Study to Evaluate the Safety and Effectiveness of USL255 in Patients With Refractory Partial-onset Seizures

Conditions

Epilepsy

Keywords

Epilepsy, partial onset seizure, adjunctive therapy

Brief summary

The purpose of this study is to examine the safety and effectiveness of USL255 as adjunctive therapy in patients with refractory partial onset-seizures.

Ilan Blatt, Steve Chung, Balduin Lawson, Huy Nguyen, Vincent Yu et al. (8 authors)

Neurology2016-04-05

10.1212/wnl.86.16_supplement.p4.222

Long-Term Efficacy of USL255 (Qudexy® XR; Topiramate Extended-Release Capsules) by Refractory Status and Age: PREVAIL OLE (P2.054)

R. Edward Hogan, Ilan Blatt, Mary Holmay, Huy Nguyen, Vincent Yu et al. (7 authors)

Neurology2016-04-05

10.1212/wnl.86.16_supplement.p2.054

Long-Term Efficacy, Safety, and Impact on Quality of Life of USL255, Qudexy™ XR (Topiramate) Extended-Release Capsules: PREVAIL OLE (P1.247)

R. Edward Hogan, Ian Blatt, Annie Clark, Bob Anders, Mark Halvorsen et al. (6 authors)

Neurology2015-04-061 citations

10.1212/wnl.84.14_supplement.p1.247

Efficacy of once-daily extended-release topiramate (USL255): a subgroup analysis based on the level of treatment resistance.

Hogan RE, Hogan RE, Blatt I, Lawson B, Nagaraddi V, Fakhoury TA, Anders B, Clark AM, Laine D, Halvorsen MB, Chung SS.

2014-10-217 citations

10.1016/j.yebeh.2014.09.061

Once-daily USL255 as adjunctive treatment of partial-onset seizures: randomized phase III study.

Chung SS, Fakhoury TA, Hogan RE, Nagaraddi VN, Blatt I, Lawson B, Arnold S, Anders B, Clark AM, Laine D, Meadows RS, Halvorsen MB, PREVAIL Study Group.

2014-06-0528 citations

10.1111/epi.12660

Long-Term Open-Label Extension (OLE) Study Evaluating USL255, Once-Daily Extended-Release Topiramate, in Patients With Partial Onset Seizures: Interim Analysis From PREVAIL OLE (P3.284)

Toufic Fakhoury, R. Edward Hogan, Ilan Blatt, Steve Chung, Bob Anders

Neurology2014-04-081 citations

10.1212/wnl.82.10_supplement.p3.284

Use of Investigator Training to Improve Seizure Classification in PREVAIL: A Phase 3, Global Study Evaluating USL255, Once-Daily Extended-Release Topiramate, in Adults With Partial-Onset Seizures (P3.280)

Bree DiVentura, Jacqueline A. French, Bob Anders, Dawn Laine

Neurology2014-04-081 citations

10.1212/wnl.82.10_supplement.p3.280

Efficacy, Safety, and Impact on Quality of Life of USL255 in Patients with Refractory Partial-Onset Seizures: The PREVAIL Study (P3.261)

Steve Chung, Toufic Fakhoury, Stephan Arnold, Balduin Lawson, Ilan Blatt et al. (9 authors)

Neurology2014-04-081 citations

10.1212/wnl.82.10_supplement.p3.261

Adverse Event Profile of USL255 in Patients with Refractory Partial-Onset Seizures: The PREVAIL Study (P3.262)

R. Edward Hogan, Stephan Arnold, Toufic Fakhoury, Bob Anders

Neurology2014-04-08

10.1212/wnl.82.10_supplement.p3.262

Comparison of Adverse Effects of USL255 and Commonly Prescribed AEDs: Assessment of Relative Risk (P3.266)

Kimford J. Meador, Frank Gilliam, R. Edward Hogan, Mary Holmay, Annie Clark et al. (6 authors)

Neurology2014-04-08

10.1212/wnl.82.10_supplement.p3.266

Efficacy of USL255 Across Partial-Onset Seizure Types and Refractory Patient Status: Subgroup Analyses From the PREVAIL Study (P3.263)

Ilan Blatt, Venkatesh Nagaraddi, R. Edward Hogan, Stephan Arnold, Balduin Lawson et al. (9 authors)

Neurology2014-04-08

10.1212/wnl.82.10_supplement.p3.263

Early Onset of Efficacy and Safety Outcomes with USL255 Treatment: The PREVAIL Study (P3.264)

Venkatesh Nagaraddi, Steve Chung, Stephan Arnold, Annie Clark, Bob Anders et al. (6 authors)

Neurology2014-04-08

10.1212/wnl.82.10_supplement.p3.264

Interventions

DRUGUSL255

DRUGPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

No

Inclusion criteria

* Subject has a confirmed diagnosis of partial-onset seizures with or without secondary generalization for at least 12 months prior to Visit 1. * Currently on a stable dosing regimen of 1 to 3 AEDs for at least 4-weeks prior to Visit 1 (12 weeks for phenobarbital and primidone). * Have a minimum of 8 partial-onset seizures and no more than 21 consecutive seizure free days, during the 8-week baseline.

Exclusion criteria

* Have a history of seizure episodes lasting less than 30 minutes in which several seizures occur with such frequency that the initiation and completion of each individual seizure cannot be distinguished, within 3 months prior to Visit 1. * Have a history of pseudoseizures, or status epilepticus, within 3 months prior to Visit 1. * Have a history of metabolic acidosis, nephrolithiasis, ureterolithiasis, or narrow angle glaucoma. * Have a history of suicidal attempts, suicidal ideation, or uncontrolled psychiatric illness within 2 years of Visit 1. * Currently taking, or have taken felbamate within the past 18 months, or have taken vigabatrin in the past. * Have taken topiramate within the past 6 months.

Design outcomes

Primary

Measure	Time frame
Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	11 weeks

Secondary

Measure	Time frame
Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.	3 weeks (weeks 1-3)
Percent Reductions From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.	3 weeks (weeks 1-3)
Percent Reduction From Baseline in Weekly (7 Day) All Seizure Frequency During the Titration Plus Maintenance Phase.	11 weeks
Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phases Compared to Baseline.	3 weeks (weeks 1-3)
Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	11 weeks
Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	8 weeks (weeks 4-11)
Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	8 weeks (weeks 4-11)
Proportion of Subjects ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	8 weeks (weeks 4-11)
Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	11 weeks

Countries

Argentina, Australia, Belgium, Canada, Chile, Germany, Greece, Hungary, India, Israel, New Zealand, Poland, Russia, South Africa, Spain, United States

Participant flow

Recruitment details

This study was conducted in 16 countries (Argentina, Australia, Belgium, Canada, Chile, Germany, Greece, Hungary, India, Israel, New Zealand, Poland, Russia, South Africa, Spain, and United States). At least 1 subject was enrolled at 66 study centers, of which 60 study centers randomly assigned at least 1 subject to study drug.

Pre-assignment details

Subject had to have a minimum of 8 partial-onset seizures and no more than 21 consecutive seizure free days during the 8-week baseline to be randomized into the trial.

Participants by arm

Arm	Count
USL255 Titration of 50 mg in weekly increments over 3 weeks to 200 mg	124
Placebo Placebo	125
Total	249

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	12	4
Overall Study	Lack of Efficacy	2	1
Overall Study	Other	1	2
Overall Study	Physician Decision	1	1
Overall Study	Protocol Discontinuation Criterion Met	1	0
Overall Study	Withdrawal by Subject	4	3

Baseline characteristics

Characteristic	USL255	Placebo	Total
Age, Continuous	37.6 Years STANDARD_DEVIATION 10.97	37.6 Years STANDARD_DEVIATION 11.11	37.6 Years STANDARD_DEVIATION 11.02
Sex: Female, Male Female	58 Participants	59 Participants	117 Participants
Sex: Female, Male Male	66 Participants	66 Participants	132 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	35 / 124	14 / 125
serious Total, serious adverse events	2 / 124	2 / 125

Outcome results

Primary

Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.

Time frame: 11 weeks

Population: Intent-to-treat (ITT): all subjects who were randomized and received at least 1 dose of study drug

Arm	Measure	Value (MEDIAN)
USL255	Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	39.5 Percent Reduction
Placebo	Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	21.65 Percent Reduction

p-value: <0.001Wilcoxon (Mann-Whitney)

95% CI: [8.53, 28.1]Hodges-Lehmann

Secondary

Percent Reduction From Baseline in Weekly (7 Day) All Seizure Frequency During the Titration Plus Maintenance Phase.

Time frame: 11 weeks

Population: Intent-to-treat (ITT): all subjects who were randomized and received at least 1 dose of study drug

Arm	Measure	Value (MEDIAN)
USL255	Percent Reduction From Baseline in Weekly (7 Day) All Seizure Frequency During the Titration Plus Maintenance Phase.	39.50 Percent Reduction
Placebo	Percent Reduction From Baseline in Weekly (7 Day) All Seizure Frequency During the Titration Plus Maintenance Phase.	21.65 Percent Reduction

p-value: <0.001Wilcoxon (Mann-Whitney)

Secondary

Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.

Time frame: 8 weeks (weeks 4-11)

Population: Intent-to-treat (ITT): all subjects who were randomized and received at least 1 dose of study drug. Note: Sample size is less than for primary outcome because some subjects discontinued study prior to the maintenance phase.

Arm	Measure	Value (MEDIAN)
USL255	Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	45.70 Percent Reduction
Placebo	Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	22.09 Percent Reduction

p-value: 0.001Wilcoxon (Mann-Whitney)

Secondary

Percent Reductions From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.

Time frame: 3 weeks (weeks 1-3)

Population: Intent-to-treat (ITT): all subjects who were randomized and received at least 1 dose of study drug

Arm	Measure	Value (MEDIAN)
USL255	Percent Reductions From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.	33.93 Percent Reduction
Placebo	Percent Reductions From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.	8.57 Percent Reduction

p-value: <0.001Wilcoxon (Mann-Whitney)

Secondary

Proportion of Subjects ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.

Time frame: 8 weeks (weeks 4-11)

Population: Intent-to-treat (ITT): all subjects who were randomized and received at least 1 dose of study drug. Note: Sample size is less than for primary outcome because some subjects discontinued study prior to the maintenance phase.

Arm	Measure	Value (NUMBER)
USL255	Proportion of Subjects ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	44.2 Percentage of participants
Placebo	Proportion of Subjects ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	30.8 Percentage of participants

p-value: 0.048Cochran-Mantel-Haenszel

Secondary

Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.

Time frame: 8 weeks (weeks 4-11)

Population: Intent-to-treat (ITT): all subjects who were randomized and received at least 1 dose of study drug. Note: Sample size is less than for primary outcome because some subjects discontinued study prior to the maintenance phase.

Arm	Measure	Group	Value (NUMBER)
USL255	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	≥25% reduction in seizure rate	72.6 Percentage of participants
USL255	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	≥75% reduction in seizure rate	26.5 Percentage of participants
USL255	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	100% reduction in seizure rate	7.1 Percentage of participants
Placebo	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	≥25% reduction in seizure rate	46.7 Percentage of participants
Placebo	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	≥75% reduction in seizure rate	9.2 Percentage of participants
Placebo	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.	100% reduction in seizure rate	3.3 Percentage of participants

Secondary

Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phases Compared to Baseline.

Time frame: 3 weeks (weeks 1-3)

Population: Intent-to-treat (ITT): all subjects who were randomized and received at least 1 dose of study drug

Arm	Measure	Group	Value (NUMBER)
USL255	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phases Compared to Baseline.	≥25% reduction in seizure rate	56.5 Percentage of participants
USL255	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phases Compared to Baseline.	≥75% reduction in seizure rate	16.9 Percentage of participants
USL255	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phases Compared to Baseline.	100% reduction in seizure rate	12.1 Percentage of participants
Placebo	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phases Compared to Baseline.	≥25% reduction in seizure rate	34.4 Percentage of participants
Placebo	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phases Compared to Baseline.	≥75% reduction in seizure rate	7.2 Percentage of participants
Placebo	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phases Compared to Baseline.	100% reduction in seizure rate	3.2 Percentage of participants

Secondary

Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.

Time frame: 11 weeks

Population: Intent-to-treat (ITT): all subjects who were randomized and received at least 1 dose of study drug

Arm	Measure	Group	Value (NUMBER)
USL255	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	≥25% reduction in seizure rate	66.9 Percentage of participants
USL255	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	≥75% reduction in seizure rate	15.3 Percentage of participants
USL255	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	100% reduction in seizure rate	3.2 Percentage of participants
Placebo	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	≥25% reduction in seizure rate	46.4 Percentage of participants
Placebo	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	≥75% reduction in seizure rate	4.8 Percentage of participants
Placebo	Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	100% reduction in seizure rate	1.6 Percentage of participants

Secondary

Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.

Time frame: 3 weeks (weeks 1-3)

Arm	Measure	Value (NUMBER)
USL255	Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.	33.9 Percentage of participants
Placebo	Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.	17.6 Percentage of participants

p-value: 0.007Cochran-Mantel-Haenszel

Secondary

Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.

Time frame: 11 weeks

Population: Intent-to-treat (ITT): all subjects who were randomized and received at least 1 dose of study drug

Arm	Measure	Value (NUMBER)
USL255	Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	37.9 Percentage of participants
Placebo	Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.	23.2 Percentage of participants

p-value: 0.013Fisher Exact

Study to Evaluate the Safety and Effectiveness of USL255 in Patients With Refractory Partial-onset Seizures

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.

Percent Reduction From Baseline in Weekly (7 Day) All Seizure Frequency During the Titration Plus Maintenance Phase.

Percent Reduction From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.

Percent Reductions From Baseline in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.

Proportion of Subjects ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.

Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Maintenance Phase Compared to Baseline.

Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phases Compared to Baseline.

Proportion of Subjects With ≥25%, ≥75%, and 100% Reduction in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.

Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Phase Compared to Baseline.

Proportion of Subjects With ≥50% Reduction (Responder Rate) in Weekly (7 Day) Partial-onset Seizure Frequency During the Titration Plus Maintenance Phase Compared to Baseline.