Epilepsies, Partial
Conditions
Keywords
Gabapentin, Epilepsies, safety
Brief summary
This investigation aims to understand the following issues in pediatric patients, as well as to assess the need of a special investigation and a post-marketing clinical study: * The frequency of treatment related adverse events. * The frequency of efficacy assessment. * Treatment related unlisted adverse events in Japanese Package Insert. * Risk factors likely to affect the frequency of treatment related adverse event.
Detailed description
All the patients whom an investigator prescribes the first gabapentin should be registered consecutively until the number of subjects reaches target number in order to extract patients enrolled into the investigation at random.
Interventions
DRUGgabapentin
According to Japanese Package Insert: For infants and children aged 3 to 12 years, a daily dosage of 10 mg/kg of gabapentin should be administered orally in 3 divided doses on the first day of treatment, and an effective dosage of 20 mg/kg should be administered to them in 3 divided doses on day 2. From day 3 on, infants aged 3 to 4 years should be maintained on the dosage of 40 mg/kg, and children aged 5 to 12 years on the dosage of 25 to 35 mg/kg administered orally in 3 divided doses, respectively (the maximum daily dosage: 1800 mg). Though the maintenance dosage may be adjusted depending on the patient's condition, the maximum daily dosage should be 50 mg/kg. At any time point, dosage should not exceed that the dosage for adults and children aged 13 years.As for children aged 13 years or over is as same as administration for adult.
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
3 Years to 15 Years
Healthy volunteers
No
Inclusion criteria
* All the pediatric subjects (aged 3-15 years) whom an investigator prescribes the first gabapentin (tablets, syrup, and switch to syrup from tablet) should be registered consecutively until the number of subjects reaches target number in order to extract patients enrolled into the investigation at random.
Exclusion criteria
* Patients who have been enrolled in the drug use investigation of Gabapen tablets in adults (protocol No. A9451163). * Patients who receive Gabapen tablets or syrup before, except for switched from tablets to syrup.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Related Adverse Events | MAX 104 weeks | A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Relatedness to gabapentin was assessed by the investigator and sponsor (Pfizer Japan Inc.). |
| Clinical Efficacy Rate | MAX 104 weeks | Clinical efficacy rate, which was defined as the percentage of participants who achieved clinical efficacy over the total number of efficacy analysis population, was presented along with the corresponding exact 2-sided 95% CI. For the basis of efficacy evaluation, frequencies of epileptic seizure were recorded during the previous 4 weeks from the treatment start date, and that from the end date of assessment period. Clinical efficacy was assessed according to the following categories: (1) effective, (2) not effective, or (3) not assessable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Risk Factors for Treatment-Related Adverse Events | MAX 104 weeks | A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Participants with treatment-related adverse events were counted by each candidate risk factor (including gender, age, and disease eligible for the survey) to assess whether these were risk factors for the treatment-related adverse events. No inferential analyses of risk factors were performed because of a small number of the events (5 events). |
| Number of Participants With Treatment-Related Adverse Events Unexpected From Japanese Package Insert | MAX 104 weeks | A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Expectedness of the adverse event was determined according to the Japanese package insert. Relatedness to gabapentin was assessed by the investigator and sponsor (Pfizer Japan Inc.). |
| Number of Participants Who Responded to Treatment With Gabapentin by Baseline Severity of Epileptic Seizure | MAX 104 weeks | Participants who responded to the treatment with gabapentin were counted by the baseline severity of epileptic seizure (mild, moderate and severe) to assess whether the baseline severity of epileptic seizure was a factor affecting the treatment efficacy. |
| Number of Participants Who Responded to Treatment With Gabapentin by Baseline Frequency of Epileptic Seizure | MAX 104 weeks | Participants who responded to the treatment with gabapentin were counted by the baseline frequency of epileptic seizure (\<=8 versus \>8 episodes/per 4 weeks) to assess whether the baseline frequency of epileptic seizure was a factor affecting the treatment efficacy. |
| Number of Participants Who Responded to Treatment With Gabapentin by Number of Concomitant Antiepileptic Drugs at Baseline | MAX 104 weeks | Participants who responded to the treatment with gabapentin were counted by the number of concomitant epileptic drugs at baseline across 5 categories (no drug, 1 drug, 2 drugs, 3 drugs, and 4 or more drugs) to assess whether the number of concomitant epileptic drugs at baseline was a factor affecting the treatment efficacy. |
| Number of Participants Who Responded to Treatment With Gabapentin by Treatment Period | MAX 104 weeks | Participants who responded to the treatment with gabapentin were counted by the treatment period (non-long term \[less than 1 year\] or long term \[1 year or more\]) to assess whether the treatment period with gabapentin was a factor affecting the treatment efficacy. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Responder Rate | MAX 104 weeks | Responder rate, which was defined as the percentage of participants whose R ratio was - 0.333 or less, was presented along with the corresponding exact 2-sided 95% CI. R ratio of - 0.333 or less corresponded to the decrease of epileptic seizure frequency by 50% or more. |
| Reduction From Baseline in Epileptic Seizure Frequency | MAX 104 weeks | Reduction from baseline in epileptic seizure frequency was defined by the following formula, where B represented the baseline frequency of epileptic seizures during the previous 4 weeks from the treatment start date, whereas T represented the frequency of epileptic seizures during the previous 4 weeks from the end of assessment period: Reduction from baseline in epileptic seizure frequency (%) = \[(T-B) / B\] X 100. The median percentages were presented along with the corresponding minimum and maximum percentages. |
| Number of Participants With Key Treatment-Related Adverse Events (Aggressive Behaviors) | MAX 104 weeks | Aggressive behaviors including affect lability and hostility were determined as key survey items by the sponsor (Pfizer Japan Inc.). These events were defined as the 101 preferred terms listed by pharmaceuticals and medical devices agency and classified according to MedDRA/J version 17.1. A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Relatedness to gabapentin was assessed by the investigator and sponsor. |
| Number of Participants With Key Treatment-Related Adverse Events (Central Nervous System Depressant Actions) | MAX 104 weeks | Central nervous system depressant actions including somnolence and ataxia were determined as key survey items by the sponsor (Pfizer Japan Inc.). These events were defined according to MedDRA/J version 17.1 as the events classified in psychiatric disorders or nervous system disorders of the system organ classes, or those classified in asthenia or gait disturbance of the preferred terms. A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Relatedness to gabapentin was assessed by the investigator and sponsor. |
| Response Ratio (R Ratio) | MAX 104 weeks | R Ratio was calculated by the following formula, where B represented the baseline frequency of epileptic seizures during the previous 4 weeks from the treatment start date, whereas T represented the frequency of epileptic seizures during the previous 4 weeks from the end of assessment period: R Ratio = (T - B) / (T + B). R Ratio is within the range of -1 to +1, and a negative value represents a reduction in the frequency of seizure. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gabapentin Tablets/Syrup For participants aged 13 years or older, 600 mg in 3 divided doses (div.) was administered on day 1 and an effective dose of 1200 mg in 3 div. was administered on day 2. From day 3 on, participants were maintained on 1200 mg to 1800 mg in 3 div. The maintenance dose was adjusted according to the symptoms (up to a maximum daily dose of 2400 mg). For participants aged 3 to 12 years, 10 mg/kg/day was administered orally in 3 div. on day 1 of the treatment, and an effective dose of 20 mg/kg/day was administered in 3 div. on day 2. From day 3 on, participants aged 3 to 4 years were maintained on 40 mg/kg/day in 3 div. and participants aged 5 to 12 years were maintained on 25 to 35 mg/kg/day in 3 div. The maintenance dose was adjusted according to the symptoms (up to a maximum dose of 50 mg/kg/day). At any time point, the dose was not exceeded that for participants aged 13 years or older. | 82 |
| Total | 82 |
Baseline characteristics
| Characteristic | Gabapentin Tablets/Syrup |
|---|---|
| Age, Customized 13 to 15 years | 14 Participants |
| Age, Customized 3 to 4 years | 14 Participants |
| Age, Customized 5 to 12 years | 54 Participants |
| Sex: Female, Male Female | 39 Participants |
| Sex: Female, Male Male | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 25 / 82 |
| serious Total, serious adverse events | 4 / 82 |
Outcome results
Primary
Clinical Efficacy Rate
Clinical efficacy rate, which was defined as the percentage of participants who achieved clinical efficacy over the total number of efficacy analysis population, was presented along with the corresponding exact 2-sided 95% CI. For the basis of efficacy evaluation, frequencies of epileptic seizure were recorded during the previous 4 weeks from the treatment start date, and that from the end date of assessment period. Clinical efficacy was assessed according to the following categories: (1) effective, (2) not effective, or (3) not assessable.
Time frame: MAX 104 weeks
Population: The analysis population comprised of the participants in the efficacy analysis population from which those with data not assessable were excluded. n=number of participants with assessable data at each post-baseline time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gabapentin Tablets/Syrup | Clinical Efficacy Rate | Week 12 (n = 73) | 56.2 Percentage of participants |
| Gabapentin Tablets/Syrup | Clinical Efficacy Rate | Week 52 (n = 52) | 57.7 Percentage of participants |
| Gabapentin Tablets/Syrup | Clinical Efficacy Rate | Week 104 (n = 14) | 64.3 Percentage of participants |
| Gabapentin Tablets/Syrup | Clinical Efficacy Rate | End of assessment period (n = 66) | 42.4 Percentage of participants |
Primary
Number of Participants With Treatment-Related Adverse Events
A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Relatedness to gabapentin was assessed by the investigator and sponsor (Pfizer Japan Inc.).
Time frame: MAX 104 weeks
Population: The safety analysis population comprised of participants who had met the inclusion criteria and had taken gabapentin at least once.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gabapentin Tablets/Syrup | Number of Participants With Treatment-Related Adverse Events | 5 Participants |
Secondary
Number of Participants Who Responded to Treatment With Gabapentin by Baseline Frequency of Epileptic Seizure
Participants who responded to the treatment with gabapentin were counted by the baseline frequency of epileptic seizure (\<=8 versus \>8 episodes/per 4 weeks) to assess whether the baseline frequency of epileptic seizure was a factor affecting the treatment efficacy.
Time frame: MAX 104 weeks
Population: The efficacy analysis population comprised of the participants who had at least one post-baseline efficacy evaluation for the clinical efficacy and seizure frequency in the safety analysis population. Participants with diseases not eligible for the survey were excluded from the efficacy analysis population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gabapentin Tablets/Syrup | Number of Participants Who Responded to Treatment With Gabapentin by Baseline Frequency of Epileptic Seizure | 15 Participants |
| Moderate | Number of Participants Who Responded to Treatment With Gabapentin by Baseline Frequency of Epileptic Seizure | 11 Participants |
| Severe | Number of Participants Who Responded to Treatment With Gabapentin by Baseline Frequency of Epileptic Seizure | 2 Participants |
Comparison: The factor tested was baseline frequency of epileptic seizure. The null hypothesis was that there was no difference between the baseline frequency of epileptic seizure and the number of participants who responded to the treatment with gabapentin.p-value: 0.018Fisher Exact
Secondary
Number of Participants Who Responded to Treatment With Gabapentin by Baseline Severity of Epileptic Seizure
Participants who responded to the treatment with gabapentin were counted by the baseline severity of epileptic seizure (mild, moderate and severe) to assess whether the baseline severity of epileptic seizure was a factor affecting the treatment efficacy.
Time frame: MAX 104 weeks
Population: The efficacy analysis population comprised of the participants who had at least one post-baseline efficacy evaluation for the clinical efficacy and seizure frequency in the safety analysis population. Participants with diseases not eligible for the survey were excluded from the efficacy analysis population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gabapentin Tablets/Syrup | Number of Participants Who Responded to Treatment With Gabapentin by Baseline Severity of Epileptic Seizure | 6 Participants |
| Moderate | Number of Participants Who Responded to Treatment With Gabapentin by Baseline Severity of Epileptic Seizure | 15 Participants |
| Severe | Number of Participants Who Responded to Treatment With Gabapentin by Baseline Severity of Epileptic Seizure | 6 Participants |
| Unknown | Number of Participants Who Responded to Treatment With Gabapentin by Baseline Severity of Epileptic Seizure | 1 Participants |
Comparison: The factor tested was baseline severity of epileptic seizure. The null hypothesis was that there was no association between the baseline severity of epileptic seizure (mild, moderate, and severe) and the number of participants who responded to the treatment with gabapentin.p-value: 0.045Fisher Exact
Comparison: The factor tested was baseline severity of epileptic seizure. The null hypothesis was that there was no ordinal trend in the number of responders to the treatment with gabapentin across the baseline severity of epileptic seizure (mild, moderate, and severe).p-value: 0.017Cochran-Armitage (EXACT)
Secondary
Number of Participants Who Responded to Treatment With Gabapentin by Number of Concomitant Antiepileptic Drugs at Baseline
Participants who responded to the treatment with gabapentin were counted by the number of concomitant epileptic drugs at baseline across 5 categories (no drug, 1 drug, 2 drugs, 3 drugs, and 4 or more drugs) to assess whether the number of concomitant epileptic drugs at baseline was a factor affecting the treatment efficacy.
Time frame: MAX 104 weeks
Population: The efficacy analysis population comprised of the participants who had at least one post-baseline efficacy evaluation for the clinical efficacy and seizure frequency in the safety analysis population. Participants with diseases not eligible for the survey were excluded from the efficacy analysis population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gabapentin Tablets/Syrup | Number of Participants Who Responded to Treatment With Gabapentin by Number of Concomitant Antiepileptic Drugs at Baseline | 1 Participants |
| Moderate | Number of Participants Who Responded to Treatment With Gabapentin by Number of Concomitant Antiepileptic Drugs at Baseline | 13 Participants |
| Severe | Number of Participants Who Responded to Treatment With Gabapentin by Number of Concomitant Antiepileptic Drugs at Baseline | 7 Participants |
| Unknown | Number of Participants Who Responded to Treatment With Gabapentin by Number of Concomitant Antiepileptic Drugs at Baseline | 4 Participants |
| Four or More Concomitant Antiepileptic Drugs | Number of Participants Who Responded to Treatment With Gabapentin by Number of Concomitant Antiepileptic Drugs at Baseline | 3 Participants |
Comparison: The factor tested was number of concomitant antiepileptic drugs at baseline. The null hypothesis was that there was no association between the number of concomitant antiepileptic drugs at baseline and the number of participants who responded to the treatment with gabapentin.p-value: 0.034Fisher Exact
Comparison: The factor tested was number of concomitant antiepileptic drugs at baseline. The null hypothesis was that there was no ordinal trend in the number of responders to the treatment with gabapentin across the increasing number of concomitant antiepileptic drugs at baseline.p-value: 0.005Cochran-Armitage (EXACT)
Secondary
Number of Participants Who Responded to Treatment With Gabapentin by Treatment Period
Participants who responded to the treatment with gabapentin were counted by the treatment period (non-long term \[less than 1 year\] or long term \[1 year or more\]) to assess whether the treatment period with gabapentin was a factor affecting the treatment efficacy.
Time frame: MAX 104 weeks
Population: The efficacy analysis population comprised of the participants who had at least one post-baseline efficacy evaluation for the clinical efficacy and seizure frequency in the safety analysis population. Participants with diseases not eligible for the survey were excluded from the efficacy analysis population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gabapentin Tablets/Syrup | Number of Participants Who Responded to Treatment With Gabapentin by Treatment Period | 2 Participants |
| Moderate | Number of Participants Who Responded to Treatment With Gabapentin by Treatment Period | 26 Participants |
Comparison: The factor tested was treatment period with gabapentin. The null hypothesis was that there was no association between the treatment period with gabapentin and the number of participants who responded to the treatment with gabapentin.p-value: <0.001Fisher Exact
Secondary
Number of Participants With Risk Factors for Treatment-Related Adverse Events
A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Participants with treatment-related adverse events were counted by each candidate risk factor (including gender, age, and disease eligible for the survey) to assess whether these were risk factors for the treatment-related adverse events. No inferential analyses of risk factors were performed because of a small number of the events (5 events).
Time frame: MAX 104 weeks
Population: The safety analysis population comprised of participants who had met the inclusion criteria and had taken gabapentin at least once. No data displayed because outcome measure has zero total participants analyzed.
Secondary
Number of Participants With Treatment-Related Adverse Events Unexpected From Japanese Package Insert
A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Expectedness of the adverse event was determined according to the Japanese package insert. Relatedness to gabapentin was assessed by the investigator and sponsor (Pfizer Japan Inc.).
Time frame: MAX 104 weeks
Population: The safety analysis population comprised of participants who had met the inclusion criteria and had taken gabapentin at least once.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gabapentin Tablets/Syrup | Number of Participants With Treatment-Related Adverse Events Unexpected From Japanese Package Insert | 0 Participants |
Other Pre-specified
Number of Participants With Key Treatment-Related Adverse Events (Aggressive Behaviors)
Aggressive behaviors including affect lability and hostility were determined as key survey items by the sponsor (Pfizer Japan Inc.). These events were defined as the 101 preferred terms listed by pharmaceuticals and medical devices agency and classified according to MedDRA/J version 17.1. A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Relatedness to gabapentin was assessed by the investigator and sponsor.
Time frame: MAX 104 weeks
Population: The safety analysis population comprised of participants who had met the inclusion criteria and had taken gabapentin at least once.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gabapentin Tablets/Syrup | Number of Participants With Key Treatment-Related Adverse Events (Aggressive Behaviors) | 1 Participants |
Other Pre-specified
Number of Participants With Key Treatment-Related Adverse Events (Central Nervous System Depressant Actions)
Central nervous system depressant actions including somnolence and ataxia were determined as key survey items by the sponsor (Pfizer Japan Inc.). These events were defined according to MedDRA/J version 17.1 as the events classified in psychiatric disorders or nervous system disorders of the system organ classes, or those classified in asthenia or gait disturbance of the preferred terms. A treatment-related adverse event was any untoward medical occurrence attributed to gabapentin in a participant who received gabapentin. Relatedness to gabapentin was assessed by the investigator and sponsor.
Time frame: MAX 104 weeks
Population: The safety analysis population comprised of participants who had met the inclusion criteria and had taken gabapentin at least once.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gabapentin Tablets/Syrup | Number of Participants With Key Treatment-Related Adverse Events (Central Nervous System Depressant Actions) | 1 Participants |
Other Pre-specified
Reduction From Baseline in Epileptic Seizure Frequency
Reduction from baseline in epileptic seizure frequency was defined by the following formula, where B represented the baseline frequency of epileptic seizures during the previous 4 weeks from the treatment start date, whereas T represented the frequency of epileptic seizures during the previous 4 weeks from the end of assessment period: Reduction from baseline in epileptic seizure frequency (%) = \[(T-B) / B\] X 100. The median percentages were presented along with the corresponding minimum and maximum percentages.
Time frame: MAX 104 weeks
Population: The analysis population comprised of the participants in the efficacy analysis population who had assessable data of the frequency of epileptic seizures at the start of gabapentin treatment and at the end of assessment period. n=number of participants with assessable data at each post-baseline time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gabapentin Tablets/Syrup | Reduction From Baseline in Epileptic Seizure Frequency | Week 12 (n = 72) | -25.0 Percentage |
| Gabapentin Tablets/Syrup | Reduction From Baseline in Epileptic Seizure Frequency | Week 52 (n = 56) | -49.0 Percentage |
| Gabapentin Tablets/Syrup | Reduction From Baseline in Epileptic Seizure Frequency | Week 104 (n = 16) | -60.0 Percentage |
| Gabapentin Tablets/Syrup | Reduction From Baseline in Epileptic Seizure Frequency | End of assessment period (n = 73) | -47.9 Percentage |
Other Pre-specified
Responder Rate
Responder rate, which was defined as the percentage of participants whose R ratio was - 0.333 or less, was presented along with the corresponding exact 2-sided 95% CI. R ratio of - 0.333 or less corresponded to the decrease of epileptic seizure frequency by 50% or more.
Time frame: MAX 104 weeks
Population: The analysis population comprised of the participants in the efficacy analysis population who had assessable data of the frequency of epileptic seizures at the start of gabapentin treatment and at the end of assessment period. n=number of participants with assessable data at each post-baseline time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gabapentin Tablets/Syrup | Responder Rate | End of assessment period (n = 73) | 49.3 Percentage of participants |
| Gabapentin Tablets/Syrup | Responder Rate | Week 12 (n = 72) | 43.1 Percentage of participants |
| Gabapentin Tablets/Syrup | Responder Rate | Week 52 (n = 56) | 50.0 Percentage of participants |
| Gabapentin Tablets/Syrup | Responder Rate | Week 104 (n = 16) | 62.5 Percentage of participants |
Other Pre-specified
Response Ratio (R Ratio)
R Ratio was calculated by the following formula, where B represented the baseline frequency of epileptic seizures during the previous 4 weeks from the treatment start date, whereas T represented the frequency of epileptic seizures during the previous 4 weeks from the end of assessment period: R Ratio = (T - B) / (T + B). R Ratio is within the range of -1 to +1, and a negative value represents a reduction in the frequency of seizure.
Time frame: MAX 104 weeks
Population: The analysis population comprised of the participants in the efficacy analysis population who had assessable data of the frequency of epileptic seizures at the start of gabapentin treatment and at the end of assessment period. n=number of participants with assessable data at each post-baseline time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gabapentin Tablets/Syrup | Response Ratio (R Ratio) | Week 12 (n = 72) | -0.332 Ratio | Standard Deviation 0.458 |
| Gabapentin Tablets/Syrup | Response Ratio (R Ratio) | Week 52 (n = 56) | -0.409 Ratio | Standard Deviation 0.491 |
| Gabapentin Tablets/Syrup | Response Ratio (R Ratio) | Week 104 (n = 16) | -0.456 Ratio | Standard Deviation 0.507 |
| Gabapentin Tablets/Syrup | Response Ratio (R Ratio) | End of assessment period (n = 73) | -0.369 Ratio | Standard Deviation 0.509 |