Open Forum Infectious Diseases PODCAST

How to Conduct a Clinical Trial During a Pandemic—An Interview with Dr. David Boulware The audio file is also available at: pages/Podcasts

Open Forum Infectious Diseases® © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]  DOI: 10.1093/ofid/ofaa277

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In episode 30 of the OFID podcast, OFID Editor in Chief Paul Sax, MD, speaks with David Boulware, MD, MPH, about the large, double-blind, internet-based trial he and his team conducted finding hydroxychloroquine is no more effective at preventing COVID-19 infection than a placebo. Hello. This is Paul Sax. I’m editor in chief of Open Forum Infectious Diseases (OFID), and this is the OFID podcast. And as a reminder, that’s O-F-I-D and not “Oh-fid.” Today I  have with me Dr. David Boulware, professor of medicine at the University of Minnesota. And for those of us in the ID [infectious diseases] / HIV [human immunodeficiency virus] world, perhaps best known for leading the important clinical trial of early versus deferred antiretroviral therapy in people with HIV-related cryptococcal meningitis. That study was published in The New England Journal of Medicine in 2014, but that’s not why he’s here with us today. I’ve invited him on to discuss another remarkable study he led, also published in The New England Journal of Medicine just recently. It’s a placebo-controlled trial of hydroxychloroquine for prevention of COVID-19 [Coronavirus Disease  2019] in people with high-risk household or occupational exposures. The study was negative – hydroxychloroquine did not prevent COVID-19 more than placebo – but nonetheless was truly innovative in how it was conducted. We’ll come to the study in more detail momentarily, but first, David, thank you for joining us. Paul, thank you for inviting me to be here. So start us off by telling us a bit about yourself. How did you get into medicine in general and into ID and clinical trials specifically? So I grew up with a sister with juvenile rheumatoid arthritis, sort of in a medical household, I guess. This is back in the ’70s and

’80s when there wasn’t a lot of therapy for rheumatoid arthritis. I  was always interested in medicine and helping other people, and that’s what drove me toward going to medical school. And clearly infectious diseases is the most exciting aspect of medicine, so why wouldn’t someone want to be an ID doc? I have no idea. I certainly understand the appeal myself, but if you talk to an orthopedic surgeon, they might disagree. Perhaps. So in medical school, I  gravitated toward travel medicine and wilderness medicine. I  did a study on injuries and illnesses of Appalachian Trail backpackers, which basically was a good reason to go hiking on the Appalachian Trail for the summer. And then did some other fun stuff on jellyfish sting inhibitors in a randomized trial, and did a randomized trial on permethrin-treated tents at a Boy Scout camp to decrease mosquito bites... a number of fun little trials as a medical student and as a resident. So you’re a clinical-trialist, and you’re generally an HIV and a TB [tuberculosis], and fungal meningitis researcher. Let’s talk now about the hydroxychloroquine post-exposure prophylaxis trial. Where and when did you get the idea to do it, and how did it come about? So on March 8th, I  was in DC and I  was getting ready to head to Boston for CROI [Conference on Retroviruses and Opportunistic Infections], and that was canceled and became a virtual conference as everyone knows. When I  came back to Minnesota on March 9th, I gathered my team together and we had four days on our calendars which were relatively open, which is quite unusual. So that morning we gathered everyone together, and at that point spread was happening of COVID in the community. It was very apparent that it was going to get much worse. So I had emailed someone at NIAID [the National Institute of Allergy and Infectious Diseases] about whether anyone was doing anything about prophylaxis, particularly post-exposure prophylaxis, for healthcare workers or household contacts who were exposed to COVID. The answer was no, that they were working on the remdesivir trial and working on rolling that out as quickly as possible. But as we sort of all stand around and say, “Yeah, someone should do something about that.” I  said, “Well, maybe that’s us.” And I  gravitated toward chloroquine and hydroxychloroquine because I knew that they were available. They’re obviously FDA [U.S. Food and Drug Administration] approved, they’re inexpensive, and I  knew that they had in-vitro antiviral activity against a number of different viruses, including HIV. So it’s one thing to think about doing a clinical trial, it’s another thing actually to pull it off. Tell me a little bit about

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have to find out about the trial, go online, enroll in the trial, and then we’re FedExing drugs to their house. So our major concern was that people would just say, “Thank you for the drug,” and take the drug and not actually fill out any surveys. So as part of the screening process, we did ask, particularly for the household contacts, who was their contact, what was their name, where were they exposed. We asked what hospital they had PCR [polymerase chain reaction] testing. For healthcare workers we asked where they worked and what they did; the zip code of where their hospital was. We didn’t ask the name of the patient they were exposed to for HIPAA [Health Insurance Portability and Accountability Act] reasons, but we collected a fair amount of information. We asked for next of kin, who should we talk to if they got sick or hospitalized. So people had to provide a number of different pieces of information as well as fill out the screening criteria correctly that would make them eligible for the trial. So I  think we screened out most people, we didn’t get any Bart Simpsons from Springfield, but we did have some 555 phone numbers and a couple of people that were a little bit phony. We were able to screen those people out as well. Obviously there would be some people maybe who weren’t real, but they would balance out in the two arms of the study. That is the beauty of the randomized trial. For most people I  think they were pretty serious. If people just wanted hydroxychloroquine you could just write a prescription or have someone write a prescription for you and take it. And be twice as likely to get the real drug. Yeah, you are twice as likely to get the real drug that way. So if you were to randomize and say, “Man, am I  going to get a vitamin or I’m going to get hydroxychloroquine?” If people really wanted hydroxychloroquine they were probably not going to enroll in our trial. But that is the beauty of a randomized trial in that if we had fake people or people that got lost to follow-up because they didn’t really want to be in the trial, they got equally balanced between the two arms. And you decided to go with a syndromic definition of COVID-19 for the people participating in the study. How how’d you make that decision? Well, the president said that everyone could get a PCR test. We actually thought when we designed it in early March, “Yes, testing was a major problem, but surely this is going to get better.” But we realized, “Well, maybe that’s not going to happen.” So we decided ideally people would get PCR testing, but if PCR testing was not available, then we were going to go with a syndromic definition for those who were not tested. That was really a very wise move. Because as you’re aware, even though testing did increase hugely in March, it was still quite limited. And a lot of people decided that if they had symptoms of COVID, they would stay home and not come in and get tested unless they were really sick. So a very important decision on your part.

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how you formulated the study design. How’d you get to decide your eligibility criteria, your end points? What were the next steps? So I did a chloroquine trial actually back when I was an ID fellow looking at HIV, and this is back in 2007. We were looking at changes in immune activation and things like that. It basically decreased immune activation and it didn’t really do much else, but I did have my protocol still. So I pulled that out and I went back and thought, “Well, what are all those inclusion and exclusion criteria?” which were still valid for the most part, and thinking about who we would want to include. We were trying to get high risk people. So we thought about healthcare workers with a high-risk exposure without PPE [personal protective equipment], or without full PPE anyway, as well as people with household contacts where one person in the household has COVID, and the other person is told to self-quarantine. So basically, we were going to target those people to enroll. And then the question was, well, how to do it? Exactly. This is where the study becomes, in my mind, remarkably innovative. How are you going to do this study? Well, we didn’t have any money. Necessity is the mother of invention, is the saying. I  had a little bit of funds that I  had squirreled away for a rainy day. So the first step was basically see what was in my account and buy some hydroxychloroquine. So we bought about $5,000 worth of hydroxychloroquine because we figured if this is the one active drug in-vitro and coronavirus explodes in the U.S. – as it did – there’s likely to be a drug shortage. So could we even get the drug was question number one. Then we decided to do an internet-based study. At the time there were very few cases in Minnesota, that has since changed. But we thought, let’s enroll everywhere around the U.S. and see if we can get particularly healthcare workers and others who might be exposed to enroll in an internet-based trial. Wow. To me, the brilliant insight here was to realize that you could do it by the internet. That’s obviously how we’re all connected these days, especially after COVID hit, because many of us are communicating extensively online. But did you worry about things like IRB [Institutional Review Board] approval and how to get the medicines to the patients, and whether the patients were going to be real...? Yes - lots of concerns. So for most of our work we work in Sub-Saharan Africa, so we’re used to doing everything ourselves. As an investigator-initiated protocol, we were able to do everything ourselves of going through the IRB and putting together the FDA investigational new drug application submission, worked through all the parts relatively quickly because we have a team that’s been together for almost a decade now. The questions of, “How would people react? Were people real?” We figured that we have pretty a motivated audience to

Yeah. So what surprised you most about doing a study like this compared to the other trials you’ve done, or just doing research in general? The hardest thing was the outside influences. Usually there’s not a lot of outside influences in Africa – there’s not people tweeting about it and upset about your trials and things like that. I  don’t recall too many cryptococcal trials that have been denounced in social media. But the trial itself ran fairly smoothly. Our lost-to-follow-up rate was under 10 percent, better than what we thought it was going to be. We thought we’d get a lot of flaky people on an internet-based trial, but most people were pretty serious and had pretty good follow up, completed most of the surveys as we asked them, and were pretty appreciative of us trying to find an answer. So it’s a negative study, as I  mentioned at the outset. Do you think this is the final word on hydroxychloroquine for prevention of COVID, or is there still a glimmer of hope there? For post-exposure prophylaxis, the question is, why didn’t it work? There’s probably two reasons – one is either it just doesn’t work, or the other option is we just didn’t get it to them quick enough. So if you read the tea leaves and look at the subgroup analyses, the people that got enrolled within one or two days of exposure did better than the people that did three or four days later. So maybe there’s a glimmer of hope there. So I’m not totally down on hydroxychloroquine, but I think clearly, based on our trial, post-exposure did not seem to work. There’s another unpublished trial in Barcelona that reportedly is a negative study. Then the hospital data has clearly been quite mixed, and the Recovery Trial in the UK [United Kingdom], as a large, randomized, controlled trial, fairly definitively said that in hospitalized patients, there’s not any benefit for hydroxychloroquine. Sure, that’s a treatment study. It’s interesting to think about taking antimalarials as pre-exposure prophylaxis. Of course, that’s something that people do all the time when they travel to malaria endemic countries. Correct. There’s a massive safety track record with that, so it’s not really a safety concern, but does it work? What criticisms have you heard from people, both within and outside of the scientific community? The criticisms within the scientific community have not been dramatic. The biggest criticism and limitation of our paper, which we acknowledged, was the lack of PCR testing. For those who were practicing medicine in March and in April, you realize that PCR testing, especially among outpatients, was a major problem. There wasn’t much we could do about that, so based on how we ran our trial, that was as a limitation. But if you’re exposed to a PCR positive person, and then you develop fever, cough, shortness of breath within a week or two, is that

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And even here in Minnesota, we didn’t really start testing outpatients until May. So in March it was pretty limited. In April for hospitalized patients it got a lot better, and the turnaround time was slightly better and healthcare workers were starting to get tested in April. But the general public really wasn’t eligible for outpatient testing until really May. So by that point, our trial was done. Our testing situation here was better than a lot of places, I  think. Because most people, even if they were healthcare workers, didn’t have access to testing within our trial, which shocked me. The fact that only 20 percent of people had access to testing who got sick. So how was the pace of enrollment, and any obstacles along the way – anticipated or otherwise? The pace was explosive at first. We went from six patients to 20, to 50, to almost 100 a day. Things were quite rapid over the first two weeks or so. Then it was about two days into our trial, the president started talking about hydroxychloroquine, and then more people were starting to talk about it. It rapidly became a very political topic during the first weeks of April. Then our enrollment fell off dramatically. Maybe that’s because of the lockdown and COVID went down, but the national cases didn’t go down that much. So rapidly it became a very political issue, which was very unfortunate for our trial. As I’ve said before, half the people thought that it worked, so it was unethical to be in a trial that randomized half the people to placebo. The other half of people, by mid-April, thought it was a dangerous medicine that had all these major cardiac risk factors. If you took it you were going to die of a cardiac arrhythmia. That wasn’t quite true either. They thought it was unethical to be in a trial with hydroxychloroquine, and soon no one wanted to be in any hydroxychloroquine trial. The enemy of science here is politics. Yeah, the politicization was not a good thing, and I  would have preferred that no one ever talked about our trial outside of the medical community. But we live in the world that we live in. So it became a very partisan issue and by basically mid-March, our enrollment trickled off to just a handful. When the FDA sent out an announcement on the dangers of hydroxychloroquine on April 24th, after that we enrolled like four people and then stopped trial enrollment basically two weeks later on May 6th. But I want to remind people listening how fast you did it. You got the idea for this study in early March and you were already up and enrolling by the end of the month. This is amazing. It was pretty rapid, yeah. We started the idea on March 9th, we enrolled our first patient on March 17th, having gone through the IRB, got an FDA approval, built a database and questionnaires. That’s just extraordinary. Pretty rapid.

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working in ICU [Intensive Care Unit] or emergency departments or anesthesia or respiratory therapists or first responders. So, fairly high risk of COVID. Excellent. That’s led by one of my colleagues, Radha Rajasingham [MD] and we’re hopeful to get some data by early July with that. One major challenge in these studies is the dramatic upswings and downswings in cases, just speaking from our experience in Boston. We had several weeks where we had so many cases it was almost impossible to enroll them all into clinical trials. The volume was overwhelming. And now it’s just the opposite. The case numbers have dropped so dramatically here. I don’t know how you’re adjusting for that, or just the fact that you’ve been doing it all around the country means it doesn’t matter. Yeah. I think it was all around the country, but the places that were hotspots six weeks ago are no longer hotspots. So by going around the country, hopefully some of that is balanced out. The PCR testing has improved markedly in that trial, which is great. We’re working on a DSMB [Data and Safety Monitoring Board] report and looked at it like, “Oh, people actually are getting PCR testing now,” which is great. So we’re hopeful to wrap that up. Then I’m hopeful to get back to my crypto world – cryptococcal disease. We’ve got a couple of fun clinical trials that are in the pipeline. We’re working on the Ambition Trial, which is single-dose liposomal amphotericin trial. We’ve got an oral amphotericin product that we’re going into a phase two trial that, in theory, if it works, will be great. It may not work, so we will find out shortly if that’s a game changer or not. Once Uganda opens up in a couple of weeks, we’re going to restart the oral amphotericin trial, which we’re excited about. Well, congratulations again, David on carrying off a really impressive study. I  was thrilled to see it published. So joining me today was Dr. David Boulware. He is a professor of medicine at University of Minnesota, and he has recently completed a fascinating study on post-exposure prophylaxis for COVID-19, just published in The New England Journal of Medicine. Thanks, David. Thank you very much, Paul.

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COVID? It’s a probable diagnosis, but certainly from a syndromic, does it decrease symptomatic disease? It did not. So you could say, “Oh, people can have influenza.” Well that’s true, but in a randomized trial, people with flu would be equally randomized between the two arms. April was the end of flu season. You have a bunch of healthcare workers who are typically required to be vaccinated by their employer. So it’s possible, but it would be pretty unlikely. So, that’s the big negative side from the scientific community, which is a very valid criticism. There are certainly people that get very excited about subgroup analyses. As most clinicians and clinical trialists know that it’s easy to over-interpret subgroup analyses. We’ll eventually release our dataset this month, and people will be able to data mine and get some P value if you adjust for this, and people with purple hair that were enrolled on a Tuesday. But when you look in the overall trial there was not overt benefit. Did you get any social media attacks or any other hate mail? There’s a lot of social media stuff, and I  found that if I  just don’t log on then it’s actually much better. So there’s vast conspiracy theories circulating that I got a sandwich from Gilead in 2018, worth $17, so therefore I’m in the pocket of big pharma. There’s other just random conspiracy theories that as a double-blind, randomized, placebo-controlled trial, I designed it to fail. So it’s interesting because as a double-blind study, I had no control over it, especially as it’s mostly self-reported. So I think it’s interesting. I didn’t expect Russian trolls and other operatives to go after me personally, but I’ll survive. Okay. So what other work is your group doing? So we’ve got two more COVID trials. One is an early treatment trial, a companion trial to this of people who had symptoms within four days. So that trial has been completed. It’s been analyzed. It’s not a perfect trial, so if people didn’t like the fact that people didn’t get PCR tested in the first trial, they may not like this one either, but I think it’s informative. Then the third trial is a PrEP [pre-exposure prophylaxis] study. We’ve got 1500 healthcare workers around the U.S., and they’re high-risk health care workers, so they’re not just people sitting in offices or labs, but frontline healthcare workers

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Open Forum Infectious Diseases PODCAST How to Conduct a Clinical Trial During a Pandemic—An Interview with Dr. David Boulware The audio file is also...
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