Hello, my name is David Rosemary and I'm the chair of Department of Dermatology at Indiana University School of Medicine. Over the next 10 minutes I'm thrilled to share some insights for conducting clinical trials and patients who have the challenging condition of alopecia areata. Please see the AAD website for a full list of my disclosures and conflicts of interest. I work with industry to further our mission of innovation in inflammatory disorders of the skin. In today's talk, we will review endpoints, differences dependent on the phases of clinical trials being conducted, special considerations regarding placebo rates for alopecia areata studies. We'll cover quite a bit on inclusion exclusion criteria, the appropriate duration of a study, and also the importance of measuring duration of response. It is important to determine what phase of a clinical trial is being conducted. The purpose of a phase one clinical trial is to evaluate the tolerability, safety, and pharmacokinetics slash pharmacodynamics of a new investigational drug on healthy volunteers or patients with disease. Pharmacokinetics are how humans process the drug and pharmacodynamics are more about the drug effects on the body. Phase one studies represent early experience with the drug in humans. Typically, there is dose escalation and a focus on safety assessment, though there may be some preliminary data on efficacy gathered. In terms of a phase two study, this is often a proof of principle trial and is useful to enrich the study with subjects that are likely to respond. Often the highest dose of medication is used, given the small number of subjects, and a continuous variable is used as an endpoint, such as mean change and SALT score. Once a medication has been proven to work, one may next conduct a dose ranging phase 2B study that broadens the population to gather how the medicine works on patients that may be more challenging. For example, patients that have failed JAK inhibitors or have alopecia areata for a longer period of time or have high inflammatory burdens, such as alopecia universalis and alopecia totalis. The phase 2A and or phase 2B are critical at informing the design of the phase three study, of which there are usually two, pivotal for regulatory approval. As opposed to a continuous variable endpoint, typically a SALT 20 is the gold standard for endpoint in a phase three, and there are key secondary and exploratory endpoints gathering information on eyebrows, eyelashes, and nails that will be captured in this larger population. In terms of objectives, we need to have clearly defined primary and secondary endpoints. Typically, hair regrowth measured by SALT score is the gold standard. The SALT score characterizes the percentage of scalp hair loss and ranges from 0 to 100. A SALT score of 100 means complete or 100% scalp hair loss, whereas a SALT score of 0 means there is no alopecia. When calculating the SALT score, the scalp is divided into quadrants, top, left, right, and back, representing 40, 18, 18, and 24% of the scalp surface area, respectively. Multiplying the percent of scalp hair loss in each of the four quadrants by the quadrant surface area and adding the four values together achieves a composite SALT score. In general, a SALT score greater than 50 is considered severe disease. In patients with severe or very severe disease, achieving a SALT score less than 20 is a meaningful improvement and often the regulatory endpoint for clinical trials. Regarding the SALT score, diffuse hair loss is also quite challenging for this system, and one can consider excluding patients with diffuse alopecia areata from studies. Also, hairstyle matters. If a patient shaves their head, you can imagine the difficulty in calculating an accurate SALT score. Additionally, for patients who have long hair, it's important to sift through and be diligent to achieve an accurate score and not miss areas of hair loss. Also note that in calculating the score, the length of the hair doesn't matter and vellus hairs don't count. There are also outcome measures that can be utilized for eyebrows as well as eyelashes. As nails may also be involved in alopecia areata, seeing how the intervention affects nails can also be useful information captured from the study. Though eyebrows, eyelashes, and nails may not be involved for every patient in a study, it is a meaningful endpoint for patients and valuable to capture response rates. Even when your study isn't powered to convincingly prove that there is a response, that added data is helpful for consideration of subsequent larger studies that may be powered to capture that information as key secondary endpoints. While the SALT score is objective, photographs tend to be very valuable conveying the impact and can look quite dramatic for publications. When taking photographs, it is important to be systematic. Taking standardized photos may not be as easy as it sounds. Having a clear background, blue tends to work well, and having set camera settings that don't change to take the photos of the patients in different positions, which cover each aspect of the scalp, eyebrows, or eyelashes. This certainly helps convey the impact of the intervention being studied. There should also be consideration of patients reported out. Why in SF-36 are common quality of life measures and studies involving psoriasis, atopic dermatitis, and hydroadenitis subvertiva. For alopecia areata, disease-specific quality of life measures are more tailored to these specific patients. It is crucial to recognize the psychological impact of hair disorders that go beyond physical symptoms, such as itch and pain. The duration of a study for alopecia areata is quite important. While systemic treatments in psoriasis usually have their endpoints at 12 or 16 weeks, treatments for alopecia areata may take longer to see an effect. We do not fully understand why some patients may be early responders and some may take more time. However, it is important to capture as many patients who might respond to treatment as possible. Often the duration of the study ranges from 24 weeks to 52 weeks for the primary endpoint. A primary endpoint prior to the six-month mark will likely miss a significant number of patients that may ultimately meet a SALT20 endpoint. We never want patients to drop out of studies, so we need to be cognizant of how long we can keep patients in a placebo arm. Because there are typically no physical symptoms, such as a reduced mobility, pain, or itch, we can run clinical trials that are placebo-controlled longer for alopecia areata than for diseases like HS, where patients may even need to have rescue options in place. Additionally, it can be quite helpful for design to have placebo arm ultimately receive treatment after the primary endpoint. This can encourage patients to continue in the study, as if the patient investigator are blinded and don't know if the patient is on therapy, then they have the hope that if they are currently not on treatment, they will ultimately get the treatment after the primary endpoint to see if it helps them. An additional consideration with study design is how long does the response hold after medication is stopped? This is valuable information that is usually captured in a Phase II or Phase III study. In the real world, patients may have an interruption in treatment, and it is important to know after how long might patients begin to lose their hair if they had an initial response. Again, the durability of response is important. We'll now discuss important tips related to the inclusion-exclusion criteria. Who is the population to study? And this may differ depending on the particular medication as well as phase of a trial. For systemic treatment, often a severe population defined as salt greater than 50 is used. One reason for this is to limit the placebo rate. It is particularly dangerous to do an alopecia areata study as an open-label design with a salt score of less than 50%, since this can be a significant placebo or vehicle response. By evaluating a more severe population, that minimizes the placebo response significantly. It is also important to consider the inflammatory burden. If patients have a larger surface area, such as alopecia totalis or universalis, and are more severe, they are less likely to respond to treatment. They may need a higher dose of medication, whereas patients with patchy alopecia and a salt score of less than 95 are more likely to respond. In a proof-of-principle study, one may want to limit the number of patients who have alopecia totalis or alopecia universalis, since the desire is to determine if the medication can work or not. And one can later decide what's the ideal population to study. The age of the population is an important consideration. The older the subjects, the more likely there is to be androgenetic alopecia. Male and female pattern hair loss can interfere with evaluating the efficacy of the intervention. It is important to understand where the real possible hairline is for a patient and also how much hair growth is truly possible. Androgenetic alopecia makes it challenging, and that's why it may be valuable to have an upper age cutoff. There are also differences in the pediatric population. It's been noted that while topicals thus far have not fared well in adults, pediatric patients are more likely to respond. So, considering a non-systemic intervention, the pediatric population may be the correct population to target. How long patients have had alopecia areata for, particularly the current episode, matters. First, it's important to have a population of patients with stable disease. Second, patients who have had alopecia areata for a long time, for instance, greater than 10 years, are less likely to regrow their hair. And so it is important to put a limit on the length of time patients have had their alopecia areata for. Even within a 10-year window, patients who have had the disease for less than four years compared to greater than four years tend to be more responsive to JAK inhibitor therapy. Should a trial be designed to include patients who have failed other trials previously? This may be a more recalcitrant population. For a proof-of-principle study, it may be helpful to exclude them or limit the number of these patients. Additionally, how is failure defined? If a patient received a JAK inhibitor for one dose and then stopped, should that patient be considered a failure? If a patient had a side effect from a JAK inhibitor, but their hair was regrowing, is that a failure to exclude from your study? If patients have concomitant scalp disease in general, these patients may need to be excluded from studies. It's important not to enroll subjects where there have other conditions that will interfere with SALT assessments or the ability to determine if the intervention can help patients with their alopecia areata. For example, it's important that patients haven't had a scarring alopecia. I also want to comment that as an autoimmune disease, patients with alopecia areata are more likely to have other autoimmune conditions, like thyroid disease, among others. Some patients have multiple autoimmune conditions, like Crohn's, RA, AA, SLE, and have polyautoimmunity. These patients are likely more recalcitrant to treatment. Interestingly, patients who have had concomitant atopic dermatitis may be more responsive to certain treatments. For example, patients with elevated IgE are more likely to respond to dupilumab and AA. And patients with a history of atopic dermatitis are more likely to respond to JAK inhibition therapy. Safety is critical in a trial. Luckily, the alopecia areata population tends to be healthy. It is usually not an elderly population being studied either. I think it's important to keep in mind this trial design always needs to prioritize the safety and wellness of participants. Luckily, this tends not to be as much of an issue in AA as some of our other dermatologic conditions. I want to emphasize the importance of a partnership with the patient. Time spent with the patient discussing the study before enrollment is extremely helpful. Also, ask yourself, is the study the best option for the patient? If not, the patient is more likely to drop out. The subject's altruism in contributing to the study is important to remember. We want subjects who are interested in a new treatment as well as benefiting society. We don't want subjects who are enrolling because they simply want an honorarium. Additionally, reimbursing patient expenses, for example, parking, is also important. How can we, as study sites, be flexible around patients? Can we give patients different options around their school or work hours? Relationships matter. Having a consistent team to maximize and build trust with the subject's important. Oftentimes, the best recruitment is from you and your own patient population where there's already an established relationship. Also, you want to have the same rater to minimize variability. And of course, we always put the patient first and act in their best interest. It's a really exciting future. JAK inhibitors have revolutionized the way we treat LOP shariata. I'm particularly looking forward to testing new targeted treatments to try to push our efficacy of existing medications and create safer options for patients with durable results. Additionally, perhaps concomitant treatments will also be helpful in the future. Can we utilize biomarkers from patients to determine optimal treatments? Additionally, while much focus has been on the more severe populations, many patients have mild or moderate disease and still need more options. Hopefully we can have future topicals as well. So a lot of work still needs to be done, and we are at the beginning of a very exciting time in the study of treatment for LOP shariata. Thank you.

alopecia areata

clinical trials

SALT score

JAK inhibitors

biomarkers