The World Health Organization (WHO) announces the Solidarity PLUS platform trial of drugs repurposed to treat COVID-19 after Solidarity trial candidates disappoint.
The World Health Organization has announced that its Solidarity PLUS platform clinical trial will test 3 drugs repurposed to treat COVID-19, after disappointing results in the Solidarity trial with drug candidates that included interferon and hydroxychloroquine.
The Solidarity PLUS trial will test artesunate, a plant derivative used for severe malaria; imatinib, an ABL tyrosine-kinase inhibitor antineoplastic; and infliximab, a tumor necrosis factor (TNF) inhibitor used in auto-immune conditions such as Crohn's Disease and rheumatoid arthritis.
"Finding more effective and accessible therapeutics for COVID-19 patients remains a critical need, and WHO is proud to lead this global effort," stated Tedros Adhanom Ghebreyesus, PhD, WHO Director-General. "I would like to thank the participating governments, pharmaceutical companies, hospitals, clinicians and patients, who have come together to do this in true global solidarity."
The platform trial enables clinical testing of more potential treatments more quickly than pharmaceutical research sites can screen, identify and develop novel agents.The size and complexity of the international trial mayhave also complicated its resumption after initial disappointments, however, according to a report in Science, from the American Association for the Advancement of Science (AAAS).
The lack of benefit from the first 4 compounds tested resulted in the Solidarity trial becoming "mired in negotiations with pharmaceutical companies and regulatory delays", related a source in the Science report.
Reached for comment, WHO Spokesperson Tarik Jasarevic told Contagion that the Solidarity trial had not been halted."Interim results of the first Solidarity trials were announced in October 2020, and the final results are expected to be announced next month," Jasarevic said."We were enrolling patients until January 2021 and patients were still being followed thereafter."
The 3 drugs in the current Solidarity PLUS trial, donated by the manufacturers, have been sent to Finland, the first country to have all approvals in place, and the likely first location for trial participant recruitment.The report in Science suggests that more than 40 drugs are under review for inclusion.A component of that review is obtaining assurance from the manufacturers that the drugs demonstrating benefit would then be available at affordable prices worldwide.
"Identifying new drugs necessitates a careful review process to ensure that the potential for success is increased," Jasarevic said."These drugs were chosen after careful consideration of available data by an independent panel of experts.The panel considered various antithrombotics, antivirals, immunomodulators and monoclonal antibodies, and chose these drugs as they were considered to have the largest potential to reduce mortality."
The current trial should expand rapidly, according to the WHO announcement, to represent "the largest global collaboration among WHO Member States."The platform trial is anticipated to involve thousands of researchers in over 600 hospitals in 52 countries, which is 16 more countries than participated in the first phase.
"For a global platform trial, it is critical to expand and give the opportunity to researchers from additional Member States," Jasarevic emphasized."Expanding to 16 new countries and 200 more hospital sites, ensuring ethical and regulatory approvals, shipping the drugs to new countries—all this takes time to achieve."
According to the filing with the ISRCTN (International Standard Randomized Controlled Trial Number) registry, the primary analysis of the Solidarity PLUS trial will assess any effects of treatment allocation on all-cause in-hospital mortality in all patients.The main secondary analyses will assess in-hospital mortality subdivided by initial respiratory support; with further analyses of the initiation of ventilation in lower-risk patients and, separately, the duration of hospital stay in lower- and higher-risk patients.Investigators indicate that the data from large numbers of participants will enable robust analysis of even moderate drug effect on mortality
The participants will be ≥18 years of age, hospitalized with laboratory-confirmed COVID-19 at one of the participating hospitals, and without contraindications to any potential study drug. Artesunate dosing will correspond to the recommended dose for severe malaria;2.4mg/kg/dose intravenously at 0, 12 and 24 hours, and every 24 hours though 7 days. Infliximab dosing will correspond to its use in treatment of psoriasis; 5mg/kg once by IV infusion over 2 hours. Imatinib dose will follow the lower end maintenance regimen for hematological malignancies; 400mg orally once daily for 14 days.
"Solidarity's adaptive study design allows for adding novel treatment arms while the trial is in progress, or discontinuing some treatment arms that are proven ineffective or unsafe," Jasarevic noted."A Global Data and Safety Monitoring Committee will keep the accumulating safety results and major outcome results under regular review.
"The WHO expert group on prioritization of therapeutics may recommend adding further treatment arms while the trial is in progress, if evidence emerges that there are suitable candidate therapeutics," Jasarevic added."Conversely, the WHO may decide to discontinue some treatment arms, especially if the Global Data and Safety Monitoring Committee reports, based on interim analyses, that one or other of the trial treatments definitely does or does not affect mortality."