Repurposed antiviral drugs for COVID-19 – interim WHO SOLIDARITY trial results
3 December 2020
Key messages
The trial found that the evaluated remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.
It is possible to conduct large, international randomized trials during a public health emergency using a simple but robust platform approach and to answer the critical public health questions.
Although the results for the first four treatment options evaluated are unpromising, the results are very informative for policy makers and clinicians worldwide. This global platform trial is efficient and with high quality and will continue to efficiently
evaluate promising new treatment options.
Why are some countries and WHO implementing the Solidarity Therapeutics Trial?
In early January 2020, when the COVID-19 outbreak was first declared, WHO activated its Research and Development Blueprint, bringing together researchers from around the world to identify the knowledge gaps and research needs to find solutions for the threat COVID-19 posed to humanity.
In February, a WHO COVID-19 research forum was convened and recommended evaluation of potential treatments in large randomized trials. A WHO expert group identified 4 repurposed antiviral drugs that might have some effect on mortality -Remdesivir, Lopinavir, Hydroxychloroquine and Interferon -beta 1a.
By March, over a thousand clinical trials to evaluate drugs to treat COVID-19 patients were initiated. The great majority were small trials involving only a few hundred patients.
Even though these treatments seemed to have potential, it was not known if they were more effective in treating COVID patients and helping them recover than the usual standard of care in each hospital.
In March, an international group of experts in clinical trials designed a core protocol for the evaluation of study drugs to treat COVID with the aim of obtaining robust evidence to answer questions of public health importance.
What is the Solidarity Therapeutics Trial?
This trial aims to evaluate several different treatments that may be effective to treat patients with COVID-19. The aim is to compare the effects on major outcomes in hospital of the local standard of care alone (the care all patients usually receive) versus the local standard of care plus one of four potential drugs to treat COVID-19.
The primary objective of this large international randomized trial is to provide reliable estimates on any effects of potential drugs to treat COVID-19 on in-hospital mortality in moderate and in severe COVID. The secondary objectives are to assess any effects of these potential drugs to treat COVID-19 on hospital duration and receipt of ventilation, and to identify any serious adverse reactions.
- To facilitate collaboration even in hospitals that have become overloaded, the protocol was designed to involve hundreds of potentially busy hospitals in dozens of countries. All trial procedures are greatly simplified but are stringent. No paper form-filling is required, and trial procedures are minimal but rigorous.
- Once a hospital has obtained approval (regulatory and ethical), electronic entry of patients who have given informed consent is done and online randomization of consented patients (via a cloud-based GCP-compliant clinical data management system) takes just a few minutes.
- Trial procedures were minimal but rigorous, with data entry through a cloud-based Good Clinical Practice-compliant clinical data management system that recorded demographic characteristics, respiratory support, coexisting illnesses, and local availability of trial drugs before generating the treatment assignment. Written informed consent was provided by patients, or if they were unable to do so, by their legal representatives.
- Consent forms were retained by signatories and archived for records. The enrolment of patients who provided consent took just a few minutes.
- Eligible patients were 18 years of age or older, were hospitalized with a diagnosis of Covid-19, were not known to have received any trial drug, were not expected to be transferred elsewhere within 72 hours, and, in the physician's view, had no contraindication to any trial drug.
- The controls for a drug were patients assigned to the standard of care at a time and place in which that drug was locally available (except that when interferon was being given only with lopinavir, its controls were patients given only lopinavir). Assignment to the standard of care at a hospital in which more than one trial drug was available would put that patient into the control group for each of those drugs.
- Each comparison between a trial drug and its control, however, was evenly randomized (in a 1:1 ratio) and unbiased, because both groups were affected equally by differences between countries or hospitals and by time trends in patient characteristics or the standard of care.
- Baseline data is collected using an electronic case-report form that includes treatment availability at the trial site, basic demographic data, level of respiratory support at enrolment, and major coexisting conditions.
- At discharge from hospital or death, online reporting of outcomes of the disease (discharge alive or death in hospital, with date and cause of death), plus brief details regarding the adherence to the assigned treatment, respiratory support in hospital (and type), and use of certain non-study drugs are documented.
- The same cloud-based system was used to report any suspected unexpected serious adverse reaction. It was also used to record death in the hospital or discharge alive (with documentation of respiratory support in the hospital, trial drug timing, use of non trial drugs, and probable cause of death).
- National and global monitors raised or resolved queries (or both) and checked progress and completeness.
- Research staff also reports suspected and unexpected serious adverse reactions (SUSAR).
- National and global monitors resolve queries and check progress and data completeness.
When did the trial start and when were the first patients enrolled?
On 22 March 2020, a large, multi-country, open-label randomized trial among hospitalized patients of these 4 drugs was initiated to assess their effect on COVID-19. Interim mortality results of this trial will be shortly published in a peer-reviewed journal and are currently available in MedRxiv.
The Solidarity trial is an adaptive trial. This means that some unpromising drugs have been dropped and others will be added. Hydroxychloroquine and Lopinavir/Ritonavir arms were discontinued on 20 June and 4 July 2020 respectively.
Which countries are participating in the Solidarity therapeutics trial?
The study is being conducted by countries and hospitals all around the world in collaboration with WHO, which acts as a co-sponsor for the research, together with 30 co-sponsoring countries, collaborating with clinicians and researchers at nearly 500 hospitals worldwide.
Patients included in the present analysis are from 30 countries from the six WHO Regions: Albania; Argentina; Austria; Belgium; Brazil; Canada; Colombia; Egypt; Finland; France; Honduras; India; Indonesia; Iran; Ireland; Italy; Kuwait; Lebanon; Lithuania; Luxembourg; Malaysia; North Macedonia; Norway; Pakistan; Peru; Philippines; Saudi Arabia; South Africa; Spain; and Switzerland.
An additional 15 countries are now joining the trial.
What were the main findings of the trial?
Remdesivir, Hydroxychloroquine, Lopinavir/Ritonavir and Interferon appeared to have little or no effect on the course of COVID-19 among hospitalized patients, as indicated by little or no effect on overall mortality, initiation of ventilation and duration of hospital stay.
The mortality findings contain 80% of the global randomized evidence on Remdesivir and most of the global randomized evidence on Interferon.
The results of the Solidarity trial are consistent with meta-analyses of mortality evidence from all major trials.
Is there any possible role for these drugs?
The unpromising overall findings of the drugs evaluated (using the given regimens) do disprove early hopes, based on smaller or non-randomized studies, that any of them substantially reduce mortality, initiation of ventilation or hospitalization duration among patients hospitalized with COVID-19.
Recruiting additional patients to further increase the precision of the results (e.g. narrower confidence intervals) may be helpful particularly for Remdesivir.
However, the main need is for better treatments with greater effect on critical outcomes (mortality, need for ventilation and duration of hospital stay). Please refer to WHO Therapeutics and COVID-19: living guideline.
Solidarity trial is still recruiting about 2000 patients per month, and an efficient factorial design will allow it to assess further treatments, such as new antivirals, immune-modulators and specific anti-SARS-Cov-2 monoclonal antibodies.
Solidarity trial only provided information on effect of these drugs among hospitalized patients. Use of the drugs in community and pre-hospital settings would have to be examined using different trial designs. Some of these trials are ongoing.
What are key lessons emerging from the experience with the Solidarity therapeutics trial?
- The achievements of the Solidarity Therapeutics trial demonstrate that large international trials are not only possible but necessary, even more so during a pandemic. Such trials offer the promise of efficiently and reliably answering critical public health questions concerning potential therapeutics.
- One of the keys to success, has been establishing an inclusive global platform to allow nearly 1 500 clinicians and more than 13 000 of their patients all around the world to contribute to the trial. Given the geographic spread of the trial, recruitment rates are maintained constant over time and are not affected by the geographic changes in COVID incidence. The larger the number entered the more accurate the results are.
- To facilitate collaboration even in hospitals that have become overloaded, patient enrolment and randomization (via the internet) and all other trial procedures are greatly simplified, but robust. This has facilitated the steady enrolment of at least 2 000 patients each month and helped ensure high rates of follow up and documentation of the patients’ outcome.
- The trial incorporates an adaptive trial design. This permits the addition of novel treatments while the trial is in progress. Conversely, it also allows to discontinue some treatments, based on interim analyses. All decisions are guided by an independent group of experts (Data Safety Monitoring Committee).
- In this pandemic, the mortality due to COVID is one of the important public health outcomes. Another important consideration is that a small proportion (but important number) of COVID patients may need assisted ventilation, which can be an added burden on the health system. Duration of hospital stay for COVID-19 patients can also be important. The Solidarity trial us evaluating the effect of drugs on these 3 important outcomes.
The Solidarity Therapeutics trial has accumulated a large part of worldwide information on the first two of these outcomes for Remdesivir and interferon and greatly contributed to the already existing evidence on Hydroxychloroquine and Lopinavir/Ritonavir.
Such a large trial must be extremely expensive, how much does it cost? Who paid for this?
This is another benefit of the Solidarity trial. It is a trial implemented thanks to the solidarity and contributions of all the countries and hospitals participating in the trial. Participating countries and hospitals covered almost all local costs and WHO covered all other study costs.
Collaborators, committee members, data analysts charged no costs, data management systems were in kind contributions (Castor EDC).
Anonymized data handling and analysis was by the Universities of Berne, Bristol and Oxford.
Remdesivir was donated by Gilead Sciences, Hydroxychloroquine by Mylan, Lopinavir by Abbvie, Cipla and Mylan, and Interferon β1a by Merck KGaA (subcutaneous) and Faron (intravenous). No funding was provided by any of the study drugs manufacturers.
What are the next steps, will the unpromising treatment arms now be abandoned, and the Solidarity Trial stopped?
Solidarity trial is still recruiting about 2 000 patients per month, and an efficient innovative (factorial) design will allow it to assess further treatments, such as new antivirals, immune-modulators and specific anti-SARS-Cov-2 monoclonal antibodies.
This global trial is ready to rapidly evaluate promising new treatment options, thanks to the contributions of nearly 500 hospitals, 1 500 clinicians and research staff and their patients and families. An additional 15 countries are now joining the Solidarity trial.
The Executive Group of the International Steering Committee of the Solidarity trial will now decide which arms will continue in the trial. This Group is also currently considering the possible additions of newer antivirals, immunomodulators, and anti-SARS-Cov-2
monoclonal antibodies in advanced development.
What are some of the most promising drugs for the treatment of COVID-19 patients?
Newer antiviral drugs, immunomodulators and anti-SARS COV-2 monoclonal antibodies are now being considered for evaluation via the Solidarity Therapeutics trial.
Even though these treatments seem to have potential, it is not known if they are more effective in treating COVID patients and helping them recover than the usual standard of care in each hospital.
With so many participating countries and hospitals surely the standards of care have varied and influenced the results?
No. The controls for a drug were patients assigned to the standard of care at a time and place in which that drug was locally available (except that when interferon was being given only with lopinavir, its controls were patients given only lopinavir). Assignment to the standard of care at a hospital in which more than one trial drug was available would put that patient into the control group for each of those drugs.
No trial drug had any definite effect on mortality, either overall or in any subgroup defined according to age, ventilation status at entry, other entry characteristics, geographic region, or corticosteroid use.
The stratified rate ratios for death in the Solidarity trial and ACTT-1 are compatible with each other, and either singly or together they are compatible with there being little or no effect of Remdesivir on mortality.
The results do not support the suggestion that Remdesivir can prevent a substantial fraction of all deaths. The confidence interval is compatible with prevention of a small fraction of all deaths, but it is also compatible with prevention of no deaths. The results are similar when we look at them according to the different variables planned for.
Performing multiple unplanned subgroup analyses with smaller numbers is not advisable as they are likely to yield spurious results (falsely indicating positive effects or negative effects just by chance).
What are the safeguards around the quality of the trial?
There are local monitors in each of the countries that oversee data quality, raise queries and document any protocol deviation or violation.
In addition, centralized monitoring by an independent academic partner was performed of the data in the global database. WHO does not have access to the database.
Are the interim results of the Solidarity Trial consistent with those coming from other clinical trials of the same drugs in similar populations?
The Solidarity Therapeutics trial has accumulated a large part of worldwide information on the first two of these outcomes for Remdesivir and interferon and greatly contributed to the already existing evidence on Hydroxychloroquine and Lopinavir/Ritonavir.
The results of the Solidarity trial are consistent with meta-analyses of mortality evidence from all major trials.
Mortality
For each drug in the study, the effect on mortality was disappointingly unpromising. No trial drug had any definite effect on mortality, either overall or in any subgroup defined according to age, ventilation s tatus at entry, other entry characteristics, geographic region, or corticosteroid use.
- The stratified rate ratios for death in the Solidarity trial and ACTT-1 are compatible with each other, and either singly or together they are compatible with there being little or no effect of remdesivir on mortality.
- The results do not support the suggestion that remdesivir can prevent a substantial fraction of all deaths. The confidence interval is compatible with prevention of a small fraction of all deaths, but it is also compatible with prevention of no deaths.
What is the WHO recommendation for the treatment of hospitalized patients with COVID-19 in light of these results?
The purpose of the trial report is not to make any recommendations.
It is a rigorous scientific report of the conduct and interim results of the Solidarity trial.
WHO independent expert panels considered these results, and all other evidence generated by major COVID-19 trials when formulating WHO recommendations. Such recommendations are part of a living guideline on clinical care for COVID-19, developed by an
international guideline development group: WHO Therapeutics and COVID-19: living guideline.
Why did mortality appear to be higher in Latin America?
One observation was that patients in Latin America were less likely to receive ventilation, however the study was not designed to assess time from onset of symptoms to ventilation so we cannot be certain that this was a contributing factor.
Importantly, differences in 28-day mortality do not appear to affect the conclusions of Remdesivir on mortality. Excluding the Latin American data would not have modified the conclusions.
Was there any evidence of specific interactions between use of steroids and interferon?
The trial did not randomize patients to receive other therapies. We recorded information about all other drugs given to each patient.
The stratified rate ratios according to age and according to ventilation status. No trial drug had any definite effect on mortality, either overall (each P>0.10) or in any subgroup defined according to age, ventilation status at entry, other entry
characteristics, geographic region, or glucocorticoid use. Unstratified comparisons yielded similarly null findings as did analyses that excluded patients receiving corticosteroids and multivariable sensitivity analyses that estimated trial drug effects
simultaneously.
For interferon beta-1a, no other large trials exist. With 4 000 patients, the rate ratio for death in the Solidarity trial was 1.16 (95% CI, 0.96 to 1.39), or 1.12 (95% CI, 0.83 to 1.51) without lopinavir co-administration; these findings suggest no mortality
reduction. Subcutaneous and intravenous interferon have different pharmacokinetic characteristics,18,19 and glucocorticoids could affect interferon signaling,20,21 but the clinical relevance of both issues is unclear. Most interferon was administered
subcutaneously, because intravenous interferon was used only in patients receiving high-flow oxygen or ventilation, and distribution of it began only in late May, just before strong evidence emerged of glucocorticoid efficacy in such patients.
Hence, few patients received intravenous interferon without a glucocorticoid. Approximately half the patients who were assigned to interferon (and half their controls) received corticosteroids, but the rate ratio for death with interferon as compared
with its control seemed unaffected by glucocorticoid use. Randomization to interferon was discontinued on October 16, but other trials continue.
A report that nebulized interferon beta-1a might be effective involved only approximately
100 patients with Covid-19 (ClinicalTrials.gov number, NCT04385095), but the ongoing placebo-controlled ACTT-3 of subcutaneous interferon beta-1a aims to involve 1000 patients (NCT04492475), with examination of time to recovery.