in The Lancet at 23.30 UK time on Wednesday 29 April 2020.

DOI 10.1016/ S0140-6736(20)31023-0

All our previous output on this subject can be seen at this weblink: www.sciencemediacentre.org/tag/covid-19

Declared interests

Prof Lang: None to declare

Prof Evans: No conflicts of interest

Dr Ward: “I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Until July 2019 I was Chief Medical Officer of Virion Biotherapeutics , which was a company developing broad spectrum RNA therapy for the treatment/prevention of respiratory virus infections.”

Prof Shakir: The Drug Safety Research Unit is an independent charity (No. 327206), which works in association with the University of Portsmouth. It receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. Gilead is providing support for a methodological project led by the DSRU as a part of a large group of pharma companies, unrelated to this product. Saad Shakir has no conflicts of interest to declare.

No others received.