Matthew F. Pullen, MD, co-author of the recent hydroxychloroquine prophylaxis trial, shares the top clinical takeaways.
Segment Description: Matthew F. Pullen, MD, infectious diseases and international medicine physician at the University of Minnesota and one of the investigators on the recent hydroxychloroquine prophylaxis trial, speaks with Contagion® about the clinical takeaways from the study, as well as what COVID-19 data will be published next.
Interview transcript (modified slightly for readability):
Contagion®: Hi, I’m Allie Ward, editorial director of Contagion®, and joining me today is Dr. Matthew Pullen from the University of Minnesota.
He was part of the team running the first randomized clinical trial of hydroxychloroquine for the post-exposure prevention of COVID-19. The team’s results were published yesterday in the New England Journal of Medicine.
Dr. Pullen, we know the trial showed no significant difference in the risk of infection following exposure in those taking hydroxychloroquine and those taking placebo, but can you explain in a bit more detail about the major clinical takeaways from this study?
Matthew Pullen, MD: This study was very specifically looking at the role of hydroxychloroquine in preventing infection in people who had recently been exposed to someone with SARS-CoV-2. We have similar protocols in health care workers who have needle sticks from patients who have HIV and hepatitis C where we provide them with specific medications very shortly after the exposure in the hopes of preventing the infection. There were some in vitro data suggesting that hydroxychloroquine might play a similar role for this infection. But what we found was that it did not prevent infection when provided within 4 days of an exposure in any of our participants. There was no statistically significant difference between the placebo group and the hydroxychloroquine group. The main takeaway would be that it's, at least for postexposure, not an effective preventative medication.
Contagion®: Can you walk us through the study design and methodology? How did you select participants, and how were they dosed?
Pullen: This is a randomized, double-blind, placebo-controlled trial—kind of the gold standard for strong clinical and medical evidence. We knew we wanted to pull from a large sample size to strengthen our power and that kind of necessitated recruiting from all over the country, especially back in March when the numbers hadn't really spiked just yet in our region. Due to that, we decided to use an online system called REDCap. It's a means of capturing survey data from participants directly. We reached out to colleagues and other universities, colleagues that were clinicians in other communities. We used social media to try to bring attention to it. We got a lot of media attention early on, which was great. We made sure to always have our website address or an email address mentioned in all the media, and you guys certainly helped with that early on. We got a lot of attention from that, a lot of participants have emailed us saying they'd seen the Contagion® webinar, or they'd read about us on CNN, or Dr. Oz. It was a unique way to run it study, but it was very cool. I’m a huge tech nerd and programmer myself, so anytime I can use technology for something like this is great.
We recruited from all over, and then we randomized participants either receiving 5 days of hydroxychloroquine or placebo, as long as they met enrolling criteria for the study. We mailed them the drug by FedEx overnight so, within 48 hours of enrolling, they received the package with medication and instructions. After that, we sent them follow-up surveys on days 1, 5, 7, 10, and 14, asking them about if they've received any testing and what the results were, what their symptoms have been lately, if they've had adverse effects from the reactions, and if anyone around them has been sick, so we try to get as much information as we could at every time point.
Contagion®: And these were primarily health care workers or people who had been exposed virus in their home, right?
Pullen: About two-thirds of the people were health care workers, which is understandable given they're the ones seeing the most SARS-CoV-2 and being exposed to it the most. We also had a pretty decent number of people who had household exposures, people that were caring for a loved one or whose loved one was a health care worker and got sick and brought it home. [It] was interesting to see that mixture as well. After following them for 2 weeks each and reaching our target power, or target sample size rather, we performed our analysis, and that's when we were able to publish.
Contagion®: Do any of the investigators hypothesize that a longer duration of post-exposure HCQ would yield a different result?
Pullen: I would never give a concrete “no” to something like that, but I would say that the evidence is probably against it in that sense. With postexposure prophylaxis, you're really in a race against time fighting the replication speed of the virus. You want to kind of head it off at the pass and find something that will combat the virus before it reaches a large number of viral particles in the body. If you can't do that in 5 days, 10 days probably won't make too much of a difference; your body is likely clearing a good deal of that within 5 days and the prophylaxis is meant to aid in that process. Like I said, I would never say a concrete “no.” [It’s] probably worth the study, but I would think that 5 days is probably long enough to have seen an effect.
Contagion®: Was your team surprised by the results?
Pullen: I think, throughout the process, most of us had kind of mixed feelings. We weren't sure how it was going to pan out, especially as some of these observational studies started coming in, some positive, some negative. With a lot of them, it's hard to really tell what to make of the data due to the inherent issues with observational studies, and then some of the issues within those studies themselves. So seeing that kind of mixed bag of results from other studies made us feel like each outcome was probably equally likely. But it was nice to get a pretty solid answer rather than something that was borderline.
Contagion®: Were there any limitations to your trial?
Pullen: Yeah, certainly. Probably the main limitation is the same one that everyone's facing, [which] is the lack of testing in the United States, especially early on. We launched this study in mid-March and, at that time, even health care workers weren't able to get tested. A large portion of our population used the US case definition to decide if they were likely coronavirus or not when they were recording symptoms after taking prophylaxis. It is a limitation that we didn't have confirmed PCRs for everyone, whether negative or positive. But unfortunately, that was just the reality we were all living in and, to some extent, still are living in in a lot of areas.
Another limitation is that all of the symptoms were patient-reported. Given that it's an online study, we weren't physically seeing every person and assessing them ourselves through physical exam. There's always flaws in recall and the subjectivity of reporting symptoms so that that's a limitation as well. But both with the lack of testing and with the self-reported symptoms, feel like the randomization means that any issues are likely equally distributed in both the placebo and the treatment group so it probably didn't affect the analysis too much at all.
Contagion®: Were there any adverse effects among the study population taking HCQ?
Pullen: The hydroxychloroquine group definitely reported gastrointestinal upset more, which is to be expected. Hydroxychloroquine certainly has a reputation for doing that. And we started with a loading dose the first day, so a higher dose, so certainly to be expected that there might be some nausea and diarrhea with that. Beyond that, we didn't really see that many adverse effects reported. We didn't see any serious adverse effects, no cardiac issues or anything like that, which we kind of expected that as well. Most of us in the group have a decent amount of experience both prescribing and taking this medication, mostly for malaria. We've all experienced the GI upset issues, but the cardiac issues really are more when it's in combination with other QT-prolonging medications. We were pleased to see that held up in our study as well [and] we didn't see anyone having heart issues from the medication.
Contagion®: What’s next? Are there plans for future studies?
Pullen: We've wrapped up our preemptive treatment trial. We're working on the analysis and manuscript for that and hoping to submit it soon. We're wrapping up our preexposure prophylaxis trial at the end of the month, and then we'll start working on that analysis. We've also been collecting serology or dried blood spots from all of our participants that are willing and we're going to do some serology epidemiology studies on seroconversion amongst these studies, as well. We've got plenty of work to keep us busy.
Contagion®: We look forward to discussing those results with you once they're available. Is there anything else you would like to add?
Pullen: I just want to say a huge, huge, huge thank you to anyone that participated in the study or helped spread the word or even just to email us with questions or showing interest in the study. We couldn't do any of this without all of those people. A lot of people emailed us apologizing for asking questions, but we love it when we get questions because sometimes it makes us really think and improve things. So, thank you to everyone who participated and reached out to us.