Most readers will have heard that this paper appeared in the NEJM late yesterday afternoon: it’s something that we haven’t had so far, an actual randomized, double-blinded, placebo-controlled hydroxychloroquine trial. This one was for post-exposure prophylaxis, a mode of treatment made famous by President Trump when he stated several times that he was taking the drug after people in the White House had tested positive.
It’s from the University of Minnesota, McGill, and the Universities of Manitoba and Alberta, studying 821 asymptomatic subjects, 719 of whom had reported high-risk exposures (either a spouse or other family member testing positive, or health care workers dealing directly with patients). The threshold was enrollment in the trial within three days of exposure, and people already showing symptoms (or a positive PCR test) were excluded from this trial and enrolled in a separate one (which has also concluded, with results coming soon) Participants took either a placebo (407 of them) or hydroxychloroquine (414 people, taking a loading dose of 800mg, then 600 mg 6 to 8 hours later, then 600 mg daily for four more days) and were surveyed regularly out to 14 days, with a follow-up at 4 to 6 weeks. Primary outcome was symptomatic illness, preferably confirmed by PCR, although that wasn’t possible in many instances.
The initial estimate (back in early March) was that 10% of the subjects would in fact develop disease, and the trial was powered to detect a 50% reduction in this number. The team realized that this was basically a guess at that point, and interim analyses were done after 25% and then 50% of the participants had gone through the entire follow-up to re-evaluate. Those revealed first that the infection rate in the control group was running a bit higher (13%), and at the second interim analysis (April 22) the sample size was accordingly allowed to reduce. At the third analysis (May 6) the trial was stopped for futility.
That means what you think it means: there was no statistical difference in infection rate between the HCQ group and the placebo group. On the plus side, no arrhythmias were known to develop in the former (albeit without ECG monitoring, so it would have had to have been severe), and dropout rates were basically identical in the two groups. Side effects were more common in the treatment group, generally GI discomfort. For those who are wondering, there were smaller numbers of people in both groups who were taking zinc supplements, and there was no difference between them, either. At day 14, participants were surveyed to see how well the placebo blinding was holding up (always an interesting measurement). 46.5% taking HCQ correctly identified that they were, 43.9% were unsure, and 10% of them believed that they had been taking the placebo instead. In the actual placebo group, 35.7% correctly thought that’s what they had been taking, 47.6% weren’t sure, and 16.7% believed that they got hydroxychloroquine. Participants who reported any side effects, no matter which group they were in, were 3.7 times as likely to believe that they received the actual hydroxychloroquine, understandably.
So this trial was negative, although one should remember that it could have missed asymptomatic cases. It also tended to enroll relatively healthy people, and can’t speak to any possible protection of high-risk groups. You may also disagree with the initial design to detect 50% reduction in infections, although the HCQ fans would likely have expected at least that much. But within those limits, it provides no evidence that there is a prophylactic effect. From what I can see, the biggest evidence to the contrary is this retrospective analysis from the Indian Council of Medical Research looking at health care workers in that country taking prophylactic doses of HCQ, which found a significant risk reduction. That’s not a controlled trial, of course (and its authors conclude with a statement beginning “Until results of clinical trials for HCQ prophylaxis become available. . .”), but it is worth taking into account. The arguing will continue.