CLINICAL STUDIES
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 ≥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). 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
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 endpoint mean pain 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
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
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 ≥50% reduction from baseline in partial seizure frequency). The following figure
displays responder rate by dose for two of the studies.
Figure 6. Responder rate by add-on epilepsy study
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.
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). 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
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 FIQ1, and longer
time to loss of overall assessment of patient status, as measured by the PGIC2.
1Time 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.”
Figure 9: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier
Analysis)
