Clinical Study Report Synopsis

Transcription

1 Clinical Study Report Synopsis A Phase 1, Multi-Centre, Randomised, Vehicle-Controlled, Double-Blinded, Explorative Clinical Trial to Evaluate a Left-Right Design in Adults with Mild to Moderate Atopic Dermatitis over a Treatment Period of Three Weeks Multi-Centre, Prospective, Randomised, Vehicle-Controlled, Double-Blinded Trial with Intra-Individual Left-Right Comparison Clinical Development and Safety Protocol Code Number: EXP-1092 Report Date: 16-Dec-2014 EudraCT Number:

2 Protocol Code Number: EXP-1092 Report Date: 16-Dec-2014 Page 2 of 5 Clinical Study Report Synopsis Statement Approval Statement, Sponsor The following persons have approved this Clinical Study Report Synopsis on behalf of using electronic signatures: Biostatistics Medical Department Approval Statement, Investigator The International Coordinating Investigator approves the Clinical Study Report Synopsis by manually signing the International Coordinating Investigator Clinical Study Report Approval Form, which is a separate document adjoined to this report. The following person has approved this Clinical Study Report Synopsis:, M.D. International Coordinating Investigator

3 Protocol Code Number: EXP-1092 Report Date: 16-Dec-2014 Page 3 of 5 Synopsis Name of Sponsor/Company: Name of Finished Product: Elidel cream 1 % Name of Active Ingredient: 10 mg/g pimecrolimus Title of Trial: A Phase 1, Multi-Centre, Randomised, Vehicle-Controlled, Double-Blinded, Explorative Clinical Trial to Evaluate a Left-Right Design in Adults with Mild to Moderate Atopic Dermatitis over a Treatment Period of Three Weeks Investigators: There were 3 Principal Investigators., M.D.,, Germany was International Coordinating Investigator. Trial Centre(s): The trial was conducted at 3 trial centres in Germany and coordinated by. Publication(s) based on the trial: None at the time of this Clinical Study Report. Trial Period: Date of first enrolment: 08-Apr-2014 Date of last enrolment: 18-Jul-2014 Date of last completed: 01-Sep-2014 Phase of Development: Phase I Objectives: Primary Objective: To validate a left-right design to detect a difference in efficacy after 3 weeks of treatment between an active treatment and a vehicle in adults with mild to moderate AD with respect to the Total Sign Score (TSS). Methodology: Two comparable and symmetrical AD affected entire target areas (ETAs) measuring cm 2, each were identified per subject and treated with Elidel cream 1 % and vehicle cream. The ETAs should have been located on one of the 4 body regions: Arms and legs on left and right; stomach and chest on left and right side (distance between the left and right lesions of at least 5 cm). The comparison of Elidel cream 1 % and vehicle cream was performed intra-individually. Screening: Check of subject s eligibility for the trial including documentation of demographic data. Baseline: Re-check of inclusion and exclusion criteria, recording of medical history and prior/concomitant medication, vital signs (blood pressure [BP] and pulse rate [PR]), pregnancy test in all women, duration of AD, lesion size of the ETAs, Investigator s Global Assessment (IGA) of overall disease severity of lesions, investigator s assessment (TSS and disease severity), subject s assessment (itching and disease severity) and transepidermal water loss (TEWL) measurement. Treatment Period: Non-occlusive topical treatment of ETAs twice daily over 3 weeks applied by the subjects. Investigator assessment (TSS and target area), subject assessment (itching and target area) and TEWL measurement, recording of concomitant medication and AEs, weighing of used tubes and treatment diary during study visits. Follow-up Period: Follow-up on all AEs classified as probably and possibly related or not related or not assessable to the IMPs 2 weeks after the subject s final visit or final outcome. Primary efficacy assessment: TSS of ETA. The TSS included the following signs of AD: Erythema, edema/papulation, oozing/crusting, excoriations, lichenification and dryness. The severity of each of the signs of AD was graded by the investigator for each of the 2 ETAs, respectively, according to the following 4-point scale: 0 = absent; 1 = mild; 2 = moderate; 3 = severe. The TSS of the ETAs was assessed by the investigator on Days 1 (baseline), 8, 15 and 22. Safety assessments: Relevant medical history of the past 5 years, concomitant medication, vital signs (BP and

4 Protocol Code Number: EXP-1092 Report Date: 16-Dec-2014 Page 4 of 5 Name of Sponsor/Company: Name of Finished Product: Elidel cream 1 % Name of Active Ingredient: 10 mg/g pimecrolimus PR), physical examination of the skin, extent of exposure to study drug, AEs. Number of Subjects (Planned and Analysed): 30 subjects planned; 30 subjects in Full Analysis Set (FAS) and Safety Set (SAF); 27 subjects in Per-Protocol Set (PPS). Diagnosis and Main Criteria for Inclusion: 1. Male or female subjects, 18 years or older 2. Subjects with atopic dermatitis with mild to moderate disease severity 3. Two symmetrical and comparable atopic dermatitis treatment areas 4. Female volunteers of childbearing potential had to either be surgically sterile or agree to use a reliable method of contraception Investigational Product, Dose and Mode of Administration, Batch Number: IMP 1: Elidel cream 1 % (10 mg/g pimecrolimus); batch no. Ch.-B. B Daily dosage: Minimum 80 mg cream (0.8 mg pimecrolimus), maximum 200 mg cream (2.0 mg pimecrolimus) Total dosage: Minimum 1.68 g cream (16.8 mg pimecrolimus), maximum 4.2 g cream (42 mg pimecrolimus) IMP 2: Vehicle cream mimicking the excipients of Elidel cream; batch no. Ch.-B ( ) Approximately 2 mg/cm 2 of IMP 1 and IMP 2 per test area (20 50 cm 2 ) were topically applied twice daily. Duration of Treatment: 21-day treatment period (a total of 42 applications) Reference Therapy, Dose and Mode of Administration, Batch Number: n.a. Criteria for Evaluation: Efficacy Primary Efficacy Endpoint TSS at end of treatment (EoT) for ETA Safety Safety was evaluated by tabulations of relevant medical history of the past 5 years, concomitant medication, vital signs (BP and PR), physical examination of the skin, extent of exposure to study drug, AEs. Subjects withdrawn from the trial, together with reason for discontinuation were to be listed. Other Safety Analyses: Outcomes of the vital signs and their changes from baseline were summarised using summary statistics Statistical Methods: Evaluation of treatment effect in ETA-TSS at EoT based on the TSS, assessed on the AD affected ETAs (primary endpoint) performed within the framework of an ANCOVA model with treatment, trial centre and baseline TSS as fixed effects and subject as random effect. The primary efficacy analysis was carried out for the FAS and the PPS analyses. All other efficacy analyses were carried out for the FAS only. FAS: The FAS included all randomised subjects who received at least one dose of IMP and had at least one post-baseline assessment. The efficacy analyses were based on the FAS. PPS: The PPS was a subset of the FAS. Subjects with major protocol deviations and subjects who discontinued the trial prematurely were excluded from the PPS. (continued)

5 Protocol Code Number: EXP-1092 Report Date: 16-Dec-2014 Page 5 of 5 Name of Sponsor/Company: Name of Finished Product: Elidel cream 1 % Name of Active Ingredient: 10 mg/g pimecrolimus Statistical Methods (continued): SAF: The SAF included all subjects who received any IMP at least once; all safety analyses were based on the SAF. Hypotheses: A hypothesis and alternative were only used to explore superiority of Elidel cream 1 % vs. vehicle. Data were evaluated descriptively. Summary Conclusions Study Population The trial was performed in 30 subjects (17 male and 13 female) aged from 18 to 75 years with mild to moderate AD. The data of 30 subjects were used for the FAS and SAF analyses and the data of 27 out of 30 subjects for the PPS analysis (3 premature discontinuations: 2x exclusion criteria, 1x unacceptable AE [moderate hypertension]). 27 subjects completed the trial as planned. In this trial, only minor procedure compliance deviations were reported that had no relevance on the outcome of the trial and did not lead to exclusion from any of the analysis sets. Efficacy Summary: In this trial, the AD left-right comparison model was found to be appropriate to detect a difference in efficacy between the moderately potent active topical Elidel cream 1 % (10 mg/g pimecrolimus) and the vehicle in adults with mild to moderate AD with respect to the TSS after 3 weeks of treatment with twice daily nonocclusive application (42 applications in total). The ANCOVA analysis demonstrated a statistically significant lower estimate of total ETA-TSS at EoT for Elidel cream 1 % (5.0) when compared to the vehicle (7.6) (Elidel cream 1 % minus vehicle = -2.5, p = ) (primary endpoint) and therefore, Elidel cream 1 % (5.0) was found to be superior to vehicle. Hence, the model has proved to be suitable for detecting effects in treatment of AD by confirming the moderately potent effect of Elidel cream 1 %. The primary aim of validating this left-right design was therefore met. The difference between Elidel cream 1 % and vehicle was further confirmed by a greater decrease of mean values in total TSS in ETA (mean changes from baseline: -3.4 vs. -0.9) at EoT (Day 22). A clear onset of treatment effect was already seen for total TSS after one week of treatment with Elidel cream 1 %. Overall, the difference in treatment effect between Elidel cream 1 % and the vehicle assessed for the primary endpoint (ETA-TSS at end of treatment) was supported by the results of other efficacy endpoints in the trial. Safety Summary: In summary, treatment with Elidel cream 1 % and the vehicle were safe and very well tolerated pertaining to all safety endpoints assessed in this trial. 10 non-serious TEAEs were reported in 7 subjects that were all assessed as not related to IMPs and not corresponding to a specific test field. 9 AEs had recovered/resolved and 1 AE (moderate pharyngitis) had an unknown outcome at the end of the trial. There were no deaths or other SAEs reported in this trial. Conclusion: Overall, the AD left-right comparison model used in this clinical trial has been validated to be sensitive for detecting differences in efficacy of a moderately effective non-steroidal topical for treatment of AD compared to vehicle. A statistically significant difference in total ETA-TSS was detected in favour of the non-steroidal product (Elidel cream 1 %) when compared to vehicle when applied twice daily in adults with mild to moderate AD over a 3-week treatment period. In this trial no safety concerns were raised for treatment with Elidel cream 1 % and the vehicle.

6 EXP-1092 Clinical Study Report Synopsis EudraCT no Dec English ELECTRONIC SIGNATURES Electronic signahtre made within edoc LEO by LEO Pharma AIS employees or employees of any LEO Pharma AIS affiliate located anywhere in the world, are to be considered to be legally binding equivalent of traditional handwritten signahtres. Meaning of Signature Department, Medical Approval - Biostatistics Approval 18-Jan :08 GMT Jan :47 GMT+01