PFIZER INC. Study Initiation Date and Completion Dates: 09 March 2000 to 09 August 2001.

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. PROPRIETARY DRUG NAME /GENERIC DRUG NAME: Dalacin / Clindamycin hydrochloride PROTOCOL NO.: 251F-INF (A ) PROTOCOL TITLE: A Double Blind Comparative Study of Oral Clindamycin Hydrochloride 300 mg BID Compared Against Oral Clarithromycin 250 mg BID in the Treatment of Acute Recurrent Tonsillitis/Pharyngitis due to Group A β-haemolytic Streptococci. A Multinational Multicentric Study Study Centres: The study involved 14 centres in 9 countries, and the number of enrolled subjects by country was: Venezuela (40 subjects), Argentina (37 subjects), Pakistan (18 subjects), Thailand (16 subjects), Philippines (13 subjects), China (12 subjects), Taiwan (9 subjects), Korea (6 subjects), and Mexico (1 subject). Study Initiation Date and Completion Dates: 09 March 2000 to 09 August Phase of Development: Phase 4 Study Objectives: To evaluate the long-term clinical and bacteriological efficacy and safety of oral clindamycin hydrochloride (HCl) capsules in acute recurrent Group A β-haemolytic streptococci (GABHS) pharyngotonsillitis, in comparison with the macrolide clarithromycin. Primary Objective: To assess the clinical and bacteriological cure rates after 10 days of treatment with oral clindamycin HCl compared with oral clarithromycin in subjects with acute recurrent tonsillitis/pharyngitis. Secondary Objectives: METHODS To assess the clinical and bacteriological recurrence rates at the 3-month follow-up visit. To assess safety of oral clindamycin HCl capsules after 10 days of treatment and at the 3-month follow-up visit. Study Design: This was a prospective, comparative, randomised, double-blind study in subjects with acute recurrent GABHS pharyngotonsillitis. Eligible subjects were randomised Page 1

2 to receive clindamycin HCl 300 mg twice daily (BID) or clarithromycin 250 mg BID. Efficacy and safety were assessed after 10 days of treatment and at the 3-month Follow-up visit. Number of Subjects (Planned and Analysed): Two hundred (200) subjects were planned to be enrolled, to achieve 150 evaluable subjects (75 subjects per treatment group). Overall, 152 subjects were enrolled (76 subjects per treatment group), and 148 subjects received at least 1 dose of study medication. Of the 152 subjectspatients enrolled, 107 subjects were clinically evaluable and 106 subjects were bacteriologically evaluable. The enrolment was closed because of the expiry of blinded clinical supplies. The study did not meet the enrolment objectives defined in the protocol. Diagnosis and Main Criteria for Inclusion: Subjects between 11 and 60 years of age, male and female, with an attack of acute tonsillitis and/or pharyngitis including fever, sore throat, dysphagia, tonsillar exudates, enlarged cervical lymph nodes, positive throat swab culture for GABHS, and a positive history of at least 2 episodes of pharyngitis or tonsillitis within 1 year prior to enrolment. Study Treatment: Oral clindamycin HCl 300 mg capsules were taken BID for 10 days. Oral clarithromycin 250 mg tablets were taken BID for 10 days. Efficacy Evaluations: The efficacy evaluations were as follows: For primary analysis the clinical endpoint recorded at Day 12 to 14 of the study and at the 3-month follow-up visit was used. The clinical evaluation was performed with the following 4 categories: Clinical cure complete disappearance of signs/symptoms at end of therapy without recurrence. Clinical cure with recurrence development of symptomatic pharyngitis documented to be caused by GABHS before or during follow-up period in subjects who were asymptomatic at the end of therapy. Clinical failure subjects who remained symptomatic with no improvement after a minimum of 4 days of therapy. Side effect failure subjects who experienced side effects necessitating early termination of study treatment. Bacteriological endpoint was recorded at Day 12 to 14 of the study and at 3 months follow-up and the evaluation was performed with the following 3 categories: Microbiologic eradication was defined as eradication of GABHS. Microbiologic persistence was defined as failure to eradicate GABHS at the end of study therapy. Page 2

3 Microbiologic recurrence was defined as initial suppression of GABHS with subsequent positive cultures for GABHS. Safety Evaluations: Safety evaluations included the following: Safety data was analysed and reported with adverse events (AEs), serious adverse events (SAEs) and withdrawal from treatment. Statistical Methods: For the purpose of presentation of summary and inference statistics the following 4 study populations were considered: Enrolled subject population; clinically evaluable population; bacteriological evaluable population and safety population. Enrolled subject population: Subjects who were randomised to treatment. Clinically Evaluable population: Subjects who satisfied the following criteria were included: Compliant with inclusion and exclusion criteria. Randomised to 1 of the treatment groups. Results of throat culture at 4 days visit indicated Streptococcus pyogenes. Subjects who took at least 4 days of medication. Subjects who did not omit 2 or more consecutive doses of medication. Subjects should not have received any additional systemic non protocol antibiotic treatment for infections other than tonsillitis or pharyngitis. Subjects with clinical efficacy evaluation after 10 days of treatment. Bacteriological Evaluable population: Subjects who satisfied the following criteria were included: Subjects included in clinically evaluable population. Subjects should have bacteriological efficacy evaluation after 10 days of treatment. Safety population: Subjects who were randomised to 1 of the treatment groups and received at least 1 dose of study medication were included in the safety population. The efficacy endpoints were measured after 10 days of treatment and 3 months follow-up and comparison between the 2 treatment groups were performed on clinically and bacteriological evaluable populations. All statistical tests were 2-tailed and were conducted with Type 1 error of Categorical variables were summarised with frequencies and percentages. Continuous variables were summarised with the measures of location mean and median; and with the measures of dispersion standard deviation, 25 th and 75 th percentiles and the range. Pearson Page 3

4 chi-squared test was used for categorical data, and the Fisher's exact test was applied for cases when the expected number of observations per cell was <5. The 95% confidence interval for the difference between the cure rates between the 2 treatment groups was calculated with Yates' formula for correction for continuity. The non parametric method, Wilcoxon sum rank test was applied for comparison between the 2 treatment groups with respect to continuous variables. The proportion of subjects who were withdrawn from each treatment group was calculated. Safety data were analysed with respect to incidence of AEs and SAEs. The AEs and SAEs were summarised for each treatment group with counts and percentages by body system, and by Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) preferred terms. Data were also summarised with respect to intensity, relation to study drug, action taken, outcome and seriousness of the event. The primary and secondary analyses were performed on the clinically and bacteriological evaluable populations. The safety data was summarised on the enrolled population. Concomitant medications were coded with Standardised UpJohn drug dictionary system system. RESULTS Subject Disposition and Demography: A total of 152 (100.0%) subjects were enrolled in this study, 76 (50.0%) subjects in each treatment group. Overall 148 (97.4%) subjects took at least 1 dose of study medication and were analysed for safety, 107 (70.4%) subjects were clinically evaluable, and 106 (69.7%) subjects were bacteriologically evaluable. Subject disposition is summarised in Table 1. Page 4

5 Table 1. Subject Disposition and Subjects Analysed Number (%) of Subjects (n[%]) Population Subset Enrolled 76 (100%) 76 (100%) 152 (100%) Randomised 76 (100%) 76 (100%) 152 (100%) Subjects took study medication 75 (98.7%) 73 (96.1%) 148 (97.4%) Subjects did not take study medication 0 (0.0%) 3 (3.9%) 3 (2.0%) Completed 49 (64.5%) 58 (76.3%) 107 (70.4%) Subjects completing each visit Screening visit 76 (100%) 76 (100%) 152 (100%) Day 4 visit 68 (89.5%) 68 (89.5%) 136 (89.5%) Day visit 53 (69.7%) 61 (80.3%) 114 (75.0%) Early termination 2 (2.6%) 1 (1.3%) 3 (2.0%) 3 months visit 46 (60.5%) 57 (75.0%) 103 (67.8%) Withdrawn 27 (35.5%) 18 (23.7%) 45 (29.6%) Adverse events 2 (2.6%) 1 (1.3%) 3 (2.0%) Protocol violation 12 (15.8%) 6 (7.9%) 18 (11.8%) Lost to follow-up 6 (7.9%) 5 (6.6%) 11 (7.2%) Protocol non-compliance 2 (2.6%) 0 (0.0%) 2 (1.3%) Lack of efficacy 1 (1.3%) 1 (1.3%) 2 (1.3%) Other 4 (5.3%) 5 (6.6%) 9 (5.9%) Analysis data set Safety evaluable subjects 75 (98.7%) 73 (96.1%) 148 (97.4%) Clinically evaluable subjects 49 (64.5%) 58 (76.3%) 107 (70.4%) Bacteriologically evaluable subjects 48 (87.9%) 58 (76.3%) 106 (69.7%) Forty-five (45) subjects were identified as clinically non-evaluable and had 1 or more reasons for non-evaluability (Table 2). Table 2. Reasons for Clinical Non-Evaluability Reasons Failure to meet entry criteria 7 (9.2%) 3 (3.9%) 10 (6.6%) Throat culture not Streptococcus pyogenes 18 (23.7%) 15 (19.7%) 33 (21.7%) Non-compliant on Day (35.5%) 18 (23.7%) 45 (29.6%) No clinical efficacy evaluation 24 (31.6%) 15 (19.7%) 39 (25.7%) Has not taken any study medication 1 (1.3%) 3 (3.9%) 4 (2.6%) Has not completed the treatment period 27 (35.5%) 18 (23.7%) 45 (29.6%) number of subjects 27 (35.5%) 18 (23.7%) 45 (29.6%) BID = Two times a day; HCl = Hydrochloride. Reasons for bacteriological non-evaluability: Forty six (46) subjects were identified as bacteriological non-evaluable and had 1 or more reasons for non-evaluability. The reasons for bacteriological non-evaluability were the same as for clinical non-evaluability with the addition of 1 subject who had no bacteriological efficacy evaluation at Day of the study. Page 5

6 Subject Demographics: A summary of demographic characteristics for all subjects is presented in Table 3. Table 3. Demographic Characteristics Baseline Demographics p-value Age (years) Number of subjects Mean (std) 29.5 (10.4) 28.3 (10.8) 28.9 (10.6) Median Range (11,55) (12,59) (11,59) Race White 26 (34.2%) 27 (35.5%) 53 (34.9%) Black 1 (1.3%) 0 (0.0%) 1 (0.7%) Asian 38 (50.0%) 36 (47.4%) 74 (48.7%) Mixed 11 (14.5%) 13 (17.1%) 24 (15.8%) Weight (kg) Number of subjects Mean (std) 61.0 (11.4) 65.4 (14.6%) 63.2 (13.2) Median Range (27,100) (30,120) (27,120) Gender Female 51 (67.1%) 48 (63.2%) 99 (65.1%) BID = Two times a day; HCl = Hydrochloride; std = Standard deviation. Results of Streptococcus pyogenes positive culture were identified in 119 (78.3%) subjects, 58 (76.3%) subjects in the clindamycin HCl 300 mg group and 61 (80.3%) subjects in the clarithromycin 250 mg group. Duration of illness at study entry indicated that 73 (98%) subjects had signs and symptoms 1 to 2 days prior to study enrolment, 60 (39.5%) subjects indicated duration of illness 3 to 4 days prior to study enrolment, 14 (9.2%) subjects indicated duration of illness 5 to 6 days prior to study enrolment and 5 (3.3%) subjects indicated duration of illness 7 or more days prior to study enrolment. The distribution of duration of illness was not statistically significant between the 2 treatment groups. Efficacy Results: Efficacy after 10 days of treatment: In the clindamycin HCl 300 mg group, the clinical cure rate was 91.8% compared with 100% in the clarithromycin 250 mg group (p=0.0411). The 95% confidence interval limits for the difference between clindamycin HCl and clarithromycin cure rates were 17.8%, 1.5%. A summary of the efficacy after 10 days of treatment is presented in Table 4. Page 6

7 Table 4. Population Clinical Efficacy After 10 Days of Treatment - Clinically Evaluable Description Clindamycin HCl n = 49 Clarithromycin n = 58 n = 107 Clinically cured 45 (91.8%) 58 (100.0%) 103 (96.3%) Not cured 4 (8.2%) 0 (0.0%) 4 (3.7%) Clinical recurrence up to 3 months post therapy: The overall recurrence rate in the study was 7.0%, with 9.5% in clindamycin HCl group compared with 5.2% in clarithromycin group (p =0.4493). The 95% confidence interval limits for the difference between clindamycin HCl and clarithromycin cure rates were 17.1% and 8.4%. A summary of the clinical recurrence up to 3 months post therapy is presented in Table 5. Table 5. Clinical Recurrence up to 3 Months Post Therapy Clinically Evaluable Population Clinical Evaluation Recurrence at 3 Months Clindamycin HCl n = 49 Clinically cured at Day 12 to 14 Clarithromycin n = 58 n = 107 Yes 4 (9.5%) 3 (5.2%) 7 (7.0%) No 38 (90.55) 55 (94.8%) 93 (93.0%) Bacteriological efficacy after 10 days of treatment: In clindamycin HCl 300 mg group, the bacteriological cure rate was 93.8% compared with 96.6% in the clarithromycin 250 mg group (p=0.6565). The 95% confidence interval limits for the difference between clindamycin HCl and clarithromycin bacteriological cure rates after 10 days of treatment were -13.1% and 7.5%. Table 6 summarises the above results. Table 6. Description Bacteriological Efficacy After 10 Days of Treatment - Bacteriological Evaluable Population Clindamycin HCl n = 48 Clarithromycin n = 58 n = 106 Bacteriologically cured 45 (93.8%) 56 (96.6%) 101 (95.3%) Bacteriological cure with recurrence 3 (6.2%) 2 (3.4%) 5 (4.7%) Bacteriological recurrence up to 3 months post therapy: In the bacteriological evaluable population it was recorded that at 3 months of follow-up the overall recurrence rate in the study was 1.2%, with 3.1% in the clindamycin HCl group compared with 0.0% in the clarithromycin group (p=0.3902). The 95% confidence interval limits for the difference between clindamycin HCl and clarithromycin bacteriological cure rates after 3 months follow-up were 11.8% and 5.6%. A summary of bacteriological recurrence up to 3 months post therapy is presented in Table 7. Page 7

8 Table 7. Bacteriological Recurrence up to 3 Months Post Therapy - Bacteriological Evaluable Population Bacteriological Evaluation Recurrence at 3 Months Clindamycin HCl n = 48 Clarithromycin n = 58 n = 106 Microbiological Microbiological 1 (3.1%) 0 (0.0%) 1 (1.2%) recurrence eradication at No microbiological Day 12 to (96.9%) 50 (100.0%) 81 (98.8%) recurrence Safety Results: Out of 152 subjects, 34 (22.4%) subjects considered for safety evaluation reported at least 1 AE. A larger percentage of subjects with AEs were observed in clindamycin 300 mg group (27.6%) compared with clarithromycin 250 mg group (17.1%). There were no deaths during this study. A summary of the number of subjects who reported 1 or more AEs during the study is presented in Table 8. Table 8. Summary of Number of Subjects who Reported 1 AEs During the Study: Safety Population n % Number Number Number n % n % of AEs of AEs of AEs subjects Subjects with no AEs Subjects with AE AEs = Adverse events; BID = Two times a day; HCl = Hydrochloride; n = Number of subjects. AEs summarised by body system and presented in decreasing order of frequency are summarised in Table 9. The most frequently reported AE was related to the digestive system (17.8%). The majority of subjects (11) with digestive system AEs experienced diarrhoea. This event was significantly more frequent in clindamycin HCl group (8 subjects; 10.5%) compared with clarithromycin (3 subjects; 4.0%; p=0.2165). Additional AEs identified as more frequent in the digestive body system were: nausea reported by 6 (4.0%) subjects with 6 reports, dyspepsia reported by 4 (2.6%) subjects with 4 reports, flatulence by 3 (2.0%) subjects with 3 reports, gastritis by 2 (1.3%) subjects with 2 reports and vomiting reported by 2 (1.3%) subjects with 2 reports. AEs related to the body system were the second most commonly reported by 6 (4.0%) subjects. In the clindamycin 300 mg group, 2 (2.6%) subjects reported AEs in this system and in the clarithromycin 250 mg group, 4 (5.3%) subjects reported similar events. The AEs reported included headache (3 subjects), abdominal pain localised (2 subjects), and abdominal pain generalised (1 subject). Nervous system AEs were the third most commonly reported by 4 (2.6%) subjects with the most frequent events, dizziness reported by 2 (1.3%) subjects with 2 reports in similar proportions reported in both treatment groups; in clindamycin 300 mg group Page 8

9 1 (1.3%) subject reported 1 event and in clarithromycin 250 mg group 1 (1.3%) subject reported 1 event. Table 9. Number of Subjects Reporting AEs in Each Body System Body System Digestive 18 (23.7%) 9 (11.8%) 27 (17.8%) Body 2 (2.6%) 4 (5.3%) 6 (4.0%) Nervous 2 (2.6%) 2 (2.6%) 4 (2.6%) Urogenital 1 (1.3%) 1 (1.3%) 2 (1.3%) Cardiovascular 1 (1.3%) 1 (1.3%) 2 (1.3%) AEs = Adverse events; BID = Two times a day; HCl = Hydrochloride. AEs leading to premature discontinuation were reported for 3 (2%) subjects. None of the subjects died during the study period. SAEs: A summary of the number of subjects in each study group who experienced SAEs is presented in Table 10. Overall 3 (2.0%) subjects reported a total of 4 SAEs. A total of 2 (2.6%) subjects in the clindamycin HCl 300 mg group reported 2 SAEs, and 1 (1.3%) subject in the clarithromycin 250 mg group reported 2 SAEs. Table 10. List Of Subjects With Serious Adverse Events Age Gender Treatment COSTART Study Action Outcome Term Related Taken 37 Female Medical termination of Drug Clindamycin Pregnancy pregnancy done on the No permanently HCl unintended request of the subject withdrawn 23 Male Clarithromycin Nausea Recovered Yes None 23 Male Clarithromycin Vomiting Recovered Yes None 41 Female Clindamycin HCl Diarrhoea Recovered Yes None COSTART = Coding Symbols for a Thesaurus of Adverse Reaction Terms; HCl = Hydrochloride. CONCLUSIONS: In conclusion therefore, the study did not meet the protocol objective of adequate subject recruitment, due to expiry of the blinded clinical supplies. However, from an analysis of the available subject pool it was apparent that the clinical and bacteriological cure rates after 10 days of treatment and recurrence rates after 3 months of treatment were comparable between the 2 treatment groups. The 2 treatment regimens were safe and the most common AEs reported were the expected gastrointestinal side effects. Page 9