Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures

Study Overview
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Brief Summary
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To compare the efficacy of pregabalin and gabapentin, as adjunctive therapy in subjects with partial seizures.

Official Title
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A Randomized, Double-blind, Parallel-group Multi-center Comparative Flexible-dose Trial Of Pregabalin Versus Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures.

Conditions
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Epilepsy, Partial Seizure Disorder, Epilepsies, Partial, Complex Partial Seizure Disorder

Intervention / Treatment
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* Drug: Pregabalin
* Drug: Gabapentin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects (male or female) must be > 18 years or ≤ 80 years of age, with a diagnosis of epilepsy with partial seizures, as defined in the International League Against Epilepsy (ILAE) classification of seizures; partial seizures may be simple or complex, with or without secondary tonic-clonic generalization. Subjects must be have been diagnosed with epilepsy for at least 2 years, and must have been unresponsive to treatment with at least two but no more than five prior antiepileptic drugs (AEDs), and at the time of study enrollment are on stable dosages of 1 or 2 standard AEDs. They must have had a 12 lead electrocardiogram (ECG) without clinically significant abnormal findings prior to randomization. Subjects must have had magnetic resonance imaging or contrast enhance computed tomography scan of the brain that demonstrated no progressive structural central nervous system abnormality at the time of the diagnosis of epilepsy. Women of childbearing potential must be established on an effective method of contraception during the study. Women should also have a negative pregnancy test prior to study entry. During the 6-week baseline period, subjects must have had a minimum of four partial seizures, with no 28 day period free of partial seizures with or without secondary generalization. A caregiver or witness must be with the subject for a sufficient duration to accurately chronicle the occurrence of seizures. These seizures must have been documented in the subject's diary. Subjects with electroencephalograph (EEG) testing done within 2 years of randomization. EEG abnormalities should be consistent with a diagnosis of focal-onset epilepsy. Signed and dated informed consent will be obtained from each subject (only include those able to consent) in accordance with the local regulatory and legal requirements. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. Subjects who are willing, but need assistance for self administered questionnaires may be considered acceptable, but must first be discussed on a case-by-case basis with the Pfizer monitor prior to any to any screening tests or procedures for the study. Exclusion Criteria: Females who are pregnant, breastfeeding, or intending to become pregnant during the course of the trial. Subjects with other neurologic illness that could impair endpoint assessment, or patients with Lennox-Gastaut syndrome, absence seizures, status epilepticus within the 12 months prior to study entry, or with seizures due to an underlying medical illness or metabolic syndrome. Subjects with clinically significant liver disease or with a calculated creatinine clearance of <60mL/min. Subjects with a history of lack of response, hypersensitivity or poor tolerability to gabapentin or pregabalin. Previous use of gabapentin or pregabalin within 2 weeks prior to screening or likelihood of engaging in these treatments during the study period. Use of prohibited medications as listed in the protocol in the absence of appropriate washout phase or the likelihood of requiring treatment during the study period with drugs not permitted by the study protocol. Participation in any other studies involving investigational or marketed products, concomitantly or within 30 days prior to entry in the study. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the subject inappropriate for entry into this trial. Subjects who are not suitable to be treated with pregabalin or gabapentin according to the respective local labeling. Subjects with a history of retinal abnormalities or treatment with retinotoxic agents.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br> | Drug: Pregabalin<br>* 150, 300, 450 mg/day administered orally TID, until seizure control/improvement or intolerable side effects<br>|
| Active Comparator: B<br> | Drug: Gabapentin<br>* 300, 600, 1200, 2000 mg/day administered orally TID, until seizure control/improvement or intolerable side effects<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in 28-day Seizure Frequency at Week 21. | The seizures were recorded by the participants, by a family member, by a caregiver, or by a legal guardian and documented in a daily seizure diary. Participant's 28-day seizure frequency of all partial seizure was assessed during double blind (TP + MP) phase compared with baseline. Total partial seizure is defined as the total number of (simple partial seizure + complex partial seizure + secondary generalized tonic clonic seizure [SGTC]). | 6 weeks Baseline, 21 weeks through End of MP for 27 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With 50% Reduction From Baseline in 28-day Seizure Rate at Week 21. | Participants who had at least 50% reduction in seizure frequency from Baseline to double-blind treatment (TP + MP) were considered as 50% responders. If percent change from baseline <= -50 then responder rate = 1 (yes) otherwise responder rate = 0 (no). | 6 weeks Baseline, 21 weeks through End of MP for 27 weeks | 
| Percentage of Participants With 75% Reduction From Baseline in 28-day Seizure Rate at Week 21. | Participants who had at least 75% reduction in seizure frequency from Baseline to double-blind treatment (TP + MP) were considered as 75% responders. If percent change from baseline <= -75 then 75% responder rate = 1 (yes) otherwise responder rate = 0 (no). Total partial seizure is defined as the total number of (simple partial seizure + complex partial seizure + SGTC). | 6 weeks Baseline, 21 weeks through End of MP for 27 weeks | 
| Percentage of Participants Without Seizures. | Seizure free for 28 days was defined as participants who have not experienced any seizure (simple partial, complex partial and SGTC) for at least 28 consecutive days from their last seizure until the end of the MP. Same participant could be seizure free for a specific type of seizure but not necessarily for the other types of seizure. | 6 weeks Baseline, 21 weeks through End of MP for 27 weeks | 
| Change From Baseline in the 28-day Secondarily Generalized Tonic-clonic (SGTC) Seizure Frequency at Week 21. | Change in SGTC = (Proportion of SGTC/All Partial Seizure rate during at the double-blind phase) - (Proportion of SGTC/All Partial Seizure rate at Baseline). Negative values indicate reduction from baseline. | 6 weeks Baseline, 21 weeks through End of MP for 27 weeks | 
| Reduction in Proportion of the 28-day SGTC Seizure Rate Over the Total Partial Seizure Rate at Week 21. | SGTC Responder is defined as a participant who shows reduction from Baseline to double-blind phase in proportion of 28-Day SGTC Seizure Rate to 28-Day All Partial Seizure Rate. | 6 weeks Baseline, 21 weeks through End of MP for 27 weeks | 
| Hospital Anxiety and Depression Scale (HADS) Score. | HADS: participant rated questionnaire with 2 subscales. Hospital Anxiety and Depression Scale - anxiety (HADS-A) assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); Hospital Anxiety and Depression Scale - depression (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 21 | 
| Medical Outcomes Study Sleep Scale (MOS-SS) Score. | Participant-rated 12-item questionnaire to assess constructs of sleep over past week; 7 subscales: sleep disturbance, snoring, awakened short of breath, sleep adequacy, somnolence (range:0-100); sleep quantity (range:0-24), optimal sleep (yes/no), and 9 item index measures of sleep disturbance provide composite scores: sleep problem summary, overall sleep problem. Except adequacy, optimal sleep and quantity, higher scores=more impairment. Scores transformed (actual raw score [RS] minus lowest possible score divided by possible RS range*100); total score range:0-100; higher score=more intensity of attribute. | Baseline, Week 21 | 
| Percentage of Participants With Optimal Sleep Assessed Using Medical Outcomes Study-Sleep Scale (MOS-SS) Score. | MOS-SS: participant-rated 12 item questionnaire to assess constructs of sleep over past week. It included 7 subscales: sleep disturbance, snoring, awakened short of breath, sleep adequacy, somnolence, sleep quantity and optimal sleep. Participants responded whether their sleep was optimal or not by choosing yes or no. Percentage of participants with optimal sleep are reported. | Baseline, Week 21 |