PFIZER INC. Study Initiation Date and Completion Dates: Information not available (Date of Statistical Report: 16 May 2004)

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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: Cleocin HCl / Clindamycin hydrochloride PROTOCOL NO: 251F-INF PROTOCOL TITLE: A Single Blind (Evaluator Blind) Comparative Study of Oral Clindamycin Hydrochloride 300 mg BID Compared Against Oral Augmentin 1g BID in the Treatment of Acute Recurrent Tonsillitis/Pharyngitis due to Group A β-haemolytic Streptococci Study Centres: A total of 27 centres in 8 countries (India, Indonesia, Malaysia, Pakistan, Philippines, Taiwan, Thailand and Venezuela) participated in this study (all 27 centres enrolled subjects). Study Initiation Date and Completion Dates: Information not available (Date of Statistical Report: 16 May 2004) Phase of Development: Phase 4 Study Objectives: The primary objective was to compare the bacteriological and clinical cure rates after 10 days of treatment of oral clindamycin 300 mg and oral in subjects with acute recurrent tonsillitis/pharyngitis due to Group A β-haemolytic streptococci (GABHS). In addition, the recurrence rate of infection in the treated subjects, in the period up to 3 months after they had completed their initial 10 days of therapy was also evaluated. The secondary objective of this study was to assess the safety of these 2 antibiotic regimens. METHODS Study Design: This was a multinational, multicentre, prospective, single-blind (evaluator blind) comparative study designed to evaluate the long-term clinical and bacteriological efficacy and safety of oral clindamycin 300 mg (comparator drug:, ie, amoxicillin and clavulanic acid) after a 10-day therapy in subjects with acute recurrent GABHS pharyngotonsillitis. Eligible subjects were randomly assigned to 1 of 2 regimens, treated for 4 to 10 consecutive days depending on the results of a throat swab culture on Day 4. Subjects with negative throat swab culture discontinued therapy, and subjects with positive rapid test continued treatment to Day 10. All subjects had a bacteriological follow-up on Day (ie, 2 days Page 1

2 after completion of the 10-day treatment period) and Month 3 and clinical follow-up at Month 3. The overall duration of subject participation in the study was 3 months (including the 10-day treatment period). Number of Subjects (Planned and Analysed): A total of 774 subjects were enrolled in this study: 384 and 390 subjects in the clindamycin 300 mg and treatment group, respectively. A total of 772 subjects received at least 1 dose of study medication. Diagnosis and Main Criteria for Inclusion: Subjects between 12 and 60 years of age, weighing 40 kg, male or female (women of childbearing potential had to use a reliable birth control method), with a current acute tonsillitis and/or pharyngitis as documented by a positive rapid diagnostic test for GABHS and a positive throat culture for Streptococcus pyogenes, and with a history of at least 2 episodes of documented tonsillar and /or pharyngeal infection within 12 months prior to enrollment. Study Treatment: Oral clindamycin 300 mg capsules were taken twice a day (BID) for 10 days. Oral tablets were taken BID for 10 days. Efficacy Evaluations: The primary efficacy measures in this study were: Bacteriological efficacy after 12 to 14 days of treatment Bacteriological recurrence rate in the period up to 3 months after the subjects completed 10 days of therapy Clinical efficacy assessed after 3 months Bacteriological efficacy at Day and at the 3-month follow-up was recorded with the following 3 categories: Microbiologic eradication was defined as eradication of GABHS at the end of study therapy and subsequent follow-up examinations. Microbiologic persistence was defined as failure to eradicate GABHS at the end of study therapy. Microbiologic recurrence was defined as initial suppression of GABHS with subsequent positive cultures for GABHS. Clinical efficacy at the 3-month follow-up was recorded with the following 4 categories: Clinical cure was defined as complete disappearance of signs and symptoms at end of therapy without recurrence. Page 2

3 Clinical cure with recurrence was defined as the 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. Safety Evaluations: Safety was evaluated by monitoring adverse events (AEs) and serious AEs (SAEs). Statistical Methods: The primary and secondary analyses were performed on the clinically and bacteriologically evaluable populations. The safety data was summarised for the enrolled population. Baseline characteristics of the enrolled study population were summarised and compared between the 2 treatment groups. The primary bacteriological efficacy endpoint collected at the 3-month follow-up visit was evaluated and a comparison between the 2 treatment groups was performed on the bacteriological evaluable population. Additional analyses of the bacteriological endpoint collected at Day were also performed. The clinical efficacy endpoint collected at the 3-months follow-up visit was evaluated and the comparison between the 2-treatment groups was performed on the clinically evaluable population. All statistical tests were 2-tailed and were conducted with type I 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 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 non-parametric method, Wilcoxon Rank sum test was applied for comparison between the 2 treatments groups with respect to continuous variables when strong deviations from normality were observed. Safety data were presented 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. Concomitant medications were coded with Standardised Upjohn Drug Dictionary System. Page 3

4 RESULTS Subject Disposition and Demography: A total of 774 subjects were enrolled in this study: 384 subjects in the clindamycin 300 mg group, and 390 in the treatment group. Overall 772 (99.7%) subjects took at least 1 dose of study medication: 383 (99.7%) subjects in the clindamycin 300 mg group and 389 (99.7%) subjects in the group. A total of 556 (71.9%) subjects completed the day treatment period and the Day visit (274 [71.5%] subjects on clindamycin 300 mg and 282 [72.3%] subjects on ) (Table 1). Overall 217 (28%) subjects prematurely discontinued study treatment, and the most frequent reasons for discontinuation were lost to follow-up, AEs, protocol violations and other. Slightly more AEs leading to premature discontinuation occurred in the clindamycin 300 mg group (6 or 1.6%) compared with the group (2 or 0.5%). Disposition of subjects, reasons for discontinuation, and evaluability status are summarised in Table 1. Table 1. Disposition of Subjects and Evaluability Status Subjects randomised 384 (100%) 390 (100%) 774 (100%) Subjects treated 383 (99.7%) 389 (99.7%) 772 (99.7%) Subjects not treated 1 (0.3%) 1 (0.3%) 2 (0.2%) Subjects who completed 274 (71.5%) 282 (72.3%) 556 (71.9%) treatment period Subjects withdrawn, by 109 (28.4%) 108 (27.7%) 217 (28.0%) Reason: AEs/SAEs 6 (1.6%) 2 (0.5%) 8 (1.0%) Protocol violation 2 (0.5%) 5 (1.3%) 7 (0.9%) Consent withdrawn 0 (0.0%) 1 (0.3%) 1 (0.1%) Lost to follow-up 9 (2.3%) 9 (2.3%) 18 (2.3%) Protocol non-compliance 2 (0.5%) 4 (1.0%) 6 (0.8%) Lack of efficacy 1 (0.3%) 0 (0.0%) 1 (0.1%) Other 89 (23.2%) 87 (22.3%) 176 (22.8%) Enrolled population 384 (100.0%) 390 (100.0%) 774 (100.0%) Safety population 383 (99.7%) 389 (99.7%) 772 (99.7%) Clinically evaluable 280 (72.9%) 280 (71.8%) 560 (70.4%) Bacteriological evaluable 242 (63.0%) 252 (64.6%) 494 (63.8%) AEs=Adverse events; n=number of subjects; SAEs=Serious adverse event Demographic data for all enrolled subjects are summarised in Table 2. Demographic characteristics were well balanced between the 2 treatment groups. The mean age at baseline was 28 years (range years), the mean weight was 59.3 kg (range kg), the proportion of males and females in the study was almost equal (46.5% male and 53.5% female), and most subjects were Asian, White and mixed. Page 4

5 Table 2. Demographic Characteristics Clindamycin 300 mg N=384 N=390 N=774 Treatment P-value Age (years) Mean±SD 28.1± ± ±10.3 Median Range (minimum-maximum) Race White 48 (12.5%) 52 (13.3%) 100 (12.9%) Black 1 (0.3%) 1 (0.3%) 2 (0.3%) Asian 301 (78.4%) 305 (78.2%) 606 (78.3%) Mixed 34 (8.9%) 32 (8.2%) 66 (8.5%) Weight (kg) Mean±SD 59.1± ± ±12.9 Median Range (minimum-maximum) Gender Male 218 (56.8%) 196 (50.3%) 414 (53.5%) Female 166 (43.2%) 194 (49.7%) 360 (46.5%) N= number of subjects; SD=Standard deviation At enrollment, S. pyogenes positive throat cultures were identified in 568 (73.4%) subjects, with 279 (72.7%) subjects on clindamycin 300 mg and 289 (74.1%) subjects on Augmentin 1 g, whereas all 774 (100%) subjects had a positive rapid direct antigen test for GABHS. For a majority of subjects (99%), the tonsils were present. Efficacy Results: Primary Efficacy Measure Bacteriological efficacy at the Day visit, after 10 days of treatment: At Day in the bacteriological evaluable population of 494 subjects, it was found that 475 (96.2%) subjects had microbiological eradication and 19 (3.8%) subjects showed microbiologic persistence. In the clindamycin 300 mg group the microbiologic eradication rate was identified in 237 (97.9%) subjects as compared with 238 (94.4%) subjects in the group (p= derived based on Fisher s exact test). Table 3 below summarises these results. In addition, the microbiologic eradication rates were calculated using the non-bacteriological evaluable population. In the non-bacteriological evaluable population there was an overall eradication rate of 90.7% (90.3%, clindamycin 300 mg; 91.3% ), p= Page 5

6 Table 3. Bacteriological Efficacy on Day 12-14, After 10 Days of Treatment Bacteriological Evaluable Population Description N=242 N=252 N=494 Microbiologic eradication 237 (97.9%) 238 (94.4%) 475 (96.2%) Microbiologic persistence 5 (2.1%) 14 (5.6%) 19 (3.8%) N=Number of subjects Bacteriological recurrence at the 3-month follow-up visit: There was no significant difference in the overall recurrence rate between clindamycin 300 mg and at 3 months of follow-up for the groups that had microbiological eradication at Day 12-14; was 0.4% in group compared with 0.8% in clindamycin 300 mg group, p= At the 3-months follow-up visit, 235 (97.1%) subjects had pathogens eradicated without recurrence in the clindamycin 300 mg group compared with 237 (94%) subjects in the group (p=0.1269). Clinical efficacy after 3 months of treatments In the clinical evaluable population of 560 subjects, at 3 months or early termination it was found that 534 (95.5%) subjects were clinically cured, 11 (2.0%) subjects were rated with clinical cure with recurrence, 9 (1.6%) subjects were rated with clinical failure, and 5 (0.9%) subjects with side effect failure. Clinically cure rates were similar in both treatment groups 95.4% in the clindamycin 300 mg group and 95.7% in the group. Clinical failure rates were higher in the group with (7 subjects or 2.5%) compared with the clindamycin 300 mg group (2 subjects or 0.7%). Side effect failure was recorded by 4 (1.4%) subjects in the clindamycin 300 mg group compared with 1 (0.4%) subject in the group. In general clinical efficacy rates observed in the 2 groups at 3 months were not found to be statistically significant (p=0.1719). In Table 4 below the clinical efficacy variable categorised as cured vs. not cured indicates that in the clinically evaluable population 13 (4.6%) subjects were not cured from the clindamycin 300 mg group compared with 12 (4.3%) subjects who were not cured from the group. The results were not found to be statistically different. Table 4. Clinical Efficacy After 3 Months/ Early Termination Clinical Evaluable Population Description N=280 N=280 N=560 Clinically cured 267 (95.4%) 267 (95.7%) 534 (95.5%) Clinically not cured 13 (4.6%) 12 (4.3%) 25 (4.5%) N=Number of subjects Investigator s assessment of progress of infection Investigator s assessment of progress of infection at 3 months or early termination indicates that in the bacteriological evaluable population, 483 (97.8%) subjects were cured with 240 (99.2%) subjects from the clindamycin 300 mg group and 243 (96.4%) subjects from the Page 6

7 group. This number of subjects is in agreement with number of subjects for whom microbiological eradication was observed at 3 months or early termination. A small percentage of subjects from the bacteriological evaluable population reported improvement (6 subjects or 1.2%); 7 (1.4%) subjects reported no change and worsening was reported by 2 (0.4%) subjects. Safety Results: In total, 94 of the 774 (12.1%) subjects considered evaluable for safety reported having experienced at least 1 AE. A larger percentage of subjects with AEs were observed in the clindamycin 300 mg group compared with the group. In the clindamycin 300 mg group 53 (13.8%) subjects reported AEs, as compared to the 41 (10.5%) subjects who reported AEs from the group. The total number of AEs reported by 94 subjects who experienced any AEs was 117. Among these, subjects in the clindamycin 300 mg group reported 66 AEs, while subjects in the group reported 51 AEs. The AEs were summarised by body system and the results are displayed in Table 5 below in decreasing order of frequency. Overall 74 (9.6%) subjects reported 86 AEs of the digestive system, and diarrhoea was the most commonly reported AE. This event was more frequent in the clindamycin 300 mg group where it was reported by 33 (8.6%) subjects with 33 events compared with, where 22 (5.6%) subjects reported 22 events. Additional digestive body system AEs were: vomiting reported by 8 (1.0%) subjects with 9 reports, nausea reported by 7 (0.9%) subjects with 7 reports, dyspepsia reported by 6 (0.8%) subjects with 6 reports. All other AEs in the digestive system were reported by 2 (0.3%) subjects or less. These AEs were dry mouth, loose stool, borborygmus, gastritis, stomatitis, and toothache and ulcer mouth. Table 5. Number of Subjects Reporting Adverse Events in Each Body System Body System N (%) N (%) N (%) Digestive 44 (11.5%) 30 (7.7%) 74 (9.6%) Body 9 (2.3%) 7 (1.8%) 16 (2.1%) Skin 4 (1.0%) 2 (2.6%) 6 (0.8%) Respiratory 3 (0.8%) 2 (0.5%) 5 (0.7%) Nervous 1 (0.3%) 2 (0.5%) 3 (0.4%) Musculo-skeletal - 1 (0.3%) 1 (0.1%) N=Number of subjects Sixteen AEs of the body as a whole were reported by a total of 16 (2.1%) subjects. The majority of these AEs were abdominal pain reported by 7 (0.9%) subjects with 7 reports, abdominal cramp reported by 5 (0.7%) subjects with 5 reports. In the clindamycin 300 mg group 9 (2.3%) subjects reported AEs in the body as a whole system, while in group 7 (1.8%) subjects reported similar events. Skin system AEs were the third most commonly reported by 6 (0.8%) subjects with the most frequent events, pruritus non-application site reported by 2 (0.3%) subjects with 2 reports, Page 7

8 followed by rash reported by 2 (0.3%) subjects with 2 reports. These AEs were reported in the clindamycin 300 mg group. In respiratory system AEs were reported by 5 (0.7%) subjects with 5 reports. These AEs were reported by 3 (0.8%) subjects in the clindamycin 300 mg group, and by 2 (0.5%) subjects in group. In total 78 (10.1%) subjects reported 100 AEs that were judged by the investigator to have been related to the study treatment. Among those in clindamycin 300 mg group, 45 (11.7%) subjects experienced 58 AEs judged as related to the treatment. This percentage was slightly higher than the reported in group, where 33 (8.5%) subjects reported 42 AEs considered by the investigator to be related to study treatment. A summary of drug related AEs representing the number and percentages of subjects by body system is presented in Table 6 below. Table 6. Summary of Drug-Related Adverse Events by Body System Enrolled Population Body System Digestive 40 (10.4%) 27 (6.9%) 67 (8.7%) Body 8 (2.1%) 5 (1.3%) 13 (1.7%) Skin 3(0.8%) 1(0.3%) 4(0.5%) Nervous 1(0.3%) 1 (0.3%) 2 (0.3%) Respiratory 1(0.3%) 1 (0.3%) 2 (0.3%) n=number of subjects There were no deaths reported during the course of this study. Only 1 subject experienced a SAE during the study. This SAE was reported in 1 female subject who received clindamycin 300 mg and was categorised under body as a whole. The subject experienced a generalised chill, which was severe in intensity. This subject required hospitalisation and the drug was permanently withdrawn. The subject fully recovered. The AE was judged by the investigator as being not related to the study medication. A total of 8 (1.0%) subjects withdrew due to an AE. In clindamycin 300 mg group, 6 (1.6%) subjects were discontinued due to AE. In the group, AEs lead to early termination of 2 (0.5%) subjects. Of the 8 AEs, 2 were severe, 1 mild and 5 AEs were considered as moderate in intensity and all the subjects were recovered. CONCLUSIONS: An evaluation of clinical efficacy after 3 months on the clinically evaluable population indicated that for group the clinical cure rate was 95.7% and for clindamycin 300 mg group the clinical cure rate was 95.4%. Based on Fisher s exact test this result was not found statistically significant (p=0.1719). Clinical failure rates were higher in the group (7 subjects or 2.5%) compared with the clindamycin 300 mg group (2 subjects or 0.7%). Side effect failure was reported by 4 (1.4%) subjects in clindamycin 300 mg group compared with 1 (0.4%) subject in the group. Page 8

9 Evaluation on the bacteriological evaluable population of bacteriological efficacy at Day of treatment indicated that the eradication rate for the clindamycin 300 mg group was 97.9% and the eradication rate for the group was 94.4%. The results were found marginally statistically significant, based on comparison with Fisher s exact test (p=0.0596). Evaluation performed on the bacteriological evaluable population of bacteriological recurrence after 3 months of follow-up indicated that the cure rate in the clindamycin 300 mg group was 97.1% and in the group was 94%. This result was not found statistically significant based on a comparison with Fisher s exact test (p=0.1269). Analysis of safety results indicated that 94 (12.1%) subjects in the study reported 117 AEs. These AEs were reported by 53 (13.8%) subjects in the clindamycin 300 mg group and 41 (10.5%) subjects in the group. The majority of these AEs were reported in the digestive body system by 74 (9.6%) subjects with 86 reports. In the digestive body system the most frequently reported AE was diarrhoea by 55 subjects with a higher proportion of 8.6% in the clindamycin 300 mg treatment group compared with 5.6% in the treatment group. The next most frequent AEs were reported in the body system, body as a whole by 16 (2.1%) subjects. In total, 78 (10.1%) subjects reported 100 AEs that were judged by the investigator to have been related to study treatment. The most commonly reported drug-related AEs were in the digestive system by 67 (8.7%) subjects with a higher percentage of 10.4% being reported in the clindamycin 300 mg group as compared with 6.9% being reported in the group. There were no deaths reported during the course of this study. One subject from the clindamycin 300 mg group reported 1 SAE, which was, generalised chill. The subject subsequently recovered and the SAE was judged by the investigator as being not related to the study medication. Premature discontinuations due to AEs occurred in 8 (1.0%) subjects. Page 9