Allergan Not Applicable AGN A Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Multiple Dose, Parallel

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1 Peripheral Neuropathy Design, Dose Ranging Study of the Safety and Efficacy of AGN in Patients with Painful Diabetic A Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Multiple Dose, Parallel Number and Title of Study: Web Results Page 1 of 5 period, patient recorded a daily average pain score of at least 2 on 5 or more days during the last 7 days of baseline period; patient completed 6 of the last 7 days of the daily average pain score during the baseline period. and no greater than 9 on the 11 point Likert Scale in daily average pain during the last 7 days of baseline exam with symmetrical onset between 6 months and 10 years prior to screening and a score of at least 3 on screening; patients had pain associated with DPN defined as: a mean daily average pain score of at least 4 the investigator section (physical assessment) of the Michigan Neuropathy Screening Instrument (MNSI) at Key Inclusion Criteria: A history of diabetes mellitus type 1 or type 2; PDPN confirmed by neurological Diagnosis: PDPN Approximately 80 patients per treatment arm were to be entered into the study for a total of approximately Diagnosis and Main Criteria for Inclusion: AGN mg, 20 mg, and 60 mg, respectively; 85 patients were randomized to receive placebo. 320 patients. Actual enrollment was 338 patients: 84, 85, and 84 patients were randomized to receive Number of Patients (Planned and Analyzed): (Early Term), and Day 35 (Exit/Follow-up). AGN mg Q 12 hours, AGN mg Q 12 hours, or AGN placebo Q 12 hours. Randomization: Patients were randomized in a ratio of 1:1:1:1 to receive AGN mg Q 12 hours, Visit Schedule: There were 8 office visits: Screening, Baseline, Day 1, Day 7, Day 14, Day 21, Day 29 ranging study Structure: Multicenter, double-blind, randomized, placebo-controlled, multiple dose, parallel design, dose Methodology: treatment of painful diabetic peripheral neuropathy (PDPN). The objective of this study was to evaluate the safety and efficacy of three dose levels of AGN in the Objectives: Study Completion Date (Last Patient Completed): 20 November 2007 Study Initiation Date (First Patient Enrolled): 24 October 2006 Studied Period: Phase of Development: 2 Publication (reference): None at the time of this report Study Center(s): 48 US centers

2 Diagnosis and Main Criteria for Inclusion (continued): Key Exclusion Criteria: Uncontrolled concurrent disease; stroke or myocardial infarction within the past year; any condition that could be adversely affected by orthostatic blood pressure changes or mild to moderate tachycardia including cardiovascular, cerebrovascular or peripheral artery disease; concurrent treatment or history of treatment within 1 year prior to the start of baseline with anti-thyroid drugs propylthiouracil (PTU) or methimazole/carbimazole; amputations that might have affected the assessment of pain associated with DPN; Beck Depression Inventory (B DI) score > 20 at baseline; and history of clinically significant hypotension (including orthostatic hypotension) Test Product, Dose and Mode of Administration: All study medications were administered as an oral capsule to be taken every 12 hours (Q 12 hrs) for 4 weeks. Study Medication strength included 3mg, 20mg, 60mg, and Placebo each administered Ql2hours. Duration of Treatment: Study Medication was administered for 4 weeks. Reference Therapy, Dose and Mode of Administration: The placebo oral capsule was matched to AGN Criteria for Evaluation: Efficacy: mean daily average pain score based on an Il-point Likert scale, percentage of patients with 30% and patients with 50% pain reduction from baseline at Day 29 in mean daily average and worst pain score, mean daily sleep interference score at Day 29, mean daily worst pain score at Day 29, Beck Depression Inventory, Short Form - McGill Pain Questionnaire (SF MPQ), Short Form - Brief Pain Inventory (SF BPI), Subject Global Impression of Change (SGIC), Medical Outcomes Study (MOS) Sleep Scale, Profile of Mood States (POMS) Standard Form, SF-36 Health Survey of Life (Neuro QOL), and rescue medication use. Safety: adverse events, physical exam, laboratory parameters, vital signs, and ECGs TM, Neuropathy-Specific Quality Web Results Page 2 of 5

3 Statistical Methods: The safety population included all patients who received any study medication. The mitt population was considered the primary analysis set and included all randomized patients who received the study medication with at least one post-baseline mean daily average pain score. For efficacy variables and any other variables except safety, all patients in the mitt population were analyzed by the treatment to which they were randomized at Day 1. The primary efficacy endpoint, mean daily average pain score, was analyzed using analysis of covariance (ANCOVA) with treatment and site as main effects, and the corresponding baseline as covariate. Within the overall ANCOVA model, a 2-sided 95% confidence interval (CI) for the difference in mean pain score between each pair of treatment groups was constructed based on the t-test. Summary statistics as well as the least-squares means from the ANCOVA model were provided by treatment group. The effect of site and treatment interaction was included in the above ANCOVA model. If the interaction was not statistically significant at the 10% level, it was removed from the final model. Secondary efficacy analyses included each of the following variables as well as changes from baseline for each: incidence of responders, patients with 30% and patients with 50% reduction of mean daily pain score from baseline at Day 29, mean daily sleep interference score at Day 29, mean daily worst pain score at Day 29, Beck Depression Inventory, SF MPQ, SF BPI, SGIC, MOS Sleep Scale, POMS Standard Form, SF- 36 Health Survey continuous variables were performed for each study visit at which they were evaluated and were analyzed using an ANCOVA model (with treatment and site effects in the model, and the corresponding baseline measure as the covariate). In each case, least-squares means were obtained from the model and the 95% CI of the difference in least-square means between each pair of treatments were constructed. Other secondary efficacy analyses were performed for SGIC and responders based on the daily pain scores at all visits after the baseline period. These categorical variables were analyzed at each visit using the Cochran-Mantel Haenszel (CMH) test adjusting for site. TM, Neuro QOL, and rescue medication use. Treatment group comparisons for these All safety analyses were performed based on the safety population, which included all patients who received any study medication. The incidence of adverse events and treatment-related adverse events was summarized. For each preferred term, the number and percent of patients reporting that adverse event was tabulated and compared using the Chi-square test or the Fisher s exact test as appropriate Web Results Page 3 of 5

4 Summary Conclusions: Patient Disposition and Demographics: A total of337 patients were included in the study in the safety population: 84, 85, and 84 patients were randomized to receive AGN mg, 20 mg, and 60mg, respectively; 84 patients were randomized to receive placebo. Forty seven (47/33 7, 13.9%) patients discontinued from the study: 22.6% (19/84) in the AGN mg group, 11.8% (10/85) in the AGN mg group, 7.1% (6/84) in the AGN mg group, and 14.3% (12/84) in the placebo group. Demographic and baseline pain characteristics were comparable among the treatment groups (all p > 0.05). Efficacy: At Week 4 (Day 29/Early Term), the reduction from baseline in mean daily average pain score was 1.4, 1.4, 1.6, and 1.6 forthe AGN mg, AGN mg, AGN mg, and placebo groups, respectively. There were no statistically significant among-group differences using last observation carried forward (LOCF), baseline observation carried forward (BOCF) or observed cases analysis. Likewise, statistically significant differences between any of the active groups and placebo were not observed in the reduction from baseline in mean daily average pain score at Days 7, 14, or 21. At Week 4 (Day 29/Early Term), the reduction from baseline in mean daily worst pain score was 1.5, 1.5, 1.8, and 1.7 forthe AGN mg, AGN mg, AGN mg, and placebo groups, respectively. There were no statistically significant among-group differences using LOCF, BOCF, or observed cases analysis. Likewise, statistically significant differences between any of the active groups and placebo were not observed in the reduction from baseline in mean daily worst pain score at Days 7, 14, or 21. At Week 4 (Day 29/Early Term), the reduction from baseline in mean daily sleep interference score was 1.5, 1.5, 1.5, and 1.6 for the AGN mg, AGN mg, AGN mg, and placebo groups, respectively. There were no statistically significant among-group differences using LOCF, BOCF, or observed cases analysis. Likewise, statistically significant differences between any of the active groups and placebo were not observed in the reduction from baseline in mean daily sleep interference score at Days 7, 14, or2l Web Results Page 4 of 5

5 Summary Conclusions (continued): Efficacy (continued): Other secondary measures included Beck Depression Inventory score, Short Form - McGill Pain Questionnaire, Brief Pain Inventory - Short Form, MOS Sleep Scale, Profile of Mood States, SF-36 Health Survey, Neuro QoL, and number of patients used rescue medication. Similar to the daily average pain score and daily worst pain score, overall the preponderance of these data did not show significant among-group differences. Safety: One or more adverse events, regardless of causality, were reported for 75.0% (63/84) of patients treated with AGN mg, 55.3% (47/85) of patients treated with AGN mg, 50.0% (42/84) of patients treated with AGN mg, compared with 48.8% (41/84) of patients treated with placebo (p = ). The most common ( 5% in any treatment group) adverse events were dizziness, diarrhea, dry mouth, headache, fatigue, and nausea, with the highest incidence typically occurring in the 60 mg treatment group. One or more treatment-related adverse events were reported for 48.8% (4 1/84) of patients treated with AGN mg, 22.4% (19/85) of patients treated with AGN mg, 19.0% (16/84) of patients treated with AGN mg, compared with 28.6% (24/84) of patients treated with placebo (p <0.001). No deaths occurred in this study. Eight patients experienced 9 serious adverse events (SAEs): 3 patients in the 60 mg group, 2 patients in the 20 mg group, 1 patient in the 3 mg group, and 2 patients in the placebo group, respectively. None of these SAEs was considered to be treatment related by the investigator and all resolved without sequelae. Conclusion: AGN was not significantly different from placebo in reducing mean average daily pain from baseline at week 4 (primary endpoint) or at any other studied timepoints at the studied doses (ie, 3 mg, 20 mg, and 60 mg). Similar results were demonstrated based on worst pain, sleep interference score, responder rate outcomes, and other secondary measures. In this study, AGN demonstrated an acceptable safety and tolerability profile Web Results Page 5 of 5