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Dear Gilead Leaders,
Congratulations on developing the antiviral remdesivir, which is now being tested for the treatment of patients with coronavirus infection. While you have had great success with antiviral drugs for HIV and hepatitis C virus infections, remdesivir could have an even greater societal benefit.
Your company has also demonstrated goodwill in the timely reporting of compassionate use of remdesivir in 61 patients with COVID-19. This series found improvement in the clinical status of 69% of patients treated with remdesivir.
The global community welcomes the fact that you will be funding randomized clinical trials of remdesivir. Obviously, the randomized trial is the best way to know whether a drug works.
This letter is to commend you for recent protocol changes to the major trial in patients with severe COVID infection but also to ask you to consider some other changes to help reduce bias and allow a clear assessment of remdesivir benefit: blinding and a placebo control.
Most clinicians welcome the decisions to increase the sample size (from 400 to 2400) and to change to a 7-point ordinal endpoint, which includes the outcomes of death, use of mechanical ventilation or extracorporeal membrane oxygenation, use of high-flow oxygen or noninvasive ventilation, low-flow oxygen, hospitalization without oxygen but other medical care, hospitalization only for protocol remdesivir, and no hospitalization, assessed on day 14.
[For those unfamiliar with the ordinal outcome endpoint, it’s often used in clinical trials of antiviral agents in hospitalized patients with influenza to increase statistical power relative to time-to-event endpoints because the follow-up in flu trials is short.]
This endpoint provides for the maximum use of clinical information. Indeed, a reduction in patients requiring aggressive measures is an important metric. The problem is that with the exception of death, the other outcomes in this endpoint depend on clinician choice. In an open-label trial, as currently planned, this could lead to bias.
It is early in the course, and the change I propose is to add blinding. You don’t want to spend millions of dollars and end up with a biased result.
Since remdesivir is an intravenous (IV) drug, you could simply add an IV placebo infusion to the standard care. While oral placebos can be quite expensive, an IV placebo infusion would be inexpensive and easy to add to standard care.
I recognize that some would bring up the ethics of a placebo infusion. That would be easy to refute because each of the four arms of the trial feature standard care plus remdesivir vs standard care alone.
With blinding and placebo control, the findings would be more reliable because they would be free from the potential biases of clinicians—who, out of the desire to have an available treatment, may consciously or unconsciously make or delay decisions to reduce oxygen and avoid mechanical ventilation in patients in the remdesivir arm.
I reached out to Andrew Althouse, PhD, a biostatistician at the University of Pittsburgh, who agreed that without a placebo control there will be problems in outcome ascertainment and uneven patient dropout. And on the matter of analyzing a changed trial, he wrote that if the treatment effect appeared consistent during the open-label and placebo period, the results could be analyzed together, but if there was a pronounced change in magnitude of treatment effect between periods, separate analyses may be required.
As I write this letter, the number of coronavirus cases is set to exceed 2 million.
Given that hundreds of thousands of humans may die from either the viral infection or the societal interventions to stop the virus, having a clear answer on whether remdesivir works is vital.
Thank you for your consideration.
John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.
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Cite this: Dear Gilead: Please Add a Placebo Arm to Remdesivir Trial - Medscape - Apr 13, 2020.
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