In this week’s special episode of The Weekly Dose Podcast we interview Dr Tobias Janowitz, a medical oncologist, assistant professor at the Cold Spring Harbor Laboratories and adjunct professor at the Feinstein Institutes. Dr Janowitz was part of a team that recently conducted a phase 2 clinical trial assessing high doses of famotidine in adults with COVID-19. The trial was conducted completely remotely and the findings were published in Gut. As well as discussing their findings, Dr Janowitz talks about the process of conducting a fully-remote trial and the greater possibilities this may hold for future clinical research.
MPR: Your recent phase 2 study which was published in Gut, investigated a high dose of famotidine which was available over-the-counter, in patients with mild-to-moderate COVID-19. Can you give me a short synopsis of your findings from this study?
Dr Janowitz: Yes. That is correct, Steve. That is what we investigated, so the executive summary of that study is that the treatment was well tolerated in these patients, that we were able to deliver the trial fully remotely, and that we found the signal that patients seem to recover earlier from their symptoms. But that was the secondary endpoint, the primary endpoint was not met, and it was a key secondary endpoint where we saw the signal and in addition, we saw biological signal indicating that inflammation resolved sooner in the patients who were taking famotidine and that inflammation and symptoms were correlated so that presumably patients got better sooner because their inflammation settled down sooner.
Okay. And you said briefly there that the primary endpoint was not met actually. Can you just define what the primary and secondary endpoints were?
That is correct. We had designed a study which would trace patient-reported outcome measures, so patients would supply us with data on their symptoms across different symptoms, 17 in total that we would score from 0 – not existing at all, 1 – mild, 2 – moderate, 3 – severe, and they then had a total symptom score every day, and we would trace the symptom score on a daily basis, and we defined the primary endpoint in concordance with FDA negotiations that was classified as day of symptom resolution when the total symptom score was below 3 or less. So then we could estimate a time to symptom resolution and that was not statistically significantly different between the arms; however, we also proposed in the pre-stipulated protocol to model all the data and then we had far more data to analyze, 1356 data points where we can essentially model the rate of symptom resolution. So how quickly do people get better or how soon they reached 50% symptom resolution and that was eight days in the famotidine arm and 11 days in the placebo arm and that is statistically significantly different with a highly significant p-value.
Can you talk a little bit about what the instigator was for your famotidine study, to study famotidine in particular, and what were the known processes of how famotidine downgrades inflammation in COVID-19?
Yes. That is a great question. So we had in the run in when the pandemic first emerged, there were data available that patients on certain medications seem to have a milder course of the disease, and famotidine was one of those medications. That is retrospective data. So the patients who were already taking the medication for other indications, as you know famotidine is taken to treat gastroesophageal reflux disease. When those patients acquired COVID, they seem to have a slightly better outcome, but those data were not unequivocal and they are also retrospective analysis, so they are not clinical gold standard studies. They are an indication of interest, if you wish. We had a small K-series where patients who had taken famotidine, and they also seem to get better sooner and then from labs at Cold Spring Harbor, and including my own lab and labs elsewhere in the world, there were mechanistic data emerging of how famotidine could be affecting the course of the disease, in particular that it was down-regulating inflammation via its cognate receptor, the H2-receptor and through down regulation of toll-like receptor-mediated inflammation and ultimately down regulation of cytokine release and you may know that cytokine release is what causes unwellness and illness in patients with COVID, sustained cytokine release, also known as cytokine storm in the severe cases. So we had mechanistic indications and some clinical indications. So we felt we were justified to design and execute randomized double blind placebo controlled early phase clinical trial with biological endpoints, which is what our study is. It is a phase 2 trial, and it has biological endpoints. In other words, it was never designed to change clinical practice, but it was designed to inform, per the clinical trial, how they should be conducted and if there was value in conducting further trials or not.
Okay. And your trial was conducted fully remotely and can you talk a little bit about the process of how participant monitoring was carried out?
Yes. And thank you for asking that question. That is really something that we are really excited about because we were able to take the trial to the patient rather than bringing the patient to the trial and that method has plasticity. We could use that in diseases other than COVID in the future, and indeed we are planning do so as you said in the introduction I am a medical oncologist by education and a scientist, so I was able to pivot to COVID trials for the purpose of this trial, but I am committed to study cancer in the future, and it is very important that we can bring trials to patients and democratize the access to clinical trials. The way that we did this was, we were screening patients and if they were eligible, we would approach them for informed consent, and if they had given consent via telephone call, we would ship to them with overnight delivery a trial kit which would have all the equipment so that they can do the at-home monitoring, measuring their weights, their respiratory function, their pulse oximetry, and that they could report daily their symptom scores using an iPad and that would be spooled to a HIPAA compliant data-safe platform, so that we could get the data remotely and use it later on for our analysis, and they would also be shipped the studying medication which would either be placebo or famotidine unbeknown to them, unbeknown to the investigator, hence the principle of a double blind trial, and they would start taking that from day one of the trial. And prior to it, we would send out remote phlebotomy service to obtain baseline blood sample so that we could then compare the biology at baseline versus how it was at day 7, day 14, day 21, and day 28 of the study.
And how did you find participant compliance and adherence to the protocol with the remote trial?
Yes. We thought it was excellent, and I would like to take this opportunity to thank our patients for the participation as I am sure you will appreciate the patients are the most important part of the clinical trial and without them nothing would happen. So we are really very grateful for their engagement. We had 55 patients on trial in the end. They all made a fair effort to participate, and we tried to unburden them so that there was not too much activity and on a daily basis we estimated that they had to spend maybe 5 to 10 minutes for trial participation and from most patients, we got very good data. Some patients were not able to submit as much data as we ideally would have liked. There were variety of reasons for that. Some patients do lose interest a little bit when they are on a clinical trial. Some patients return back to work and other priorities figure in their life, so they cannot commit as much to the trial anymore but by and large, concordance with the trial and the data densities were excellent. We had about 5% missing data.
So some people have theorized that remote trials have the capability to democratize clinical trials and maybe get to people with different socioeconomic backgrounds, is this an exciting prospect for people such as yourself, scientists, and medical researchers, and how do you see the possibilities that this opens up?
Steve, I think that is an excellent question and as I highlighted at the beginning, the method has plasticity and this is something that we should all think about. I think democratization of clinical trials affects two aspects. One, access for patients in a broad sense including patients who would normally not participate in clinical trial or have traditionally been reluctant or had limited access to it and I will speak to that in a minute but also it involves making healthcare systems able to participate, especially those who care for patients who would normally not participate in clinical trials. So we found that the remote technology and recruiting patients remotely and then bringing the trial to them was excellent with regard to access to clinical trials. We had 33% Black African-American patients in our trial and 25% Hispanic patients in our trial. So we captured two groups of patients who are traditionally underrepresented in clinical trials in the United States, and we are really pleased to have that, and that was facilitated in part as well through our collaborations with Northwell Health and New York Health and Hospitals, both of whom provide clinical care to patient populations from a broad ethnicity background, and the other aspect is access to clinical trial delivery by healthcare systems that normally do not participate and here remote trials also are powerful because they fulfill two things, one they can be delivered cost effectively as we demonstrated and if you get really deep data on the patients you may not need that many patients to get a signal as evidenced by our pre-stipulated secondary endpoint which we deliberately pre-stipulated because we knew that we would have deep data density there and it was sufficient to capture a strong signal from 55 patients. So if you think about that if we made this technology available broadly and we published all of your data on how to deliver the study, healthcare systems that normally would say, “Clinical trials are beyond our reach for resource management reasons” would suddenly be potentially able to say, “Okay. We want the clinical study, and we bring in small number of people with sufficient expertise. We do not need a large team because we are doing small custom-made trials in collaboration with and remote healthcare monitoring devices or providers,” and so that would be a really powerful way to tackle the problem and on both dimensions. Perhaps, it is possible to do informative early phase clinical trials with fewer patients and so as a consequence, smaller healthcare providers in rural settings maybe able to initiate a clinical study that is informative to the community, something that is largely unthinkable at the moment. And those are two important points to democratize clinical trials as you say. What I think is the important bit is to enable the community of patients, researchers, and clinicians to do more to provide an evidence base for our clinical practice and how we want to develop it.
Yes. And there was a study just released today. I am hesitant even mentioning because I cannot remember who published it but it did a 10-year study on demographics of clinical trial participants and they found yet again that Black population in the US was seriously underrepresented.
Yes. I think that is a really important problem to solve, and I heard that our study makes a slow contribution to the pool of ideas and also to the evidence base that it can be solved. If you take nothing else away from our study then at least it shows that we were able to provide good access to a variety of patients, and we shall followup with deeper data still. We are currently collecting data on socioeconomic background, and we are planning to provide community with even more data information on the trial delivery and the trial method so that other clinicians, scientists, and physicians can learn from our experience. We can factor our experience into their design for future studies.
Yes. And famotidine as I mentioned earlier is available over-the-counter under the brand name Pepcid, what would you say to clinicians who maybe have patients who have heard about your research and see that taking high doses of famotidine might alleviate some of their symptoms, and so would you have any advice to give to clinicians whose patients maybe asking about this treatment?
Yes. That is an very important question. I am glad and thankful that you raised it because I think there needs to be a firm answer on this. Our trial is an early phase clinical trial that explores the biology and explores the methodology and also gives first indication that there may be an effect but it is not definitive, it is not a practice-changing trial, it is not a trial that should be used as a justification for clinical practice. So my answer to clinicians would be please read our manuscript and please explore patients can participate on further trials that are informative to advance the field but please do not refer to our manuscript and think that it is a definitive clinical study that should guide your clinical practice at this point.
Yes. And regards to this exact field of study, is there any next steps? Do you plan to do a bigger trial with more participants?
Yes. That again is a very important and good question, and the truthful answer is, “I do not quite yet know,” and we are waiting still for all the incoming responses to our study. There have been some very positive responses. Other people have said, “Okay. The result is not overwhelming. I would want to see more to get engaged,” so we are – – out who would be a good partner? How could we do this? Which patient population is the right population? What have we learned from the first trial, and how to do a larger trial better? And so that reflects the processes ongoing. There is an additional point that is worth considering. The COVID is an ever changing entity as I am sure we now all appreciate, consequently delivering success with clinical studies within the realm of COVID actually surprisingly difficult I find and you can gather that from the fact that there are not that many trials that have been conducted by academic institutions in particular that have been informative. I think our trial for all its weaknesses and for all its limitations is one example where a smaller academic institution was able to make a contribution to the peer-reviewed literature on an early phase clinical trial. There are few others who have done it but it is not as many as you would expect it because it is very difficult. The main thing is the disease is waxing and waning in its numbers and eligibility criteria can be changing. There are variances coming through. All of these things have to be considered, and so I think before we start into exploring a larger trial, a followup trial we have to carefully examine that it can be feasible because the first obligation I think is also to patients. We want to enroll them into trials that you can feasibly deliver because otherwise it unethical if you enroll them into a small trial that fizzles out and you never do anything with it. That not so nice. Sometimes it cannot be avoided because there are unforeseen circumstances but ideally you want to close the study out and report the results.
Okay. Some fantastic points raised there, and we have actually gone over our time a little bit. I always just like to ask a guest, is there anything that I have not asked or anything that you would like to mention of your future research
Yes. I would like to say watch this place. We are trying to follow-up from this. We have a number of new ideas on how to modulate disease and how to study that modulation, and we want to build on this experience, and we invite others to join us and to exchange ideas with us. We do not claim that we have all the answers, but we hope that we have provided a small piece to the puzzle, and what I would also like to say is I would like to thank you, Steve for such a thoughtful interview, and I would like to thank you audience for listening in, and I am always open to receive feedback, and so please encourage your audience to reach out if further questions arise, and we will try our best to answer their questions.
Yes. We will have the link to the trial on the website on the page for the podcast so everyone can read it there. I would like to say thank you to Dr. Janowitz for taking the time to join us today and a really fascinating conversation.
Thank you. The pleasure was all mine.