Public Disclosure Synopsis
Protocol A9451165 – 12 November 2014 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Neurontin/Gabapentin
PROTOCOL NO.: A9451165
PROTOCOL TITLE: A 52 weeks, open-label, multicenter study evaluating the efficacy
and safety of gabapentin as adjunctive therapy in pediatric patients who have completed
the 12 weeks treatment in Study A9451162 (Final report)
Study Center(s): 22 centers in Japan (excluding the center with no subject enrolled)
Study Initiation and Final Completion Dates: 28 May 2008 (date of the first informedconsent) to 22 December 2010 (date of last observation)

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Phase of Development: Phase 3
Study Objective(s): To evaluate the safety and efficacy of gabapentin administered for
52 weeks as concomitant therapy for the treatment of partial seizures (includingsecondarily generalized seizures) in pediatric epilepsy subjects who completed thetreatment period of Study A9451162 and chose to continue gabapentin therapy.
METHODS
Study Design: This study was conducted in Japan as a multicenter, open-label, clinicalstudy in pediatric epilepsy subjects who have completed the treatment period of thepreceding Study A9451162 and who chose to continue gabapentin therapy. The present
study consisted of a 52-week treatment period and a 1-week follow-up period. Subjects
who completed the 52-week treatment period or were withdrawn from the study enteredthe 1-week follow-up period, where the study treatment was tapered off before it wascompletely terminated.
Study schedule is presented in Table 1.

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Protocol A9451165 – 12 November 2014 – Final

Table 1.

Study Schedule

Baseline
Week 0

Week
8

Week
16

Week
24

Week
36

Week 52 or
Withdrawal

Visit 1 a)Visit 2±14days

Visit 3±14days

Visit 4±14days

Visit 5±14days

Visit 6

Follow-Up
Period1 weekafter Week
52 or
Withdrawal
Visit 7±14 days

0 to +3 days

Treatment Period
Procedures

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Informed ConsentX
Inclusion/Exclusion
X
Criteria
Complications(X)
Body Temperature, Pulse
(X)
X
X
X
X
X
X
Rate, Blood Pressure
Height
(X)
X
X
X
X
X
Weight
(X)
X
X
X
X
X
X
Physical Examinations(X)
X
X
Neurological Tests(X)
X
X
Clinical Laboratory Test
Hematology
(X)
X
X
X
X
X
Urinalysis
(X)
X
X
X
X
X
Pregnancy Test (urine) b)(X)
X
Plasma Gabapentin
Concentration c)Concomitant Medication,
(X)
X
X
X
X
X
X
Therapy
Treatment Compliance
X
X
X
X
X
X
Evaluation of Seizures d)XXXXXAdverse Events e)
Serious Adverse Events f)(X): Test results conducted on Visit 6 of Study A9451162 was used.
a) Visit 6 of Study A9451162.
b) Only conducted on females of childbearing potential.
c) To be performed every visit if subject was given higher doses than those given in Study A9451162.
d) Baseline symptom characteristics of Study A9451162 were used as the baseline symptom characteristics
for the present study.
e) Adverse events were reported from the first dose of study drug to 7 days after the last dose of study drug.
f) Serious adverse events were reported from the date of informed consent to 28 days after the last dose ofstudy drug.

Number of Subjects (Planned and Analyzed):
Planned: Not Applicable
Analyzed: 65 subjects
Diagnosis and Main Criteria for Inclusion: Pediatric epilepsy subjects who chose tocontinue gabapentin therapy after completing the treatment period of Study A9451162,
and were consented to participate in the present study by their parents or legal guardians
were enrolled. Female subjects of childbearing potential were also required to have anegative urine pregnancy test result at baseline visit. Subjects with any of the following
at baseline were excluded from the study: drug-related seizures or acute-phase disease;aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, blood

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Protocol A9451165 – 12 November 2014 – Finalurea nitrogen (BUN), or creatinine level greater than or equal to twice the upper limit ofnormal; white blood cell counts below 3000/mm3; or neutrophil counts below 1500/mm3.
Study Treatment: Subjects received gabapentin three times daily for a duration of 52
weeks with dosing intervals not exceeding 12 hours. The doses were adjusted within therange of maintenance doses as shown in Table 2. However, they could be increased up tothe maximum dose of 2400 mg per day, according to need.
Table 2.

Formulation and Dosage of Gabapentin by AgeAge
3, 4 years
5 to 12 years
Formulation
250 mg/5 mL Oral solution
Maintenance doses
40 mg/kg/day a)
25 to 35 mg/kg/day a)b)
Maximum doses
50 mg/kg/day
50 mg/kg/day b)a) The daily dose should not exceed 1800 mg.
b) The daily dose should not exceed 2400 mg.

13 to 15 years
200 mg tablet
1200 or 1800 mg/day
2400 mg/day

Subjects who had completed the treatment period or who were discontinued from study
entered the 1-week follow-up period, where the study treatment was tapered off before it
was completely terminatd.

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Efficacy Endpoints: As secondary endpoints, the Response Ratio (R Ratio), theresponder rate, and the percent change in seizure frequency (PCH) were assessed at each
visit during the 52-week treatment period in the study.
Pharmacokinetic Endpoints: As secondary endpoints, pharmacokinetics of gabapentin
in pediatric subjects was evaluated.
Safety Evaluations: As the primary endpoint, the safety of gabapentin (adverse events,serious adverse events, discontinuation due to adverse events, results of clinicallaboratory tests, blood pressure, pulse rate, and body weight) was assessed:

Serious and non-serious adverse event monitoring (throughout study)Clinical laboratory testing/measurements (Weeks 8, 16, 24 and 36, and 1 week aftercompletion/discontinuation)

Blood pressure, pulse rate, and body weight measurements [Weeks 8, 16, 24, 36 and52, at discontinuation (if applicable), and 1 week after completion/discontinuation]

Statistical Methods:
Efficacy Analysis: The intent-to-treat (ITT) population used as the efficacy analysis
population consisted of subjects who received at least 1 dose of the study medication andin whom the number of seizures used for efficacy assessment had been counted in boththe baseline and treatment periods. In order to assess the time course of seizure frequency,secondary endpoints (R Ratio and responder rate) were calculated at every visit from
Week 1 to Week 52, which corresponds to 13 and 64 weeks from the start of gabapentin
treatment, counting from the preceding Study (A9451162). The baseline symptom
characteristics recorded at Study A9451162 was used as the baseline symptom
characteristics for the present study.

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Protocol A9451165 – 12 November 2014 – Final

Pharmacokinetic Analysis: To assess the pharmacokinetics of gabapentin in pediatricsubjects, a population pharmacokinetic analysis was performed in pediatric subjects withat least 1 measurement of plasma gabapentin concentration after the start of studytreatment.
Safety Analysis: The safety analysis population consisted of subjects who received atleast 1 dose of the study medication. Safety data and other observations were summarized
and tabulated according to formats and algorithms defined in Pfizer Data Standard. The
baseline data recorded at Study A9451162 was used as the baseline data for the presentstudy. Any adverse events occurring after start of treatment in the present study, orexisting adverse events from preceding study increasing in severity after start of treatmentin this study, will be counted as treatment emergent adverse events. For adverse events,
the incidences were tabulated by system organ class and by event. The incidences werealso tabulated by causal relationship with the study drug and by adverse event severity.
Furthermore, data were summarized for clinical laboratory tests, blood pressure, pulse
rate, body weight, physical examination and neurological examination.
RESULTS

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Subject Disposition and Demography: Of the subjects who completed the treatment
period in Study A9451162, all 65 subjects eligible for screening were enrolled to thepresent study and were treated with the study medication. Table 3 presents a summary of
subject disposition and subjects analyzed.
Table 3.

Subject Disposition and Subjects Analyzed
Number of Subjects (%)
65
65
44 (67.7)
21 (32.3)

Enrolled
TreatedCompleted
Discontinued
Adverse event
Related to Study Drug
2 (3.1)
Not Related to Study Drug
2 (3.1)
Ineligibility based on the inclusion/exclusion criteria
2 (3.1)
Insufficient clinical response
12 (18.5)
Study consent withdrawal
1 (1.5)
Other a)2 (3.1)Analyzed for Efficacy
Intent to Treat (ITT)
65 (100)
Analyzed for Safety
Adverse events65 (100)
Laboratory data
65 (100)a) One chose to receive other treatment and another failed to make scheduled visit

Demographics and baseline characteristics are presented in Table 4.

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Protocol A9451165 – 12 November 2014 – Final

Table 4.

Demographics and Baseline Characteristics

Number of subjects evaluatedSex, nAge (years), n (%)

Weight (kg)
Duration of Disease (years)
Epileptic Seizure Type, n (%)
Number of ConcomitantAntiepileptic Drugs, n (%)

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Number of ConcomitantAntiepleptic Drug History, n (%)

MalesFemales
3-4 years
5-12 years≥13 years
Mean (SD)
Range
Mean (SD)
Range
Mean
Range
Simple Partial
Complex Partial
Secondarily Generalized12301234≥5N=6538278 (12.3)
42 (64.6)
15 (23.1)
9.1 (3.6)
3-16
32.8 (16.8)
12-88
6.8
1.4-15.5
27 (41.5)
59 (90.8)
35 (53.8)
7 (10.8)
25 (38.5)
33 (50.8)
5 (7.7)7 (10.8)
15 (23.1)
12 (18.5)
7 (10.8)
19 (29.2)

Efficacy Results: In the ITT population, the mean R Ratio for partial seizures at each
assessment time point ranged from −0.327 to −0.256 during the treatment periods, andthere was no great fluctuation in the response (Table 5).
Table 5.

R Ratio (ITT)PeriodWeek 1 to 8Week 9 to 16 Week 17 to 24 Week 25 to 36 Week 37 to 52
Number of65
60
5854
47Subjects
Mean0.263
0.256
0.3000.2800.327
Standard deviation
0.31410.35130.36710.37530.3712
95% CI[0.341,[0.347,[0.396,[0.382,[0.436,[Lower Limit,
0.185]
0.166]
0.203]
0.177]
0.218]Upper Limit]
R Ratio = (T−B) / (T＋B)
T = the total number of seizures at each assessment time point converted to seizure frequency per 28 days
(i.e., the number of seizures per 28 days)
B = the total number of seizures for the 6-week baseline period converted to seizure frequency per 28 days
(i.e., the number of seizures per 28 days)
CI= confidence interval

In the ITT population, the responder rate for partial seizures was maintained in the rangeof 35.4% to 46.8% throughout the treatment period after the start of treatment (Table 6).

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Protocol A9451165 – 12 November 2014 – Final

Table 6.

Responder Rate (ITT)PeriodWeek 1 to 8
Number of Subjects
65
Number of Responder23
Responder Rate (%)
35.4
95% CI[Lower Limit,[23.9, 48.2]
Upper Limit]
CI= confidence interval

Week 9 to 16602440.0

Week 17 to 24 Week 25 to 36 Week 37 to 52
5854
47
23
2222
39.7
40.7
46.8

[27.6, 53.5][27.1, 53.4][27.6, 55.0][32.1, 61.9]

In the ITT population, the median PCH resulted in the range of 49.2 to 33.0 during thetreatment period (Table 7).
Table 7.

PCH (ITT)

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PeriodWeek 1 to 8
Week 9 to 16
Week 17 to 24
Week 25 to 36 Week 37 to 52
Number of65
60
5854
47
Subjects
Median
34.2
33.0
42.0
41.6
49.2
Range
(100.0, 63.1) (100.0, 99.8)(100.0, 112.5) (100.0, 110.7) (100.0, 131.7)(Min, Max)
PCH = 100(T−B) / B
T = the total number of seizures at each assessment time point converted to seizure frequency per 28 days
(i.e., the number of seizures per 28 days)
B = the total number of seizures for the 6-week baseline period converted to seizure frequency per 28 days
(i.e., the number of seizures per 28 days)

Pharmacokinetic Results: Pharmacokinetic results are described in the report preparedseparately.
Safety Results: In this study, 207 all-causality adverse events were reported in 58(89.2%) of 65 subjects, and 17 treatment-related adverse events were reported in 13(20.0%) of 65 subjects. An overview of adverse events is presented in Table 8.
Table 8.

Summary of Adverse Events

Subjects evaluable for safety
Number of subjects with an AE (%)
Number of AEs
Number of subjects with a serious AE
Number of subjects with a severe AE
Number of subjects withdrawn due to AEs (%)
Number of subjects with dose reduction ortemporary interruption due to AEs (%)

All-Causality65
58 (89.2)
207
2 (3.1)1 (1.5)4 (6.2)Treatment-Related65
13 (20.0)
1700
2 (3.1)2 (3.1)2 (3.1)All-causality adverse events (with an incidence of 5 % or higher), not including serious
adverse events, are presented in Table 9. The most common all-causality adverse eventswere nasopharyngitis in 28 subjects (43.1%), somnolence in 10 subjects (15.4%),
influenza in 9 subjects (13.8%), pyrexia in 8 subjects (12.3%), and diarrhoea in 7 subjects(10.8%). Of all adverse events (207 events), most of them were classified as mild (190events) or moderate (15 events) in severity.

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Protocol A9451165 – 12 November 2014 – FinalTable 9.

All-Causality Non-Serious Adverse Events (Incidence ≥5%)
MedDRA System Organ Classs
Preferred Term (ver.13.1)

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Subjects evaluable for adverse events
Gastrointestinal Disorders
Dental cariesDiarrhoea
Vomiting
General Disorders and Administration Site Conditions
Pyrexia
Infections and Infestations
Bronchitis
Influenza
Nasopharyngitis
Pharyngitis
Upper respiratory tract infection
Injury, Poisoning and Procedural Complications
Arthropod bite
Fall
Nervous system Disorders
Somnolence
Skin and Subcutaneous Tissue Disorders
EczemaN (%)
65
5 (7.7)7 (10.8)
4 (6.2)8 (12.3)
4 (6.2)9 (13.8)
28 (43.1)
4 (6.2)4 (6.2)4 (6.2)4 (6.2)10 (15.4)
4 (6.2)Treatment-related adverse events, not including serious adverse events, are presented inTable 10. All the events were classified as mild or moderate in severity.
Table 10. Treatment-Related Non-Serious Adverse Events
MedDRA System Organ Classs
Preferred Term (ver.13.1)
Subjects evaluable for adverse events
Gastrointestinal Disorders
Salivary hypersecretion
Infections and Infestations
Nasopharyngitis
Investigations
Blood alkaline phosphatase increased
Metabolism and Nutrition Disorders
Decreased appetite
Nervous System Disorders
Convulsion
Somnolence
Psychiatric Disorders
Aggression

N (%)
65
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)
1 (1.5)7 (10.8)
1 (1.5)

No deaths were reported in this study. Serious adverse events occurred in 2 subjects inthis study (Table 11). All the events were assessed as not related to the study drug.

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Table 11. Serious Adverse Events
Age/Sex
19/Female

210/Male

MedDRA (version 13.1)
Preferred Term
Encephalopathy
Status epilepticus
Bronchopneumonia

Latest doseCausality

Outcome

765 mg
765mg
600 mgUnrelated
Unrelated
Unrelated

Recovered
Recovered
Recovered

Adverse events that resulted in treatment discontinuation are presented in Table 12. The
adverse events considered not related to the study drug were mild convulsion in 1 subject,
severe and serious encephalopathy and status epilepticus in 1 subject. Moderate agitation(1 subject) and mild aggression (1 subject) were considered related to the study drug. All
aforementioned events resolved after treatment discontinuation.
Table 12. Discontinuations Due to Adverse Events
MedDRA (version 13.1)
Preferred Term
Convulsion
1 3/Male
2 9/Female
Encephalopathy
Status epilepticus
Agitation
3 10/FemaleAggression
4 9/Malea) Confirmed recovered at a follow-up.

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Age/Sex

Causality

Severity

OutcomeUnrelated
Unrelated
Unrelated
RelatedRelatedMild
SevereSevereModerate
Mild

Recovered
Recovered
Recovered
Unrecovered a)
Unrecovered a)

Two subjects experienced adverse events related to study drug (mild somnolence andmild insomnia) and underwent dose reduction. Both events resolved after dose reduction.
No severe or serious adverse events related to laboratory abnormalities were reported. Noadverse events related to laboratory abnormalities resulted in treatment discontinuation,dose reduction, or treatment interruption. The results of physical examination showed
gingival swelling in 1 subject; the event was assessed as not related to the study drug. No
clinically significant abnormal findings were noted for other safety-related tests.
CONCLUSION(S): This study was conducted to evaluate the safety and efficacy ofgabapentin administered for 52 weeks as concomitant therapy in pediatric epilepsy
subjects with partial seizures (including secondarily generalized seizures) who completedthe treatment period of the preceding Study A9451162 and chose to continue gabapentin
therapy.
In the study, all 65 subjects received the study medication. Of these 65 subjects, 44(67.7%) completed the study, and 21 (32.3%) were discontinued from the study.
The mean R Ratio and responder rate for all partial seizures at each assessment point werein the range of −0.327 to −0.256 and 35.4% to 46.8%, respectively. The median PCH for
all partial seizures at each assessment point were in the range of −49.2 to −33.0. Theseresults suggest that long-term administration has no significant influence on the effect ofgabapentin.

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Protocol A9451165 – 12 November 2014 – Final

All-causality adverse events were reported in 58 of the 65 subjects enrolled. Common
adverse events were nasopharyngitis, somnolence, influenza, pyrexia, and diarrhoea.
Serious adverse events occurred in 2 subjects. These events were considered not related
to the study drug. Other adverse events reported in the study were classified as mild or
moderate in severity. Treatment-related adverse events were reported in 13 of the 65
subjects enrolled. The most common treatment-related adverse event was somnolence.
Treatment-related adverse events were all classified as mild in severity, except forsomnolence, convulsion and agitation all experienced in 1 subject each, which wereclassified to be moderate. Four adverse events resulted in treatment discontinuation, andall of such events resolved after treatment discontinuation. No new safety and tolerability
related concerns about long-term gabapentin administration was indicated from the study
results; the adverse event profiles observed in this study showed no significant difference
to those seen in overseas study (Study 945-86/186) or the preceding study (StudyA9451162).

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These study results demonstrate the safety, tolerability and efficacy of long-term
administration of gabapentin in pediatric epilepsy patients with partial seizures.

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