CLINICAL STUDIES

14.1 Neuropathic pain associated with diabetic peripheral neuropathy 14.2 Postherpetic Neuralgia 14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures 14.4 Management of Fibromyalgia 1 2 14 14.1 Neuropathic pain associated with diabetic peripheral neuropathy The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose.

Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years.

A total of 89% of patients completed Studies DPN 1 and DPN 2.

The patients had a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).

The baseline mean pain scores across the two studies ranged from 6.1 to 6.7.

Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin.

Patients recorded their pain daily in a diary.

Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three times a day with placebo.

Treatment with LYRICA 100 and 200 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

There was no evidence of a greater effect on pain scores of the 200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose dependent adverse reactions [see Adverse Reactions (6.1)].

For a range of degrees of improvement in pain from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that degree of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 1: Patients Achieving Various Levels of Pain Relief – Study DPN 1 Study DPN 2: This 8-week study compared LYRICA 100 mg three times a day with placebo.

Treatment with LYRICA 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

For various degrees of improvement in pain from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that degree of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 2: Patients Achieving Various Levels of Pain Relief – Study DPN 2 14.2 Postherpetic Neuralgia The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies.

These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain).

Seventy-three percent of patients completed the studies.

The baseline mean pain scores across the 3 studies ranged from 6 to 7.

Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin.

Patients recorded their pain daily in a diary.

Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice daily with placebo.

Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg, or placebo twice daily.

Patients with creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily.

In patients with creatinine clearance greater than 60 mL/min treatment with all doses of LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by higher rates of discontinuation due to adverse reactions.

For various degrees of improvement in pain from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that degree of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 3: Patients Achieving Various Levels of Pain Relief – Study PHN 1 Study PHN 2: This 8-week study compared LYRICA 100 or 200 mg three times a day with placebo, with doses assigned based on creatinine clearance.

Patients with creatinine clearance between 30 to 60 mL/min were treated with 100 mg three times a day, and patients with creatinine clearance greater than 60 mL/min were treated with 200 mg three times daily.

Treatment with LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

For various degrees of improvement in pain from baseline to study endpoint, Figure 4 shows the fraction of patients achieving that degree of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 4: Patients Achieving Various Levels of Pain Relief – Study PHN 2 Study PHN 3: This 8-week study compared LYRICA 50 or 100 mg three times a day with placebo with doses assigned regardless of creatinine clearance.

Treatment with LYRICA 50 and 100 mg three times a day statistically significantly improved the endpain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.

Patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by markedly higher rates of discontinuation due to adverse reactions.

For various degrees of improvement in pain from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that degree of improvement.

The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 5: Patients Achieving Various Levels of Pain Relief – Study PHN 3 14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients.

Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs).

Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline.

During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks.

The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively.

Approximately half of the patients were taking 2 concurrent AEDs at baseline.

Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies.

Table 7 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.

Table 7: Seizure Response in Controlled, Add-On Epilepsy Studies Daily Dose of Pregabalin Dosing Regimen N Baseline Seizure Frequency/mo Median % Change from Baseline p-value, vs.

placebo Study E1 Placebo BID 100 9.5 0 50 mg/day BID 88 10.3 -9 0.4230 150 mg/day BID 86 8.8 -35 0.0001 300 mg/day BID 90 9.8 -37 0.0001 600 mg/day BID 89 9.0 -51 0.0001 Study E2 Placebo TID 96 9.3 1 150 mg/day TID 99 11.5 -17 0.0007 600 mg/day TID 92 12.3 -43 0.0001 Study E3 Placebo BID/TID 98 11 -1 600 mg/day BID 103 9.5 -36 0.0001 600 mg/day TID 111 10 -48 0.0001 In the first study (E1), there was evidence of a dose-response relationship for total daily doses of Lyrica between 150 and 600 mg/day; a dose of 50 mg/day was not effective.

In the first study (E1), each daily dose was divided into two equal doses (twice a day dosing).

In the second study (E2), each daily dose was divided into three equal doses (three times a day dosing).

In the third study (E3), the same total daily dose was divided into two equal doses for one group (twice a day dosing) and three equal doses for another group (three times a day dosing).

While the three times a day dosing group in Study E3 performed numerically better than the twice a day dosing group, this difference was small and not statistically significant.

A secondary outcome measure included the responder rate (proportion of patients with greater than or equal to 50% reduction from baseline in partial seizure frequency).

The following figure displays responder rate by dose for two of the studies.

Figure 7.

Seizure Reduction by Dose (All Partial Onset Seizures) for Studies E1, E2, and E3 Subset evaluations of the antiseizure efficacy of LYRICA showed no clinically important differences as a function of age, gender, or race.

14.4 Management of Fibromyalgia The efficacy of LYRICA for management of fibromyalgia was established in one 14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2).

Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites).

The studies showed a reduction in pain by visual analog scale.

In addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the Fibromyalgia Impact Questionnaire (FIQ).

Study F1: This 14-week study compared LYRICA total daily doses of 300 mg, 450 mg and 600 mg with placebo.

Patients were enrolled with a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS).

The baseline mean pain score in this trial was 6.7.

Responders to placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study.

A total of 64% of patients randomized to LYRICA completed the study.

There was no evidence of a greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was evidence of dose-dependent adverse reactions [see Adverse Reactions (6.1)].

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

The results are summarized in Figure 8 and Table 8.

For various degrees of improvement in pain from baseline to study endpoint, Figure 8 shows the fraction of patients achieving that degree of improvement.

The figure is cumulative.

Patients who did not complete the study were assigned 0% improvement.

Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 8: Patients Achieving Various Levels of Pain Relief – Fibromyalgia Study F1 Table 8: Patient Global Response in Fibromyalgia Study F1 Patient Global Impression of Change Treatment Group (mg/day) % Any Improvement 95% CI Placebo 47.6 (40.0,55.2) PGB 300 68.1 (60.9, 75.3) PGB 450 77.8 (71.5, 84.0) PGB 600 66.1 (59.1, 73.1) PGB = Pregabalin Study F2: This randomized withdrawal study compared LYRICA with placebo.

Patients were titrated during a 6-week open-label dose optimization phase to a total daily dose of 300 mg, 450 mg, or 600 mg.

Patients were considered to be responders if they had both: 1) at least a 50% reduction in pain (VAS) and, 2) rated their overall improvement on the PGIC as “much improved” or “very much improved.” Those who responded to treatment were then randomized in the double-blind treatment phase to either the dose achieved in the open-label phase or to placebo.

Patients were treated for up to 6 months following randomization.

Efficacy was assessed by time to loss of therapeutic response, defined as 1) less than 30% reduction in pain (VAS) from open-label baseline during two consecutive visits of the double-blind phase, or 2) worsening of FM symptoms necessitating an alternative treatment.

Fifty-four percent of patients were able to titrate to an effective and tolerable dose of LYRICA during the 6-week open-label phase.

Of the patients entering the randomized treatment phase assigned to remain on LYRICA, 38% of patients completed 26 weeks of treatment versus 19% of placebo-treated patients.

When considering return of pain or withdrawal due to adverse events as loss of response (LTR), treatment with LYRICA resulted in a longer time to loss of therapeutic response than treatment with placebo.

Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients remained on study drug and maintained a therapeutic response to Week 26 of the study.

Treatment with LYRICA also resulted in a longer time to loss of response based on the FIQ 1, and longer time to loss of overall assessment of patient status, as measured by the PGIC 2.

Figure 9: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier Analysis) 1 Time to worsening of the FIQ was defined as the time to a 1-point increase from double-blind baseline in each of the subscales, and a 5-point increase from double-blind baseline evaluation for the FIQ total score.

2 Time to PGIC lack of improvement was defined as time to PGIC assessments indicating less improvement than “much improvement.” Lyrica 03 Lyrica 04 Lyrica 05 Lyrica 06 Lyrica 07 Lyrica 08 Lyrica 09 Lyrica 10 Lyrica 11