There was no clinical benefit to hydroxychloroquine (HCQ) as COVID-19 pre-exposure prophylaxis among a small sample of hospital-based healthcare professionals, a randomized trial stopped early for futility found.
Participants randomized to receive HCQ daily for 8 weeks had no significant difference in infection rates versus those randomized to receive placebo (6.3% vs 6.6%, respectively, P >0.99), reported Ravi Amaravadi, MD, of the University of Pennsylvania in Philadelphia, and colleagues.
While median change in QTc baseline did not differ, overall adverse events were significantly more common in the HCQ arm than the placebo group, the authors wrote in the study online in JAMA Internal Medicine.
They noted that the trial enrolled 123 participants of a planned 200, but was terminated early for futility. After the second interim analysis, when 100 participants completed the study, four HCQ participants and three placebo participants converted to positive SARS-CoV-2 status, so the data safety monitoring board recommended early termination of the study.
HCQ has been out of the news recently, but researchers pointed to a study examining the drug as post-exposure prophylaxis with a 5-day course. While it did not demonstrate clinical benefit, the authors noted key limitations to this trial — namely that the primary outcome was “symptoms consistent with infection” and that most patients did not have infection assessed via reverse-transcriptase polymerase chain reaction (RT-PCR) testing. This raised concerns about type II error from asymptomatic participants, the researchers said.
They sought to examine daily HCQ as pre-exposure prophylaxis in hospital-based healthcare workers via RT-PCR testing of nasopharyngeal swabs, as well as serologic antibody testing from participants at baseline and at 4 and 8 weeks of treatment.
The Prevention and Treatment of COVID-19 With Hydroxychloroquine (PATCH) trial took place at two teaching hospitals in Philadelphia from April 9 to July 14. Hospitals had uniform policies regarding healthcare worker use of personal protective equipment, including masks, eyewear, and gowns and screening patients for COVID-19 symptoms.
Eligible participants included physicians, nurses, certified nursing assistants, emergency technicians, and respiratory therapists who worked 20 hours or more per week in hospital-based units, had no history of SARS-CoV-2 infection nor COVID-19 symptoms in the 2 weeks prior to enrollment.
The primary outcome was the rate of conversion to SARS-CoV-2-positive status via nasopharyngeal swab during 8 weeks of study participation.
The 132 initial participants who were randomized were a median age of 33, almost 70% were women, and 83% were white. More than half worked in the emergency department, while 37% worked in the internal medicine ward. About two-thirds of participants were nurses, while 21% were physicians.
Overall, 64 participants in the HCQ arm and 61 in the placebo arm were evaluable for the primary outcome, the authors noted, though 12 HCQ participants and 10 placebo participants discontinued study treatment early.
There were eight infections throughout the study period, none requiring hospitalization. All were either asymptomatic or had “mild disease and fully recovered.”
At the end of the study period, the authors noted, four SARS-CoV-2-positive participants treated with HCQ versus three treated with placebo had an IgG antibody against SARS-CoV-2.
The safety arm was comprised of 65 participants in each arm who took at least one dose of the study medication, with a significantly higher percentage of adverse events among those who took hydroxychloroquine versus placebo (45% vs 26%, respectively, P=0.03). HCQ participants also reported significantly increased diarrhea versus placebo.
However, there were no differences in cardiac events, such as syncope and arrhythmias, and no significant difference in QTc between the two groups.
Limitations to the data include insufficient power, due to the small sample size, meaning that the researchers could not “exclude the possibility of an undetected modest potential prophylactic effect of hydroxychloroquine.” In addition, the team could not quantify the frequency or timing of participant exposures to SARS-CoV-2.
“We cannot recommend the routine use of hydroxychloroquine among [healthcare workers] to prevent COVID-19,” the authors concluded.
This study received philanthropic donations from Leonard and Madlyn Abramson and Mark and Cecilia Vonderheide.
Amaravadi is the scientific founder and holds equity in Pinpoint Therapeutics. He is co-inventor on patents covering autophagy inhibitors for cancer and a consultant for cancer-related programs at Sprint Biosciences, Deciphera, and Immunaccel. Co-authors disclosed support from Becton Dickinson, Gilead, and royalty income from patents licensed to Novartis unrelated to hydroxychloroquine.