Good afternoon. My name is Alexa Kimball, and I'm very pleased to present to you Hydrodinitis suppurativa clinical trials, tips and tricks. I'm a professor of dermatology here at Harvard Medical School, and I've been doing clinical trials in hydrodinitis suppurativa for the past 15 years. It's been really an extraordinary journey, taking from a period of time where we didn't really even have an actionable outcome measure to be used in phase 2 and phase 3 programs, to a really much more straightforward and established method for both designing and conducting these studies, as well as interpreting the results. I'm going to walk you through six different agenda items, starting with endpoint design, schematic of the study and sample size calculations, placebo rates, eligibility, concomitant treatments, and other things that you will need to be thinking about during the course of the study. Design considerations. Choosing your endpoint for your study is, of course, one of the most important things that you need to do before you start to design the overall program. There are three types of lesions typically recognized in HS studies, abscesses, fistulas, and nodules. Within these three categories, there are also two types of fistulas, draining and non-draining, and two types of nodules, inflammatory and non-inflammatory. The current gold standard scoring system is called the high score, which is a 50% reduction in the sum of abscesses and inflammatory nodules, with no increase in fistulas or abscesses. The reason why the high score is designed this way is because a patient could have a nodule convert to a fistula, which would, of course, be worsening of disease and yet appear as a slightly lower nodule count. We are currently seeing the field move increasingly towards a high score 75 and a high score 90, as the efficacy bar is continuing to get higher. Importantly, as you probably already noticed, the high score does not include fistulas in its count of efficacy. Part of the reason why is because not every patient has a fistula, and when they do occur, they are often smaller in number. The field is currently trying to develop other scoring systems that might incorporate fistulas into the endpoints in a more effective and meaningful way. For smaller power trials, rather than using a dichotomous endpoint like the high score 50, you can consider a continuous variable, such as a change in the sum of abscesses and nodules. Other scoring systems have been developed. If you are assessing fistulas because it is important, either because of the mechanism of action of your medication that might work better on fistulas than on, say, nodules, you can consider other endpoints. The IHS-IV, for example, weights nodules with a count of 1, abscesses with a count of 2, and fistulas with a count of 4. You can also use a change in fistula count, either absolute or percentage numbers. Patient-reported outcomes commonly used include the Dermatology Life Quality Index, the high score, and the pain, which is usually conducted using a visual analog scale. As you design your study schema and calculate your sample sizes, there are a number of considerations to take into account. The first is that HS is a heterogeneous disease with quite a bit of underlying variability, so calculating the right sample size is key. Unfortunately, because of this variability, larger sample sizes are typically needed than we see in some other studies. Open-label studies are also therefore not recommended, as there have been failures in therapies that look promising in open-label studies. The field is starting to move towards active control studies, although the standard today, at the time of this taping, is still placebo-controlled studies, sometimes including a reference arm of another medication, which can be helpful in determining the overall integrity of the study. Platform, or umbrella, designs have been very successful for programs where testing more than one drug at a time, One of the advantages of this kind of design is it minimizes the number of patients who need to be on placebo, which is, of course, a great advantage to those patients. So don't be intimidated by elevated placebo rates that you might find in HS studies, but do plan for them. Many HS patients have natural swings in condition that cross the high-score range of placebo-controlled studies. Many HS patients have natural swings in condition that cross the high-score 50 threshold, and placebo rates can be in the 25% to 30% range on a regular basis. Higher levels of efficacy, such as the high-score 75 and high-score 90, bring lower placebo rates, but may also require larger sample sizes, since fewer patients achieve them, and the difference in terms of achievement between placebo and success may be somewhat smaller. But most importantly, make sure your sample size is adequate and ensure that your investigators are well-trained in grading and rating to minimize any bias that may affect your assessment of the placebo population. In terms of eligibility requirements, you may want to consider the stage of disease. Early staging is typically the most common, with early one patients typically not having scarring, early two patients having modest levels of atrophic scarring, and early three having more severe tunneling and scarring, generally speaking. You want to consider the level of activity required to enter, which is usually around five nodules or abscesses for moderate to severe disease. And you want to consider eligibility based on prior treatments, component antibiotics, and pain medications, especially if pain is an endpoint. One strategy is to stratify or cap certain groups if you're concerned about over-weighting in one direction or another. For example, you can cap the percentage of patients on concomitant antibiotics to 10% or 20% to minimize the impact they may have on the rest of the study. Determining the right drug dosing is, of course, important as well. Moderate to severe HS patients in most studies tend to have a mean weight of greater than 90 kilograms in clinical trials. So understand if there are pharmacokinetic implications for any treatment that you are testing. They also seem to have relatively low bioavailability. So in general, the recommendation is to consider higher doses for this patient population. Loading doses or loading dose periods are very typical in studies of moderate to severe patients. You will also need to design a plan for concomitant treatments. During the study, this plan needs to include addressing what to do about pain medications. HS patients will have flares during the course of the study, which will require treatment of some sort, including pain or rescue therapies. Therefore, you'll also want to decide what types of rescue therapies you want to allow, which could include incision and drainage or intralesional chemilab or antibiotics. There are also several important considerations to build into your study design. Try to maintain the same grader and rater, particularly at baseline and key endpoints, to help minimize variability in a study where patient variability is already known to be somewhat of an issue in terms of scoring. Rating is typically done best with assistance as the rater needs to be wearing gloves to examine the patients properly and may not be able to write or use a tablet easily. Patients are very engaged in H studies, but sometimes run into transportation or scheduling issues. So having some flexibility in visit availability is really important. Lastly, I just want to comment how fun it is to conduct clinical trials at this time in HS. We are making so much progress and there's nothing more rewarding than helping some of these patients find treatments that are effective and relieve both their distress and disability. It is a truly great time for patients. Thank you.

Hidradenitis Suppurativa

clinical trials

HiSCR scoring

platform designs

patient variability