Epilepsies, Partial
Conditions
Keywords
Partial onset epilepsy, Partial onset seizures
Brief summary
Evaluation of the safety and efficacy of Oxcarbazepine XR as adjunctive treatment for adults with partial onset seizures
Detailed description
Multicenter, double-blind, randomized, placebo-controlled, three-arm. parallel-group study of the efficacy and safety of extended-release oxcarbazepine in the treatment of adults with refractory partial onset epilepsy.
Interventions
DRUGPlacebo
Non-active tablet identical to study drug tablets
DRUG2400mg SPN-804
tablets containing 600mg OXC XR, identical to non-active tablets
DRUG1200mg SPN-804
two active tablets and two non-active tablets, all identical
Sponsors
Parexel
Supernus Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Capable of complying with the study procedures. * Able to provide written informed consent * Male or female aged 18 to 65 years, inclusive. * Diagnosis of partial onset seizures * Minimum of three seizures per 28 days * Receiving treatment with 1-3 AEDs * Refractory to at least one AED * No progressive neurological conditions by recent MRI/CT * Adequate birth control in women of child-bearing potential
Exclusion criteria
* Refractory to OXC for reasons of efficacy * Recent status epilepticus * Recent non-epileptic seizures * Current diagnosis of major depression * Recent suicidal plan or intent or more than one attempt * Current use of oxcarbazepine, felbamate for \< 18 months, phenytoin with levels \>15mcg/mL or frequent need for rescue benzodiazepines * Current use of sodium-lowering non-seizure medications. * Clinically significant hepatic, renal, or cardiovascular function * History of recent substance abuse * Females who are pregnant or lactating. * Hypersensitivity to OXC or related drugs * Difficulty swallowing study medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PCH(T), ITT | Change at 16 weeks (4wks Titration + 12 wks Maintenance) compared to Baseline | Percent change (PCH) in seizure frequency per 28d relative to Baseline, Treatment Phase (PCH\[T\]), Intent-to-Treat population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Seizure-Free Rates, ITT | At the end of 16 weeks (4 wks Titration + 12 wks Maintenance) | Percent of patients seizure-free during Treatment Phase, Intent-to-Treat population |
| PCH(M)- ITT | Change at 12 weeks (Maintenance Period) compared to Baseline | Percent change in seizure frequency per 28 days relative to Baseline, Maintenance Period (PCH\[M\]), Intent-to-Treat population |
| Responder Rate, ITT | At the end of 16 weeks (4 wks Titration + 12 wks Maintenance) | Percent of patients with a positive response, defined as a 50% or greater reduction in seizure frequency per 28 days relative to Baseline, Treatment Phase, Intent-to-Treat population |
| Seizure Free Rate, ITT, (M) | At the end of 12 weeks (Maintenance Period) | Percent of patients seizure-free during Maintenance, Intent-to-Treat population |
Countries
Bulgaria, Canada, Croatia, Mexico, Poland, Romania, Russia, United States
Participant flow
Recruitment details
Adult patients with refractory partial onset epilepsy were recruited from December 2009 to March 2011 at clinical sites in 8 countries.
Pre-assignment details
Patients had at least three partial seizures per 28 days during an 8 week Baseline Period. Subjects were receiving treatment with one to three antiepileptic drugs and were on stable treatment for a minimum of 4 weeks. Subjects with a diagnosis other than partial epilepsy were excluded.
Participants by arm
| Arm | Count |
|---|---|
| 2400mg/Day SPN-804 2400mg SPN-804O once daily | 123 |
| 1200mg/Day SPN-804 1200mg SPN-804O given once daily | 122 |
| Placebo Placebo given once daily. | 121 |
| Total | 366 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 37 | 18 | 10 |
| Overall Study | Lost to Follow-up | 1 | 5 | 2 |
| Overall Study | Other | 2 | 0 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Subject Non-compliance | 1 | 6 | 4 |
| Overall Study | Withdrawal by Subject | 11 | 10 | 6 |
Baseline characteristics
| Characteristic | 1200mg/Day SPN-804 | Placebo | 2400mg/Day SPN-804 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 122 Participants | 121 Participants | 123 Participants | 366 Participants |
| Age, Continuous | 39.1 years STANDARD_DEVIATION 11.51 | 39.1 years STANDARD_DEVIATION 12.49 | 38.5 years STANDARD_DEVIATION 11.58 | 38.9 years STANDARD_DEVIATION 11.84 |
| Region of Enrollment Bulgaria | 18 participants | 18 participants | 17 participants | 53 participants |
| Region of Enrollment Canada | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Croatia | 7 participants | 12 participants | 10 participants | 29 participants |
| Region of Enrollment Mexico | 16 participants | 14 participants | 15 participants | 45 participants |
| Region of Enrollment Poland | 16 participants | 13 participants | 25 participants | 54 participants |
| Region of Enrollment Romania | 10 participants | 6 participants | 8 participants | 24 participants |
| Region of Enrollment Russian Federation | 31 participants | 31 participants | 28 participants | 90 participants |
| Region of Enrollment United States | 23 participants | 26 participants | 20 participants | 69 participants |
| Sex: Female, Male Female | 71 Participants | 67 Participants | 64 Participants | 202 Participants |
| Sex: Female, Male Male | 51 Participants | 54 Participants | 59 Participants | 164 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 69 / 123 | 57 / 122 | 55 / 121 |
| serious Total, serious adverse events | 10 / 123 | 7 / 122 | 7 / 121 |
Outcome results
Primary
PCH(T), ITT
Percent change (PCH) in seizure frequency per 28d relative to Baseline, Treatment Phase (PCH\[T\]), Intent-to-Treat population.
Time frame: Change at 16 weeks (4wks Titration + 12 wks Maintenance) compared to Baseline
Population: All safety population subjects with baseline Seizure Diary data and at least one visit during the Treatment Phase (ITT population). Subjects must have had at least 3 consecutive weeks of Seizure Diary data (SDD) in the Baseline Phase and at least 14 consecutive days of SDD after starting study drug.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| 2400mg/Day SPN-804 | PCH(T), ITT | -42.90 percentage of change | Full Range 53.11 |
| 1200mg/Day SPN-804 | PCH(T), ITT | -38.20 percentage of change | Full Range 69.84 |
| Placebo | PCH(T), ITT | -28.70 percentage of change | Full Range 67.34 |
Comparison: A Wilcoxon rank-sum test was used to test the hypothesis of equal median reduction in PCH(T) from baseline between SPN-804 and placebo. The sample size of 120 patients per treatment arm provides over 95% power to detect a difference of 31% to 42% between placebo and 2400mg SPN-804 at a two-sided 0.025 level for an overall Type I error rate of 0.050.p-value: =0.00395% CI: [-30.4, -5.8]Wilcoxon (Mann-Whitney)
Comparison: A Wilcoxon rank-sum test was used to test the hypothesis of equal median reduction in PCH(T) from baseline between SPN-804 and placebo. The sample size of 120 patients per treatment arm provides over 95% power to detect a difference of 24% to 32% between placebo and 1200mg SPN-804 at a two-sided 0.025 level for an overall Type I error rate of 0.050.p-value: =0.07895% CI: [-22.3, 1.2]Wilcoxon (Mann-Whitney)
Secondary
PCH(M)- ITT
Percent change in seizure frequency per 28 days relative to Baseline, Maintenance Period (PCH\[M\]), Intent-to-Treat population
Time frame: Change at 12 weeks (Maintenance Period) compared to Baseline
Population: All safety population subjects with adequate baseline Seizure Diary data (at least three consecutive weeks) and at least one visit during the Titration Period and one visit during the Maintenance Period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 2400mg/Day SPN-804 | PCH(M)- ITT | -49.15 percentage of change |
| 1200mg/Day SPN-804 | PCH(M)- ITT | -35.30 percentage of change |
| Placebo | PCH(M)- ITT | -32.90 percentage of change |
Comparison: A Wilcoxon rank-sum test was used to test the hypothesis of equal median reduction in PCH(M) from baseline between SPN-804 and placebo. The sample size of 120 patients per treatment arm provides over 95% power to detect a difference of 31% to 42% between placebo and 2400mg SPN-804 at a two-sided 0.025 level for an overall Type I error rate of 0.050.p-value: =0.00395% CI: [-33, -6.3]Wilcoxon (Mann-Whitney)
Comparison: A Wilcoxon rank-sum test was used to test the hypothesis of equal median reduction in PCH(M) from baseline between SPN-804 and placebo. The sample size of 120 patients per treatment arm provides over 95% power to detect a difference of 24% to 32% between placebo and 1200mg SPN-804 at a two-sided 0.025 level for an overall Type I error rate of 0.050.p-value: =0.58995% CI: [-16.2, 9.7]Wilcoxon (Mann-Whitney)
Secondary
Responder Rate, ITT
Percent of patients with a positive response, defined as a 50% or greater reduction in seizure frequency per 28 days relative to Baseline, Treatment Phase, Intent-to-Treat population
Time frame: At the end of 16 weeks (4 wks Titration + 12 wks Maintenance)
Population: All safety population subjects with baseline Seizure Diary data and at least one visit during the Treatment Phase (ITT population). Subjects must have had at least 3 consecutive weeks of Seizure Diary data (SDD) in the Baseline Phase and at least 14 consecutive days of SDD after starting study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2400mg/Day SPN-804 | Responder Rate, ITT | 50 percentage of patients |
| 1200mg/Day SPN-804 | Responder Rate, ITT | 44 percentage of patients |
| Placebo | Responder Rate, ITT | 34 percentage of patients |
Comparison: The treatment response was analyzed using a logistic regression model with treatment group as a factor and country (or cluster), age, sex, and baseline seizure frequency per 28 days as explanatory variables.p-value: =0.01895% CI: [1.126, 3.494]Regression, Logistic
Comparison: The treatment response was analyzed using a logistic regression model with treatment group as a factor and country (or cluster), age, sex, and baseline seizure frequency per 28 days as explanatory variables.p-value: =0.07595% CI: [0.95, 2.937]Regression, Logistic
Secondary
Seizure Free Rate, ITT, (M)
Percent of patients seizure-free during Maintenance, Intent-to-Treat population
Time frame: At the end of 12 weeks (Maintenance Period)
Population: All safety population subjects with adequate baseline Seizure Diary data (at least three consecutive weeks) and at least one visit during the Titration Period and one visit during the Maintenance Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2400mg/Day SPN-804 | Seizure Free Rate, ITT, (M) | 17 percentage of patients |
| 1200mg/Day SPN-804 | Seizure Free Rate, ITT, (M) | 4 percentage of patients |
| Placebo | Seizure Free Rate, ITT, (M) | 7 percentage of patients |
Comparison: Pairwise comparisons of OXC XR 2400mg/day vs. placebo seizure-free rates during the Maintenance Period were made by means of Fisher's exact test for the ITT population.p-value: =0.008Fisher Exact
Comparison: Pairwise comparisons of OXC XR 1200mg/day vs. placebo seizure-free rates during the Maintenance Period were made by means of Fisher's exact test for the ITT population.p-value: =0.0546Fisher Exact
Secondary
Seizure-Free Rates, ITT
Percent of patients seizure-free during Treatment Phase, Intent-to-Treat population
Time frame: At the end of 16 weeks (4 wks Titration + 12 wks Maintenance)
Population: All safety population subjects with baseline Seizure Diary data and at least one visit during the Treatment Phase (ITT population). Subjects must have had at least 3 consecutive weeks of Seizure Diary data (SDD) in the Baseline Phase and at least 14 consecutive days of SDD after starting study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2400mg/Day SPN-804 | Seizure-Free Rates, ITT | 14 percentage of patients |
| 1200mg/Day SPN-804 | Seizure-Free Rates, ITT | 6 percentage of patients |
| Placebo | Seizure-Free Rates, ITT | 4 percentage of patients |
Comparison: Pairwise comparisons of OXC XR 2400mg/day vs. placebo seizure-free rates during the Treatment Phase were made by means of Fisher's exact test for the ITT population.p-value: =0.013Fisher Exact
Comparison: Pairwise comparisons of OXC XR 1200mg/day vs. placebo seizure-free rates during the Treatment Phase were made by means of Fisher's exact test for the ITT population.p-value: =0.528Fisher Exact