“Solidarity” clinical trial for COVID-19 treatments
UPDATE: Solidarity Trial reports interim results
Solidarity is an international clinical trial to help find an effective treatment for COVID-19, launched by the World Health Organization and partners. It is one of the largest international randomized trials for COVID-19 treatments, enrolling almost 12 000 patients in 500 hospital sites in over 30 countries.
The Solidarity Trial is evaluating the effect of drugs on 3 important outcomes in COVID-19 patients: mortality, need for assisted ventilation and duration of hospital stay.
The Solidarity Trial compares treatment options against standard of care to assess their relative effectiveness against COVID-19. By enrolling patients in multiple countries, the Solidarity Trial aims to evaluate whether any of the drugs improve survival or reduce the need for ventilation or duration of hospital stay. Other drugs may be added based on emerging evidence.
In general, until there is sufficient evidence, WHO cautions against physicians and medical associations recommending or administering unproven treatments to patients with COVID-19 or people self-medicating with them. WHO guidance on compassionate use can be found here.
Latest update on on treatment arms
The Solidarity Trial published interim results on 15 October 2020. It found that all 4 treatments evaluated (remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon) had little or no effect on overall mortality, initiation of ventilation and duration of hospital stay in hospitalized patients.
The Solidarity Trial is considering evaluating other treatments, to continue the search for effective COVID-19 therapeutics.
So far, only corticosteroids have been proven effective against severe and critical COVID-19.
Previously, on 4 July 2020, WHO had accepted the recommendation from the Solidarity Trial’s International Steering Committee to discontinue the trial’s hydroxychloroquine and lopinavir/ritonavir arms.
The International Steering Committee formulated the recommendation in light of the evidence for hydroxychloroquine vs standard-of-care and for lopinavir/ritonavir vs standard-of-care from the Solidarity Trial interim results, and from a review of the evidence from all trials presented at the 1-2 July WHO Summit on COVID-19 research and innovation.
These interim trial results showed that hydroxychloroquine and lopinavir/ritonavir produce little or no reduction in the mortality of hospitalized COVID-19 patients when compared to standard of care. Solidarity Trial investigators interrupted the trials with immediate effect.
For each of the drugs, the interim results did not provide solid evidence of increased mortality. There were, however, some associated safety signals in the clinical laboratory findings of the add-on Discovery trial, a participant in the Solidarity Trial. These will also be reported in the peer-reviewed publication.
This decision applies only to the conduct of the Solidarity Trial in hospitalized patients and does not affect the possible evaluation in other studies of hydroxychloroquine or lopinavir/ritonavir in non-hospitalized patients or as pre- or post-exposure prophylaxis for COVID-19.
Rationale
The pressure COVID-19 puts on health systems means that WHO considered the need for speed and scale in the trial.
Enrolling patients in one single randomized trial will help facilitate the robust worldwide comparison of unproven treatments. This will overcome the risk of multiple small trials not generating the strong evidence needed to determine the relative effectiveness of potential treatments.
Participation in Solidarity
As of 2 October 2020, over 12 000 patients had been recruited in 500 participating hospitals worldwide. The Solidarity Trial is ongoing in 30 countries among the 43 countries that have approvals to begin recruiting. Overall, 116 countries in all 6 WHO regions have joined or expressed an interest in joining the trial,
Each participating country is a sponsor to the trial in its country and supports its implementation, including financially. WHO is actively supporting them with:
- identification of hospitals participating in the trial;
- training of hospital clinicians on the web-based randomization and data system;
- shipping the trial drugs as requested by each participating country.
The greater the number of patients enrolled, the faster results will be generated. WHO is facilitating access to thousands of treatment courses for the trial through donations from a number of manufacturers. WHO is also inviting developers and companies to collaborate on ensuring affordability and availability of the treatment options if they prove effective.
Support for Solidarity
How the Solidarity Trial works
Simplified trial procedures
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.
Who is included in the study?
Patients maybe included if they have COVID-19, are in hospital and consented to be in the trial. Eligible patients are age ≥18 years, hospitalized with a diagnosis of COVID-19, not known to have received any study drug, without anticipated transfer elsewhere within 72 hours, and, in their physician’s view, with no contra-indication to any study drug.
Data collection and monitoring
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.
Research staff also reports suspected and unexpected serious adverse reactions (SUSAR).
National and global monitors resolve queries and check progress and data completeness.
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.
Interim trial analyses are monitored by a Global Data and Safety Monitoring Committee, which is an independent group of experts.
An adaptive trial
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.
Countries, or particular groups of hospitals, may want to collaborate in making further serial measurements or observations, relating to areas such as virology, blood gases or chemistry and lung imaging. It also possible to incorporate documentation of
other aspects of disease status, for example, through linking in electronic healthcare records and routine medical databases. While well-organized additional research studies of the natural history of the disease or of the effects of the trial treatments
could well be valuable, they are not core requirements.