Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 17 NOV 2014 BAY no / IMPACT no Page: 1 of 9 2. Synopsis Date of report: 20 JUN 2014 Study title: A randomized, double-blind, vehicle-controlled, multicenter, parallel-group clinical trial to assess the safety and efficacy of Azelaic Acid Foam, 15% topically applied twice daily for 12 weeks in patients with papulopustular rosacea Sponsor s study number: ( ) NCT number: EudraCT number: Sponsor: National Clinical Trial (NCT) number: NCT Not applicable Bayer HealthCare Clinical phase: 3 Study objectives: The primary objective of this study was: To determine the efficacy of Azelaic Acid (AzA) Foam, 15% compared to vehicle topically applied twice daily in papulopustular rosacea evaluated by therapeutic success rate according to Investigator's Global Assessment (IGA) and nominal change in inflammatory lesion count from baseline to end of treatment The secondary objectives of this study were: To determine the efficacy of AzA Foam, 15% compared to vehicle topically applied twice daily in papulopustular rosacea evaluated by therapeutic response rate according to IGA and percentage change in inflammatory lesion count from baseline to end of treatment To assess the safety and tolerability of topical AzA Foam, 15% and vehicle applied non-occlusive at a daily dose of 1 g foam for a total of 12 weeks including evaluation of local cutaneous adverse events (AEs) To assess the effect of AzA Foam, 15% and vehicle on erythema, telangiectasia and facial skin color To assess self-reported outcome parameters via the subject's global assessments on treatment response and tolerability as well as the subject's opinion on cosmetic acceptability and use in facial areas next to the hair line

3 17 NOV 2014 BAY no / IMPACT no Page: 2 of 9 To assess the effect of AzA Foam, 15% and vehicle on parameters of quality of life in papulopustular rosacea evaluated using the Rosacea quality of life (RosaQoL), the Dermatology Life Quality Index (DLQI), and the EuroQol Group Questionnaire - 5 Dimensions - 5 Levels (EQ-5D- 5L) To assess long-term effects of the treatment and recurrence of the disease in a 4-week follow-up phase Test drug: Azelaic Acid Foam, 15% (BAY ) Name of active ingredient(s): Azelaic Acid Dose: 0.5 g AzA Foam, 15% applied twice daily (BID), for a total of 1 g AzA Foam, 15% daily (corresponds to a daily dose of 150 mg AzA) Route of administration: Topical, nonocclusive on facial skin Duration of treatment: Reference drug: Dose: Route of administration: Duration of treatment: Indication: Diagnosis and main criteria for inclusion: Study design: 12 weeks Vehicle foam 0.5 g foam applied BID, for a total of 1 g foam daily Topical, nonocclusive on facial skin 12 weeks Papulopustular rosacea Subjects with papulopustular rosacea who fulfilled all the following criteria were selected for the study. Male or female subject aged 18 years; Diagnosis of papulopustular rosacea (IGA score of moderate or severe) presenting a minimum of 12 and no more than 50 inflammatory lesions (papules and/or pustules) and persistent erythema with or without telangiectasia; Free of any clinically significant disease, which could have interfered with the study; and All parameters were determined during the screening and at baseline prior to administration of study drug if not otherwise stated. This was a randomized, double-blind, vehicle-controlled,

4 17 NOV 2014 BAY no / IMPACT no Page: 3 of 9 multicenter phase 3 study carried out in two parallel groups of subjects with papulopustular rosacea. Subjects received either twice-daily (morning and evening) AzA Foam, 15% or twice-daily (morning and evening) vehicle. The study duration for each subject, including screening visit, baseline visit, treatment duration including the end-of-treatment visit, and end-of-study visit was up to 17 weeks. Methodology Study center(s): Publication(s) based on the study (references): The study comprised a total of 5-6 ambulatory visits for each subject. At Visit 1 (Day 0), eligibility of the subject was confirmed, baseline measures for efficacy parameters were obtained, and the selected subject was randomized. Screening and baseline visits may have coincided. During the 12-week treatment period of the study, each randomized subject received topical applications of AzA Foam, 15% or vehicle applied to the face without occlusion twice daily. Evaluation of efficacy and safety parameters were completed after 4, 8, and 12 weeks treatment (end-of-treatment visit). Afterwards, there was a 4-week follow-up period that included the end-of-study visit (week 16). Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version study centers in US. None at the time of report creation Study period: Early termination First subject, first visit: Last subject, last visit: Not applicable 24 SEP JAN 2014 Number of subjects: Planned: It was planned to enroll 960 subjects in the active treatment phase, equally distributed to both treatment groups by randomization. Analyzed: 961 subjects were randomized with study drug dispensed (484 in the AzA Foam, 15% group and 477 in the vehicle group). 961 subjects were included in the full analysis set (FAS) which comprised all subjects who were randomized and study medication was dispensed.

5 17 NOV 2014 BAY no / IMPACT no Page: 4 of 9 More details are given in the section on study subjects below. Criteria for evaluation Efficacy Safety: Statistical methods: The co-primary efficacy variables were: Therapeutic success rate according to dichotomized IGA (success=clear or minimal; failure= mild, moderate, or severe) Nominal change in the inflammatory lesion count The secondary efficacy variables were: Percent change in inflammatory lesion count; Therapeutic response rate according to dichotomized IGA (responder=clear, minimal, or mild; nonresponder=moderate or severe) Grouped change in erythema rating (improved, no change, or worsened) The further secondary efficacy variables were: Absolute values of IGA, inflammatory lesion count, and erythema rating Telangiectasia rating Facial skin color rating Subject s global assessment of treatment response Subject s global assessment of tolerability Subject s opinion on cosmetic acceptability Subject s opinion on practicability of product use in facial areas next to the hairline Grouped changes of IGA and rating of telangiectasia Self-reported quality of life parameters: Rosacea quality of life (RosaQoL), Dermatology Life Quality Index (DLQI), and EuroQol Group Questionnaire - 5 Dimensions (EQ- 5D-5L) Safety assessments were adverse event (AE) assessments. Co-primary assessment: Investigator's Global Assessment The following null (H0,1) and alternative (HA,1) hypotheses were evaluated in a confirmatory manner for the end of treatment: H0,1: The 'success' rate of the IGA in the AzA Foam, 15%

6 17 NOV 2014 BAY no / IMPACT no Page: 5 of 9 group is equal or smaller compared to the vehicle group. HA,1: The 'success' rate of the IGA in the AzA Foam, 15% group is greater compared to the vehicle group. To evaluate H0,1, a Cochran Mantel-Haenszel (CMH) test controlling for centers was performed. A one-sided 2.5% significance level was used. Point estimates (odds ratio) of the analysis and 95% confidence intervals (CI) are presented. Co-primary assessment: inflammatory lesion count The following null (H0,2) and alternative (HA,2) hypotheses were evaluated in a confirmatory manner for the end of treatment: H0,2: The mean nominal change from baseline of inflammatory lesion count in the AzA Foam, 15% group was equal or greater compared to the vehicle group. HA,2: The mean nominal change from baseline of inflammatory lesion count in the AzA Foam, 15% group was smaller compared to the vehicle group. To evaluate H0,2, an analysis of covariance (ANCOVA) model was used, where the nominal change in inflammatory lesion count at end of treatment was the response variable, treatment group (AzA Foam, 15% or vehicle) and study center were the factors, and the baseline number of lesions was the covariate. A Type III Sum of Squares (SS) F-test of the treatment effect (H0,2 versus HA,2) was performed at a one-sided 2.5% significance level comparing the least-squares mean values for the two treatments. Statistical significance was needed for the confirmatory analysis of both co-primary variables at the end of treatment to show superiority of AzA Foam, 15% to vehicle. Secondary efficacy variables Secondary efficacy variables were to be tested in a confirmatory manner only if statistical significance was shown for both primary efficacy variables. The confirmatory testing of secondary efficacy variables for the end of treatment time point was to be based on the FAS population using LOCF and was to be analyzed in the following hierarchical order: Percent change in inflammatory lesion count Responder rate Grouped change in erythema rating As predefined in the Statistical Analysis plan, confirmatory testing stopped after the analysis of the grouped change in erythema

7 17 NOV 2014 BAY no / IMPACT no Page: 6 of 9 rating. In addition, all statistical analyses of the secondary efficacy endpoints were conducted for the FAS and PPS using observed data. To evaluate percent change in inflammatory lesion count, an ANCOVA model was used. To evaluate responder rate and grouped change in erythema rating, CMH tests controlling for centers were performed using one-sided 2.5% significance levels. Further secondary efficacy variables Detailed descriptions of the methods of analysis of each of the further efficacy variables are provided in the Statistical Analysis Plan. Safety variables Descriptive Statistics Substantial protocol changes: There were 2 protocol amendments. Amendment 1 on 13 APR 2012 was implemented to incorporate changes of the wording of descriptions in the IGA to include key protocol exclusions for the PPS population, to specify the approximate number of participating centers and the approximate number of subjects per center in this study, and to incorporate changes to ensure a design and conduct of the study that reduces the occurrence of missing data that otherwise would have to be imputed by LOCF and/or alternate methods of handling missing data. Furthermore, a method of assessing treatment-by-center interaction for the absolute change in lesion count endpoint was introduced. Amendment 2 on 20 AUG 2012 was implemented to incorporate changes of the wording of a description in the IGA, as suggested by the Food and Drug Administration (FDA). Both amendments were implemented before first patient first visit. Study subjects There were 1156 subjects screened and 961 subjects randomized with study drug dispensed (484 in the AzA Foam, 15% group and 477 in the vehicle group). The 2 treatment groups were well balanced in terms of demographic and baseline characteristics. The overall mean age was 51.5 years, with 82.8% of subjects <65 years of age. A majority of subjects were female (73.0%) and white (95.5%). At baseline, the overall mean lesion count was 21.4 and most subjects had a moderate IGA score (86.8%). A total of 143 (14.9%) subjects discontinued the treatment phase prematurely, 64 (13.2%) subjects in the AzA Foam, 15% group and 79 (16.6%) subjects in the vehicle group. The most

8 17 NOV 2014 BAY no / IMPACT no Page: 7 of 9 frequent reasons for discontinuing during the treatment phase were: withdrawal by subject and lost to follow up. Six (1.2%) subjects discontinued the treatment phase due to AEs in the AzA Foam, 15% group versus 12 (2.5%) in the vehicle group. Efficacy evaluation Primary efficacy was assessed in terms of IGA success rate and inflammatory lesion counts at the end of treatment in the FAS (LOCF) population. The IGA success rate in the AzA Foam, 15% group was 32.0% versus 23.5% in the vehicle group (P<0.001, one sided). Mean nominal inflammatory lesion counts at baseline (21.7 and 21.2, respectively) decreased by an average of 13.2 lesions (AzA Foam, 15%) and 10.3 lesions (vehicle). This difference was statistically significant (P<0.001, one sided). In summary, these analyses showed the superior efficacy of AzA Foam, 15% over vehicle. Secondary efficacy variables included the percent change in inflammatory lesion count, IGA response rate at end of treatment, and grouped change in erythema rating in the FAS (LOCF) population. Percent change in inflammatory lesion counts at end of treatment in the AzA Foam, 15% group was -60.6% versus -49.5% in vehicle subjects. This difference was also statistically significant (P<0.001, one sided). The IGA response rate at the end of treatment in the AzA Foam, 15% group was 66.1% versus 54.5% in vehicle subjects (P<0.001, one sided). Further, there was a statistically significant treatment difference in favor of the AzA Foam, 15% group (P<0.001, one sided) with regard to grouped change in erythema rating at the end of treatment. An improvement was reported in 61.4% of the subjects in the AzA Foam, 15% group as compared with 51.4% of subjects in the vehicle group at end of treatment. These analyses further supported the superior efficacy of AzA Foam, 15% over vehicle, beyond which was demonstrated by the primary endpoint analyses. During the 4-week follow-up phase (after end of treatment), efficacy parameters (IGA based success rate and nominal change in inflammatory lesion count) of the 2 treatment groups seemed to converge. This convergence of the efficacy parameters between the treatment groups indicates that, although a cure for papulopustular rosacea could not be achieved, the disease activity of this chronic condition was returning rather slowly after the end of treatment. At baseline a majority of subjects in both groups (91.1% in the AzA Foam, 15% group and 91.8% in the vehicle group) were rated as having moderate or severe erythema. At the end of treatment, most subjects had an erythema score of clear or almost clear or mild in both the AzA Foam, 15% (9.3% and 51.7%, respectively) and vehicle (8.4% and 41.9%, respectively) groups. As expected, no relevant difference between treatment groups was observed for the grouped change analysis of telangiectasia. The majority of subjects in both treatment groups showed no worsening. There was some improvement seen in both treatment groups; this improvement was statistically significant using the CMH van Elteren test but not with the Wilcoxon ranksum test. It is known that the presence of erythema may interfere with telangiectasia assessment; differences of telangiectasia ratings like a greater improvement seen in the AzA Foam, 15% group may thus be due to different effects on erythema between the two treatments groups. However, it can be concluded that the majority of subjects in both

9 17 NOV 2014 BAY no / IMPACT no Page: 8 of 9 treatment groups showed no worsening and telangiectasias were generally not affected by the treatment. In the assessment of the subject s facial skin color, both treatment groups showed similar values at baseline, with a majority of subjects showing normal skin color or barely visible skin-lightening compared to skin outside the treatment area (face). At end of treatment, this remained similar, with a majority of subjects again showing normal skin color or barely visible skin-lightening as compared with skin outside the treatment area. There were no meaningful or statistically significant differences between the treatment groups. According to the subject s global assessment of treatment response, 57.3% of subjects in the AzA Foam, 15% group had an excellent or good response, versus only 44.5% of subjects in the vehicle group. The treatment difference was statistically significant (P<0.001). Subject s global assessment of treatment response results are in line with the IGA rating results. The subject s global assessment of local tolerability showed that 67.9% of subjects in the AzA Foam, 15% group and 70.6% of subjects in the vehicle group assessed tolerability as excellent or good, demonstrating a good local tolerability of both treatments. The subject s opinion regarding cosmetic acceptability showed a rating of very good or good for 66.3% of subjects in the AzA Foam, 15% group and 61.5% in the vehicle group, demonstrating good cosmetic acceptability of both treatments. According to the subject s opinion on practicability of product use in facial areas next to the hairline, >70% of subjects in both treatment groups assessed the product as very good or good. Regarding the self-reported quality of life parameters of RosaQoL and EQ-5D, there were small improvements in both treatment groups, with no statistical significance between the groups. Regarding the DLQI, analysis of the grouped overall score at the end of treatment showed a significant treatment difference (P=0.017). Mean changes from baseline for overall scores were -2.6 in the AzA Foam, 15% group and -2.1 in the vehicle group (P=0.019). The wellestablished DLQI showed a significant difference between the treatment groups in favor of AzA Foam, 15%. Subgroup analyses were carried out to assess the effects of baseline inflammatory lesion count, sex, age and race on the primary efficacy measures (IGA success rate and inflammatory lesion count). A treatment effect in favor of AzA Foam, 15% (versus vehicle) was consistently seen in virtually every subgroup. In summary, the analyses of subgroups did not reveal a clear indication of specific efficacy effects for any of the tested subgroups that were not in line with the effects that were observed for the population as a whole. Safety evaluation A single subject in the vehicle group died during the study. The death was accidental and the event (fatal head trauma) was considered unrelated to the study drug both by Investigator as well as by Sponsor assessment. Serious adverse events (all of which were considered unrelated to study drug by the Investigator as well as by Sponsor assessment) were reported for 3 subjects in the AzA Foam, 15% group (bilateral deep vein thrombosis, congestive heart

10 17 NOV 2014 BAY no / IMPACT no Page: 9 of 9 failure, and hepatotoxicity) and 4 subjects in the vehicle group (worsening bipolar disorder, internal bleeding, stomach virus, and the fatal head trauma reported above). There were no drug-related SAEs. A single subject (in the AzA Foam, 15% group) had a positive pregnancy test. This subject had a negative test at Baseline and a positive test at Week 12/end of treatment. Follow-up with this subject is continuing. Treatment-emergent AEs were reported more frequently for subjects in the AzA Foam, 15% group (30.8%) than in the vehicle group (24.9%). Drug-related AEs were reported more frequently for subjects in the AzA Foam, 15% group (7.6%) than for subjects in the vehicle group (4.6%). The observed drug-related TEAEs were predominantly cutaneous in nature and were local (occurred at the application site). There were 3 non-cutaneous AEs occurring in the AzA Foam, 15% group (headache [2 cases], dysgeusia) and 1 non-cutaneous AE occurring in the vehicle group (nausea) that were considered to be drug-related by the investigator. The percentage of subjects with AEs leading to withdrawal from study drug treatment was generally low and higher in the vehicle group (1.2% in the AzA Foam, 15% group and 2.3% in the vehicle group). Cutaneous AEs were reported more frequently for subjects in the AzA Foam, 15% group (11.4%) than in the vehicle group (7.3%). The most common of these TEAEs were application site pain (3.5% in the AzA Foam, 15% group and 1.3% in the vehicle group), application site pruritus (1.4% and 0.4%, respectively), application site dryness (1.0% and 0.6%, respectively), and application site erythema (0.8% and 0.8%, respectively). Twelve subjects (4 in the AzA Foam, 15% group and 8 in the vehicle group) discontinued study drug because of cutaneous AEs. Cutaneous AEs were more prevalent during the first 4 weeks of study treatment than they were during the remainder of the study. Overall conclusions AzA Foam, 15%, this 12-week study supports the efficacy of AzA Foam, 15% applied twicedaily in subjects with papulopustular rosacea. AzA Foam, 15% demonstrates a statistically significant increase in efficacy over vehicle in both primary measures of efficacy: 1) the therapeutic success rate according to the dichotomized Investigator s Global Assessment and 2) the nominal change from baseline inflammatory lesion count. During the 4-week follow-up phase, these main efficacy parameters seemed to converge for the two treatment groups, although some beneficial treatment effect was still persistent in the AzA Foam, 15% treated group. AzA Foam, 15% and vehicle foam were well tolerated. Drug-related adverse events were predominantly local cutaneous events, of mild to moderate intensity, which recovered/resolved at end of study. There were no serious drug-related adverse events. The percentage of subjects with AEs leading to withdrawal from study treatment was low overall, and higher in the vehicle group compared to the AzA Foam, 15% group. The general prevalence of drug-related adverse events decreased over the study course.