A press release from the pharmaceutical company Gilead has announced results of stage 3 trial of their antiviral drug remdesivir in moderate COVID-19 patients.
Prof Martin Landray, Professor of Medicine & Epidemiology, Nuffield Department of Population Health, University of Oxford, said:
“It is very difficult to comment on a press release without the underpinning protocol and data. We already know from a previous randomised controlled trial that remdesivir reduces the time taken for hospitalised patients to recover from COVID-19. We still don’t know whether remdesivir improves survival. This current report adds very little new information. The suggestion that improvements seen with 5 days of treatment are not seen with 10 days of treatment seems biologically implausible and more likely reflects the play-of-chance in a fairly small study.”
Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:
“The full data from this study have not been released into the public domain, but the announced headline results are compatible with existing data reported from the ACTT trial and the initial SIMPLE trial comparing 5 days to 10 days remdesivir which were published in the NEJM in late May.”
“Full presentation of the data are awaited, but the results are comparable with data previously published exploring the outcomes of 5 vs 10 days treatment with remdesivir.”
“This data extends the extent of information already reported, and enables a comparison of 5 days treatment with SOC, previous reports had compared 10 days treatment plus SOC to SOC alone, while a separate, uncontrolled trial compared 5 to 10 days treatment with remdesivir plus SOC without a control arm. The release reports a statistically significant increase in clinical improvement by Day 11 (Hazard ratio 1.65, p=0.017) compared to SOC alone for the 5 day regimen, although the table shows that ~70% of subjects receiving SOC plus 5 days remdesivir had a 2 point improvement at day 11 compared to ~61% of patients in the SOC only group, which is not a 65% increase in proportion, making the press release a little difficult to follow.
“As in the previous uncontrolled study comparing 5 days therapy with 10 days therapy, the receipt of 10 days treatment did not result in even better outcomes, indeed as in the previous trial, the outcomes were slightly worse on the 10 day regimen than in the 5 day regimen. The reasons for this are unclear, however in vitro studies have shown that viral resistance to remdesivir can emerge. This potential needs to be further explored on samples from the completed and ongoing clinical trials.”
“The authors have not commented on the make-up of the recruited population; there are important high risk features including male sex, BAME race, and comorbidities which, if imbalanced across the treatment arms, might confound the outcome. The full results are required to assess this possibility.”
The implication for practice is that 5 days therapy with remdesivir may be effective and is not improved by extending treatment in patients with symptomatic disease not hypoxic at the time of starting therapy. In addition the relative improvement in subjects treated earlier with less severe symptoms at outset is larger than in the ACTT study, where efficacy was lost in patients with more severe symptoms treated later than 10 days post symptom onset. This is not unexpected as the peak viral load occurs at/shortly after first onset of symptoms suggesting that treatment should begin as early as possible to avert need for ICU admission and death.
Dr Gillies O’Bryan-Tear, Chair, Policy and Communications Group, Faculty of Pharmaceutical Medicine, said:
“This is the third randomised study of remdesivir in Covid-10 patients, this time in hospitalised patients with “moderate” disease (not defined in the press release). There was three treatment groups – a five day course, a ten day course, and “standard of care” which presumably would be supportive care only such as oxygen. The primary endpoint was a composite score based on various markers of clinical status at 11 days, including hospital discharge, levels of oxygen required, mortality and need for ventilatory support. The endpoint was not fully described in the press release and is different from the simpler endpoint in the previous study of remdesivir in severe Covid disease, which used time to recovery or duration of hospitalisation as the endpoint. Composite endpoints are often used to detect differences between treatments in less sick patients, since they increase the sensitivity of the endpoint by capturing more markers of disease. It is a valid, and common, method in clinical trials.
“The study enrolled a sufficient number of patients – 600 – to be able to detect a difference in each group from standard of care, and the 5 day course of remdesivir was associated with a significant improvement in the primary endpoint. Curiously, the ten day course did not achieve significance, though there was a trend towards improvement, and the reasons for this remain to be elucidated: the reasons may include a different profile of patients admitted to the two groups, although with nearly 200 patients in each group that would be unusual in a randomised study, though not impossible.
“Mortality was not improved significantly but there were only 6 deaths overall, so not enough to see an effect if any (although no deaths occurred in the 5 day group), because the study only included moderately severe patients. In the previous NIAID study, mortality was not improved significantly either, but there was a trend towards improvement, and many more deaths.
“Gilead claimed that the five day course “led to similar clinical improvements as a 10-day course”. This I believe overstates the results: the 10-day course did not achieve significance against standard of care, and although there was a trend towards improvement in the 10-day group, we do not know if the study was powered to directly compare the 5 and 10-day groups. If the study was not designed to directly compare the 5 and 10 day groups, this claim would not be sustainable, so again we need to await the full report. The lack of a significant effect of the 10-day course, requires an explanation, as noted.
“In any event, this second (of three) positive trial for Covid-19 confirms that the drug is active in the disease, and has now been shown to be effective in both severe and moderately ill patients. Although mortality was not improved in this trial, there were too few deaths to determine an effect, and hopefully the extension of this trial, which is enrolling now, will shed further light. Experience with other antiviral agents would suggest that if patients are treated earlier in the course of disease, the effect should be greater, so we await the results of the expansion trial with interest.
“With two studies now positive (the third study in China enrolled too few patients to determine the outcome), it is likely that regulatory authorities worldwide will approve this agent in Covid-19 – once the necessary data compilation and approval processes are complete, which will take several months.”
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“We are all waiting for some good news about a therapy that works in Covid-19, but at the moment the evidence is thin and companies need to provide proper data rather than just press releases.
“They need to share sufficient information for everyone to see what impact the drug has. Here they emphasise an odds ratio related to an improvement on an ordered 7 point scale. The data show that there is only a small difference between the groups in improvement; the control group have about 60% of patients improving by at least 2 points, and 66% by at least one point. The 10-day treated group have about an extra 4% improving by 2 points or 1 point; while the 5 day treated group fare slightly better with another 9 to 10% showing improvement. These improvements are not dramatic – they are not a ‘game changer’ in the terrible jargon, but at least there is some genuine evidence of improvement. For the patients it is good news that few died, but the evidence therefore that remdesivir improves mortality in these patients is uncertain and limited.
“The 7 point scale from the trial details on Clinicaltrials.gov seems to be:
2. Hospitalized, on invasive mechanical ventilation or Extracorporeal Membrane Oxygenation (ECMO)
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices
4. Hospitalized, requiring low flow supplemental oxygen
5. Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care (coronavirus (COVID-19) related or otherwise)
6. Hospitalized, not requiring supplemental oxygen – no longer required ongoing medical care (other than per protocol remdesivir administration
7. Not hospitalized.
“It is clear that moving two points down on this scale is worthwhile but the meaning of a one or two point difference is rather variable depending on where the patient starts.
“Remdesivir is one of the only drugs to show some promise, but the benefits are not large and we need to have more transparent data before we can form a good judgement.”
Prof Martin Landray: “Co-chief investigator of the RECOVERY trial of potential treatments for COVID-19 (funded by UKRI and NIHR). Research funding to University of Oxford received from Novartis, Boehringer Ingelheim, and Merck Sharp & Dohme. Infrastructure and core funding received from Health Data Research UK, NIHR Oxford Biomedical Research Centre, UK Biobank Ltd, MRC Population Health Research Unit, and British Heart Foundation Centre for Research Excellence. Employee of University of Oxford with salary supported by Li Ka Shing Foundation, Health Data Research UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, and National Health Service.”
Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”
Dr Gillies O’Bryan-Tear: “Nil.”
Prof Stephen Evans: No conflicts of interest. I am funded (1 day/week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator or any grants obtained from them. I am the statistician to the “meta-Data Safety and Monitoring Board” for CEPI [https://cepi.net/]. I will probably be paid for my attendance at meetings and expenses for travel.