Epilepsies, Partial
Conditions
Keywords
Epilepsy, partial seizures, pregabalin monotherapy, double-blind and randomized trial
Brief summary
This study will determine the safety and efficacy of pregabalin (Lyrica) when administered by itself (without any other anti-epileptic medication) to epilepsy subjects for the treatment of partial seizures. The duration of the trial is about 6 months.
Detailed description
After review of the interim analysis results, the independent Data Monitoring Committee (DMC) recommended to stop the study based on positive efficacy findings for the primary efficacy endpoint according to pre-specified stopping rules. Pfizer accepted the DMC recommendation and made the decision to stop the study on September 7, 2011.
Interventions
DRUGpregabalin 600 mg/day
pregabalin 600 mg/day (300mg BID), duration is 20 weeks.
DRUGpregabalin 150 mg/day
pregabalin 150 mg/day (75mg BID), duration is 20 weeks.
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of epilepsy with partial seizures. * Males or females, age 18 years or older. * Documented history of at least 4 partial seizures in the 8 weeks prior to the screening visit. * Stable treatment with 1 to 2 anti-epileptic drugs in the 8 weeks prior to the screening visit.
Exclusion criteria
* Current diagnosis of febrile seizures or seizures related to an ongoing acute medical event. * Seizures occurring only in cluster patterns, or seizures of a metabolic, toxic or infectious origin. * Primary generalized epilepsy or status epilepticus within the previous year.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in the Pregabalin 600 mg/Day Treatment Group Discontinuing the Study Due to at Least 1 Pre-Defined Seizure Exit Criteria | Week 2 up to Week 18 | Participants who discontinued due to: episode of status epilepticus (SE); secondarily generalized tonic-clonic (SGTC) seizure if none within 2 years of study entry; 28-day study seizure rate during double-blind phase (DBP) greater than (\>)2 times maximum (Max) 28-day study seizure rate during baseline phase (BLP); 2-day study seizure rate during DBP \>2 times Max 2-day study seizure rate during BLP; or unacceptable clinically significant increase in frequency/intensity of seizure activity. Determined as exit rate:(1-Kaplan-Meier \[KM\] product limit estimate for survival function) \* 100% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Completing 20 Weeks of Double-Blind Treatment | Randomization up to Week 20 | — |
| Percentage of Participants Who Met Protocol-Specified Exit Events | Week 2 up to Week 18 | Percentage of participants experiencing any of the following (could have had more than 1): 1) episode of SE; 2) SGTC seizure if none had been experienced within 2 years of study entry; 3) 28-day study seizure rate during DBP \>2 times the Max 28-day study seizure rate during BLP; 4) 2-day study seizure rate during the DBP \>2 times the Max 2-day study seizure rate during BLP; or 5) unacceptable clinically significant increase in frequency/intensity of seizure activity |
| Mean Time on Pregabalin Monotherapy | Week 2 to Week 20 | — |
| Percentage of Participants in the Pregabalin 150 mg/Day Treatment Group Discontinuing the Study Due to at Least 1 Pre-Defined Seizure Exit Criteria | Week 2 up to Week 18 | Participants who discontinued due to: episode of SE; SGTC seizure if none within 2 years of study entry; 28-day study seizure rate during DBP \>2 times Max 28-day study seizure rate during BLP; 2-day study seizure rate during DBP \>2 times Max 2-day study seizure rate during BLP; or unacceptable clinically significant increase in frequency/intensity of seizure activity. Determined as exit rate, defined as (1-KM product limit estimate for survival function) \* 100% |
| Pregabalin Population Pharmacokinetics (PK) | Baseline up to 20 weeks | Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules. |
| Pregabalin Exposure-Response Analysis | Day 126 | Percentage of participants predicted to exit the study due to any seizure exit criteria at Day 126. The exit rate at Day 126 was predicted using the final model (log normal distribution with respect to treatment group) and the parameter estimates. |
| Percentage of Seizure-Free Participants by Study Phase | Day 1 up to Day 140 | Percentage of participants who were seizure-free during the last 28 days on double-blind study medication (monotherapy phase, Days 112-140), during the monotherapy portion of the double-blind treatment phase (Days 56-140), and during all of the double-blind treatment phase (Days 1-140) |
Countries
Czechia, Hong Kong, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pregabalin 150 mg/Day Pregabalin 75 milligram (mg) capsules, administered orally twice daily (BID), for up to a 20-week Double-Blind Treatment Phase, which included an 8-week conversion period (antiepileptic drug \[AED\] taper) and a 12-week pregabalin Monotherapy Period, followed by a 1-week Titration/Taper phase. | 32 |
| Pregabalin 600 mg/Day Pregabalin 300 mg capsules, administered orally, BID for up to a 20-week Double-Blind Treatment Phase, which included an 8-week conversion period (2-week pregabalin dose escalation/6-week AED taper) and a 12-week pregabalin Monotherapy Period, followed by a 1-week Titration/Taper phase. Dose escalation to 600 mg/day occurred over 2 weeks as follows: 75 mg BID on Days 1-7, 150 mg BID on Days 8-14, and 300 mg BID from Day 15 up to Week 20. | 129 |
| Total | 161 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 21 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 10 | 24 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Noncompliance/Investigator discretion | 0 | 2 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 8 |
Baseline characteristics
| Characteristic | Pregabalin 150 mg/Day | Pregabalin 600 mg/Day | Total |
|---|---|---|---|
| Age, Continuous | 35.2 years STANDARD_DEVIATION 12.4 | 39.9 years STANDARD_DEVIATION 13.2 | 39.0 years STANDARD_DEVIATION 13.2 |
| Sex: Female, Male Female | 18 Participants | 71 Participants | 89 Participants |
| Sex: Female, Male Male | 14 Participants | 58 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 32 | 75 / 129 |
| serious Total, serious adverse events | 1 / 32 | 17 / 129 |
Outcome results
Primary
Percentage of Participants in the Pregabalin 600 mg/Day Treatment Group Discontinuing the Study Due to at Least 1 Pre-Defined Seizure Exit Criteria
Participants who discontinued due to: episode of status epilepticus (SE); secondarily generalized tonic-clonic (SGTC) seizure if none within 2 years of study entry; 28-day study seizure rate during double-blind phase (DBP) greater than (\>)2 times maximum (Max) 28-day study seizure rate during baseline phase (BLP); 2-day study seizure rate during DBP \>2 times Max 2-day study seizure rate during BLP; or unacceptable clinically significant increase in frequency/intensity of seizure activity. Determined as exit rate:(1-Kaplan-Meier \[KM\] product limit estimate for survival function) \* 100%
Time frame: Week 2 up to Week 18
Population: Modified Intent to Treat (MITT) Efficacy Set: The first 125 participants randomized who received at least 1 dose of pregabalin in DB treatment phase, had BL seizure assessment, and participated in DB efficacy assessment after Week 2. Number of participants analyzed (N)= number of MITT participants with discontinuation/completion data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin 600 mg/Day | Percentage of Participants in the Pregabalin 600 mg/Day Treatment Group Discontinuing the Study Due to at Least 1 Pre-Defined Seizure Exit Criteria | 31.9 Percentage of Participants |
Comparison: Null hypothesis (H0): Exit rate greater than or equal to (≥)74%p-value: <0.001Wald Test
Comparison: H0: Exite rate ≥68%p-value: <0.001Wald Test
Secondary
Mean Time on Pregabalin Monotherapy
Time frame: Week 2 to Week 20
Population: MITT Full Study Set; N=number of participants entering Monotherapy Period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin 600 mg/Day | Mean Time on Pregabalin Monotherapy | 73.8 Days | Standard Deviation 30.15 |
| Pregabalin 600 mg/Day | Mean Time on Pregabalin Monotherapy | 78.0 Days | Standard Deviation 28.24 |
Secondary
Percentage of Participants Completing 20 Weeks of Double-Blind Treatment
Time frame: Randomization up to Week 20
Population: MITT Full Study Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin 600 mg/Day | Percentage of Participants Completing 20 Weeks of Double-Blind Treatment | 53.6 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Completing 20 Weeks of Double-Blind Treatment | 58.3 Percentage of Participants |
Secondary
Percentage of Participants in the Pregabalin 150 mg/Day Treatment Group Discontinuing the Study Due to at Least 1 Pre-Defined Seizure Exit Criteria
Participants who discontinued due to: episode of SE; SGTC seizure if none within 2 years of study entry; 28-day study seizure rate during DBP \>2 times Max 28-day study seizure rate during BLP; 2-day study seizure rate during DBP \>2 times Max 2-day study seizure rate during BLP; or unacceptable clinically significant increase in frequency/intensity of seizure activity. Determined as exit rate, defined as (1-KM product limit estimate for survival function) \* 100%
Time frame: Week 2 up to Week 18
Population: MITT Full Study Set: all randomized participants who met the MITT definition (received at least 1 dose of pregabalin in DB treatment phase, had BL seizure assessment, and participated in DB efficacy assessment after Week 2)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin 600 mg/Day | Percentage of Participants in the Pregabalin 150 mg/Day Treatment Group Discontinuing the Study Due to at Least 1 Pre-Defined Seizure Exit Criteria | 37.7 Percentage of Participants |
Comparison: H0: Exit rate ≥74%p-value: <0.001Wald test
Comparison: H0: Exit rate ≥68%p-value: 0.001Wald test
Secondary
Percentage of Participants Who Met Protocol-Specified Exit Events
Percentage of participants experiencing any of the following (could have had more than 1): 1) episode of SE; 2) SGTC seizure if none had been experienced within 2 years of study entry; 3) 28-day study seizure rate during DBP \>2 times the Max 28-day study seizure rate during BLP; 4) 2-day study seizure rate during the DBP \>2 times the Max 2-day study seizure rate during BLP; or 5) unacceptable clinically significant increase in frequency/intensity of seizure activity
Time frame: Week 2 up to Week 18
Population: MITT Efficacy Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | Status Epilepticus | 0 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | SGTC Seizure (not experienced in previous 2 years) | 0 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | 28-Day Seizure Rate >2 times Max Baseline Rate | 13.0 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | 2-Day Seizure Rate >2 times Max Baseline Rate | 13.0 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | Increased Frequency/Intensity of Seizure Activity | 17.4 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | Total | 39.1 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | Increased Frequency/Intensity of Seizure Activity | 14.7 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | Status Epilepticus | 1.0 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | 2-Day Seizure Rate >2 times Max Baseline Rate | 7.8 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | SGTC Seizure (not experienced in previous 2 years) | 2.9 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | Total | 28.4 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Participants Who Met Protocol-Specified Exit Events | 28-Day Seizure Rate >2 times Max Baseline Rate | 10.8 Percentage of Participants |
Secondary
Percentage of Seizure-Free Participants by Study Phase
Percentage of participants who were seizure-free during the last 28 days on double-blind study medication (monotherapy phase, Days 112-140), during the monotherapy portion of the double-blind treatment phase (Days 56-140), and during all of the double-blind treatment phase (Days 1-140)
Time frame: Day 1 up to Day 140
Population: MITT Full Study Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pregabalin 600 mg/Day | Percentage of Seizure-Free Participants by Study Phase | Last 28 Days of Monotherapy (Days 112-140) | 17.9 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Seizure-Free Participants by Study Phase | Monotherapy (Days 56-140) | 7.1 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Seizure-Free Participants by Study Phase | Entire Double-Blind Treatment (Days 1-140) | 0 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Seizure-Free Participants by Study Phase | Last 28 Days of Monotherapy (Days 112-140) | 12.5 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Seizure-Free Participants by Study Phase | Monotherapy (Days 56-140) | 6.7 Percentage of Participants |
| Pregabalin 600 mg/Day | Percentage of Seizure-Free Participants by Study Phase | Entire Double-Blind Treatment (Days 1-140) | 1.7 Percentage of Participants |
Secondary
Pregabalin Exposure-Response Analysis
Percentage of participants predicted to exit the study due to any seizure exit criteria at Day 126. The exit rate at Day 126 was predicted using the final model (log normal distribution with respect to treatment group) and the parameter estimates.
Time frame: Day 126
Population: MITT Full Study Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin 600 mg/Day | Pregabalin Exposure-Response Analysis | 37.2 Percentage of Participants |
| Pregabalin 600 mg/Day | Pregabalin Exposure-Response Analysis | 26.3 Percentage of Participants |
Secondary
Pregabalin Population Pharmacokinetics (PK)
Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules.
Time frame: Baseline up to 20 weeks
Population: Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules.