Once-A-Day Pregabalin For Partial Seizures

Study Overview
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Brief Summary
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Approximately 30% percent of subjects with partial seizures are refractory to treatment with single or combination antiepileptic drugs. The present study will compare the efficacy of two different dosages of pregabalin CR dosed once daily as compared to placebo, when used as adjunctive therapy in subjects requiring adjunctive therapy for partial onset epilepsy, using a randomized, parallel group design.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multi-center Trial Of Pregabalin Controlled Release Formulation As Adjunctive Therapy In Adults With Partial Onset Seizures

Conditions
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Partial Seizures, Epilepsies, Partial

Intervention / Treatment
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* Drug: pregabalin
* Drug: pregabalin
* Drug: pregabalin
* Drug: pregabalin
* Drug: pregabalin
* Drug: pregabalin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of epilepsy with partial onset seizures (seizures may be simple or complex, with or without evolution into a bilateral, convulsive seizure) Currently taking 1 to 3 anti-epilepsy medicines (AEDs) at stable dosages, and who have taken at least 2 prior (or ongoing) AEDs Exclusion Criteria: Primary generalized seizures (for example, absence, myoclonic seizures or Lennox-Gastaut Syndrome) Status epilepticus within one year prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pregabalin CR 330 mg<br> | Drug: pregabalin<br>* Controlled Release Tablets, 82.5 mg, once per day (QD) for 3 days<br>Drug: pregabalin<br>* Controlled Release Tablets, 165 mg, once per day (QD) for 11 days<br>Drug: pregabalin<br>* Controlled Release Tablets, 330 mg, once per day (QD) for the remainder of the double-blind treatment phase (max is 12 weeks)<br>Drug: pregabalin<br>* Controlled Release Tablets, 165 mg, once per day (QD) for 7 days<br>|
| Experimental: pregabalin CR 165 mg<br> | Drug: pregabalin<br>* Controlled Release Tablets, 82.5 mg, once per day (QD) for 3 days<br>Drug: pregabalin<br>* Controlled Release Tablets, 165 mg, once per day (QD) for the remainder of the up-titration and double-blind treatment and taper phases (max 14.5 weeks)<br>|
| Placebo Comparator: Placebo<br> | Drug: placebo<br>* matched to the active drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Log Transformed (Loge) 28-day Seizure Rate for All Partial Onset Seizures During the Double-blind Treatment Phase | Seizures were recorded and documented in a daily Seizure Diary by the participants, family member, caregiver, or legal guardian. Simple partial seizures without a visible motor component (ie, lacking visible movements during the seizure) were not counted toward eligibility, or in the primary or secondary efficacy analyses. Natural logarithm of the 28-day seizure rate was reported in this outcome measure. | Week 0 to Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a ≥50% Reduction in the 28-day Partial Seizure Rate From Baseline During the Double-blind Treatment Phase | Seizures were recorded and documented in a daily Seizure Diary by the participants, family member, caregiver, or legal guardian. Simple partial seizures without a visible motor component (ie, lacking visible movements during the seizure) were not counted toward eligibility, or in the primary or secondary efficacy analyses. Participants who had a ≥50% reduction in the 28-day partial seizure rate from baseline were defined as a responder, otherwise they were default as a non-responder. | Week 0 to Week 14 | 
| Percentage Change From Baseline in 28-day Partial Seizure Rate During the Double-blind Treatment Phase | Seizures were recorded and documented in a daily Seizure Diary by the participants, family member, caregiver, or legal guardian. Simple partial seizures without a visible motor component (ie, lacking visible movements during the seizure) were not counted toward eligibility, or in the primary or secondary efficacy analyses. Natural logarithm of the 28-day seizure rate was reported in this outcome measure. | Week 0 to Week 14 | 
| Frequency of Secondary Generalized Tonic-clonic Seizures (SGTC) During the Double-blind Treatment Phase | Seizures were recorded and documented in a daily Seizure Diary by the participants, family member, caregiver, or legal guardian. Simple partial seizures without a visible motor component (ie, lacking visible movements during the seizure) were not counted toward eligibility, or in the primary or secondary efficacy analyses. | Week 0 to Week 14 | 
| Log Transformed 28-day SGTC Rate for All SGTCs During the Double-blind Maintenance Phase | Seizures were recorded and documented in a daily Seizure Diary by the participants, family member, caregiver, or legal guardian. Simple partial seizures without a visible motor component (ie, lacking visible movements during the seizure) were not counted toward eligibility, or in the primary or secondary efficacy analyses. Natural logarithm of the 28-day seizure rate was reported in this outcome measure. | Week 2 to Week 14 | 
| Percentage of Participants With ≥50% Reduction in 28-day SGTC Seizure Rate From Baseline During the Double-blind Treatment Phase | Seizures were recorded and documented in a daily Seizure Diary by the participants, family member, caregiver, or legal guardian. Simple partial seizures without a visible motor component (ie, lacking visible movements during the seizure) were not counted toward eligibility, or in the primary or secondary efficacy analyses. | Week 0 to Week 14 | 
| Loge 28-day Seizure Rate for All Partial Onset Seizures During the Double-blind Maintenance Phase | Seizures were recorded and documented in a daily Seizure Diary by the participants, family member, caregiver, or legal guardian. Simple partial seizures without a visible motor component (ie, lacking visible movements during the seizure) were not counted toward eligibility, or in the primary or secondary efficacy analyses. Natural logarithm of the 28-day seizure rate was reported in this outcome measure. | Week 2 to Week 14 | 
| Change From Baseline in Hospital Anxiety and Depression Scale - Anxiety (HADS-A) Total Score at Week 14 | HADS: participant rated questionnaire with 2 subscales. HADS-A assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D assesses state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score 0 to 21 for each subscale; higher score indicates greater severity of anxiety and depression symptoms. | Baseline, Week 14 | 
| Change From Baseline in Hospital Anxiety and Depression Scale - Depression (HADS-D) Total Score at Week 14 | HADS: participant rated questionnaire with 2 subscales. HADS-A assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D assesses state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score 0 to 21 for each subscale; higher score indicates greater severity of anxiety and depression symptoms. | Baseline, Week 14 | 
| Change From Baseline in Medical Outcomes Study Sleep Scale (MOS-SS) - Sleep Disturbance Score at Week 14 | Participant-rated 12-item questionnaire to assess key constructs of sleep over the past week. 7 subscales: sleep disturbance, snoring, awakened short of breath or with headache, sleep adequacy, and somnolence (range:0-100); sleep quantity (range:0-24), and optimal sleep (yes: 1, no: 0). 6 and 9 item index measures of sleep disturbance were constructed to provide composite scores. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range * 100); total score range: 0 to 100; higher score = greater intensity of attribute. | Baseline, Week 14 | 
| Change From Baseline in MOS-SS - Snoring Score at Week 14 | Participant-rated 12-item questionnaire to assess key constructs of sleep over the past week. 7 subscales: sleep disturbance, snoring, awakened short of breath or with headache, sleep adequacy, and somnolence (range:0-100); sleep quantity (range:0-24), and optimal sleep (yes: 1, no: 0). 6 and 9 item index measures of sleep disturbance were constructed to provide composite scores. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range * 100); total score range: 0 to 100; higher score = greater intensity of attribute. | Baseline, Week 14 | 
| Change From Baseline in MOS-SS - Awaken Short of Breath or With Headache Score at Week 14 | Participant-rated 12-item questionnaire to assess key constructs of sleep over the past week. 7 subscales: sleep disturbance, snoring, awakened short of breath or with headache, sleep adequacy, and somnolence (range:0-100); sleep quantity (range:0-24), and optimal sleep (yes: 1, no: 0). 6 and 9 item index measures of sleep disturbance were constructed to provide composite scores. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range * 100); total score range: 0 to 100; higher score = greater intensity of attribute. | Baseline, Week 14 | 
| Change From Baseline in MOS-SS - Quantity of Sleep (Hours) at Week 14 | Participant-rated 12-item questionnaire to assess key constructs of sleep over the past week. 7 subscales: sleep disturbance, snoring, awakened short of breath or with headache, sleep adequacy, and somnolence (range:0-100); sleep quantity (range:0-24), and optimal sleep (yes: 1, no: 0). 6 and 9 item index measures of sleep disturbance were constructed to provide composite scores. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range * 100); total score range: 0 to 100; higher score = greater intensity of attribute. | Baseline, Week 14 | 
| Change From Baseline in MOS-SS - Sleep Adequacy Score at Week 14 | Participant-rated 12-item questionnaire to assess key constructs of sleep over the past week. 7 subscales: sleep disturbance, snoring, awakened short of breath or with headache, sleep adequacy, and somnolence (range:0-100); sleep quantity (range:0-24), and optimal sleep (yes: 1, no: 0). 6 and 9 item index measures of sleep disturbance were constructed to provide composite scores. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range * 100); total score range: 0 to 100; higher score = greater intensity of attribute. | Baseline, Week 14 | 
| Change From Baseline in MOS-SS - Sleep Somnolence Score at Week 14 | Participant-rated 12-item questionnaire to assess key constructs of sleep over the past week. 7 subscales: sleep disturbance, snoring, awakened short of breath or with headache, sleep adequacy, and somnolence (range:0-100); sleep quantity (range:0-24), and optimal sleep (yes: 1, no: 0). 6 and 9 item index measures of sleep disturbance were constructed to provide composite scores. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range * 100); total score range: 0 to 100; higher score = greater intensity of attribute. | Baseline, Week 14 | 
| Change From Baseline in MOS-SS - Sleep Problems Index I Score at Week 14 | Participant-rated 12-item questionnaire to assess key constructs of sleep over the past week. 7 subscales: sleep disturbance, snoring, awakened short of breath or with headache, sleep adequacy, and somnolence (range:0-100); sleep quantity (range:0-24), and optimal sleep (yes: 1, no: 0). 6 and 9 item index measures of sleep disturbance were constructed to provide composite scores. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range * 100); total score range: 0 to 100; higher score = greater intensity of attribute. | Baseline, Week 14 | 
| Change From Baseline in Medical Outcomes Study Sleep Scale (MOS-SS) - Sleep Problems Index II Score at Week 14 | Participant-rated 12-item questionnaire to assess key constructs of sleep over the past week. 7 subscales: sleep disturbance, snoring, awakened short of breath or with headache, sleep adequacy, and somnolence (range:0-100); sleep quantity (range:0-24), and optimal sleep (yes: 1, no: 0). 6 and 9 item index measures of sleep disturbance were constructed to provide composite scores. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range * 100); total score range: 0 to 100; higher score = greater intensity of attribute. | Baseline, Week 14 | 
| Percent of Participants Reporting Optimal Sleep on the MOS-SS - Optimal Sleep Subscale | Optimal sleep was considered between 7 to 8 hours of average sleep per night inclusive, while average sleep less than or greater than the 7 to 8 hour of average sleep per night was non-optimal. | Week 14 | 
| Benefit, Satisfaction, and Willingness to Continue Measure (BSW): Benefit From Treatment Question | The BSW consisted of 3 single-item measures designed to capture the participant's perception of the effect of treatment in terms of the relative benefit, their satisfaction, and their intention or willingness to continue on therapy. The BSW was read aloud to the participant by the investigator or designated center personnel and then was given to the participant to complete independently. | Week 14 | 
| BSW: Satisfaction From Treatment Question | The BSW consisted of 3 single-item measures designed to capture the participant's perception of the effect of treatment in terms of the relative benefit, their satisfaction, and their intention or willingness to continue on therapy. The BSW was read aloud to the participant by the investigator or designated center personnel and then was given to the participant to complete independently. | Week 14 | 
| BSW: Willingness to Continue Question | The BSW consisted of 3 single-item measures designed to capture the participant's perception of the effect of treatment in terms of the relative benefit, their satisfaction, and their intention or willingness to continue on therapy. The BSW was read aloud to the participant by the investigator or designated center personnel and then was given to the participant to complete independently. | Week 14 | 
| Percentage of Participants With New or Intensified Physical Examination Findings During the Double-blind Treatment Phase | Physical examinations included general appearance (including hight at baseline), vital sign (sitting heart rate and sitting blood pressure), weight, skin (examination for the presence of rash), HEENT (examinatin of head, eyes, ears, nose and throat), chest ausculation of lung fields), cardiovascular (ausculatin of heart sounds (S1 and S2) and for the presence of murmurs, gallops, or rubs), gastrointestinal (abdominal rigidity and tenderness), an extremities (e.g. edema). Clinically significant physical examination abnormalities were considered as adverse events based on investigator's discretion. | Day 1 to Week 15 | 
| Percentage of Participants With New or Intensified Neurological Examination Findings During the Double-blind Treatment Phase | Neurological examinations included level of consciousness, mental status, cranial nerve assessment, muscle strength, reflexes, pin prick and vibratory sensation (the latter using a 128-Hz tuning fork), coordination and gait. | Day 1 to Week 15 | 
| Percentage of Participants With Self-injurious or Suicidal Ideation or Behavior on Columbia Classification Algorithm of Suicide Assessment (C-CASA) | C-CASA is described as a standardized suicidal rating system. The C-CASA has eight categories (4 suicidal events: completed suicide, suicide attempt, preparatory act toward imminent suicidal behavior (PAISB), and suicidal ideation; 2 nonsuicidal events: self-injurious behavior, no suicidal intent (SIB-NSI) and other no deliberate self-harm, and 2 indeterminate or potentially suicidal events: self-injurious behavior, suicidal intent unknown and not enough information) that distinguish suicidal events from nonsuicidal events and indeterminate or potentially suicidal events. | Week -8 (Screening), Week 0 (Baseline), and Week 14 (double-blind treatment phase) | 
| Percentage of Participants With a Relevant Increase in Sitting Blood Pressure (BP) From Baseline During the Double-blind Treatment Phase | Physical examinations included general appearance (including hight at baseline), vital sign (sitting heart rate and sitting blood pressure), weight, skin (examination for the presence of rash), HEENT (examinatin of head, eyes, ears, nose and throat), chest (ausculation of lung fields), cardiovascular (ausculatin of heart sounds (S1 and S2) and for the presence of murmurs, gallops, or rubs), gastrointestinal(abdominal rigidity and tenderness), an extremities (e.g. edema). | Day 1 to Week 15 | 
| Percentage of Participants With Corrected QT (QTc) Interval Greater Than or Equal to 450 ms | The original ECG was reviewed by the investigator and kept on site as part of source documentation. A central ECG reader was also used for this study. QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett's formula (QTcB) were calculated. | Week 15 | 
| Percentage of Participants With Relevant ECG Interval-increases From Baseline During the Double-blind Treatment Phase | The original ECG was reviewed by the investigator and kept on site as part of source documentation. A central ECG reader was also used for this study. 25/50% represents ≥25% or ≥50% increase over baseline respectively, based on cut points. Cut points are 100 ms for QRS and 200 ms for PR. | Week 15 | 
| Percentage of Participants With Laboratory Test Abnormalities During the Study | Laboratory samples in hematology, chemistry, and urinalysis were analyzed by a cental laboratory. Any laboratory value that was identified as clinically significant was reported as an AE. LLN: Lower limit of normal, ULN: Uper limit of normal, RBC: Red Blood Cell, WBC: White Blood Cell, AST: Aspartate Aminotransferase, ALT: Alanine Aminotransferase, BUN: Blood Urea Nitrogen | Day 1 to Week 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Partial epilepsy, partial seizures, epilepsy, seizures, adjunctive therapy, intervention, controlled-release, placebo-controlled, seizure