Clinical Study Synopsis

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1 Clinical Study Synopsis 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 labeling 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 HealthCare AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare 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 bayerhealthcare.com apply to the contents of this file.

2 Study Sponsor: Study Number: CC Study Phase: Official Study Title: Clinical Trial Results Synopsis Study Design Description Bayer Healthcare Pharmaceuticals Inc N/A Therapeutic Area: Analgesics NCT Single dose methodology pilot study comparing the safety and efficacy of naproxen, ibuprofen and placebo in treatment of pain secondary to dental impaction surgery Test Product Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Aleve (Naproxen, BAYH6689), mg Naproxen Single dose of Naproxen mg (NAP 187.5) capsule, orally with 4 ounces of water Reference Therapy/ Reference Therapy: Ibuprofen 200 mg Matching Dose and Mode of Administration: Duration of Treatment: Upto 8 hours Single dose of ibuprofen 200 mg (IBU 200) or matching placebo capsule, orally with 4 ounces of water Studied period: Date of first subjects first visit: Dec 1990 Date of last subjects last visit: Apr 1991 Study Center(s): One investigational site treated 81 subjects at one center located in USA Methodology: This single center, single-dose, randomized, double-blind, parallel and placebo- and active- controlled study was designed for 75 evaluable subjects. Subjects were randomly assigned to one of the 3 treatment groups (placebo, naproxen or ibuprofen). Pain response was evaluated immediately prior to administration of study drug, one hour after administration and hourly thereafter up to 8 hours. Pain intensity and pain relief were measured on categorical scales and subjects were asked if their pain was at least half gone from baseline at each time point. Subjects remained in the study for up to 8 hours. Back up analgesic medications was available for those subjects who experienced insufficient pain relief from the study medication. At the post-operative follow-up evaluation, the subjects self-rating records were reviewed. Indication/ Main Inclusion Criteria: Subjects at least 15 years of age, with at least moderate post operative pain following surgical removal of one or 2 third molars on the same side of the mouth (atleast one of which was partial bony or complete bony impaction) were included in the study. Page 1 of 4

3 Study Objectives: Evaluation Criteria: Statistical Methods: Overall: To determine the relative analgesic efficacy and adverse effect liability of single oral doses of naproxen compared to ibuprofen and placebo in the treatment of postoperative dental pain following the surgical removal of one or 2 impacted third molars. In addition, results from this study were used to determine the feasibility and sample size for a potential future definitive study or studies. Efficacy (Primary): The primary efficacy variables were obtained by computing the summed pain intensity difference (SPID) scores on the categorical scale and total pain relief (TOTPAR) scores for each subject over the entire 8-hours study period. Efficacy (Secondary): -SPID and TOTPAR scores: 4- and 6-hour scores. -Peak PID: Maximum PID score on the categorical scale. -Peak relief: Maximum pain relief score. -Pain half gone: Proportion of time points at which pain was reported as half gone. -Relief onset: Time at which the subject first reported at least "some" pain relief -Global evaluation: The "end-of-study" overall evaluation. -Use of backup medication: Time at which the subject used backup medication. Safety: Safety was evaluated based on adverse events observed by study personnel or reported by the subjects. Efficacy (Primary): Continuous efficacy variables were analyzed by applying a one way analysis of variance (ANOVA) model with treatment as the main effect and with two-tailed least significant-difference tests being performed for pairwise comparisons. Efficacy (Secondary): Secondary efficacy variables were analyzed using analysis of variance, with the exception of the time related variables. The generalized Wilcoxon test was used to compare the three treatment groups for the two time related-variables, time to taking backup medication and time to relief onset. Safety: All reported adverse events were analyzed by treatment group and summarized by the number of subjects reporting adverse events, severity, relationship to study drug and body system. Likelihood ratio chi-square tests were used to compare the numbers of subjects in each treatment group reporting one or more adverse event. Number of Subjects: Out of the 88 subjects enrolled in the study, 81 subjects were randomized. Eighty subjects were included in the safety analysis since one subject was lost to follow up. Three of the 80 subjects were Page 2 of 4

4 excluded for the efficacy analysis since one subject missed more than one evaluation point, one more subject was excluded due to a protocol violation and one subject had consumed an analgesic on the study day. Study Results Results Summary Subject Disposition and Baseline A total of 88 subjects were enrolled in the study, out of which 81 subjects were randomized into one of the 3 study groups (NAP 187.5, IBU 200 or ). Out of the 81 subjects, all except one subject (lost to follow up) were included in the safety analysis. A total of 77 subjects out of the 80 subjects were included in the efficacy analysis; 26 subjects received naproxen, 25 received ibuprofen and 26 subjects received placebo. Out of the 81 randomized subjects, 21 subjects completed the study (8 subjects each in NAP and IBU 200 groups and 5 subjects in the placebo group). A total of 60 subjects withdrew prematurely from the study. One of the subjects was lost to follow up, 2 subjects due to the noncompliance with the protocol, one subject due to inappropriate enrollment and 56 subjects withdrew from the study due to the need of backup medications (18 in NAP 187.5, 17 in IBU 200 and 21 in placebo). The 3 treatment groups were similar in terms of baseline demographic parameters. Subjects ranged from 17 to 39 years in age (mean: 24.7 years). There were more females than males in the study (56% versus 44%). Most (84%) of the subjects were Caucasian. Subjects weighed between 90 pounds and 250 pounds (mean: pounds). Fourteen (18%) subjects had one tooth extracted, 61(79%) had 2 teeth extracted and 2 (3%) had 3 teeth extracted. Sixty seven (87%) of the subjects had one impacted tooth extraction and 10 (13%) had 2 impacted teeth extraction. The time between surgery and the first dose of study medication ranged from 12 minutes to slightly over 4 hours (mean: 1.6 hours). Moderate pain was reported by 74 (96%) subjects at baseline, and 3 (4%) reported severe pain. Results Summary Efficacy IBU 200 appeared to have slightly higher (better) analgesic responses than NAP for most of the derived efficacy measures, however no statistically significant difference was observed in any of the efficacy parameters among the 3 treatment groups. In general, trends favored the two active treatments over placebo. The only primary efficacy variable with a statistically significant overall treatment effect was the 4-hour SPID score. For 4-hour SPID, IBU 200 was significantly superior to placebo (p=0.010). The 6- and 8-hour SPIDs did not have significant overall treatment effects but the LSD multiple comparison procedure showed that IBU 200 demonstrated significantly better analgesia than placebo (p=0.021 for 6-hour SPID and p=0.044 for 8-hour SPID). No significant differences were found between NAP and placebo for any of the efficacy variables analyzed. No significant differences between NAP and IBU 200 were observed at any hourly evaluation for either PID or relief, but IBU 200 was found to be significantly superior to placebo for PID at 2, 3 and 4 hours after dosing and for relief at 2 hours after dosing. No significant differences (p=0.167) were detected among the 3 treatment groups in the subjects overall global rating of the treatment. No statistically significant (p 0.278) differences among the 3 treatment groups was observed for the time to relief onset. Forty six percent of the subjects in the placebo group experienced 'some' pain relief during the study and more than 50% of the subjects in both NAP and IBU 200 experienced 'some' relief within 2 hours of the drug administration. No statistically significant differences (p 0.246) among the 3 treatment groups was observed for backup medication usage. More than 75% of the subjects in the placebo group required backup medication. About 50% of the subjects in the NAP and IBU 200 groups took Page 3 of 4

5 backup medication within 4 hours after dosing and less than 75% of them needed backup medication throughout the 8-hour study period. Table1: Eight-Hour Efficacy Analysis (N=77) N=26 N=26 N=25 Variable Mean SD Mean SD Mean SD P-Value 8 hr SPID (Cat) hr TOTPAR SPID: Summed Pain Intensity Difference; TOTPAR: Total Pain Relief; hr: Hour ;Cat: Categorical Results Summary Safety Twelve (15%) of the 80 subjects reported a total of 17 adverse events. Two of 27 (7%) subjects in the placebo group reported 2 adverse events, 5 of 27 (19%) in NAP reported 8 adverse events, 5 of 26 (19%) in IBU 200 reported 7 adverse events. The adverse events typically consisted of somnolence, headache, or nausea. All the events were recorded as 'mild' (85%) except 2 (12%) events (asthenia in IBU 200 and somnolence in NAP 187.5) which were graded to be 'moderate' in severity). None of adverse events were severe. Four of the total 17 adverse events (24%) was considered "probably not related to the study medication", 11 of the 17 (65%) was recorded as "unknown" in terms of the relation to the study drug and 2 of the 17 (11%) (dry mouth in and asthenia in IBU 200) were considered "probably related to the study drug". Conclusion(s) In this study, there were no statistically significant differences between NAP mg and IBU 200 mg for any of the derived efficacy measures. The ranks for the three treatment groups in order of more favorable analgesic responses were as follows IBU 200>NAP 187.5>placebo. The same order of groups (IBU 200>NAP 187.5> placebo) was observed for relief onset time and remedication time. Based on these results, it was concluded that hundreds of subjects would be needed to separate the two active treatments because of the small difference in analgesic response observed between these two groups. No further definitive study was recommended. Date Created or Date Last Updated: 07 Sep 2011 Page 4 of 4