Trial Outcomes & Findings for Study of Retigabine Immediate Release as Adjunctive Therapy to Specified Monotherapy Antiepileptic Treatments in Adults With Partial-Onset Seizures (NCT NCT01227902)

Results Overview

The number of participants experiencing a \>=50% reduction from Baseline (BL) in POS frequency during the Treatment Phase (TP) (i.e., Titration Phase and Flexible Dose Evaluation \[FDE\] Phase) was measured. A POS has its onset in a limited area on one side of the brain. POSs may remain limited or may spread to involve both sides of the brain. For both the Baseline Phase and the TP, seizure frequency was calculated as a 28-day rate using the following formula: 28 x {\[(number of countable partial seizures in Phase) + (10 x number of days with innumerable seizures in Phase) + (number of occurrences of status epilepticus in Phase)\] / number of applicable days in the Phase}, where all days in the Phase are considered applicable (including days with 0 seizures), except for days on which the participant failed to complete the Seizure Diary. \>= 50% reduction from BL is calculated as 100 x (28-day partial seizure rate \[PSR\] for the TP - 28-day PSR for the BL Phase) / 28-day PSR for the BL Phase.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

203 participants

Primary outcome timeframe

From Baseline through Week 20 (Day 140)/Early Withdrawal

Results posted on

2014-10-17

Participant Flow

Study 113905 was an open-label, multi-center, multi-country study of retigabine using a flexible dosing regimen in adult participants (\>=18 years old) with partial-onset seizures. Eligible participants must have been taking one of the following antiepileptic drug treatments: carbamazepine/oxcarbazepine, lamotrigine, levetiracetam, or valproic acid.

Eligible participants were required to have had at least 4 partial seizures during the 8-week Baseline Phase and must have been receiving a stable dose of one of the prespecified monotherapy antiepileptic drug treatments.

Participant milestones

Participant milestones
Measure	RTG Flexible Dose Plus C/O Along with concurrent carbamazepine/oxcarbazepine (C/O), participants initiated treatment with retigabine (RTG) immediate release (IR) at 150 milligrams per day (mg/day) (50 mg thrice a day \[TID\]) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Lamotrigine Along with concurrent lamotrigine, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Levetiracetam Along with concurrent leveteracetam, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Valproic Acid Along with concurrent valproic acid, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.
Overall Study STARTED	56	51	44	52
Overall Study COMPLETED	38	38	25	42
Overall Study NOT COMPLETED	18	13	19	10

Reasons for withdrawal

Reasons for withdrawal
Measure	RTG Flexible Dose Plus C/O Along with concurrent carbamazepine/oxcarbazepine (C/O), participants initiated treatment with retigabine (RTG) immediate release (IR) at 150 milligrams per day (mg/day) (50 mg thrice a day \[TID\]) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Lamotrigine Along with concurrent lamotrigine, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Levetiracetam Along with concurrent leveteracetam, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Valproic Acid Along with concurrent valproic acid, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.
Overall Study Adverse Event	12	8	11	4
Overall Study Lack of Efficacy	1	2	2	1
Overall Study Protocol Violation	1	0	0	0
Overall Study Lost to Follow-up	0	0	1	2
Overall Study Physician Decision	0	1	1	0
Overall Study Withdrawal by Subject	4	2	4	3

Baseline Characteristics

Study of Retigabine Immediate Release as Adjunctive Therapy to Specified Monotherapy Antiepileptic Treatments in Adults With Partial-Onset Seizures

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	RTG Flexible Dose Plus C/O n=56 Participants Along with concurrent carbamazepine/oxcarbazepine (C/O), participants initiated treatment with retigabine (RTG) immediate release (IR) at 150 milligrams per day (mg/day) (50 mg thrice a day \[TID\]) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Lamotrigine n=51 Participants Along with concurrent lamotrigine, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Levetiracetam n=44 Participants Along with concurrent leveteracetam, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Valproic Acid n=52 Participants Along with concurrent valproic acid, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	Total n=203 Participants Total of all reporting groups
Age, Continuous	40.6 Years STANDARD_DEVIATION 14.99 • n=93 Participants	38.2 Years STANDARD_DEVIATION 11.91 • n=4 Participants	37.0 Years STANDARD_DEVIATION 14.94 • n=27 Participants	40.3 Years STANDARD_DEVIATION 14.05 • n=483 Participants	39.1 Years STANDARD_DEVIATION 14.00 • n=36 Participants
Sex: Female, Male Female	33 Participants n=93 Participants	26 Participants n=4 Participants	25 Participants n=27 Participants	26 Participants n=483 Participants	110 Participants n=36 Participants
Sex: Female, Male Male	23 Participants n=93 Participants	25 Participants n=4 Participants	19 Participants n=27 Participants	26 Participants n=483 Participants	93 Participants n=36 Participants
Race/Ethnicity, Customized Asian - Central/South Asian Heritage	1 participants n=93 Participants	1 participants n=4 Participants	0 participants n=27 Participants	0 participants n=483 Participants	2 participants n=36 Participants
Race/Ethnicity, Customized Asian - South East Asian Heritage	0 participants n=93 Participants	5 participants n=4 Participants	5 participants n=27 Participants	3 participants n=483 Participants	13 participants n=36 Participants
Race/Ethnicity, Customized White - White/Caucasian/European	55 participants n=93 Participants	45 participants n=4 Participants	39 participants n=27 Participants	49 participants n=483 Participants	188 participants n=36 Participants

PRIMARY outcome

Timeframe: From Baseline through Week 20 (Day 140)/Early Withdrawal

Population: Intent-to-Treat (ITT) Population: all participants in the Safety Population (all participants who took at least one dose of investigational product) who provided at least one post-Baseline efficacy assessment

The number of participants experiencing a \>=50% reduction from Baseline (BL) in POS frequency during the Treatment Phase (TP) (i.e., Titration Phase and Flexible Dose Evaluation \[FDE\] Phase) was measured. A POS has its onset in a limited area on one side of the brain. POSs may remain limited or may spread to involve both sides of the brain. For both the Baseline Phase and the TP, seizure frequency was calculated as a 28-day rate using the following formula: 28 x {\[(number of countable partial seizures in Phase) + (10 x number of days with innumerable seizures in Phase) + (number of occurrences of status epilepticus in Phase)\] / number of applicable days in the Phase}, where all days in the Phase are considered applicable (including days with 0 seizures), except for days on which the participant failed to complete the Seizure Diary. \>= 50% reduction from BL is calculated as 100 x (28-day partial seizure rate \[PSR\] for the TP - 28-day PSR for the BL Phase) / 28-day PSR for the BL Phase.

Outcome measures

Outcome measures
Measure	RTG Flexible Dose Plus C/O n=55 Participants Along with concurrent carbamazepine/oxcarbazepine (C/O), participants initiated treatment with retigabine (RTG) immediate release (IR) at 150 milligrams per day (mg/day) (50 mg thrice a day \[TID\]) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Lamotrigine n=50 Participants Along with concurrent lamotrigine, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Levetiracetam n=44 Participants Along with concurrent leveteracetam, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Valproic Acid n=51 Participants Along with concurrent valproic acid, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	Total n=200 Participants All four antiepileptic drug treatment arms combined
Number of Participants With a >=50% Reduction in Partial-onset Seizure (POS) Frequency From Baseline	22 participants	16 participants	22 participants	29 participants	89 participants

SECONDARY outcome

Timeframe: From Baseline through Week 20 (Day 140)/Early Withdrawal

Population: ITT Population

Participants were assessed for the percent change from Baseline in seizure frequency; changes were categorized as Any Decrease (\>0 to 25%, 25 to \<50%, 50 to 75%, \>75 to 100%) or No Change or Any Increase (\>25%, 0 to 25%). A partial-onset seizure is a seizure that has its onset in a limited area on one side of the brain. Partial-onset seizures may remain limited or may spread to involve both sides of the brain.

Outcome measures

Outcome measures
Measure	RTG Flexible Dose Plus C/O n=55 Participants Along with concurrent carbamazepine/oxcarbazepine (C/O), participants initiated treatment with retigabine (RTG) immediate release (IR) at 150 milligrams per day (mg/day) (50 mg thrice a day \[TID\]) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Lamotrigine n=50 Participants Along with concurrent lamotrigine, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Levetiracetam n=44 Participants Along with concurrent leveteracetam, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Valproic Acid n=51 Participants Along with concurrent valproic acid, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	Total n=200 Participants All four antiepileptic drug treatment arms combined
Number of Participants With the Indicated Reduction or Increase From Baseline in Partial-onset Seizure Frequency Any decrease	43 participants	43 participants	36 participants	44 participants	166 participants
Number of Participants With the Indicated Reduction or Increase From Baseline in Partial-onset Seizure Frequency >0 to <25% decrease	16 participants	10 participants	6 participants	7 participants	39 participants
Number of Participants With the Indicated Reduction or Increase From Baseline in Partial-onset Seizure Frequency 25 to <50% decrease	5 participants	17 participants	8 participants	8 participants	38 participants
Number of Participants With the Indicated Reduction or Increase From Baseline in Partial-onset Seizure Frequency 50 to 75% decrease	10 participants	8 participants	14 participants	17 participants	49 participants
Number of Participants With the Indicated Reduction or Increase From Baseline in Partial-onset Seizure Frequency >75 to 100% decrease	12 participants	8 participants	8 participants	12 participants	40 participants
Number of Participants With the Indicated Reduction or Increase From Baseline in Partial-onset Seizure Frequency No change or any increase	12 participants	7 participants	8 participants	7 participants	34 participants
Number of Participants With the Indicated Reduction or Increase From Baseline in Partial-onset Seizure Frequency >25% increase	10 participants	4 participants	5 participants	6 participants	25 participants
Number of Participants With the Indicated Reduction or Increase From Baseline in Partial-onset Seizure Frequency 0 to 25% increase	2 participants	3 participants	3 participants	1 participants	9 participants

SECONDARY outcome

Timeframe: From Baseline through Week 20 (Day 140)/Early Withdrawal

Population: ITT Population

The number of participants experiencing a \>=25%, \>=75%, and 100% reduction from Baseline in partial-onset seizure frequency during the Treatment Phase (TP) (i.e., Titration Phase and Flexible Dose Evaluation \[FDE\] Phase) was measured. A partial-onset seizure is a seizure that has its onset in a limited area on one side of the brain. Partial-onset seizures may remain limited or may spread to involve both sides of the brain.

Outcome measures

Outcome measures
Measure	RTG Flexible Dose Plus C/O n=55 Participants Along with concurrent carbamazepine/oxcarbazepine (C/O), participants initiated treatment with retigabine (RTG) immediate release (IR) at 150 milligrams per day (mg/day) (50 mg thrice a day \[TID\]) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Lamotrigine n=50 Participants Along with concurrent lamotrigine, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Levetiracetam n=44 Participants Along with concurrent leveteracetam, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	RTG Flexible Dose Plus Valproic Acid n=51 Participants Along with concurrent valproic acid, participants initiated treatment with RTG IR at 150 mg/day (50 mg TID) and titrated to 600 mg/day (200 mg/day TID) over a 4-week Titration Phase. This was followed by a 16-week Flexible Dose Evaluation Phase, during which the dose could be increased or decreased on a weekly basis between 50 and 150 mg/day, depending on efficacy and tolerability, with the total dose staying between 300 and 1200 mg/day. Participants who were unable to tolerate a minimum dose of 300 mg/day were discontinued from the study.	Total n=200 Participants All four antiepileptic drug treatment arms combined
Number of Participants With a >=25%, >=75%, or 100% Reduction in Partial-onset Seizure Frequency From Baseline >=25%	27 participants	33 participants	30 participants	37 participants	127 participants
Number of Participants With a >=25%, >=75%, or 100% Reduction in Partial-onset Seizure Frequency From Baseline >=75%	12 participants	8 participants	8 participants	12 participants	40 participants
Number of Participants With a >=25%, >=75%, or 100% Reduction in Partial-onset Seizure Frequency From Baseline 100%	0 participants	2 participants	1 participants	2 participants	5 participants

SECONDARY outcome

Timeframe: From Baseline through Week 20 (Day 140)/Early Withdrawal

Population: ITT Population

Percent change from Baseline was calculated as the difference in the partial-onset seizure frequency (Treatment Phase minus the Baseline Phase) divided by the Baseline Phase frequency, multiplied by 100. Negative values indicate reductions from Baseline. A partial-onset seizure is a seizure that has its onset in a limited area on one side of the brain. Partial-onset seizures may remain limited or may spread to involve both sides of the brain.