PFIZER INC. GENERIC DRUG NAME and/or COMPOUND NUMBER: 5% Spironolactone Cream/ PF

Transcription

1 PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. GENERIC DRUG NAME and/or COMPOUND NUMBER: 5% Spironolactone Cream/ PF PROTOCOL NO.: S PROTOCOL TITLE: A Multicenter, Double Blind, Vehicle Controlled Study of Topical 5% Spironolactone Cream in the Treatment of Nodulocystic Acne Study Centres: A total of 8 centres in the United States took part in the study. Study Initiation Date and Primary Completion or Completion Dates: 26 January 1990 to 31 October 1990 Phase of Development: Phase 2 Study Objective: To evaluate the efficacy and safety of 5% w/w spironolactone cream applied 3 times per day, in comparison with its vehicle, in subjects with nodulocystic acne METHODS Study Design: This was a randomised, double blind, multicentre vehicle controlled comparison of 5% spironolactone cream applied topically in the treatment of subjects with nodulocystic acne. The duration of treatment was 24 weeks with 18 weeks double blinded and the last 6 weeks open label with all subjects treated with the active drug. There were 10 scheduled study visits: pre study (within 14 days of the first dose); Week 0, 3, 6, 9, 12, 15, 18, and 21 of treatment; and Week 24. Number of Subjects (Planned and Analysed): In order to achieve a target sample size of 80 fully evaluable subjects, approximately 100 subjects were planned to enrol in the study, with each study centre enrolling at least 20 subjects A total of 76 subjects were enrolled and received the study treatment and, of these, 44 completed the study. Diagnosis and Main Criteria for Inclusion: Subjects were male or female outpatients, aged between 12 and 45 years, with nodulocystic acne with a minimum of 6 inflamed nodular and/or cystic lesions of the face, each lesion measuring greater than 4 mm in the largest diameter. Study Treatment: Spironolactone was supplied as 5% w/w cream, and the comparator was the same formulation but without spironolactone. Both active and vehicle medications were supplied in 30 gram tubes. In addition, subjects were supplied with 1 bar of non irritating Page 1

2 soap and 1 bottle of shampoo. Subjects were requested to apply an adequate amount of spironolactone cream (approximately 1 inch) to cover the entire face 3 times per day after washing the face with soap and water, and patting dry. Subjects were instructed not to wash their face for at least 3 hours after each application. After 18 weeks of double-blind treatment, the last 6 weeks were open-label, with all subjects receiving the active study drug. Efficacy Evaluations: Primary endpoints: Assessment of the reduction of nodulocystic lesions, inflammatory lesions and non inflammatory lesions at the end of the study, with respect to their baseline counts determined by lesion counts. Efficacy evaluations were conducted at baseline (Week 0) and at 3 week intervals thereafter until the end of the study. The investigator s assessment of the overall clinical response to treatment was made at the Week 18 and 24 visits. Safety Evaluations: The safety of spironolactone in this subject population was evaluated throughout the study. The variables assessed included adverse event (AE) monitoring, clinical laboratory evaluations (CLEs) and vital sign measurements. CLEs included hematology, biochemistry and urinalysis. Statistical Methods: All subjects who received at least 1 dose of study medication were included in final safety analysis. Chi square test of significance was used to examine between group differences that were greater than 5%. Laboratory data were examined using scatter plots, shift tables and change from baseline values. Shift tables were analysed using McNemar s or Stuart-Maxwell test, as appropriate. Sign tests and t tests were used to analyse changes from baseline values. Vital signs and dermatological examination data were analysed using repeated measures analysis of variance. The nominal statistical significance was assessed at the 0.05 level. RESULTS Subject Disposition and Demography: A total of 76 subjects were enrolled in the study; all 76 subjects received the study drug. The study population consisted of 43 (57%) male and 33 (43%) female subjects, with a median age of 21 years (range years). The demographic and baseline characteristics of all 76 subjects are presented in Table 1. Page 2

3 Table 1. Demographics and Baseline Characteristics Placebo Spironolactone p-value Age (years) N a Mean Standard deviation Median Range Race/Ethnic origin, n (%) Caucasian 27 (73) 24 (62) b Black 1 (3) 4 (10) Hispanic 8 (22) 10 (26) Asian 0 (0) 1 (3) Others 1 (3) 0 (0) Total 37 (100) 39 (100) Gender, n (%) Male 21 (57) 22 (56) b Female 16 (43) 17 (44) Total 37 (100) 39 (100) Height (in) N a Mean Standard deviation Median Range Weight (lb) N a Mean Standard deviation Median Range a : p-value from two-sample t-test : p-value from Fisher s exact test N/n: Number of subjects; in: Inches; lb: Pounds As shown in Table 2, a total of 32 subjects were discontinued from the study, with the majority of discontinuations being due to protocol non compliance (15 subjects). Table 2. Reasons for Study Termination Reason a Placebo n (%) Spironolactone n (%) Lost to follow-up 4 (11) 3 (8) Discovery of pre-existing violation 1 (3) 4 (10) Protocol non-compliance 5 (14) 10 (26) Treatment failure 2 (5) 3 (8) Adverse sign or symptom 0 (0) 0 (0) Total 12 (32) 20 (52) Lost to follow-up 4 (11) 3 (8) Withdrawn 8 (22) 17 (44) Completed study 25 (68) 19 (49) Randomized 37 (100) 39 (100) a : Mutually exclusive and exhaustive categories n: Number of subjects Page 3

4 Efficacy Results: The efficacy data were not assessed. Safety Results: AEs were reported for both the double blind and open label periods. The most frequently occurring AEs during the double blind period are shown in Table 3. All 76 subjects received the study treatment (37 received placebo and 39 received spironolactone in the double blind period), and 44 completed the study (25 in the placebo group and 19 in the spironolactone group). Double Blind Period Forty six (61%) of 76 subjects enrolled in the study experienced AEs. Of these, 21 (57%) were from the 37 subjects who received placebo, and 25 (64%) were from the 39 subjects who received spironolactone. The AEs reported for more than 3 subjects across both treatment groups were headache, upper respiratory tract infection, rhinitis, coughing and pain. Table 3. Adverse Events for >3% Subjects Overall, Number (%) of Subjects, Safety Population Number (%) of Subjects Adverse Event Placebo Spironolactone Injury-accidental 0 (0) 3 (8) Pain 2 (5) 2 (5) Influenza like symptoms 3 (8) 0 (0) Headache 8 (22) 13 (33) Dysmenorrhoea 0 (0) 3 (8) Infection 0 (0) 2 (5) Upper respiratory tract infection 3 (8) 5 (13) Rhinitis 4 (11) 4 (10) Coughing 3 (8) 1 (3) Two subjects experienced 4 severe events. These included 1 spironolactone subject who experienced a severe infection in the genital area on Day 65 of treatment; the infection lasted for 6 days. The subject was hospitalised for this infection and the event was resolved. One placebo subject experienced asthenia, heart palpitation and heart valve disorder (mitral valve prolapse) on Day 19 of treatment. All of these 4 events were considered to be severe, but were not considered to be related to the study treatment. All other reported AEs were mild in severity, except for facial oedema, headache, dental abscess, bacterial infection, pruritus and conjunctivitis in the placebo group, and accidental injury (dog bite), pain in cystic lesions, headache, earache, tendinitis, ear infection, upper respiratory tract infection and pharyngitis in the spironolactone group. Irritation reported in a placebo treated subject was the only event considered to be probably related to the study treatment. Five events that were related to the skin were also reported. Page 4

5 Open-Label Period Seven subjects (9%) experienced AEs, the majority of which were mild in severity. Mild headache was observed in 6 subjects, moderate headache in 1 subject and mild sore throat in another. None of the events were considered to be related to the study treatment. Overall for the study, none of the AEs resulted in withdrawal of a subject from the study. There were no deaths during the study period. There was 1 reported serious AE the case of infection in the genital area of 1 spironolactone subject, as described above. CONCLUSIONS: Spironolactone 5% cream and its vehicle were generally well tolerated, with only 5 AEs involving the skin (none directly attributable to spironolactone) when used topically for weeks to treat nodulocystic acne. Page 5