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 AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer AG. 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 bayer.com apply to the contents of this file.

2 Study Sponsor: Clinical Trial Results Synopsis Bayer HealthCare AG Study Number: ( ) Study Phase: IV Interventional Study Design Description NCT Official Study Title: A multicenter, double-blind clinical trial to assess the efficacy and tolerability of topical azelaic acid gel 15% once daily compared to topical azelaic acid gel 15% twice daily in subjects with papulopustular rosacea Therapeutic Area: Dermatology Test Product Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Finacea (Azelaic Acid Gel 15%, BAY ) Azelaic Acid Gel 15% (AzA) Group 1: Azelaic acid 15% gel was applied once daily along with once-daily gel base (vehicle/placebo). The gel was applied to the entire facial area (cheeks, chin, forehead, and nose). The subjects were advised that approximately 1 inch of gel (0.5 g) was to be used per application for the entire facial area and was to be rubbed. The gel was applied once in the morning and once in the evening. Reference Therapy/Placebo Reference Therapy: Azelaic acid Dose and Mode of Administration: Group 2: Azelaic acid 15% gel was applied twice daily. The gel was applied to the entire facial area (cheeks, chin, forehead, and nose). Subjects were advised that approximately 1 inch of gel (0.5 g) was to be used per application for the entire facial area and was to be rubbed. The gel was applied once in the morning and once in the evening. Duration of Treatment: Subjects continued the treatment for 12 weeks. Studied period: Date of first subject s first visit: 29 DEC 2006 Date of last subject s last visit: 06 JUN 2007 Premature Study Suspension / Termination: Substantial Study Protocol Amendments: No The study was conducted according to the study protocol final version from 02 NOV 2006 and included no substantial amendments. Study Center(s): This study was conducted at 7 centers in the United States. Methodology: This was a 12-week, multicenter, double-blind, randomized, vehicle-controlled, parallel-group study. The subjects were examined by the investigator at baseline, after Page 1 of 8

3 Indication/Main Inclusion Criteria: Week 4 (Day 28), after Week 8 (Day 56), and after Week 12 (Day 84). At each of these visits, treatment efficacy was assessed from the lesion counts and the intensity of signs and symptoms of rosacea. The lesion count, erythema, and telangiectasia were combined into an overall Investigator's Global Assessment (IGA) score, which contributed to the primary efficacy variable. At Week 12, the investigator and the subjects provided the rating of overall improvement with the study treatment (secondary efficacy variable). The subjects' opinion on cosmetic acceptability was also recorded and the subjects were asked to maintain a usage diary in which they recorded the date and time of medication application. Other secondary efficacy variables were derived from the data used for estimating the primary efficacy variable. These included IGA scores at end of study; nominal IGA scores; changes from baseline in nominal IGA scores; total count (sum) of facial inflammatory papules and pustules; absolute and percent change in sum of facial inflammatory papules and pustules from baseline; investigator's rating of erythema and telangiectasia intensity; and grouped changes from baseline in investigator's rating of erythema and telangiectasia intensity. Safety was assessed at each control visit via recording of adverse events (AEs) and serious AEs (SAEs) throughout the study and the subjects' opinion on local tolerability at end of the therapy. By definition, for this study, all AEs were regarded as treatment emergent, ie, not seen before treatment, or if already present before treatment, worsened after start of treatment. Indication Papulopustular rosacea (subtype 2 rosacea) Study Objectives: Overall: Evaluation Criteria: Main inclusion criteria Papulopustular facial rosacea (subtype 2 rosacea) with a minimum of 10 and a maximum of 50 inflamed papules and/or pustules, persistent erythema, and telangiectasia. Both male and female subjects Age of at least 18 years Assessment of the efficacy and tolerability of topical azelaic acid (AzA) gel 15% once daily compared to topical AzA gel 15% twice daily in patients with papulopustular rosacea. Efficacy (Primary): Investigator s Global Assessment: The actual disease status and treatment efficacy were primarily evaluated by IGA based on a 7-point static scoring system from 0 to 6 (categorized as clear, minimal, mild, mild to moderate, moderate, moderate to severe, and severe) within the confinement of papulopustular rosacea (subtype 2 rosacea). The scoring was based on evaluation of lesion count, erythema (rated from none [either no visible erythema or minimal residual erythema] to severe [red to purple hue, either centrofacial or generalized to whole face]), and telangiectasia (rated from none [no telangiectasia] to severe [many fine vessels Page 2 of 8

4 and/or large vessels discernible, involved more than 30% of the facial area]). Efficacy (Secondary): Investigator's Global Assessment of response: Subject response status, based on the IGA at end of the study (a subject who reached an IGA score of clear, minimal, or mild was categorized as a responder, and a subject with any other score was classified as a non-responder). Investigator's Global Assessment score: Nominal IGA scores (0 [clear] to 6 [severe]) Changes from baseline (IGA scores): Change in IGA was calculated as the IGA nominal score during treatment minus the IGA nominal score at baseline ranging from 7 to +7. Total count (sum) of facial inflammatory papules and pustules Absolute change in the sum of facial inflammatory papules and pustules from baseline Percent change in the sum of facial inflammatory papules and pustules from baseline Investigator's rating of erythema intensity (0 [none] to 4 [severe]) Changes from baseline in investigator's rating of erythema intensity Grouped change from baseline in investigator's rating of erythema intensity, classified as improved, no change, or worse Investigator's rating of telangiectasia intensity (0 [none] to 4 [severe]) Change from baseline in investigator's rating of telangiectasia intensity Grouped change from baseline in investigator's rating of telangiectasia intensity, classified as improved, no change, or worse The investigator's assessment of overall improvement at end of the treatment (expressed on a 5-point scale as follows: excellent improvement, marked improvement, moderate improvement, no improvement, and deterioration) Subjects' assessment of overall improvement at end of the treatment (expressed on a 5-point scale as follows: excellent improvement, good improvement, fair improvement, no improvement, and worse) Subjects opinion on cosmetic acceptability (expressed on a 5- point scale as follows: very good, good, satisfactory, poor, and no opinion) Safety: Adverse events: All AEs were assessed and documented by the investigator according to their seriousness, intensity (mild, moderate, or severe), causal relationship to study drug and study conduct, and main pattern (occurring after every drug Page 3 of 8

5 administration, occurring intermittently or continuously, and any other pattern). Subjects' opinion on tolerability: The subjective opinion was expressed in accordance with a 6-point scale as follows: excellent, good, acceptable despite minor irritation, less acceptable due to continuous irritation, non acceptable, and no opinion. Statistical Methods: Efficacy was evaluated using the following analysis sets: Full analysis set (FAS): All subjects who were randomized and had investigational product dispensed. The subjects who missed assessment during the treatment period were excluded from some analyses. Per protocol set (PPS): The PPS is a subset of the FAS. It included the subjects who were dispensed the study drug and completed the 12-week treatment without major protocol deviations. The primary analysis set for evaluation of the efficacy variables was the FAS using last observation carried forward (LOCF) data. Additionally, the primary efficacy variable and the secondary efficacy variable were analyzed for each treatment visit after baseline and on the PPS. Safety was analyzed using safety analysis set (SAF), which included all the subjects who were dispensed the study drug, even if the medication was not applied. The SAF was identical to the FAS. Efficacy (Primary): Descriptive statistics (n, mean, standard deviation, median, quartiles, minimum, and maximum) were calculated and summary tables were created. The primary efficacy analysis was the assessment of the efficacy of the modified regimen (AzA once daily) in comparison to standard treatment (AzA twice daily) concerning success rate at end of the study. The success rate was compared for differences between treatments using the centeradjusted Cochran-Mantel-Haenszel test with modified ridit scores. The statistical tests were non-confirmatory, and a two-sided 5% significance level was applied. Efficacy (Secondary): Summary tables were created for all original and derived efficacy and safety parameters as well as for population characteristics. Frequency counts by treatment were made for each qualitative variable. Descriptive statistics were calculated for each quantitative variable and selected qualitative variables. Safety: The incidence of local and systemic treatment-emergent AEs were assessed and tabulated. The tabulations included the intensity and the duration of the AEs, as well as the investigator's assessment of the causal relationship of the AEs to the investigational products. Subject opinions about local tolerability were tabulated as well. Page 4 of 8

6 Number of Subjects: Descriptive statistics were calculated for safety evaluations of AEs. Planned: 100 subjects Screened: 101 subjects Randomized: 92 subjects (45 subjects in AzA 15% once-a-day regimen and 47 subjects in AzA 15% twice-a-day regimen) Analyzed: 92 subjects Study Results Results Summary Subject Disposition and Baseline Of 101 subjects, all 92 randomized subjects were included in the FAS and SAF. Five subjects discontinued from the study prematurely. Withdrawal of consent was the primary reason for premature discontinuation (2 subjects in the AzA once-daily group and 1 subject in the AzA twice-daily group). In addition, 1 subject in the AzA once-daily group was dispensed the study medication but never used it, and 1 subject in the AzA twice-daily group lost to follow-up. A total of 22 subjects were excluded from the PPS: 11 subjects in the AzA once-daily group and 11 subjects in the AzA twice-daily group. Missing more than seven doses of study medication was the most common reason for exclusion from the PPS. Six subjects in the AzA once-daily group and seven subjects in the AzA twice-daily group were excluded for missing more than seven doses of the study medication (treatment deviation). In the AzA once-daily group, the subjects were also excluded for study medication not administered, Week 12 visit on Day 93, use of Tazorac (a prohibited medication), and premature discontinuation from the study (due to withdrawal of consent in 2 subjects). In the AzA twice-daily group, the subjects were also excluded for Baseline visit 7 days before the start of treatment, Week 12 visit on Day 76, and premature discontinuation from the study (due to no improvement in 1 subject and withdrawal of consent in 1 subject). There were no statistically significant differences in demographics or baseline characteristics between the treatment groups. The study population (FAS and PPS both were similar) had a median age of 49 years (range: 22-81), and was predominately female (69.6%) and Caucasian (95.7%). Overall, 43 subjects (46.7%) had previously used medication for the treatment of rosacea. The median duration of rosacea was 60 months (range: 9-360) in the AzA once-daily group and 48 months (range: 4-372) in the AzA twice-daily group. The mean inflammatory lesion count (sum of papules and pustules) at baseline was 17.9 lesions in the AzA once-daily group and 19.0 lesions in the AzA twice-daily group. The majority of subjects in both treatment groups had baseline IGA of rosacea classifications of mild to moderate (22.2% in the AzA once-daily group and 25.5% in the AzA twice-daily group) or moderate (51.1% in the AzA once-daily group and 38.3% in the AzA twice-daily group). Results Summary Efficacy Primary efficacy variable: Investigator s Global Assessment: There were no statistically significant differences between the groups in the primary efficacy endpoint of IGA of treatment success when study sites were pooled for analysis. Both the AzA once-daily and AzA twice-daily groups had a success rate of approximately 30% (28.9% in the AzA once-daily group and 31.9% in the AzA twice-daily group). Azelaic acid when used once or twice daily was able to elicit treatment success in approximately 30% of subjects, a treatment response in approximately 53% of subjects, improve erythema in approximately 27% of subjects, and improve telangiectasia in approximately 15% of subjects. The percentage of patients considered to be a treatment success in the PPS was slightly higher compared with the FAS. In the PPS, treatment success was achieved by 12 of Page 5 of 8

7 34 patients (35.3%) in the AzA once-daily group and by 13 of 36 patients (36.1%) in the AzA twice-daily group at end of the study (p=0.9432). Secondary efficacy variables: Investigator s Global Assessment of response: At end of the study, the percentage of subjects achieving treatment success (treatment responders) was similar in both the treatment groups (24 of 45 subjects (53.3%) in the AzA once-daily group and 26 of 47 subjects (55.3%) in the AzA twice-daily group). The percentage of patients considered to have a treatment response in the PPS was slightly higher compared with the FAS. In the PPS, treatment response was achieved by 21 of 34 patients (61.8%) in the AzA once-daily group and by 22 of 36 patients (61.1%) in the AzA twice-daily group at end of the study (p=0.9552). Investigator s Global Assessment scores : At baseline, none of the subjects had IGA scores of clear, minimal, or severe. In the FAS, the mean IGA score was 3.6 in the AzA once-daily group and 3.8 in the AzA twice-daily group. The mean IGA score at end of the study was 2.4 in the AzA once-daily group and 2.2 in the AzA twicedaily group. Changes from baseline (IGA scores): In the FAS, the mean change in IGA scores from baseline was 1.3 in the AzA once-daily group and 1.6 in the AzA twice-daily group. Although the AzA twice-daily group had a slightly larger decrease from baseline, the difference was not statistically significant (p=0.3810). The change from baseline to end of the study in IGA in the PPS was similar to that in the FAS. Total count (sum) of facial inflammatory papules and pustules: In the FAS, the mean nominal value of sum of facial inflammatory papules and pustules at baseline and at end of the study was 17.9 and 6.5, respectively, for the AzA oncedaily group and 19.0 and 6.1, respectively, for the AzA twice-daily group. Absolute change in the sum of facial inflammatory papules and pustules from baseline: The change from baseline to end of the study in facial inflammatory lesion count in the PPS was similar to that in the FAS. In the PPS, the AzA once-daily group had a mean reduction of 11.5 lesions and the AzA twice-daily group had a mean reduction of 11.8 lesions (p=0.8245). Percent change in the sum of facial inflammatory papules and pustules from baseline: The percent change in facial inflammatory lesion count from baseline to end of the study in the PPS was comparable to the FAS for the AzA twice-daily group, but the PPS had a greater than 5% reduction compared to the FAS in the AzA oncedaily group. In the PPS, the AzA once-daily group had a mean percent reduction of 69.5% and the AzA twice-daily group had a mean percent reduction of 71.2% (p=0.7586). Investigator's rating of erythema intensity: In the FAS, the mean nominal value of erythema intensity rating (1 [none] to 4 [severe]) at baseline and at end of the study was 2.8 and 2.6, respectively, for the AzA once-daily group and 2.9 and 2.7, respectively, for the AzA twice-daily group. Changes from baseline in investigator's rating of erythema intensity: In the FAS, the change in erythema intensity from baseline was not significantly different in the two treatment groups (p=0.7571). The change from baseline to end of the study in erythema intensity in the PPS was similar to that in the FAS. Grouped change from baseline in investigator's rating of erythema intensity: In the FAS, the majority of subjects in both the treatment groups showed no change from baseline to end of the study in erythema intensity, but a worsening was noted for a higher percentage of subjects in the AzA once-daily group (5 subjects; 11.1%) compared to the twice-daily group (2 subjects; 4.3%). The difference between the Page 6 of 8

8 groups was not statistically significant at any time point (p= at end of the study). The grouped change from baseline to end of the study in erythema intensity in the PPS was similar to the FAS. Investigator's rating of telangiectasia intensity: In the FAS, the nominal value of telangiectasia intensity rating (1 [none] to 4 [severe]) at baseline and at end of the study was 2.6 and 2.5, respectively, for AzA once-daily group and 2.6 and 2.4, respectively, in the AzA twice-daily group. Changes from baseline in investigator's rating of telangiectasia intensity: In the FAS, the mean change from baseline to end of the study was not significantly different in the two treatment groups (p=0.2060). The change from baseline to end of the study in telangiectasia intensity in the PPS was similar to that in the FAS. Grouped change from baseline in investigator's rating of telangiectasia intensity: In the FAS, the majority of subjects in each treatment group did not experience any change in their telangiectasia intensity during the study. A similar percentage of subjects in each treatment group noted improvement (7 subjects [15.6%] in the AzA once-daily group and 7 subjects [14.9%] in the AzA twice-daily group), but 6 subjects (13.3%) in the AzA once-daily group experienced a worsening of their telangiectasia during the study compared with no subjects in the AzA twicedaily group. The difference between the groups was not statistically significant at any time point (p= at end of the study). The grouped change from baseline to end of the study in telangiectasia intensity in the PPS was similar to that in the FAS. Investigator s assessment of overall improvement at end of the treatment: In the FAS, the Investigator s assessment of overall improvement had a median value of 2.0 or marked improvement in the AzA once-daily group and a median of 3.0 or moderate improvement in the AzA twice-daily group. The difference between the treatment groups was not statistically significant (p=0.3815). The investigator s assessment of overall improvement in the PPS was similar to that in the FAS. Subjects' assessment of overall improvement at end of the treatment: The subjects' assessment of overall improvement had a median value of 2.0 or good improvement in both the groups. One subject in the AzA once-daily group and 2 subjects in the AzA twice-daily group ranked their change as worse. Six subjects in the AzA once-daily group and 2 subjects in the AzA twice-daily group did not have improvement, according to the subjects' assessment. The difference between the treatment groups was not statistically significant (p=0.8230). The subjects' assessment of overall improvement in the PPS was similar to that in the FAS. Subjects' opinion on cosmetic acceptability: The Subjects opinions at end of the study on cosmetic acceptability were similar in each treatment group for the FAS (p=0.5943). The median rating in the AzA once-daily group was 1.0 or very good and the median rating in the AzA twice-daily group was 2.0 or good. The opinions on cosmetic acceptability were similar in the FAS and the PPS. Results Summary Safety Adverse events: Over 40% of subjects in each treatment group experienced drugrelated AEs during the study (46.7% in the AzA once-daily group and 40.4% in the AzA twice-daily group). However, the majority of AEs were transient in duration and mild or moderate in intensity. No subject died during the study and none withdrew from the study due to an AE. Only one treatment-emergent SAE occurred during the study: a subject in the AzA once-daily group experienced severe chest pain that was not related to the study drug. The incidence of cutaneous AEs was higher in the AzA once-daily group (44.4%) compared with the AzA twice-daily group (38.3%). The most frequently occurring cutaneous symptoms were skin burning sensation, skin pain, and pruritus, the majority of which were considered to be drug related. In this study, AzA once daily plus vehicle Page 7 of 8

9 once daily did not lead to less local irritation than AzA twice daily. There were high percentage of subjects in both treatment groups with baseline facial skin signs and symptoms. For example, burning sensation was experienced prior to the study treatment by 26.7% of subjects in the AzA once-daily group and by 14.9% of subjects in the AzA twice-daily group. Subjects with rosacea often report highly sensitive skin, and previous studies have shown cutaneous AEs in subjects treated with vehicle only. It is difficult to directly associate cutaneous AEs with AzA, with vehicle, or with rosacea itself. Subjects' opinion on tolerability: The fact that the subjects did not discontinue use of the study drug due to AEs and that the majority of subjects rated the local tolerability of AzA as good or excellent indicates that AzA is generally safe and well tolerated by subjects. Conclusion(s) In this study, AzA once-daily and the AzA twice-daily dosing regimens showed similar efficacy and tolerability in the subjects. Azelaic acid 15% gel, either once daily or twice daily, for a period of 12 weeks was safe, well-tolerated, and efficacious in the treatment of moderate to severe papulopustular rosacea. Further studies of a larger scale to examine the efficacy of once-daily dosing of AzA in pursuit of a labeling change are warranted on the basis of the results of this study. Publication(s): None at the time this report was created Date Created or Date Last Updated: 30 APR 2014 Date of Clinical Study Report: 03 DEC 2007 Page 8 of 8

10 Appendix to Clinical Study Synopsis Product Identification Information Product Type Drug US Brand/Trade Name(s) Finacea Brand/Trade Name(s) ex-us Azelan, Finacea 15% gel, Skinoren, Skinoren gel, Zelaika, Generic Name Azelaic Acid Main Product Company Code BAY Other Company Code(s) n. a. Chemical Description Nonanedioic acid Other Product Aliases SH H 655 BA Date of last Update/Change: 30 May 2012