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1 2. SYNOPSIS Title of Study: A phase III comparative study of the pharmacokinetic/pharmacodynamic and safety profiles of extended release, regular release and placebo during a 12 hour observation in post-extraction dental pain. Investigators: James R. Fricke, D.D.S., M.S.D. Study Centers: Pharmaco LSR Health Research Center, 2901 North IH-35, Austin, TX Publication (reference): Study Period: Date of first enrollment: Date of last completed: Phase of Development: 3 Objective: The overall objective of this study was to evaluate over a 12 hour observation period the pharmacokinetic, pharmacodynamic, efficacy and safety profiles of a single dose of 600 mg extended release caplets compared to equivalent total doses of regular release 200 mg caplets administered in three different dosing regimens, and placebo in the treatment of moderate to severe post-operative dental pain resulting from three or four third molar extractions including at least one partial or complete bony impacted third mandibular molar. Methodology: This study was a double-blind, randomized, parallel, placebo-controlled, single-center, PK/PD, dental pain study. All patients who met the entrance criteria were enrolled in one of two study subgroups. One sub-group of patients had both pharmacokinetic and pharmacodynamic evaluations 1

2 (PK group); the other sub-group of patients had only the analgesic efficacy evaluations (non-pk group). A separate randomization schedule was used for each of the two subgroups. Patients assessments of pain intensity and pain relief as well as blood samples for plasma analysis were obtained at the study site at Hours 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 4.5, 5, 6, 7, 8, 8.5, 9, 10, 11, and 12. A stopwatch technique was used to measure the onset of meaningful pain relief. Number of Subjects (planned and analyzed): A total of 210 patients were entered into the study; 208 patients were eligible for the efficacy analyses. Diagnosis and Main Criteria for Inclusion: The patients evaluated in this study consisted of male or non-pregnant and non-lactating female out-patient volunteers, 16 years of age or older, complaining of moderate to severe pain following the surgical extraction of three or four third molars with at least one partial or complete bony impacted third mandibular molar. The term impacted included: partial bony impaction; bony impaction; or complicated bony impaction. Test Product, Dose and Mode of Administration, Batch Number: Ibuprofen Extended Release 600 mg caplet (z-4003; C ), oral Ibuprofen Regular Release 200 mg caplet (z-4004; C-243-7C), oral Duration of Treatment: The following five treatments were administered over eight hours: Ibuprofen Extended Release 600 mg single dose at 0 hour Ibuprofen Regular Release 600 mg single dose at 0 hour Ibuprofen Regular Release 400 mg at 0 hour; 200 mg at 4 hours Ibuprofen Regular Release 200 mg at 0, 4, and 8 hours Placebo 2

3 Reference Therapy, Dose and Mode of Administration, Batch Number: Placebo caplet (z-4005; C B), oral Criteria for Evaluation: Efficacy: Patients assessments of pain intensity and pain relief as well as blood samples for plasma analysis were obtained at the study site at Hours 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 4.5, 5, 6, 7, 8, 8.5, 9, 10, 11, and 12. A stopwatch technique was used to measure the onset of meaningful pain relief. Safety: Statistical Methods: SUMMARY - CONCLUSIONS Efficacy Results: Only the efficacy and safety results are provided in this report; the PK/PD results are not included in this report. Demographic and Baseline Characteristics: Table 1-1 summarizes the demographic parameters for the 210 patients. There were no statistically significant differences among treatments for any demographic variable, for any baseline variables (p > 0.65), or pretreatment vital signs (p > 0.42). 3

4 Pain Intensity Evaluations Table 1-2 summarizes the differences between treatments on the pain intensity evaluations. Overall, for the Hour 0 to Hour 12 area comparisons, all treatments were significantly better than placebo (p < 0.001). Ibuprofen regular release 400/200/0 showed superiority over extended release (p = 0.01) and regular release 200/200/200 (p = 0.03). Figure 1-1 summarizes the results for pain intensity differences over time. 4

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6 Pain Relief Evaluations Table 1-3 summarizes the differences between treatments on the pain relief evaluations. Overall, for the Hour 0 to Hour 12 area comparisons, all treatments were significantly better than placebo (p < 0.01) and regular release 400/200/0 showed superiority over extended release (p = 0.002), regular release 200/200/200 (p = 0.003) and regular release 600/0/0 (p = 0.05). 6

7 Time to Rescue (Remedication) All active treatments had significantly longer times to remedication than did placebo (p < 0.004). Ibuprofen extended release was not significantly different from regular release 200/200/200 (p = 0.43) or regular release 600/0/0 (p = 0.23). However, regular release 400/200/0 had significantly longer times to remedication than extended release (p = 0.02). Only marginally significant differences were observed in the comparisons between the regular release treatments (p > 0.06). Time to Onset All active treatments had significantly shorter times to onset than placebo (p < 0.007). Ibuprofen extended release was not significantly different from regular release 200/200/200 (p = 0.86). The regular release regimens with 7

8 larger doses earlier had at least marginally significantly shorter times to onset than extended release (p < 0.08). Overall Rating of Study Medication All active treatments had significantly better Overall Ratings than placebo (p < 0.001). Ibuprofen extended release was not significantly different form regular release 200/200/200 (p = 0.50) and had significantly worse Overall Ratings than regular release treatments with larger doses earlier (p < 0.01). Safety Results: Table 1-4 summarizes the adverse drug experiences (ADEs) that were reported in this study. The overall ADE rate was not statistically significant different among the five groups (p = 0.86). The majority of all ADEs as well as drug-related or possibly drug-related ADEs reported in each treatment group were nausea, vomiting and headache. Ibuprofen was well tolerated. There were no deaths or serious ADEs that required the submission of a safety report. 8

9 Conclusions: The results of this study demonstrated that in the comparisons among the extended release treatment, the regular release treatments and placebo, similar trends were found for hourly pain intensity differences from baseline, hourly pain relief evaluations, time to onset, time to rescue and overall rating of study medication. In virtually all comparisons between active treatments and placebo, the active treatments were significantly better than placebo. Ibuprofen extended release was not significantly different from regular release 200/200/200. Furthermore, the regular release treatments that provided doses greater than 200 mg during the first four hours demonstrated significantly greater efficacy than the extended release and regular release 200/200/200 treatments. In general, regular release 600/0/0 did not demonstrate greater efficacy than regular release 400/200/0 during this interval reflecting observations from controlled clinical trials that doses greater than 400 mg were no more effective than the 400 mg dose. The somewhat longer duration of efficacy of regular release 400/200/0 compared with extended release may have been due to the cumulative effect of the 400 mg loading dose plus the sustained blood levels from the second 200 mg dose of at four hours. The statistically significantly greater efficacy of the regular release treatments compared to placebo demonstrated the validity of the dental extraction analgesic model used in this study. The treatment superiority of extended release over placebo in this analgesic model demonstrated that the dental pain model had sensitivity through the 12 hour observation period. This is particularly relevant since it can be assumed that the pain in this model does not abate in 12 hours and often returns to baseline levels in the absence of adequate analgesic treatment. Ibuprofen extended release was well tolerated in this clinical trial. There were no overall differences between groups with respect to total ADEs, drug-related ADEs or possibly drug-related ADEs. No deaths or serious ADEs that required the submission of a safety report were reported in this study for any treatment group. Date of the Report: October 13,