Trial Outcomes & Findings for Dose-Optimization, Adjunctive Treatment Study of Ezogabine/Retigabine Immediate Release in Partial-onset Seizures (NCT NCT01721317)

Results Overview

The efficacy of ezogabine/retigabine IR as an adjunctive treatment was to be evaluated by the percent change in the total partial seizure frequency, which was recorded by participants in the daily seizure calendar. The total 28-day POS rate is defined as the total number of POS reported during the evaluation period divided by the total number of applicable days during the evaluation period with this quotient multiplied by 28 days. The applicable days are the days in which the participant had non-missing seizure data (i.e., either 0 or \> 0 seizures recorded). Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Recruitment status

TERMINATED

Study phase

PHASE4

Target enrollment

6 participants

Primary outcome timeframe

Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase)

Results posted on

2020-12-30

Participant Flow

This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study comparing ezogabine/retigabine immediate release (IR) with placebo, as adjunctive treatment in adults with partial-onset seizures. The study was prematurely discontinued after randomizing only 6 of the planned 208 participants.

The study consisted of a 2-week (or less) Screening Phase, an 8-week Baseline Phase, a 2-week Titration Phase, an 8-week Dose-Optimization Phase, an 8-week Maintenance Phase, and a 3-week Taper Phase.

Participant milestones

Participant milestones
Measure	Placebo Participants received matching ezogabine/retigabine IR placebo orally three times a day (TID) in equally or unequally divided doses.	Ezogabine/Retigabine IR Participants received investigator-selected daily doses of 600 milligrams (mg)/day, 750 mg/day, 900 mg/day, 1050 mg/day or 1200 mg/day of ezogabine/retigabine IR. The study drug was taken orally TID in equally or unequally divided doses.
Overall Study STARTED	2	4
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	2	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received matching ezogabine/retigabine IR placebo orally three times a day (TID) in equally or unequally divided doses.	Ezogabine/Retigabine IR Participants received investigator-selected daily doses of 600 milligrams (mg)/day, 750 mg/day, 900 mg/day, 1050 mg/day or 1200 mg/day of ezogabine/retigabine IR. The study drug was taken orally TID in equally or unequally divided doses.
Overall Study Study Closed / Terminated	2	2
Overall Study Physician Decision	0	1
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Dose-Optimization, Adjunctive Treatment Study of Ezogabine/Retigabine Immediate Release in Partial-onset Seizures

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=2 Participants Participants received matching ezogabine/retigabine IR placebo orally TID in equally or unequally divided doses.	Ezogabine/Retigabine IR n=4 Participants Participants received investigator-selected daily doses of 600 mg/day, 750 mg/day, 900 mg/day, 1050 mg/day or 1200 mg/day of ezogabine/retigabine IR. The study drug was taken orally TID in equally or unequally divided doses.	Total n=6 Participants Total of all reporting groups
Age, Continuous	42.5 Years STANDARD_DEVIATION 10.61 • n=5 Participants	42.8 Years STANDARD_DEVIATION 16.32 • n=7 Participants	42.7 Years STANDARD_DEVIATION 13.50 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase)

Population: Intent-to-Treat (ITT) Population: all randomized participants who received \>= 1 dose of study medication and who had \>= 1 post-Baseline seizure diary day with \>= 0 seizures recorded.

The efficacy of ezogabine/retigabine IR as an adjunctive treatment was to be evaluated by the percent change in the total partial seizure frequency, which was recorded by participants in the daily seizure calendar. The total 28-day POS rate is defined as the total number of POS reported during the evaluation period divided by the total number of applicable days during the evaluation period with this quotient multiplied by 28 days. The applicable days are the days in which the participant had non-missing seizure data (i.e., either 0 or \> 0 seizures recorded). Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase)

Population: ITT Population

The percent change in 28-day total POS frequency within each stratum (sodium channel blocker or non-sodium channel blocker) background antiepileptic drug (AED) was to be summarized as the supportive analysis. The total 28-day POS value is defined as the total number of POS reported during the evaluation period divided by the total number of applicable days during the evaluation period with this quotient multiplied by 28 days. The applicable days are the days in which the participant had non-missing seizure data (i.e., either 0 or \> 0 seizures recorded). Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 3 (start of Dose -Optimization Phase) to Week 18 (end of Maintenance Phase)

Population: ITT Population

The efficacy of ezogabine/retigabine IR as an adjunctive treatment was to be evaluated by the percent change in total partial seizure frequency during the Dose-Optimization Phase and Maintenance Phase. The total 28-day POS value is defined as the total number of POS reported during the evaluation period divided by the total number of applicable days during the evaluation period with this quotient multiplied by 28 days. The applicable days are the days in which the participant had non-missing seizure data (i.e., either 0 or \> 0 seizures recorded). Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 0 (end of Baseline Phase) through Week 18 (end of Maintenance Phase)

Population: ITT Population

Participants (par.) experiencing \>= 50% reduction from Baseline to the end of the Double-Blind Phase in 28-day total POS were to be reported. Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 3 (start of Dose-Optimization Phase) to Week 18 (end of Maintenance Phase)

Population: ITT Population

Participants without seizures during the interval of Maintenance Phase and the Dose-Optimization Phase + Maintenance Phase were to be reported. Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 0 (end of Baseline Phase) to Week 18 (end of Maintenance Phase)

Population: ITT Population

The change in number of seizure free days during the Double-Blind period, the Maintenance Phase and the Dose-Optimization Phase + Maintenance Phase were to be reported. Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 3 (start of Dose -Optimization Phase) to Week 18 (end of Maintenance Phase)

Population: ITT Population

The effect of ezogabine/retigabine IR as an adjunctive treatment on health outcomes was to be evaluated on the basis of functional status and productivity. Participants were asked to complete the paper functional status diary to collect information to assess how the participant's functional status is affected by their epilepsy symptoms. Participants were asked to rate their epilepsy-related worry, activity limitations, and productivity (missed work or school). Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 0 (end of Baseline Phase) to Week 21 (end of Taper Phase)

Population: Safety Population: all randomized participants who receive \>= 1 dose of study medication.

The safety and tolerability of ezogabine/retigabine IR was to be evaluated by recording the incidence of new seizure types in participants without a history of these seizure types. Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 11 (start of Maintenance Phase) to Week 18 (end of Maintenance Phase)

Population: Safety Population

The safety and tolerability of ezogabine/retigabine IR was to be evaluated by recording the number of participants at each dose during the Maintenance Phase and the average maintenance dose over all participants. Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 0 (end of Baseline Phase) to Week 21 (end of Taper Phase)

Population: Safety Population

The safety and tolerability of ezogabine/retigabine IR was to be evaluated by recording the incidence of participants with early study discontinuation.

Outcome measures

Outcome measures
Measure	Placebo n=2 Participants Participants received matching ezogabine/retigabine IR placebo orally TID in equally or unequally divided doses.	Ezogabine/Retigabine IR n=4 Participants Participants received investigator-selected daily doses of 600 mg/day, 750 mg/day, 900 mg/day, 1050 mg/day or 1200 mg/day of ezogabine/retigabine IR. The study drug was taken orally TID in equally or unequally divided doses.
Number of Participants With Early Study Discontinuation	2 Participants	4 Participants

SECONDARY outcome

Timeframe: Screening, Week 0 (end of Baseline Phase), Week 2 (end of Titration Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase)

Population: Safety Population

Change from Baseline in body weight was to be assessed. Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Screening, Week 0 (end of Baseline Phase), Week 2 (end of Titration Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase)

Population: Safety Population

Change from Baseline in blood pressure was to be assessed. Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Screening, Week 0 (end of Baseline Phase), Week 2 (end of Titration Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase)

Population: Safety Population

Change from Baseline in heart rate was to be assessed. Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Screening, Week 0 (end of Baseline Phase), Week 2 (end of Titration Phase), Week 10 (end of Dose-Optimization Phase), Week 18 (end of Maintenance Phase) and Week 21 (end of Taper Phase)

Population: Safety Population

Change from Baseline in the QT interval using Bazett's correction (QTcB) and QT interval using Fridericia's correction were to be assessed. Due to the study being prematurely terminated, there was not sufficient data to summarize or evaluate this endpoint.