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1 2. SYNOPSIS Title of Study: A 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: Donald R. Mehlisch, MD., D.D.S., M.S.D. Study Centers: Biomedical Research Group, Inc., 3200 Red River, Suite 300, Austin, TX Publication (reference): Study Period: Date of first enrollment: Date of last completed: Phase of Development: Objective: The overall objective of this study was to evaluate over a 12 hour observation period the pharmacokinetic (PK), pharmacodynamic (PD), efficacy and safety profiles of a single dose of 600 mg extended release caplets compared to equivalent total doses of regular release caplets (marketed OTC product), administered in divided doses every four hours, and placebo in the treatment of moderate to severe postoperative 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. Only the efficacy and safety results are reported; the PK/PD results are not included in this report. 1

2 All patients who met the entrance criteria were enrolled in one of two study sub-groups at an approximately 1:1 ratio. One sub-group of patients had both pharmacokinetic and pharmacodynamic evaluations (PK group), and 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 sub-groups, and patients from both subgroups were assigned at random to one of the five treatments. 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 200 patients were entered into the study; 197 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 a least one partial or complete bony impacted third mandibular molar. The term impacted included: partial bony impaction; bony impaction; complicated bony impaction (Types 3 through 5). Test Product, Dose and Mode of Administration, Batch Number: Ibuprofen Extended Release 600 mg, caplet oral (z-4000; C ) Ibuprofen Regular Release 600 mg, caplet oral (z-4001; C-243-7C) Duration of Treatment: The following five treatments were administered over eight hours: Ibuprofen Extended Release 600 mg single dose Ibuprofen Regular Release 200 mg at 0, 4, and 8 hours Ibuprofen Regular Release 400 mg; 200 mg at 4 hours Ibuprofen Regular Release 600 mg single dose Placebo 2

3 Reference Therapy, Dose and Mode of Administration, Batch Number: Placebo, caplet oral (z-4002; C B) Criteria for Evaluation: Efficacy Safety: Statistical Methods: SUMMARY - CONCLUSIONS Efficacy Results: Demographic and Baseline Characteristics: Table 1-1 summarizes the demographic parameters for the 200 patients randomized and the 197 patients in the efficacy analyses. 3

4 There were no statistically significant differences among treatments for Sex and Race (p>0.09). For Age, the differences among treatments was statistically significant in both the all patients randomized population (p=0.01) and the efficacy evaluable population (p=0.02). There were no significant differences among treatments for baseline pain or surgery parameters (p > 0.13) or on the pre-treatment vital signs (p > 0.20). 4

5 Efficacy Analysis: The primary outcome measures used to assess the effectiveness of study drugs were the hourly pain intensity differences from baseline, the hourly pain relief measures, the time to rescue, time to onset, and the overall rating of study medication. Pain Intensity Evaluations Table 1-2 shows the significance levels for pain intensity differences area under the curve comparisons. All treatments were significantly better than placebo (p < 0.001) for all intervals. During the first four hours, the Ibuprofen Regular Release 600/0/0 treatment had a significantly greater area under the curve than the Ibuprofen Extended Release treatment (p = 0.03). Ibuprofen Extended Release did not differ from any Ibuprofen Regular Release regimen for any other comparison. Pain Relief Evaluations Table 1-3 shows the significance levels for pain relief evaluations area under the curve comparisons. All treatments were significantly better than placebo (p < 0.001) for all measures. In the first 4 hours the 600/0/0 treatment had a significantly larger area under the curve than the extended release treatment (p = 0.02). Ibuprofen Extended Release did not differ from any Ibuprofen Regular Release regimen for any other comparison. 5

6 Time to Rescue All treatments had a significantly longer time to Rescue than placebo with no significant differences between Ibuprofen Extended Release and any Ibuprofen Regular Release regimen. Time to Onset Of Meaningful Relief All treatments had significantly shorter Time to Onset of Meaningful Relief than did placebo (p < 0.001). There were no significant differences between Ibuprofen Extended Release and any of the Ibuprofen Regular Release regimens. Overall Rating of Study Medication All treatments had significantly better Overall Ratings than placebo (p < 0.001). No other differences between treatments were found to be statistically significant (p > 0.15). Safety Results: Table 1-4 summarizes all adverse drug experiences (ADEs) that were reported in this study. The incidence of patients reporting ADEs among the five groups was not statistically significant (0.09). There were no deaths or serious ADEs reported. No safety report submission was required. For the four treatments and placebo, headache, nausea, somnolence and vomiting were the most frequently reported ADEs. 6

7 Conclusions: All treatments (i.e. both Extended Release 600 mg and all Regular Release regimens) were significantly better than placebo consistently across all measures of efficacy. Ibuprofen Extended Release 600 mg provided constant and adequate relief over 12 hours comparable to Ibuprofen Regular Release 200/200/200. There was no diminishing of relief over the 12 hours such as that seen with Ibuprofen Regular Release 600/0/0 or Ibuprofen Regular Release 400/200/0. Ibuprofen 600 mg regular release was superior to extended release over the first four hours of pain measures. Ibuprofen Extended Release was comparable to Ibuprofen Regular Release 400/200/0 and Ibuprofen Regular Release 600/0/0 in area under the curve measures from 0-12 hours for pain intensity differences and pain relief. 7

8 Patients taking Ibuprofen Extended Release obtained Onset of Meaningful Relief as fast or faster than did patients on any of the Ibuprofen Regular Release regimens. Ibuprofen Extended Release was comparable to Ibuprofen Regular Release 600/0/0, Ibuprofen Regular Release 400/200/0 and Ibuprofen Regular Release 200/200/200 in Overall Rating of Study Medication. Ibuprofen extended release was well tolerated and demonstrated a safety profile comparable to current OTC doses of. No deaths or serious ADEs were reported in this study for any treatment group. Date of the Report: January 14,