Results • At 16 weeks during the first treatment cycle, a higher proportion of moderate and severe lesions at baseline treated with diacerein 1% ointment achieved treatment success, as compared with vehicle-treated lesions (58% vs 40%; P=.036) (Figure 4) • Similarly, at 16 weeks, the proportion of lesions treated with diacerein 1% ointment showing a 2-point reduction in IGA score trended higher, as compared with vehicle-treated lesions (70% vs 47%; P=.067) (Figure 5) Figure 4. Percentage of moderate and severe lesions achieving treatment success (IGA 0/1 and a 2-point reduction) 58% 40% Diacerein (n=76) Placebo (n=58) -18 P er ce nt 100 80 60 40 20 0 70% 47% Diacerein (n=76) Placebo (n=58) -23 P er ce nt 100 80 60 40 20 0 P=.036 P=.067 • The mean absolute change in the IGA score from baseline to the end of the follow-up period at 16 weeks was significantly greater for diacerein-treated lesions vs vehicle-treated lesions (2.4 vs 1.7; P=.001) • The mean IGA for diacerein-treated lesions was significantly lower than that of vehicle-treated lesions at 16 weeks (1.08 vs 1.74; P=.004) (Figure 6) Figure 6. Mean IGA at each study visit (baseline, 4 weeks, 16 weeks) 3.49 2.54 1.08 3.43 2.79 1.74 0 1 2 3 4 M ea n IG A (S E M ) Baseline 4 weeks 16 weeks P=.004 Diacerein (n=76) Placebo (n=58) Diacerein (n=76) Placebo (n=58) SEM=standard error of the mean. • A reduction in blister counts positively correlated to improvements in overall disease severity (Figure 7) Figure 7. Linear relationship between mean IGA score and total blister counta M ea n IG A S co re Total Blister Count Pearson correlation coefficient=0.4855 (P=.001) M ea n IG A S co re Total Blister Count Pearson correlation coefficient=0.4855 (P=.001) Conclusion • Analysis of the Phase 2 diacerein 1% ointment study demonstrated that more moderate or severe lesions achieved treatment success with diacerein than with placebo – Treatment success was defined as the proportion of lesions resolving to IGA 0 or 1 with a minimum 2-point reduction in the IGA score • A reduction in blister counts positively correlated to improvements in overall disease severity • In addition, a significantly greater mean reduction in the IGA score from baseline was achieved with diacerein as compared with placebo Introduction • A Phase 2 study of diacerein 1% topical ointment in patients with epidermolysis bullosa simplex (EBS) has demonstrated efficacy as compared with placebo with regard to blister count reduction • Static scales that measure a clinician’s global impression of disease severity at a single time point are widely used in clinical trials for dermatological conditions and, although EBS scales exist in clinical practice, a standardized static scale for assessing EBS severity has yet to be developed • This report presents an analysis of data from the first treatment course and corresponding follow-up in the phase 2 crossover trial, was conducted to validate a novel, EBS-specific 5-point Investigator’s Global Assessment (IGA) scale based on efficacy data generated from the phase-2 study to measure the effects of diacerein 1% ointment vs vehicle control in the treatment of EBS Analysis Objectives • End points for the analysis of the Phase 2 data were as follows: – Primary end point was the proportion of patients with moderate to severe lesions who achieved “treatment success” at year 1 • Treatment success was defined as an IGA disease severity grade of 0 or 1 at Visit 3 (Week 16) with at least a 2-point reduction in the IGA score, as compared with Visit 2 (Week 0) at year 1 • The χ2 test was used to determine the statistically significant difference between the diacerein 1% ointment and the control ointment treatment groups – Additional end points included the proportion of patients from baseline to week 16 with a 2-pointreduction and the mean decrease in IGA Phase 2, Randomized, Controlled Original Study Design • Treatment in a 4-week intervention period, with a 3-month follow-up, was conducted in 2 successive years, with a cross-over of patients after the first year (Figure 1) • Secondary end points included the recurrence of blisters after a 12-week follow-up, a reduction of pain and pruritus, and quality of life measurements Figure 1. Diacerein 1% topical ointment for the treatment of EBS Indication Generalized, severe EBS Primary objective Reduction of blister numbers (by 40%) in the treated skin area (3% of body surface) vs placebo after 4 weeks Study design Cross-over design, randomized, double-blind, vehicle-controlled Part 1: Intervention phase for 4 weeks; Part 2: 3-month follow-up Study population Generalized, severe EBS with K14 or K5 gene mutations, age 4-19 yr Number of patients 17 Therapy Once-daily, self-application for 4 weeks Study nurse visits Time points for assessments Year 1 4 weeks 3 months V0 T0 1 2 3 4 V1 V2 5 6 7 V3 Follow-up Follow-up Diacerein Placebo Year 2 4 weeks 3 months V4 8 9 10 11 12 V5 V6 13 14 15 V7 Follow-up Follow-up Diacerein Placebo Study nurse visits Time points for assessments Year 1 4 weeks 3 months V0 T0 1 2 3 4 V1 V2 5 6 7 V3 Follow-up Follow-up Diacerein Placebo Year 2 4 weeks 3 months V4 8 9 10 11 12 V5 V6 13 14 15 V7 Follow-up Follow-up Diacerein Placebo Original Phase 2 Efficacy at 4 and 16 Weeks of Year 1 • Significantly more patients in the diacerein group achieved the primary end point of >40% reduction in blister numbers at both 4 weeks and at the end of the follow-up period at 16 weeks of year 1 (Figure 2) Figure 2. (A) Proportion of patients with >40% reduction in blister numbers at 4 weeks (T4) and 3 months (T7). (B) Representative images of improvements in lesions. 86% 100% 14% 57% T4 T7 p-values were calculated using a one-sided, Bernard’s test for superiority. P er ce nt 100 80 60 40 20 0 P=.007 P=.038 Diacerein Placebo 86% 100% 14% 57% T4 T7 p-values were calculated using a one-sided, Bernard’s test for superiority. P er ce nt 100 80 60 40 20 0 P=.007 P=.038 Diacerein Placebo IGA Scale for Analysis • The IGA is the investigator’s clinical assessment of the average overall severity of all EBS lesions, considered together, at a particular time point (Table 1) Table 1. Investigator’s Global Assessment (IGA) scale for EBS Score Definition 0 = Clear No blisters, no erosions, minimal erythema and/or pigmentary changes may be present 1 = Near Clear 2 or fewer small blisters, faint signs of erosion may be present, barely perceptible evidence of crusting, slight erythema 2 = Mild Predominantly small and some medium blisters, minimal erosions, clear crusting, definite well-defined erythema 3 = Moderate Mix of small and medium blisters, definite erosions, limited areas of crusting, marked erythema 4 = Severe Mix of medium and large blisters, marked erosions, ulceration may be present, marked and extensive crusting, intense erythema Methods for Analysis • Each photograph taken during the Phase 2 blister-counting analysis study was labelled by patient ID (1001-2011), visit number (0-7), and location to ensure a complete list of available areas for analysis • For patients with several affected locations in a sequence of visits, these locations were split into separate images to allow for independent analysis • Photographs of the same location were displayed together on the same page, resulting in some pages with several photographs but one rating area. Patients without images for all visits were not included in the IGA analysis • Following the organization of the photographs using this method, a 164- page IGA Rating Document was developed • Each page contained a photograph (or photographs) of an affected location of a patient on the left side of the page and the IGA rating scale on the right of the page, with a checkbox for the dermatologist to check, indicating the IGA score that he or she assigned to the affected area (Figure 3) Please check box (✓) for appropriate IGA score: 0 Clear No blisters, no erosions, no crusting, minimal erythema and/or pigmentary changes may be present Score Definition 1 Near Clear 2 or fewer small blisters, faint signs of erosion may be present, barely perceptible evidence of crusting, slight erythema 2 Mild Predominantly small and some medium blisters, minimal erosions, clear crusting, definite well-defined erythema 3 Moderate Mix of small and medium blisters, definite erosions, limited areas of crusting, marked erythema 4 Severe Mix of medium and large blisters, marked erosions, ulceration may be present, marked and extensive crusting, intense erythema Please check box (✓) for appropriate IGA score: 0 Clear No blisters, no erosions, no crusting, minimal erythema and/or pigmentary changes may be present Score Definition 1 Near Clear 2 or fewer small blisters, faint signs of erosion may be present, barely perceptible evidence of crusting, slight erythema 2 Mild Predominantly small and some medium blisters, minimal erosions, clear crusting, definite well-defined erythema 3 Moderate Mix of small and medium blisters, definite erosions, limited areas of crusting, marked erythema 4 Severe Mix of medium and large blisters, marked erosions, ulceration may be present, marked and extensive crusting, intense erythema Figure 3. Example of IGA Rating Document layout • 10 leading dermatologists and EB experts from the US, Europe, and Australia were selected to blindly review and rate the photographs using the IGA scale • Each investigator was mailed a packet that contained instructions for the IGA assessment project, an IGA Training Manual, an IGA Rating Document, and a prepaid return label and envelope • The photographs mailed to each dermatologist were randomly sorted during printing. Thus, each dermatologist reviewed the same photographs • 10 investigators rated all photographs independently using the IGA scale and reported the one integer that best described the average overall severity of all the EBS lesions considered together Use of an Investigator’s Global Assessment Scale to Evaluate Disease Severity in Patients With Epidermolysis Bullosa Simplex Johann W. Bauer1, Amy Paller2, Jemima E. Mellerio3, Alain Hovnanian4, John J. Pan5, Panagiotis Zografos5, Greg P. Licholai5, and Dedee F. Murrell6 1Department of Dermatology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria; 2Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3Department of Pediatric and Genetic Dermatology, St. John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom; 4Department of Genetics, Imagine Institute, University Paris Descartes, Paris, France; 5Department of Medical Affairs, Castle Creek Pharmaceuticals LLC, Parsippany, NJ, USA, 6Department of Dermatology, St George Hospital, and Faculty of Medicine, University of New South Wales, Sydney, Australia Reference Bauer J. Diacerein for the treatment of epidermolysis bullosa – a phase II randomized, placebo controlled, double-blind multi-center clinical trial. Presented at AAD, 2017. Figure 5. Percentage of lesions with a 2-point reduction in IGA score 58% 40% Diacerein (n=76) Placebo (n=58) -18 P er ce nt 100 80 60 40 20 0 70% 47% Diacerein (n=76) Placebo (n=58) -23 P er ce nt 100 80 60 40 20 0 P=.036 P=.067 aThe correlation was between the total blister count and the mean (over lesions) IGA score for the 14 patients who have the IGA scores available. Blister count data are available for each of the 3 timepoints (baseline, 4 weeks, and 16 weeks) for each of the 14 patients (N=42 timepoints) • Danielle Greenblatt, Consultant Dermatologist, Department of Pediatric and Genetic Dermatology, St. John’s Institute of Dermatology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK • Anna Bruckner, Colorado Children’s Hospital, Aurora, CO, USA • Aida Lugo-Somolinos, Department of Dermatology, University of North Carolina - Chapel Hill, NC, USA • Joyce Teng, Stanford University Department of Dermatology, Stanford, CA, USA • Ena Sokol, University Medical Center-Groningen, The Netherlands • John Browning, Texas Dermatology and Laser Specialists Research Unit, San Antonio, TX, USA • Emily Becker, Texas Dermatology and Laser Specialists Research Unit, San Antonio, TX, USA • Special thanks to Sean Kelly, Operations Manager at CCP, for his efforts in creating the rating document from randomized pictures, data collection and organization of source data files and preparing the results tables Editorial support was provided by p-value communications. Acknowledgments The authors wish to thank the following investigators who participated in the analysis project: Start V0 2 weeks V1 4 weeks V2 4 months V3 P LA C E B O D IA C E R E IN A. B.