Diacerein orphan drug development for epidermolysis bullosa simplex: A phase 2/3 randomized, placebo-controlled, double-blind clinical trial Verena Wally,

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Diacerein orphan drug development for epidermolysis bullosa simplex: A phase 2/3 randomized, placebo-controlled, double-blind clinical trial Verena Wally, PhD, Alain Hovnanian, MD, Juliette Ly, PhD, Hana Buckova, MD, Victoria Brunner, MS, Thomas Lettner, PhD, Michael Ablinger, MS, Thomas K. Felder, PhD, Peter Hofbauer, MPharm, Martin Wolkersdorfer, PhD, Florian B. Lagler, MD, Wolfgang Hitzl, PhD, Martin Laimer, MD, Sophie Kitzmüller, PhD, Anja Diem, MD, Johann W. Bauer, MD, MBA Journal of the American Academy of Dermatology Volume 78, Issue 5, Pages 892-901.e7 (May 2018) DOI: 10.1016/j.jaad.2018.01.019 Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Journal of the American Academy of Dermatology 2018 78, 892-901 Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Fig 1 Generalized severe epidermolysis bullosa simplex. Overview of study design, patient screening, and enrolment. The trial was conducted over 2 successive trial periods (TPs), with a crossover of groups after period 1 and an extensive washout. In TP2, a placebo group and a diacerein group received medication for 4 weeks and were followed up for 3 months. Time points of study nurse visits (V) and data collection (T) are indicated. Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Fig 2 Generalized severe epidermolysis bullosa simplex. Blister classification. Single blisters were defined as a count of 1. Blister nests derived from 1 healing blister were defined as a count of 1. Redness without convexes was not counted. Only time points for which good quality photographs were available (good resolution, clear visualization of blisters) were included in the final evaluations. Blisters were counted in the context of the whole treatment to distinguish between active and healing blisters. Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Fig 3 Generalized severe epidermolysis bullosa simplex. Flowchart according to Consolidated Standards of Reporting Trials 2010 showing numbers of patients who were screened, randomized, and assigned to the 2 treatment arms. Dropouts and secondary recruitments are indicated. *For details on patient numbers included in respective evaluations, see Supplemental Table I. AE, Adverse event. Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Fig 4 Generalized severe epidermolysis bullosa simplex. Primary end point evaluation. A, Representative pictures of 1 diacerein- and 1 placebo-treated patient. B, Results from trial period 1. C, Results from trial period 2. D, Percentages with corresponding 95% confidence intervals (CIs) are given. P values for differences between the diacerein and placebo groups at the respective time points (T) are given. Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Fig 5 Generalized severe epidermolysis bullosa simplex. Evolution in blister number for diacerein and placebo in the course of the trial. A and B, Means with 95% confidence intervals (CIs) are shown; P values are 2 sided. Absolute blister numbers between the start and end of the intervention, as well as between the start and end of follow-up, were significantly different for the diacerein group but not for the placebo group. C, Blister numbers were significantly different between the diacerein and placebo groups at 4 weeks and 4 months after treatment initiation. The mean number of blisters at the beginning of each trial period was 6.2 for both the diacerein- and the placebo-treated patients. The mean difference between groups was 2.5 blisters after 4 weeks of treatment and 3.4 blisters after the follow-up. Means with 95% CIs are shown; P values are 2 sided. Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Fig 6 Generalized severe epidermolysis bullosa simplex. Secondary end point evaluation. Percentage of patients for period 2 reaching at least 90% of the initial blister number at the end of the follow-up period. *Indicates statistically significant differences between the respective groups. Means with 95% confidence intervals (CIs) are shown; the Barnard exact test, *P values are 1 sided; †P value is 2 sided. Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Supplemental Fig 1 Assessment of pruritus and pain. Pain (A) and pruritus (B) were assessed by the study nurse at each visit by using a visual analogue scale with continuous numbers from 0 to 10, where 0 indicated no pain/pruritus and 10 indicated significant pain/pruritus. Pruritus and pain, which were recorded at each visit by the study nurse, showed no significant differences over time or between groups. Means and 95% confidence intervals are given. The low percentage of body surface area treated, individual differences in pain sensation (which resulted in widely differing scores at the beginning of the treatment), and difficulty in separating the perception of pain and pruritus in the treated body surface area from that in the rest of the body are the reason for this outcome. Interestingly, the question on the quality of life questionnaire asking about pruritus and pain had a significant outcome, still indicating an impact of the treatment on the sensation of pain and pruritus (see Supplemental Fig 2). Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Supplemental Fig 2 Assessment of quality of life. Quality of life was assessed by using the same questionnaire as utilized in the pilot study. Patients were asked to complete the 8 questions of the questionnaire at the T0/T7 and the T8/T15 visits (A). Analysis of quality of life assessments was performed for patients who completed both treatment periods. For question 1, on pruritus and pain (“Has your skin been itching recently or have you had pain?”), a positive treatment effect was demonstrated that was stronger for diacerein than for placebo. For the majority of all other questions, the trend was similar, although it was not strong enough to reject the null hypothesis (ie, no positive effect of the treatment). Calculation of the score distribution before and after the treatment showed no significant change in the score level for the placebo group for any of the questions, whereas for the diacerein group, there was a significant change in the score level for the first question, on overall pain and pruritus (B and C). Quality of life data were analyzed by using 2 different testing approaches based on relative effects (a nonparametric Behrens-Fisher situationS2): score distribution before and after the treatment and score change distributions. Interestingly, the impact of pain and pruritus in this disease rated the highest scores in the patients' quality of life assessment, but these scores did not correspond to the nurse-recorded scores on the analogue scale. We assume that this difference may be accounted for by the low percentage of body surface area treated, individual differences in pain sensation (which resulted in widely differing scores at the beginning of the treatment), and difficulty in separating the perception of pain and pruritus in the treated body surface area from that in the rest of the body. Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Supplemental Fig 3 Generalized severe epidermolysis bullosa simplex. Clinical pictures of treated body surface areas of patients from the diacerein group, representing different response rates are shown. A, Patients with blister numbers reduced by more than 60% from start of treatment. B and C, Representative pictures of patients with reduction in blister numbers by 40% to 60% and less than 40% (nonresponders), respectively. Only patients from the diacerein group are shown. Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions

Supplemental Fig 4 Generalized severe epidermolysis bullosa simplex. Clinical pictures of treated body surface areas of patients with a reduction in blister numbers greater than 40% only after the follow-up. Photographs of 2 of the 6 patients from the diacerein group meeting this criteria are shown. Neither of the patients had reached greater than 40% reduction in blister numbers after the intervention phase. Journal of the American Academy of Dermatology 2018 78, 892-901.e7DOI: (10.1016/j.jaad.2018.01.019) Copyright © 2018 American Academy of Dermatology, Inc. Terms and Conditions