Clinical Updates on Potential COVID-19 Treatments

We are back where we started.

The remarkable outpouring of medical information that we are seeing with the coronavirus disease 2019 (COVID-19) pandemic is unprecedented. Clinical trials are ongoing all around the world on treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Also, at last count, there were 200 vaccines in various stages of development.

Two of the most reported on agents to treat the infection have been hydroxychloroquine/chloroquine and remdesivir. These drugs have been the victims of a rush to develop an effective treatment.

Trials have been poorly designed, often lacking control groups or enrolling small numbers of patients. To date, there is no convincing evidence to recommend or not recommend use of these treatments for severe COVID-19 disease, with at least 113 trials in progress.

In 2 small, uncontrolled studies from China, both hydroxychloroquine and chloroquine were reported to be effective against SARS-CoV-2. The findings were weak, lacked scientific scrutiny, and were poorly received by the medical community. Yet, because there was nothing else to use, the drugs generated considerable scientific and public interest.

In a world in which the half-life of news about the pandemic is fleeting, it has become difficult to keep up with what is happening. To the practicing physician, it is a nightmare to keep up with the scientific developments and the demands of patients who are often ill-informed about what is true.

It has not been helpful that there has been public disagreement among top government officials about what treatment options are viable for COVID-19. These types of discussions have traditionally not played out on television, but rather in boardrooms and laboratories not open to the public.

As of April 1, 2020, there were as many as 33 trials ongoing with hydroxychloroquine, with or without azithromycin. By April 14, 2020, Oxford University reported 114 studies, mostly unblinded.

At that time, 5 trials had been published using hydroxychloroquine or chloroquine with or without other agents: an open-label non-randomized trial in which patients were given hydroxychloroquine or hydroxychloroquine plus azithromycin; an open-label, randomized, placebo-controlled study of hydroxychloroquine; and 3 other studies, 1 a randomized comparison of hydroxychloroquine with standard care, 1 a case series, and 1 an observational study designed to emulate a randomized, controlled trial in 181 patients.

Oxford commented on the trials that had been completed and placed in the public domain. The first trial to gain notoriety was from France (Gautret et al. Int J Antimicrob Agents 2020 Mar 20: 105949).

• Thirty-six patients, 6 treated with hydroxychloroquine 600 mg daily plus azithromycin 500 mg day 1, 250 mg days 2 to 5. Fourteen treated with hydroxychloroquine alone, 16 patients in control arm. Six patients were lost to follow-up. In addition, 5 patients on hydroxychloroquine had events during the trial, 3 went to ICU, 1 died, and 1 dropped out due to nausea.
• It was not possible from the record to tell what the difference in viral loads were between the treatment and control arm at the beginning of the trial. In some cases, no viral testing was done in controls.
• Only 1 point in time were tests for the presence of virus done. This was done on day 5. The reported results were negative in 3 of 9 patients in the control arm and 12 of 19 in the treatment arm.
• When you look at the numbers, 19 of the 20 patients in the treatment group were counted (1 died). In the placebo group, 12 out of 16 were counted. There were 6 patients lost to follow-up but 2 must have been subsequently counted.

The researchers reported this as a positive study, but there were several problems identified.

• Adverse effects were not recorded.
• Only 1 data point was used to check for viral presence. In the study, there were 3 subjects who were negative and then turned positive.
• The viral loads were incompletely reported and the methodology was not consistent.
• Despite the claims of the researchers, the study does not muster scientific standards to call it positive. The P value was .23 using Fisher’s exact test. This P value indicates the results were not significant.

Study 2, (Chinese Clinical Trial Registry: ChiCTR2000029559) examined the efficacy of hydroxychloroquine in patients with COVID-19 in a randomized clinical trial.

• The study was poorly designed and conducted. The exclusion criteria were not maintained, leading to bias. The trial was supposed to be double-blinded but was not.
• The study design was to include adults 30 to 60 years of age but enrolled many subjects as young as 18 years of age. They did not stratify the results according to age with confounded the results. You would expect younger patients to do better than older patients.
• The control group was administered many different combinations of medications, which confounded the results.
• One endpoint used CT scans and improvement, but the results were not blinded to the radiologist.
• The study failed to achieve any statistical significance but was reported positive based on limited information, such as length of time it took for fever to decrease, reduction in cough, or CT scan improvement. The ways these outcomes were measured was unclear.

Study 3 (Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, Ling Y, Huang D, Song S, Zhang D, Qian Z, Li T, Shen Y, Lu H) was a pilot study of hydroxychloroquine in the treatment of patients with COVID-19 (Journal of Zhejiang University March 2020. DOI:10.3785/j.issn.1008-9292.2020.03.03).

• Thirty patients with mild disease were randomized to receive hydroxychloroquine plus standard treatment versus standard treatment. After 7 days, throat swabs were negative in 13 hydroxychloroquine patients and in 14 usual care patients.

Study 4 was titled “No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection” (Molina et al. Médecine et Maladies Infectieuses 2020; in press. doi:https://doi.org/10.1016/j.medmal.2020.03.006).

• Eleven patients all treated with hydroxychloroquine plus usual care. One patient died and 1 patient withdrew for QT prolongation. After 5 days, 8 of the remaining 9 patients were still positive for the virus.

Study 5, titled “No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial” (Mahévas et al. medRxiv 2020 https://doi.org/10.1101/2020.04.10.20060699), was the best designed study of the published trials.

• The study authors concluded at the end of the trial that, “These results do not support the use of hydroxychloroquine in patients hospitalized for documented SARS-CoV-2-positive hypoxic pneumonia.”

We had 5 published studies as of April 14, 2020. Hydroxychloroquine failed to show significant benefit in mild disease, patients with pneumonia, and patients with serious disease. None of these trials addressed the significant adverse effects that hydroxychloroquine and azithromycin can both cause, including prolonged QT leading to fatal arrhythmias.

In light of the above, on April 22, 2020, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, specifically advised not using these 2 drugs to treat SARS-CoV-2 except in clinical trials.

An expert panel from the National Institutes of Health issued treatment guidelines, including the use of masks, issues related to mechanical ventilation, and the use of medications. With regard to medications, the panel said there is no indication that antibiotics should be used.

Corticosteroids in ventilated patients without acute respiratory distress syndrome should not be used. There was insufficient evidence to recommend for or against immunomodulating therapy in patients with severe disease.

In mild disease, the risk outweighs the benefits. Low dose corticosteroids can be used in patients with refractory shock. Without mentioning hydroxychloroquine, chloroquine, or remdesivir by name, the panel did not recommend or not recommend their use in severely ill patients. Recent conflicting results about remdesivir have many researchers recommending against its use until more trials are completed.

I spoke with several researchers at Rutgers Medical School who are conducting trials with hydroxychloroquine and they had no plans to discontinue their trials that are in progress and don’t have any preliminary data to report.