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: Lyrica /pregabalin PROTOCOL NO.: 1008-034 PROTOCOL TITLE: Pregabalin BID Add-On Trial: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multicenter Study in Patients With Partial Seizures (Protocol 1008-034) Study Center(s): 71 US centers and 5 centers in Canada Study Initiation Date and Primary Completion or Completion Dates: 11 November 1998 to 17 September 1999 Phase of Development: Phase 3 Study Objective(s): The objectives of this study were to evaluate the efficacy and safety of 4 dosages of pregabalin administered BID as add-on treatment in patients with partial seizures. METHODS Study Design: Following screening and an 8-week baseline period, patients entered a 12- week, randomized, double-blind, parallel-group, placebo-controlled, multicenter study. Randomization was to either placebo, or to 1 of 4 pregabalin dose groups: 50, 150, 300, or 600 mg/day administered BID. Current antiepileptic drug (AED) therapy was maintained. Clinic visits were scheduled on Days -56 and -28 during baseline, Day -1 at randomization, Days 14, 28, 56, and 84 during double-blind, and one follow-up visit during the interval Days 98-112. Number of Subjects (Planned and Analyzed): Planned: 400 patients randomized, 80 per treatment arm (assuming approximately a 10% loss in primary efficacy population, defined as Evaluable, would provide a minimum of 70 patients per treatment arm to be included in the primary analysis. Analyzed: A total of 455 patients were randomized to treatment: 100 to placebo; 88 to pregabalin 50 mg/day; 88 to pregabalin 150 mg/day; 90 to pregabalin 300 mg/day; and 89 to pregabalin 600 mg/day. Two patients randomized to receive pregabalin 150 mg/day did not take any study medication and were not included in efficacy or safety analyses. Page 1
Diagnosis and Main Criteria for Inclusion: Men or nonpregnant, nonlactating women 12 years of age and older, of any race, weighing at least 40 kg (88 lb) with partial seizures (simple partial, complex partial, and/or secondarily generalized tonic clonic) were eligible. Patients were included who failed to have adequate seizure control in the past while on standard AEDs and continued to be receive 1 to 3 standard AEDs at doses within an acceptable therapeutic range. Study Treatment: Capsules; pregabalin 25 mg, pregabalin 100 mg, and matching placebo. Administration: capsules administered twice daily (BID). Duration of treatment: 12 weeks. Efficacy Evaluations: Primary: The primary criterion to establish the efficacy of pregabalin was the reduction in the frequency of all partial seizures during the double-blind period compared with the baseline period. For each patient, the baseline period was defined as Study Days -56 to -1. The double-blind period was defined as starting on Study Day 1 and ending on the day the patient withdrew from or completed the study. The number of days in the treatment period for a given patient could have been less or greater than the 12 weeks planned for in the protocol. The observed seizure rate during baseline and double-blind was standardized for a 28-day period. Patients with no double-blind seizure data had their baseline seizure rate carried forward into the double-blind period in order to include all ITT patients. Because the amount of diary data and duration of time in the double-blind period of the study varied from patient to patient, the 28-day seizure rate was defined as follows: Period in the above formula was either the baseline phase or double-blind phase of the study. Secondary: The secondary efficacy parameters were: Responder rate, which was defined as the percent of patients who had at least a 50% reduction in 28-day frequency of seizures during treatment compared with baseline; and Percent change, which was defined as percent change in 28-day seizure frequency during treatment compared with baseline. Additional secondary parameters assessed by descriptive statistics were: The length of seizure-free intervals and the number of seizure-free days per a 28-day period; and RRatio, responder rate, and percent change for each seizure type. Pharmacokinetic Evaluations: Pharmacokinetic: Standard plasma/serum AED concentration and plasma pregabalin concentrations were assessed periodically during the study. Page 2
Safety Evaluations: Safety was evaluated by recording adverse events at each clinic visit; frequency and intensity of adverse events were summarized and evaluated Physical (including vital signs assessments) and neurological examinations were performed at each clinic visit during the study. 12-lead electrocardiogram (ECG) with a 2-minute cardiac rhythm strip were obtained at baseline (Day -56) and during double-blind at Days 14 and 84. Laboratory tests including hematology, blood chemistry, and urinalysis were obtained at baseline (Day -56), at randomization (Day -1), during double-blind (Days 14, 28, 56, and 84) and at follow-up (Days 98-112). Pregnancy testing was performed at each clinic visit during the study. Visual examinations (acuity, funduscopy, and visual fields) were performed baseline (Day -56) and at the termination of double-blind (Day 84); visual-related adverse events were also reviewed. Statistical Methods: The primary efficacy parameter was response ratio (RRatio or symmetrized percent change) as a comparison of baseline 28-day partial seizure rate (B) with treatment 28-day partial seizure rate (T) according to the formula: RRatio = [(T- B)/(T+B)] 100. Analysis was performed using an analysis of variance (ANOVA) model with treatment (as main effect) and center (clusters) and RRatio as the dependent variable (= 0.049, 2-sided). Secondary efficacy parameters were the responder rate, defined as the proportion of patients who had a 50% reduction in seizure rate during treatment as compared to baseline, and the percent change (PCH) in 28-day seizure rates in treatment compared to baseline. The responder rate was compared between treatments using a Cochran-Mantel-Haenszel chisquare analysis stratified by center (clusters). RRatio, responder rate, and percent change were also summarized by seizure type. The length of seizure-free intervals and the number of seizure-free days per a 28-day period planned evaluation) and number and percent of patients who were seizure free (ad hoc analysis) were also assessed. The primary analysis population was the intent-to-treat (ITT) population (all patients randomized who received at least one dose of study medication). The secondary analysis population was the evaluable population (all patients randomized who received at least 28 days of study medication and had a minimum of 28 days of seizure diary data within both the baseline phase and the double-blind phase). Page 3
RESULTS Subject Disposition and Demography: Patient disposition, including the number of patients withdrawing during baseline, is summarized in Table 1. Table 1. Summary of Patient Disposition [Number (%) of Patients] A total of 455 patients were randomized to treatment, and 453 received treatment (ITT). Two patients randomized to the 150 mg/day group did not take study medication, Patient 010004 changed AEDs during baseline and Patient 033007 withdrew consent. Patient characteristics in the randomized population were comparable to those of the patients in the ITT population discussed in the following paragraphs. In general, patient characteristics were similar across the 5 treatment groups for the ITT population (Table 2). Of the 453 patients in the ITT population, 100 were randomized to the placebo group, 88 to the 50 mg/day pregabalin group, 86 to the 150 mg/day pregabalin group, 90 to the 300 mg/day pregabalin group, and 89 to the 600 mg/day pregabalin group. Patients were primarily white (85%) and at screening had a mean age of 38 years (range, 12 through 75 years), with a mean age of 14 years at diagnosis of epilepsy. Page 4
Table 2. Summary of Patient Characteristics: ITT Population Efficacy Results: Overview: On the basis of the primary efficacy parameter, RRatio, efficacy was demonstrated at doses of 600, 300, and 150 mg/day of pregabalin. Consistent results were seen with regard to the secondary efficacy parameters. Patients in the 600, 300, and 150 mg/day pregabalin groups had statistically significantly greater responder rates compared to placebo. Pregabalin showed a significant linear response (decrease in RRatio value, increase in responder rate) with increasing dose. Based on the RRatio, all pregabalin treatment groups, except for the 50 mg/day group, showed statistically significantly greater reductions in seizures compared to the placebo group (based on the Ruberg step down procedure for controlling the overall type I error rate at 0.049). The 150 mg/day group was a minimum effective dose. Mean RRatio data are summarized in Figure 1. Page 5
Figure 1. Mean Change in All Partial Seizure (RRatio ITT Populaiton) Responder rate: A patient was classified as a responder if they experienced at least a 50% reduction in seizure frequency compared to the baseline. All pregabalin groups, except for the 50 mg/day group, had statistically significantly greater responder rates, compared to placebo. Percent change: The median percent change from baseline for the ITT population was -51% in the 600 mg/day, -37% in the 300 mg/day, -35% in the 150 mg/day, -9% in the 50 mg/day pregabalin groups and 0% in the placebo group. These results support the RRatio results. Results by seizure type: In general, the efficacy endpoint for each seizure type showed similar trends to those seen for all partial seizures combined, with dose-related reductions over the entire double-blind period seen at doses of 600, 300, and 150 mg/day. Pharmacokinetic and Other Results: Pharmacokinetic: Three hundred and eleven patients from this study were included in the pharmacokinetic analysis. A total of 558 plasma samples from patients randomized to pregabalin and considered to be at steady-state (patient continued for at least 48 hours without a missed dose or dosage adjustment) and collected within 18 hours from the last dose taken were included in the analysis. The plasma pregabalin concentrations associated with a daily dose of 50, 150, 300, and 600 mg/day averaged (range) 0.569 (0.06-5.02), 1.63 (0.31-5.71), 2.84 (0.06-11.2), and 5.47 (0.18-12.5) ug/ml, respectively. Page 6
Safety Results: Overview: The percentage of patients with one or more adverse events was higher for the 600 (89%) and 300 mg/day (84%) pregabalin groups than for the placebo group (74%); with a similar pattern seen for associated adverse events. The percentages of patients in the 150 and 50 mg/day treated groups with adverse events and with associated adverse events in any and all body system(s) were comparable to that of placebo. Table 3. TESS (Treatment Emergent Signs or Symptoms) Adverse Events Occurring in 3% Total Pregabalin Patients By Decreasing Frequency [Number (%) of Patients] The majority of adverse events in the placebo and in all pregabalin groups were mild or moderate in intensity. However, the proportion of patients with moderate or severe adverse events was higher in the 600 mg/day pregabalin group. The severe adverse events were mostly CNS in nature. Table 4 summarizes the withdrawals due to adverse events. Page 7
Table 4. Summary of Withdrawals Due to TESS Adverse Events Occurring in 3 Pregabalin Patients [Number (%) of Patients] No deaths occurred during the study. Serious adverse events that occurred in the study are summarized in Table 5. Table 5. Table Summary of Serious Adverse Events (TESS) [Number (%) of Patients] Vision assessments: There is no evidence of a dose-related increase in the frequency of treatment-emergent visual abnormalities in this study. Page 8
Pediatric Data: Too few patients were enrolled in the study to derive definitive conclusions regarding efficacy or safety in pediatric patients. Pediatric data for 11 patients between 12 and 16 years of age were available in Study 1008-034. Of the 10 children who received pregabalin, 6 (60.0%) experienced at least 1 adverse event: 2 were randomized to pregabalin 600 mg/day, 2 to 300 mg/day, 1 to150 mg/day, and 1 to 50 mg/day. Five of the 6 children with adverse events had events related to the central nervous system. Fewer children experienced dizziness (1 of 10 patients, 10.0%) compared to the pregabalin-treated patients in the total epilepsy population (219 of 758 patients, 28.9%), and none of the children experienced somnolence. Four children had adverse events related to emotional/behavioral changes (hostility, agitation and personality disorder, agitation, emotional lability); 2 of these children had a history of behavioral problems. One patient withdrew from the study due to hostility; the other 3 patients were maintained on their assigned doses and completed the study. None of the adverse events related to emotional/behavioral changes met the criteria for a serious adverse event and all were mild or moderate in intensity. One child who received placebo did not experience any adverse events. CONCLUSION(S): In patients with partial seizures not adequately controlled with available AEDs: Pregabalin administered BID at doses of 150, 300, and 600 mg/day is highly effective as add-on therapy when compared to placebo, exhibiting a clear dose response in the primary and secondary efficacy parameters. Pregabalin 50 mg/day is a no effect dose, while 150 mg/day is the minimum effective dose. Pregabalin, with no initial titration, is well-tolerated at doses of 50, 150, and 300 mg/day, and is well-tolerated by most patients at 600 mg/day. The pharmacokinetics of pregabalin are dose-proportional and predictable. Page 9