PhRMA Web Synopsis
Protocol A9451162 – 29 October 2010 –Final

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: Neurontin® / Gabapentin
THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See United States
Package Insert (USPI)NATIONAL CLINICAL TRIAL NO.: NCT00603473
PROTOCOL NO.: A9451162
PROTOCOL TITLE: An Open-Label, Multicenter Study Evaluating, the Efficacy, Safetyand Pharmacokinetics of Gabapentin as Adjunctive Therapy in Pediatric Patients With PartialSeizures When Other Antiepileptic Drugs Do Not Provide Satisfactory Effects

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Study Center(s): Twenty-seven (27) centers in Japan
Study Initiation and Completion Dates: 10 January 2008 to 24 December 2009
Phase of Development: Phase 3
Study Objective(s): The study evaluated the efficacy, safety and pharmacokinetics ofgabapentin administered for 12 weeks as adjunctive therapy in pediatric epilepsy patientswith partial seizures (with or without secondarily generalized seizures) without a satisfactory
response to other antiepileptic drugs. To demonstrate the efficacy, it was confirmed that theupper limit of the 95% confidence interval (CI) of the Response Ratio (R Ratio) (mean) for
gabapentin in the present study would be below the R Ratio (least squares mean) for placebo
in an international study (Protocol No. 945-86/186) conducted outside of Japan.
METHODS
Study Design: This study was an open-label, non-controlled multicenter study in pediatricepilepsy patients with partial seizures without a satisfactory response to other antiepileptic
drugs.
Subject’s participation consisted of a 6-week baseline period, a 12-week treatment period,
and a 1-week follow-up period. Subjects who had completed the treatment period andwanted to continue gabapentin therapy were provided with an opportunity of entering a 52week long-term extension study (Protocol No. A9451165). Subjects who had completed thetreatment period and did not want to continue gabapentin therapy or who were withdrawn
from the study entered the follow-up period, where the study treatment was tapered off over
1 week to complete it 1 week after the end of treatment period or withdrawal. The study
design is outlined in Figure 1.

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Protocol A9451162 – 29 October 2010 –Final

Figure 1. Study Design
Long-term extension study
Baseline period

Treatment period

6-weeks

12-weeks

Follow-up period
1-weekNumber of Subjects (Planned and Analyzed):
Planned: 95 subjects to be enrolled and 85 subjects to be included in the primary efficacy
analysis population (modified intent-to-treat [MITT] population).

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Analyzed: 90 subjects were enrolled, 89 subjects were treated and 86 subjects were included
MITT population.
Diagnosis and Main Criteria for Inclusion: To be enrolled in the study, subjects wererequired to be aged between 3 and 15 years, have partial seizures (defined by theInternational League Against Epilepsy; with or without secondary generalized seizures)
which could not be controlled satisfactorily with existing antiepileptic drugs, to haveexperienced at least 4 seizure episodes within the 6-week baseline period and at least 1
episode for each 2 weeks of the baseline period, and to be receiving 1 to 3 antiepileptic drugs
at screening.
Study Treatment:(1)Treatment period

As shown in Table 1, subjects received gabapentin three times daily for a duration of 12weeks (each dosing interval should not exceed 12 hours). The dosage of oral solution for
subjects aged 3 to 12 years was calculated based on their body weight. As shown in Table 2,
the dose was titrated for the first 3 days of the treatment period. After Day 3, the dose wasadjusted if necessary within the range of maintenance doses. As a general rule, dose
adjustment was done at planned visits. The maximum daily dose was 600 mg for Day 1,1200 mg for Day 2, and 1800 mg for Day 3 and thereafter.
Table 1. Study Drug
Drug
gabapentin

Potency
250 mg/5 mL
200 mgFormulation
Oral solution containing 250 mg of gabapentin per 5 mL
Film-coated tablets containing 200 mg of gabapentin per tablet

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Protocol A9451162 – 29 October 2010 –Final

Table 2. Formulation and Dosage of Gabapentin by AgeAge3, 4 years
5 to 12 years
Formulation
250 mg/5 mL Oral solution
Day 1
10 mg/kg/daya
10 mg/kg/daya
bDay 220 mg/kg/day
20 mg/kg/dayb
After Day 340 mg/kg/dayc
25 to 35 mg/kg/dayc(maintenance doses)
a: The daily dose should not exceed 600 mg.
b: The daily dose should not exceed 1200 mg.
c: The daily dose should not exceed 1800 mg.

(2)

13 to 15 years
200 mg tablet
600 mg/day
1200 mg/day
1200 mg or 1800 mg/day

Follow-up period

Subjects who had completed the treatment period and did not want to continue gabapentin
therapy or who were withdrawn from the study entered the follow-up period, where the study
treatment was tapered off over 1 week to complete it 1 week after the end of treatment period
or withdrawal.

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Entry into the long-term extension study (A9451165)

Subjects who had completed the treatment period and wanted to continue gabapentin therapy
entered the 52-week long-term extension study (A9451165). These subjects entering thelong-term study started to receive study drugs for the long-term study at Week 12 visit.
Efficacy Evaluations:(1)

Primary endpoint

The R Ratio calculated by the following equation was assessed as the primary endpoint:
R Ratio = (T−B) / (T+B)
T = seizure frequency per 28 days (i.e., the number of seizures per 28 days) calculated fromthe total number of seizures for the 12-week treatment period
B = seizure frequency per 28 days (i.e., the number of seizures per 28 days) calculated fromthe total number of seizures for the 6-week baseline period(2)Secondary endpoints

The following 3 variables were assessed as secondary endpoints:• Responder rate (defined as the proportion of subjects with a 50% or greater reduction in theseizure frequency per 28 days for the 12-week treatment period in comparison with thefrequency per 28 days for the 6-week baseline period)• Percent change in seizure frequency (PCH)
PCH = 100 (T−B) / BPage 3

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Protocol A9451162 – 29 October 2010 –Final• R Ratio and PCH for individual types of partial seizures
Pharmacokinetic Evaluations: Pharmacokinetics of gabapentin in pediatric subjects wereevaluated as secondary endpoint, based on gabapentin concentrations in plasma samples
collected at Weeks 4 (Visit 4), 8 (Visit 5), 12 (Visit 6) / Early termination visit.
Safety Evaluations: As secondary endpoint, adverse events, serious adverse events,
withdrawals due to adverse events, results of clinical laboratory tests, blood pressure, pulserate, body weight, and 12-lead electrocardiogram (ECG).
Statistical Methods:
Efficacy analysis
In the study, the MITT and intent-to-treat (ITT) populations were used as primary andsecondary efficacy analysis populations, respectively. Each population was defined asfollows:

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MITT population:
Subjects who have received the study medication for at least 28 days
and in whom the number of epileptic seizures used for efficacy assessment has been counted
for at least 28 days in both the baseline and treatment periods.
ITT population:
Subjects who have received at least 1 dose of the study medication andin whom the number of epileptic seizures used for efficacy assessment has been counted inboth the baseline and treatment periods.
In the analysis of the primary efficacy endpoint, it was confirmed that the upper limit of the95% CI of the R Ratio (mean) for gabapentin in the present study would be below the R
Ratio (least squares mean) of −0.072 for placebo in the international study (945-86/186).
The MITT population was used as the primary efficacy analysis population. The same
analysis was done in the ITT population used as the secondary efficacy analysis population toassess the robustness of analytical results from the MITT population. The secondary
endpoints were also analyzed in both the MITT and ITT populations. For the PCH regarded
as a continuous variable, summary statistics (five-number summary, mean, standard
deviation, and 95% CI) were calculated. The responder rate and its 95% CI were estimated,with whether or not the responder criteria were met as a binary variable.
Pharmacokinetic analysis
To assess the pharmacokinetics of gabapentin in pediatric subjects, a population
pharmacokinetic analysis was performed in pediatric subjects with at least 1 measurement ofplasma gabapentin concentration after the start of study treatment.
Safety analysis
The safety analysis population consisted of subjects who received at least 1 dose of the studymedication. Safety data and other observations were summarized and tabulated for clinicalreview in accordance with the sponsor’s in-house standards, “Pfizer Data Standard (PDS).”

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Protocol A9451162 – 29 October 2010 –Final

For adverse events, the incidences were tabulated by system organ class and by event. The
incidences were also tabulated by causal relationship with the study drug and by severity ofadverse event. Furthermore, data were summarized for clinical laboratory tests, bloodpressure, pulse rate, body weight, height, 12-lead ECG, physical examination, andneurological examination.
RESULTS
Subject Disposition and Demography: Ninety (90) subjects were screened and enrolled in
the study. Of them, 89 received the study treatment, while 1 withdrew consent. Of thoseenrolled, 80 subjects (88.9%) completed the study, whereas 9 (10.0%) were withdrawn fromthe study. The reason for withdrawal was reported as adverse events in 4 subjects, lack ofefficacy in 4, and other in 1 (Table 3).

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Among the subjects enrolled, 1 subject who did not receive the study medication because ofconsent withdrawal was excluded from the ITT and safety analysis populations. Eighty-six(86) subjects were included in the MITT population; those excluded from the population
were 1 subject excluded from the ITT population, 2 subjects withdrawn from the study
because of adverse events, and 1 subject meeting any exclusion criterion, with the duration ofstudy treatment or epileptic seizure counting less than 28 days.
Table 3. Disposition of Patients (Number of Subjects [%])
Number of Subjects
Assigned to Study Treatment
TreatedCompletedDiscontinued
Related to Study Drug
Adverse event
Lack of efficacy
Not Related to Study Drug
Adverse event
OtheraAnalyzed for Efficacy
Intent to Treat (ITT)Modified Intent to Treat (MITT)
Analyzed for Safety
Adverse events
Laboratory data
a: A subject meeting any exclusion criterion.

90
8980 (88.9)
9 (10.0)73421
189 (98.9)
86 (95.6)
89 (98.9)
89 (98.9)

Among the 89 subjects who received the study medication, the mean age was 8.7 years(range, 3 to 15 years), the mean body weight was 30.5 kg (range, 11.4 to 85.6 kg), the mean
duration of disease was 6.6 years (range, 1.0 to 15.2 years), and 49 were males and 40 werefemales. The most common type of epileptic seizure was complex partial seizure in 91.0%
of subjects. Simple partial and secondarily generalized seizures were found in 41.6% and51.7%, respectively. Most subjects were using 3 (44.9%) or 2 (43.8%) concomitant

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Protocol A9451162 – 29 October 2010 –Finalantiepileptic drugs. The highest proportion of the subjects (41.6%) had tried and failed 5 ormore antiepileptic drugs on the baseline characteristics.
Efficacy Results: In the MITT population, the upper limit of the 95% CI for the mean RRatio (Weeks 1 to 12), which was assessed as the primary endpoint, was −0.096; it wasbelow the R Ratio (least squares mean) of −0.072 for placebo in the international study (94586/186). The mean R Ratio for partial seizures by assessment period was −0.158 (95% CI,−0.221 to −0.096) for Weeks 1 to 12 (Table 4). Analytical results of R Ratio in the ITT
population were the same as those in the MITT population and supported the MITT results.
Table 4. Response Ratio (MITT)

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Number of Evaluable Subjects
R Ratio (Week 1 to Week 12, Mean)
Standard deviation
95% confidence interval [Lower Limit, Upper Limit]

86−0.1580.2915[−0.221, −0.096]

In the MITT population, the responder rate for partial seizures by assessment period was
19.8% (17 responders) for Weeks 1 to 12 (Table 5). Analytical results of responder rate in
the ITT population were the same as those in the MITT population and supported the MITTresults.
Table 5. Responder Rate (MITT)
Number of Evaluable Subjects
Responder rate (Week 1 to Week 12, Mean)
The Number of Responder
95% confidence interval [Lower Limit, Upper Limit]

86
19.8%
17
[12.0, 29.8]

In the MITT population, the median PCH for partial seizures by assessment period was−24.4% for Weeks 1 to 12 (Table 6). Analytical results of PCH in the ITT population were
the same as those in the MITT population and supported the MITT results.
Table 6. PCH [%] (MITT)
Number of Evaluable Subjects
PCH (Week 1 to Week 12)
MedianRange (Min, Max)

86
−24.4
(−100.0, 192.9)

Analytical results of R Ratio, responder rate, and PCH by type of epileptic seizure (simple
partial, complex partial, and secondarily generalized seizures) indicate a reduction in seizure
frequency after treatment with gabapentin for all types of seizures. These effects weresustained throughout the treatment period.

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Protocol A9451162 – 29 October 2010 –Final

Safety Results: In the study, 218 all-causality adverse events were reported in 78 of 89
subjects treated. Of them, 73 events in 47 subjects were assessed as treatment-related(Table 7). These adverse events were classified as mild or moderate in severity. No subject
died in this study. All-causality serious adverse events occurred in 3 subjects, but notreatment-related serious adverse events were reported in the study. All-causality adverseevents resulted in study withdrawal in 4 subjects and dose reduction or treatment interruption
in 4 subjects. All of these events, except 1 resulting in study withdrawal, were assessed astreatment-related.
Table 7. Summary of Adverse Events
All-causality89
78 (87.6)
218
30
4 (4.5)Treatment-related
89
47 (52.8)
7300
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Number of Subjects Analyzed for Safety
Number of subjects with an AE (%)
Number of AEs
Number of subjects with an SAEa
Number of subjects with a severe AE
Number of subjects withdrawn due to AEs (%)
Number of subjects with dose reduction or4 (4.5)
4 (4.5)
temporary interruption due to AEs (%)
a: The number of subjects with any serious adverse event was based on information from the safety database.

All-causality adverse events observed in ≥ 3% of subjects are presented in Table 8. Common
all-causality adverse events (with an incidence of 10% or higher) were somnolence in 35
subjects (39.3%), nasopharyngitis in 24 subjects (27.0%), and influenza in 9 subjects (10.1%).
Table 8. All-causality Adverse Events (Incidence ≥ 3%)
Number of Subjects Analyzed for Safety
MedDRA (version 12.1) Preferred Term
Number of subjects with an AE (%)
Somnolence
Nasopharyngitis
InfluenzaPharyngitis
Fall
Diarrhoea
Contusion
Pyrexia
Rash
Upper respiratory tract infection
Conjunctivitis
NauseaRhinitis
Excoriation
Increased appetite
AtaxiaConvulsion

89
78 (87.6)
35 (39.3)
24 (27.0)
9 (10.1)
7 (7.9)7 (7.9)6 (6.7)6 (6.7)5 (5.6)5 (5.6)4 (4.5)3 (3.4)3 (3.4)3 (3.4)3 (3.4)3 (3.4)3 (3.4)3 (3.4)

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Protocol A9451162 – 29 October 2010 –Final

Treatment-related adverse events observed in ≥ 2% of subjects are presented in Table 9.
Common treatment-related adverse event was somnolence reported in 35 subjects (39.3%).
Other treatment-related adverse events occurred in 3 subjects (3.4%) or less.
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Number of Subjects Analyzed for Safety
MedDRA (version 12.1) Preferred Term
Number of subjects with an AE (%)
Somnolence
Convulsion
Increased appetite
NauseaSalivary hypersecretion
Weight increased
AtaxiaAffect lability
Mood altered
Rash8947 (52.8)
35 (39.3)
3 (3.4)3 (3.4)2 (2.2)2 (2.2)2 (2.2)2 (2.2)2 (2.2)2 (2.2)2 (2.2)A list of subjects who discontinued due to adverse events is presented in Table 10. Adverse
events resulting in study withdrawal were reported in 4 subjects: rash in 1 subject, attention
deficit/hyperactivity disorder in 1 subject, convulsion in 1 subject, and increased appetite andmood altered in 1 subject (2 events in 1 subject). These events were classified as mild or
moderate, and none of them were assessed as serious. The rash, convulsion, and increased
appetite and mood altered in 3 subjects were assessed as treatment-related. All the adverse
events reported in the 4 subjects resolved with the discontinuation of treatment.
Table 10. Discontinuations Due to Adverse Events
Age/Sex MedDRA (version 12.1) Preferred Term Causality Severity
6/Female Rash
Related Moderate
9/Female Attention deficit/hyperactivity disorder Unrelated Moderate
11/Male Convulsion
Related Moderate
10/Female Increased appetite
RelatedMild
Mood altered
RelatedMild
a: Confirmed recovered at a follow-up.

OutcomeRecovered
Recovered
Still presenta
Recovered
RecoveredNo subject died in this study. Other serious adverse events are presented in Table 11. In thestudy, serious adverse events occurred in 3 subjects: pharyngitis reported during thetreatment period in 1 subject, gastroenteritis reported before the start of study treatment in 1
subject, and bacterial infection reported after the completion of the study in 1 subject. All theevents were assessed as not related to the study drug.

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Protocol A9451162 – 29 October 2010 –Final

Table 11. Serious Adverse Events
Age/Sex
4/Male13/Male9/MaleMedDRA (version 12.1) Preferred Term
Gastroenteritis
Pharyngitis
Bacterial infection

Latest dose
Causality
PredoseNot applicable1800 mg/day
Not-related
100 mg/day
Not-related

OutcomeRecovered
Recovered
RecoveredNo severe or serious adverse events related to laboratory abnormalities were reported. No
adverse events related to laboratory abnormalities resulted in treatment withdrawal, dose
reduction, or treatment interruption.
CONCLUSION(S): An open-label, non-controlled multicenter study was conducted inJapan to evaluate the efficacy, safety and pharmacokinetics of gabapentin administered for
12 weeks as adjunctive therapy with other antiepileptic drugs in pediatric epilepsy subjects
with partial seizures without a satisfactory response to other antiepileptic drugs.

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In the MITT population, the mean R Ratio for partial seizures for the 12-week treatment
period was −0.158 (95% CI, −0.221 to −0.096). This confirms that the upper limit of the95% CI is below the R Ratio (least squares mean) of −0.072 for placebo in the international
study (945-86/186).
Adverse events were reported in 78 of 89 subjects treated with gabapentin. These adverse
events were classified as mild or moderate in severity. Common adverse events weresomnolence, nasopharyngitis, and influenza. Adverse events resulting in study withdrawal
were reported in 4 subjects (rash, attention deficit/hyperactivity disorder, convulsion, andincreased appetite and mood altered). All the events resolved with the discontinuation oftreatment. A serious adverse event (pharyngitis) was reported during the treatment period in
1 subject. The event was assessed as not related to the study drug.
Gabapentin was efficacious in this study as adjunctive therapy in pediatric epilepsy patients
aged from 3 to 15 years old with other antiepileptic drugs. Gabapentin was safe and welltolerated in pediatric epilepsy patients in Japan.

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