With the current coronavirus pandemic and the possibility of repurposing medications for treatment, understanding clinical trials is critical. Most people who have not conducted or participated as a subject in clinical trials, including our president, have little or no knowledge of what they entail, how they are conducted, and their critical importance. Over 45 years, the author has conducted more than 100 clinical trials, including designing trials and obtaining regulatory approval for many.
The process of evaluating a medication begins with Phase I trials that determine safety. These were completed decades ago for hydroxychloroquine. Phase II trials establish whether or not the medication is effective for the intended disease and determine the appropriate dosing. Phase III trials are then conducted to provide more information, typically in 500-1,000 patients.
Clinical trials must be registered at clinicaltrials.gov and approved by an institutional review board, an organization established and accredited to protect the human subjects who participate in clinical trials. After being informed about potential benefits and harms of the trial, each subject must sign an informed-consent form approved by the review board, in order to participate.
Although a medication approved for one disease, may be prescribed βoff labelβ for a different disease, there are multiple unknowns if this is done without clinical trials. Information obtained from a clinical trial includes efficacy, safety and appropriate dosing. At this time, the approved doses of hydroxychloroquine vary from 400 mg once weekly as prophylaxis (prevention) for malaria, to 2,000 mg over 48 hours for treatment of malaria. For rheumatoid arthritis, the approved doses are 400 to 600 mg daily, and for systemic lupus erythematosus (lupus) 200 to 400 mg daily. In order to treat COVID-19, without a clinical trial, how would the appropriate dose be chosen?
Decreased kidney and liver function, which occur with aging and multiple diseases, increase the likelihood of adverse events and require a decreased dose of many medications. At least 11 drugs and drug classes can have harmful interactions with hydroxychloroquine. Adverse events associated with hydroxychloroquine involve the following body systems: musculoskeletal; skin; blood and lymphatic; cardiovascular; ears and balance; eyes; gastrointestinal; liver; immune; psychiatric; and nervous system. Examples include rashes, bone marrow damage, nausea and vomiting, liver failure, muscle damage, psychosis, suicide, seizures, blindness due to retinal damage, heart failure, life threatening arrhythmias, and death.
Clinical trials of hydroxychloroquine as treatment or prevention of COVID-19 should include several different doses as well as placebo treatment, in order to evaluate efficacy and the best dosage regimen. In a setting where cases are numerous, enrollment could be completed in a few weeks. The duration of treatment could be as short as two to three weeks, since that is the usual duration of the illness. Thus, a trial could be completed in one to two months. Twenty-one trials of hydroxychloroquine for prevention or treatment of COVID-19 are currently registered on clinicaltrials.gov.
The president states that βyou have nothing to loseβ by treating now with hydroxychloroquine. If the function of your nervous system and your heart, or your life itself are βnothing,β then he is correct.
Understanding the basics of clinical trials, and the fact that these could be completed quickly for treatment of COVID-19 with hydroxychloroquine, makes it clear that waiting for the results of clinical trials for this disease is appropriate.
