The fate of confirmatory clinical trials for Remdesivir for treatment of COVID-19

Remdesivir, as the first highly touted drug to treat COVID-19 patients, has now been approved for emergency use authorization in several countries. The focus of fighting COVID-19 seems to shift to the safe and effective vaccine development. Unfortunately, the efficacy of Remdesivir has not been confirmed due to the flaws in the study design (for example, no placebo control) or due to the issues in the study conduct (for example, early discontinuation of the study resulted in underpowered studies) .

• Despite the Hype, Gilead’s Remdesivir Will Do Nothing to End the Coronavirus Pandemic
• Remdesivir alone is not enough, researchers conclude in first major Covid-19 trial of the drug
• Data Monitoring for the Chinese Clinical Trials of Remdesivir in Treating Patients with COVID-19 During the Pandemic Crisis
• Gilead to end coronavirus drug trials, adding to access worry: researchers

In a previous post, six pivotal studies were listed for Remdesivir. These six studies were also listed in the article by Singh et al Remdesivir in COVID-19: A critical review of pharmacology, pre-clinical and clinical studies.

The table below listed the status (fate) of these studies.

Protocol Title	Study Features	Fate of Studies
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe COVID-19	Gilead Sciences Phase III, initially planned for 400 subjects, then increased to 2400, and then 6000 subjects Two  arms: Standard of care + Remdesivir for 5 days, Standard of care + Remdesivir for 10 days	Enrolment was stopped early after 397 subjects were randomized.   Results were published in NEJM (Goldman et al “Remdesivir for 5 or 10 Days in Patients with Severe Covid-19“ Conclusion: “In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined.” It is noted that the study design was flawed and should have included a third arm with Standard of Care without Remdesivir. The data from this study was further compared to the external control group and results were announced in a recent press release "Comparative Analysis of Phase 3 SIMPLE-Severe Study and Real-World Retrospective Cohort of Patients Diagnosed with Severe COVID-19 Receiving Standard of Care" to show the statistically significant reduction in mortality in Remdesivir group.
A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate COVID-19 Compared to Standard of Care Treatment	Gilead Sciences Phase III, initially planned for 600 subjects, then increased to 1600 subjects Three arms: Remdesivir for 5 days, Remdesivir for 10 days, Standard of care	The study is active, but not recruiting new patients. The enrolment has stopped. The results have not been published yet. Gilead announces results in a press release “Gilead Announces Results From Phase 3 Trial of Remdesivir in Patients With Moderate COVID-19” Study Demonstrates 5-Day Treatment Course of Remdesivir Resulted in Significantly Greater Clinical Improvement Versus Treatment with Standard of Care Alone Data Add to Body of Evidence from Prior Studies Demonstrating Benefit of Remdesivir in Hospitalized Patients with COVID-19 The results were later published in JAMA "Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients with Moderate Covid-19" Also see the articles “More evidence remdesivir helps some coronavirus patients”  “Gilead's remdesivir shows modest improvement in moderate COVID-19 patients” “A slice of half-baked remde­sivir da­ta takes a dark turn — but we're still wait­ing for a de­fin­i­tive study”
A Phase 3 Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Mild and Moderate 2019-nCoV Respiratory Disease.	Capital Medical University/Chinese Academy of Medical Sciences Phase III, 308 Subjects Two arms: Remdesivir, placebo Mainland China only	The study was suspended (The epidemic of COVID-19 has been controlled well at present, no eligible patients can be recruited).  The results have not been published yet.  See “Second trial testing Gilead's remdesivir in COVID-19 suspended in China”
A Phase 3 Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Severe 2019-nCoV Respiratory Disease.	Capital Medical University Phase III, 453 Subjects Two arms: Remdesivir, placebo Mainland China only	The study was terminated after 237 patients were enrolled and randomly (158 in remdesivir and 79 in placebo) (The epidemic of COVID-19 has been controlled well in China, no eligible patients can be enrolled at present.) Results were published at Lancet Wang et al “Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial” Conclusion: “In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.”
A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults	National Institute of Allergy and Infectious Diseases (NIAID) Phase II, planned 440 Subjects (protocol specified 394 subjects), actual enrolment: 1063 subjects at the time of DMC review) Two arms: Placebo, Remdesivir with additional arms to be added Multi-National: US, Japan, South Korea, Singapore	The study was stopped after the interim analyses.  Preliminary results were published in NEJM by Beigel et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report Conclusion: “Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection.” The results from this study were the basis for FDA to issue Emergency Use Authorization for Remdesivir. Subsequently, several other countries followed suit. It is disappointing that the study was stopped after inconclusive or not convincing results from the interim analyses. There was no mention if there was a pre-specified stopping rule and whether the boundaries for stopping the study had been crossed.  Also see: Inside the NIH’s controversial decision to stop its big remdesivir study The final report was later published in NEJM (on Oct 8). Results were better than those reported in the preliminary report (median recovery time was shorten by 5 days). The final report concluded "Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection."
Multi-centre, Adaptive, Randomized Trial of the Safety and Efficacy of Treatments of COVID-19 in Hospitalized Adults	Institut National de la Santé Et de la Recherche Médicale, France Phase III, 3100 Subjects Four arms: Remdesivir, Lopinavir/ritonavir, Interferon Beta-1A, Hydroxychloroquine, Standard of care France Only	This study is funded by WHO and is called DIsCoVeRy in clinicaltrials.gov and SOLIDARITY trial in ISRCTN registration. The interim results were published in a paper "Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results". It concludes "These Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials." The results were disputed by the manufacturer of Remdesirvir Gilead.