University of Minnesota Medical School researchers have published the results from the first randomised clinical trial testing hydroxychloroquine for the post-exposure prevention of COVID-19. The trial results determined that hydroxychloroquine was not able to prevent the development of COVID-19 any better than a placebo. Further, 40% of trial participants taking hydroxychloroquine developed non-serious side effects – predominantly nausea, upset stomach or diarrhoea. However, the trial found no serious side effects or cardiac complications from taking hydroxychloroquine.
The randomised placebo-controlled trial, which rapidly launched on 17 March, tested if hydroxychloroquine could prevent COVID-19 infection in healthy persons after exposure to someone with COVID-19. The trial enrolled 821 non-hospitalised adults from across the US and Canada, who were exposed to COVID-19 from someone living in their same household or as a healthcare worker or first responder. Half of the participants received five days of hydroxychloroquine while the other half received five days of a placebo. The trial was a double-blind trial, meaning that neither the participants nor the researchers knew what the participants received. Participants were followed for two weeks to see who developed symptomatic COVID-19.
Overall, approximately 12% of those given hydroxychloroquine developed COVID-19 versus approximately 14% given the vitamin placebo (folate). This was not a statistical difference, and even if there was a statistical difference, this would equate to treating 42 persons with hydroxychloroquine in order to prevent one infection. There was no further benefit to prevent infection among those who also took zinc or vitamin C.
Dr David Boulware, the senior investigator of the trial and infectious disease physician at the University of Minnesota, launched the trial with the hope that an inexpensive, widely-available, oral medication could prevent or treat coronavirus early in the disease before people are sick enough to need hospital care.
“Our objective was to answer the question of whether hydroxychloroquine worked to prevent disease or did not work,” Boulware said. “While we are disappointed that this did not prevent COVID-19, we are pleased that we were able to provide a conclusive answer. Our objective was to find an answer.”
This trial launched within nine days of beginning the project through the work of a team of University of Minnesota infectious disease physicians from the medical school – Drs Matthew Pullen, Sarah Lofgren, Caleb Skipper and Radha Rajasingham; statisticians Ananta Bangdiwala, Nicole Engen and Dr Kathy Hullsiek from the School of Public Health; pharmacologist Dr Melanie Nicol from the College of Pharmacy; among many students, trainees and M Health Fairview investigational pharmacy staff. The trial was in collaboration with McGill University, University of Manitoba and University of Alberta.
“I think in the setting of post-exposure prophylaxis, it doesn’t seem to work,” said Sarah Lofgren, an assistant professor at the University of Minnesota who is a co-author of the study. Other studies of hydroxychloroquine are ongoing. Also, the World Health Organisation said it is resuming a clinical trial testing hydroxychloroquine as a treatment after pausing it over safety concerns.
“This is not the end of the story with hydroxychloroquine,” said Ashish Jha, the director of the Harvard Global Health Institute. But given the data, he said, if there is any benefit to giving the drug to prevent infection, “it’s going to be small.”
The same group of researchers is also planning to publish the results of trials testing the drug as a treatment and as a “pre-exposure prophylaxis” – that is, before any exposure to SARS-CoV-2, the virus that causes COVID-19.
Even though the study used the gold standard methodology of conducting clinical research, outside researchers saw significant limitations. The study was conducted in an unusual way: over the internet, without patients being seen by study doctors.
“It just continues to extend the case that the drug is lacking significant efficacy,” said Eric Topol, the director of the Scripps Research Translational Institute. He said that the results are consistent with small randomised trials that were conducted in China and with most observational studies. But while he said that the safety results are encouraging, he worried that the study, because of size and other limitations, might not completely rule out such issues.
Steven Nissen, a cardiologist and veteran clinical trialist at the Cleveland Clinic, was much harsher. The fact that patients self-reported their data and that one in five did not take all their doses of the study drug, as well as the study’s small size, made him less than confident that the study could entirely rule out that hydroxychloroquine had some preventative effect. He emphasized that more studies of the drug, which was widely prescribed during the initial months of the COVID-19 pandemic, have not been completed.
“Absence of evidence is not evidence of absence,” Nissen said. “Poor quality data does not help it only confuses the world. That’s exactly where we find ourselves, in a state of confusion.”
David Boulware, a professor of medicine at the University of Minnesota Medical School, said he thought up the study, which was also far cheaper to run than a conventional clinical trial, precisely because he saw a need to get something done with minimal resources.
Robert Califf, the former US Food and Drug Administration commissioner who now works at Alphabet, said there were “lots of flaws” in the study but it was still “a great effort,” providing the best evidence yet about hydroxychloroquine’s utility. He said he would favour doing another study with viral testing. The dozens of other clinical trials being conducted may give a clearer answer.
Background: Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.
Methods: We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.
Results: We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was −2.4 percentage points (95% confidence interval, −7.0 to 2.2; P=0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
Conclusions: After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure.
David R Boulware, Matthew F Pullen, Ananta S Bangdiwala, Katelyn A Pastick, Sarah M Lofgren, Elizabeth C Okafor, Caleb P Skipper, Alanna A Nascene, Melanie R Nicol, Mahsa Abassi, Nicole W Engen, Matthew P Cheng, Derek LaBar, Sylvain A Lother, Lauren J MacKenzie, Glen Drobot, Nicole Marten, Ryan Zarychanski, Lauren E Kelly, Ilan S Schwartz, Emily G McDonald, Radha Rajasingham, Todd C Lee, Kathy H Hullsiek