No survival benefit from remdesivir, hydroxychloroquine, lopinavir/r or interferon-β1a in moderate and severe COVID-19: interim results from the WHO SOLIDARITY study

11 November 2020. Related: COVID-19: investigational drugs, COVID-19.

Simon Collins, HIV i-Base

On 15 October 2020, the World Health Organization published results from the large international SOLIDARITY study, ahead of peer review. The findings included that none of the four treatments reduced deaths in people hospitalised with moderate or severe COVID-19. [1, 2]

While some of these drugs were already known not to work (hydroxychloroquine and lopinavir/r), it was hoped that the results for interferon-β1a and for the approved drug remdesivir would be better – although they have already been challenged due to the study design.

Launched in March 2020, the SOLIDARITY study randomised 11,266 participants hospitalised with COVID-19 to one of four open-label treatment groups: (i) remdesivir (n=2750), (ii) hydroxychloroquine (n=954), (iii) lopinavir/r (n=1411) and (iv) interferon-β1a, initially with lopinavir/r (n=651) but from 4 July as a single treatment (n=1412), or to a control group receiving standard of care in each country but without any of the study drugs, even if available (n=4088).

The study was run at more than 400 hospital sites in 30 countries and required minimum reporting other than survival outcomes and a few baseline characteristics. This design was to broaden participation from different settings at a time when hospital resources were limited. However, it also limits the data available for interpreting more complicated results. Additional details will be available from some European countries in a substudy of SOLIDARITY called DISCOVERY.  [3, 4]

The primary endpoint was mortality, measured by death in hospital within 28 days of joining the study. Follow-up was stopped after first discharge from hospital (ie subsequent outcomes are not recorded).

Unusually, the decision to release the interim results was decided by a steering group who were still blinded to the study results. The study was also designed without estimates for the number of people to be enrolled or the number of deaths that would be needed to produce definitive results. Results were stratified by severity of COVID-19 at baseline as moderate or severe depending on whether or not a participant was already ventilated.

Limited data available on baseline characteristics included 62% men and history of comorbidities included 25% diabetes, 21% heart disease, 6% chronic lung disease, 5% asthma and 1% chronic liver disease. Current smoking was reported for 7%.

By age, 35% were 50 years old or younger, 45% were 51 to 69 and 19% were 70 or older. When joining the study, 63% were on oxygen, 8% of all participants were already ventilated and 38% had already been hospitalised for two or more days.

By region, 22% were from Europe or Canada, 17% were from Latin America and 61% were from Asia and Africa.

There were 1253 deaths at median of 8 days (IQR: 4 to 14). Mortality was 12% overall but 39% in participants who were already ventilated at randomisation.

None of the study drugs reduced mortality compared to the control arm. There were no differences in any baseline subgroups including for ventilation, initiation of ventilation or time in hospital. Deaths for each drug reported as rate ratios with 95% CIs are included in Table 1 below, with the confidence intervals highlighted as being more important than either the rate ratio or p-value as these were all within the range of previously published studies (but also adding that narrower intervals would have been helpful). Adherence was reported as >93% in all groups, defined by still being on allocated treatment halfway through the dosing schedule.

Table 1: Mortality rate ratios (95%CI) from interim analysis of the SOLIDARITY study

In addition to these results, the researchers also included meta-analyses of outcomes from other studies of each drug. Also, in terms of participant numbers, the SOLIDARITY study now provides more than 75% of total randomised results available on remdesivir and interferon.

Most controversially, the researchers report that “this absolutely excludes the suggestion that remdesivir can prevent a substantial fraction of all deaths”. Taking this further, they write the results are “compatible with prevention of no deaths” and that “this would be consistent with the lack of reduction in the initiation of ventilation or the duration of hospitalisation”. However, they also note that benefits might be seen in some subpopulations.

The study is being led by WHO, but local costs were covered by participating countries and all study drugs were donated by the manufacturers.

comment

These results are significant for the size of this randomised study and it is surprising that their publication, even though ahead of peer review, hasn’t generated more coverage in mainstream media.

While producing clear evidence on lack of survival benefit, the news is difficult and disappointing for not finding more positive results, including for remdesivir which is already approved for COVID-19. However, as an antiviral, remdesivir would be expected to be more active in earlier stages of COVID-19.

Gilead Sciences (who developed remdesivir) have challenged the results as “inconsistent with more robust evidence from multiple randomised controlled studies published in peer-reviewed journals”, noting that WHO have also prequalified remdesivir. [5]

Even though the hydroxychloroquine, lopinavir/r and interferon arms have now been discontinued, the SOLIDARITY study is still ongoing (with remdesivir) and is recruiting about 2000 patients per month. Although the factorial design allows it to add further investigational treatments including immune-modulators and monoclonal antibodies, it is unclear whether new drugs have already been added. [2]

However, as this publication has commented many times, future studies should be looking at combination therapies and planning for longer follow-up. This is needed to capture important outcomes related to long-term recovery that were not appreciated earlier in the epidemic.

References

1. WHO SOLIDARITY Trial Consortium. Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results.
   https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1
2. WHO press statement. Solidarity Therapeutics Trial produces conclusive evidence on the effectiveness of repurposed drugs for COVID-19 in record time. (15 Octoner 2020).
   https://www.who.int/news/item/15-10-2020-solidarity-therapeutics-trial-produces-conclusive-evidence-on-the-effectiveness-of-repurposed-drugs-for-covid-19-in-record-time
3. Trial of treatments for COVID-19 in hospitalized adults (DISCOVERY).
   https://clinicaltrials.gov/ct2/show/NCT04315948
4. Public health emergency SOLIDARITY trial of treatments for COVID-19 infection in hospitalized patients. ISRCTN83971151.
   http://www.isrctn.com/ISRCTN83971151
5. Gilead press statement. Gilead Sciences statement on the Solidarity trial. (15 October 2020).
   https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-the-solidarity-trial

This report was first posted on 20 October 2020.