Generalized Tonic Clonic Seizures
Conditions
Keywords
Primary Generalized Tonic Clonic Seizures, Epilepsy, Safety, Efficacy, Tolerability, Pregabalin, Lyrica, Adjunctive treatment, Placebo Controlled, Blinded
Brief summary
The study is designed to evaluate the safety, tolerability and efficacy of two doses of pregabalin as add-on treatment in pediatric and adult subjects with Primary Generalized Tonic-Clonic (PGTC) seizures as compared to placebo. It is hypothesized that both doses of pregabalin will demonstrated superior efficacy when compared to placebo by reducing PGTC seizure frequency and that pregabalin will be safe and well tolerated.
Interventions
Pregabalin, either liquid or capsule, dosed twice daily, escalated up to a maximum of 300 mg/day beginning at Randomization to Taper Phase, then tapered down to a maximum dose of 150 mg/day during 1 week Taper Phase to End of Study/Early Termination.
Pregabalin, either liquid or capsule, dosed twice daily, escalated up to a maximum of 600 mg/day beginning at Randomization to Taper Phase, then tapered down to a maximum of 150 mg/day during 1 week Taper Phase to End of Study/Early Termination.
DRUGPlacebo
Placebo, either liquid or capsule, dosed twice daily beginning at Randomization to End of Study/Early Termination.
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
5 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Seizures classified as Primary Generalized Tonic Clonic Seizures * Must have at least 1 PGTC seizure in the 8 weeks prior to screening * Must have a minimum of 3 PGTC seizures during the 8-week baseline phase and at least 1 PGTC in each 4-week period of the baseline phase * Currently receiving adequate and stable dosage of 1 to 3 anti-epileptic treatments (stable within 28 days of screening) * Signed informed consent and assent if a minor * Ability to comply with daily seizure and dosing diary requirements and all study procedures
Exclusion criteria
* A current diagnosis of febrile seizures, or seizures related to an ongoing acute medical illness * Focal seizures (simple partial, complex partial, or partial becoming secondarily generalized) * Status Epilepticus within 1 year prior to screening * Lennox-Gastaut syndrome, infantile spasms, Benign Epilepsy with Centrotemporal Spikes (BECTS) and Dravet syndrome * Seizures related to drugs, alcohol, or acute medical illness * Any change in anti-epileptic treatment regimen (type of medication or dose; VNS alteration) within 28 days of the screening visit or during the baseline phase * Progressive or potentially progressive structural CNS lesion or a progressive encephalopathy. * Progressive inborn errors of metabolism.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Log-transformed (Log) 28-day Seizure Rate for All Primary Generalized Tonic-Clonic (PGTC) Seizures During 12-Week Double-Blind Treatment Phase | Day 1 up to Week 12 | All PGTC seizures experienced during treatment phase were recorded by the participants or their parents/legal guardian in a daily seizure diary. 28-day seizure rate for all PGTC seizures= (\[number of seizures in the double blind treatment phase\] divided by \[number of days in double blind treatment phase minus {-} number of missing diary days in treatment phase\])\*28. For log-transformation, the quantity 1 was added to the 28-day seizure rate for all participants to account for any possible 0 seizure incidence. This resulted in final calculation as: log transformed (28-day seizure rate +1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 50 Percent (%) or Greater Reduction From Baseline in 28-day Primary Generalized Tonic-clonic (PGTC) Seizure Rate During the 12-Week Double-blind Treatment Phase | Day 1 up to Week 12 | Percentage of participants with 50% or greater reduction from baseline in 28-day seizure rate during the 12 week double blind treatment phase were reported. 28-day seizure rate for all PGTC seizures= (\[number of seizures in the double blind treatment phase\] divided by \[number of days in double blind treatment phase minus {-} number of missing diary days in treatment phase\])\*28. |
Countries
Austria, Belarus, Bosnia and Herzegovina, Bulgaria, China, Croatia, Denmark, France, Greece, Hungary, India, Lebanon, Malaysia, Montenegro, Philippines, Poland, Romania, Russia, Serbia, Slovakia, South Korea, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
The study was conducted at multiple sites in 21 countries in 219 participants between 03 April 2013 and 20 February 2019.
Participants by arm
| Arm | Count |
|---|---|
| Pregabalin 5 mg/kg/Day or 7 mg/kg/Day or 300 mg/Day Participants aged less than (\<) 17 years received Pregabalin, orally, twice daily in equally divided doses, for the double-blind treatment phase of 12 weeks in following manner: 1) body weight greater than or equal to (\>=)30 kg: Pregabalin 5 milligram per kilogram per day (mg/kg/day) as capsule or oral solution (using oral solution of strength 20 milligram per milliliter \[mg/mL\]), up to a maximum of 300 milligram per day (mg/day); 2) body weight \<30 kg: pregabalin 7 mg/kg/day as oral solution (using oral solution of strength 20 mg/mL), up to a maximum of 300 mg/day. Participants aged \>=17 years received Pregabalin 300 mg/day, capsule or oral solution, orally twice daily in equally divided doses, for the double-blind treatment phase of 12 weeks. | 75 |
| Pregabalin 10 mg/kg/Day or 14 mg/kg/Day or 600 mg/Day Participants aged \<17 years received Pregabalin, orally, twice daily in equally divided doses, for the double-blind treatment phase of 12 weeks in following manner: 1) body weight \>=30 kg: Pregabalin 10 mg/kg/day as capsule or oral solution (using oral solution of strength 20 mg/mL), up to a maximum of 600 mg/day; 2) body weight \<30 kg: pregabalin 14 mg/kg/day as oral solution (using oral solution of strength 20 mg/mL), up to a maximum of 600 mg/day. Participants aged \>=17 years received Pregabalin 600 mg/day, capsule or oral solution, orally twice daily in equally divided doses, for the double-blind treatment phase of 12 weeks. | 72 |
| Placebo Participants aged \<17 years received placebo matched to Pregabalin, orally, twice daily for the double-blind treatment phase of 12 weeks (in the form of solution for \<30 kg participants; in the form of capsule or liquid oral solution for \>=30 kg participants). Participants aged \>=17 years received placebo matched to Pregabalin, in the form of capsule or liquid oral solution, orally, twice daily for the double-blind treatment phase of 12 weeks. | 72 |
| Total | 219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 5 | 2 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Other | 1 | 1 | 1 |
| Overall Study | Pregnancy | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 4 | 1 |
Baseline characteristics
| Characteristic | Pregabalin 5 mg/kg/Day or 7 mg/kg/Day or 300 mg/Day | Pregabalin 10 mg/kg/Day or 14 mg/kg/Day or 600 mg/Day | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 24.0 years STANDARD_DEVIATION 13.3 | 25.4 years STANDARD_DEVIATION 12.7 | 26.2 years STANDARD_DEVIATION 13.2 | 25.2 years STANDARD_DEVIATION 13.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 8 Participants | 6 Participants | 22 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 67 Participants | 64 Participants | 65 Participants | 196 Participants |
| Sex: Female, Male Female | 42 Participants | 39 Participants | 40 Participants | 121 Participants |
| Sex: Female, Male Male | 33 Participants | 33 Participants | 32 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 72 | 1 / 72 |
| other Total, other adverse events | 39 / 75 | 41 / 72 | 36 / 72 |
| serious Total, serious adverse events | 2 / 75 | 2 / 72 | 3 / 72 |
Outcome results
Primary
Log-transformed (Log) 28-day Seizure Rate for All Primary Generalized Tonic-Clonic (PGTC) Seizures During 12-Week Double-Blind Treatment Phase
All PGTC seizures experienced during treatment phase were recorded by the participants or their parents/legal guardian in a daily seizure diary. 28-day seizure rate for all PGTC seizures= (\[number of seizures in the double blind treatment phase\] divided by \[number of days in double blind treatment phase minus {-} number of missing diary days in treatment phase\])\*28. For log-transformation, the quantity 1 was added to the 28-day seizure rate for all participants to account for any possible 0 seizure incidence. This resulted in final calculation as: log transformed (28-day seizure rate +1).
Time frame: Day 1 up to Week 12
Population: ITT population included all randomized participants who took at least 1 dose of investigational product during the double-blind treatment phase, have a baseline value and at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pregabalin 5 mg/kg/Day or 7 mg/kg/Day or 300 mg/Day | Log-transformed (Log) 28-day Seizure Rate for All Primary Generalized Tonic-Clonic (PGTC) Seizures During 12-Week Double-Blind Treatment Phase | 1.17 Seizure per 28 days | Standard Error 0.097 |
| Pregabalin 10 mg/kg/Day or 14 mg/kg/Day or 600 mg/Day | Log-transformed (Log) 28-day Seizure Rate for All Primary Generalized Tonic-Clonic (PGTC) Seizures During 12-Week Double-Blind Treatment Phase | 1.13 Seizure per 28 days | Standard Error 0.095 |
| Placebo | Log-transformed (Log) 28-day Seizure Rate for All Primary Generalized Tonic-Clonic (PGTC) Seizures During 12-Week Double-Blind Treatment Phase | 1.14 Seizure per 28 days | Standard Error 0.098 |
Comparison: Estimates and p-values from an ANCOVA model including fixed effects for log transformed baseline value, region, age strata, and treatment group.p-value: 0.812195% CI: [-0.15, 0.19]ANCOVA
Comparison: Estimates and p-values from an ANCOVA model including fixed effects for log transformed baseline value, region, age strata, and treatment group.p-value: 0.888995% CI: [-0.19, 0.16]ANCOVA
Secondary
Percentage of Participants With at Least 50 Percent (%) or Greater Reduction From Baseline in 28-day Primary Generalized Tonic-clonic (PGTC) Seizure Rate During the 12-Week Double-blind Treatment Phase
Percentage of participants with 50% or greater reduction from baseline in 28-day seizure rate during the 12 week double blind treatment phase were reported. 28-day seizure rate for all PGTC seizures= (\[number of seizures in the double blind treatment phase\] divided by \[number of days in double blind treatment phase minus {-} number of missing diary days in treatment phase\])\*28.
Time frame: Day 1 up to Week 12
Population: ITT population included all randomized participants who took at least 1 dose of investigational product during the double-blind treatment phase, have a baseline value and at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pregabalin 5 mg/kg/Day or 7 mg/kg/Day or 300 mg/Day | Percentage of Participants With at Least 50 Percent (%) or Greater Reduction From Baseline in 28-day Primary Generalized Tonic-clonic (PGTC) Seizure Rate During the 12-Week Double-blind Treatment Phase | 41.3 percentage of participants |
| Pregabalin 10 mg/kg/Day or 14 mg/kg/Day or 600 mg/Day | Percentage of Participants With at Least 50 Percent (%) or Greater Reduction From Baseline in 28-day Primary Generalized Tonic-clonic (PGTC) Seizure Rate During the 12-Week Double-blind Treatment Phase | 38.9 percentage of participants |
| Placebo | Percentage of Participants With at Least 50 Percent (%) or Greater Reduction From Baseline in 28-day Primary Generalized Tonic-clonic (PGTC) Seizure Rate During the 12-Week Double-blind Treatment Phase | 41.7 percentage of participants |
p-value: 0.797395% CI: [0.548, 2.186]Regression, Logistic
p-value: 0.847495% CI: [0.465, 1.877]Regression, Logistic