An Evaluation of the Efficacy and Safety of E2007 in Patients With Painful Diabetic Neuropathy

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy and safety of Perampanel in patients with painful diabetic neuropathy.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, parallel-group study. This is a 5-arm, 21-week study comprised of up to a 2-week Screening period, a 15-week Dose-Escalation and Maintenance Phase using 4 doses of E2007 (2 mg, 4 mg, 6 mg, and 8 mg) or placebo, and a 4-week, single-blind placebo Follow-Up Phase. Patients will be randomly assigned to one of the five treatment groups. Those patients assigned to receive either 4 mg, 6 mg, or 8 mg E2007 will be escalated to the appropriate dose according to an escalation schedule. All patients will take four identical-looking tablets on a daily basis for the entire study duration for blinding purposes.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial to Evaluate the Efficacy and Safety of E2007 in Patients With Painful Diabetic Neuropathy

Conditions
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Diabetic Neuropathy

Intervention / Treatment
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* Drug: Placebo
* Drug: E2007 (2 mg)
* Drug: E2007 (4 mg)
* Drug: E2007 (6 mg)
* Drug: E2007 (8 mg)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: To be included, patients must meet all of the following: Provide written informed consent, prior to entering the study or undergoing any study procedures Male and female patients ≥18 years of age will be eligible for enrollment. Females should be either not of childbearing potential as a result of surgery or menopause (1 year after onset), or of childbearing potential and practicing a medically acceptable method of contraception (e.g., abstinence, a barrier method plus spermicide, or intrauterine device [IUD]) for at least 1 month before Screening (Visit 1) and for 1 month after the end of the study (Visit 8). They must also have a negative serum beta-human chorionic gonadotropin (ß-hCG) at Screening (Visit 1). Those females using hormonal contraceptives must also be using an additional approved method of contraception (e.g., a barrier method plus spermicide or IUD) starting with the Baseline Phase and continuing throughout the study period. Have Type I or Type II diabetes with painful, distal, symmetrical, sensory-motor neuropathy attributed to diabetes, of at least 12 months duration Have pain that has been stable over the past 6 months and, in the opinion of the investigator, not in an identifiably improving or worsening trend Have hemoglobin A1c ≤ 11% Score of ≥ 40 mm on the visual analog scale (VAS) of the short form McGill Pain Questionnaire (SF-MPQ) at both Screening (Visit 1) and Baseline (Visit 2 prior to randomization) Have completed the patient diary for at least 6 of the 7 days prior to Baseline (Visit 2) Have average daily pain score of ≥ 4, on 11-point Likert-type numeric rating scale during the 7 days prior to Baseline (to be obtained from the patient diary) Be reliable, willing, and able to cooperate with all study procedures including the following: accurately fill out the diary on a daily basis return for study visits on the required dates accurately and reliably report symptoms (including treatment-emergent signs and symptoms) take study drug as required by protocol Be on stable antidiabetic treatment (insulin, oral agents, or lifestyle) that is not anticipated to change during the course of the study, except if medically required Be on stable analgesic treatment (same medication and dose) or stable nonpharmacological pain treatment for at least 4 weeks prior to Screening (Visit 1) and remain on this stable treatment throughout the study (unless otherwise directed by a physician). Nonpharmacologic pain treatment includes the following: relaxation/hypnosis, physical or occupational therapy, counseling, etc. Episodic or periodic treatments such as monthly injections for treatment of pain (e.g., local anesthetics) will not be permitted. EXCLUSION CRITERIA: Patients with any one of the following will be excluded. Patients with any condition that could interfere with the conduct of the study or confound efficacy evaluations including the following: Pain or neuropathy from another cause (including central pain, radiculopathy, painful arthritis, etc.) Skin or soft-tissue lesions in the area affected by neuropathy that are painful or could alter sensation Amputation, other than toes Patients motivated by secondary gain, or where there is a negative-incentive to achieving pain and functional pain relief (eg, litigation). This will be determined by the patient's medical history. Patients with clinically significant, progressive, or potentially unstable disease of any body system including cardiovascular, gastrointestinal, CNS, psychiatric, endocrine (other than diabetes), or immunologic, including patients with any of the following broad disease categories: Systemic infections (e.g., human immunodeficiency virus [HIV], hepatitis, tuberculosis [TB], syphilis) History of past (within the past 12 months) or present drug or alcohol abuse as per the Diagnostic and Statistical Manual - 4th Edition (DSM IV) criteria History of acute coronary syndrome within the past 12 months Active cancer within the previous 5 years Systemic chemotherapy or immunotherapy within the past 5 years History of major depression, bipolar disease, psychosis or suicidal ideation or attempts within the past 5 years Patients with any of the following laboratory abnormalities at Screening (Visit 1) or Baseline (Visit 2): Clinically significant electrocardiogram (ECG) abnormality, including prolonged QTc (defined as QTc ≥ 450 msec) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 1.5 times the upper limit of normal (ULN) White blood cell (WBC) count ≤ 2500/μL, absolute neutrophil count ≤ 1000/μL, platelet count < 100,000 Positive urine drug screen for drugs of abuse, except those prescribed by a properly licensed practitioner (e.g., opioids such as codeine for neuropathic pain) Other clinically significant laboratory values Exposure to an investigational drug (including E2007) within the 30 days prior to Screening (Visit 1) or any prior exposure to E2007.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo tablets, once daily, for 15 weeks (taken orally).<br>|
| Active Comparator: Perampanel 2mg<br> | Drug: E2007 (2 mg)<br>* Perampanel, 2 mg once daily, for 15 weeks (taken orally).<br>* Other names: Perampanel;|
| Active Comparator: Perampanel 4mg<br> | Drug: E2007 (4 mg)<br>* Perampanel, 2 mg once daily for three weeks, followed by 4 mg, once daily, for 12 weeks (taken orally).<br>* Other names: Perampanel;|
| Active Comparator: Perampanel 6mg<br> | Drug: E2007 (6 mg)<br>* Perampanel, 2 mg once daily for three weeks, followed by 4 mg once daily, for three weeks and 6 mg, once daily, for nine weeks (taken orally).<br>* Other names: Perampanel;|
| Active Comparator: Perampanel 8mg<br> | Drug: E2007 (8 mg)<br>* Perampanel, 2 mg once daily, for three weeks, followed by 4 mg, once daily for three weeks, 6 mg once daily for three weeks and 8 mg, once daily, for six weeks (taken orally).<br>* Other names: Perampanel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average Pain Scores From Baseline to Week 15/End of Treatment (EOT) | Average of last 7 available scores prior to the visit, based on 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). This is based on a modified baseline observation carried forward (BOCF). | Baseline to Week 15/EOT | 
| Responder Rate: Analysis of the Change in Pain Score From Baseline to Week 15/EOT in Subjects Who Had at Least a 30% Reduction in Pain Score | Average pain scores were calculated as the average of last 7 available scores prior to the visit, based on 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). This is based on a modified BOCF. | Baseline to Week 15/EOT | 
| Responder Rate: Analysis of the Change in Pain Score From Baseline to Week 15/EOT in Subjects Who Had at Least a 50% Reduction in Pain Score | Average pain scores were calculated as the average of last 7 available scores prior to the visit, based on 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). This is based on a modified BOCF. | Baseline to Week 15/EOT | 
| Mean Change in Average Pain Scores From Baseline at Each Study Week | Average pain scores were calculated as the average of last 7 available scores prior to the visit, based on 11-point Likert-type numerical rating scale for pain (0=no pain, to 10=worst possible pain). Last on-treatment value refers to last 7 days of available diary data while subject was on double-blind study drug. | Baseline, Week 1 to Week 17 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average Sleep Interference Scores From Baseline to Week 15/EOT | Average of last 7 available scores prior to the visit, based on 11-point Likert-type numerical rating scale for sleep interference (0=pain did not interfere with sleep, to 10=pain completely interfered with sleep [unable to sleep]). Based on modified BOCF. | Baseline to Week 15/EOT | 
| Change in Short Form - McGill Pain Questionnaire (SF-MPQ) From Baseline to Week 15/EOT | SF-MPQ sensory score = sum of intensity scores for descriptors 1-11 (throbbing, shooting, stabbing, sharp, cramping, gnawing, hot-burning, aching, heavy, tender, splitting). Each descriptor scored as 0=none, 1=mild, 2=moderate, or 3=severe. Range of possible sensory scores, 0 to 33, with a score of 33 being the most severe intensity. | Baseline and Week 15/EOT | 
| Analysis of Patient Global Impression of Change (PGIC) at Week 15/EOT | At the EOT (Visit 7) or Early Withdrawal Visit (as appropriate), the subject assessed his/her status compared to how they felt before entering the study. This assessment included an evaluation of pain frequency and intensity, the occurrence of AEs, and overall functional status using a 7-point scale where 1=very much improved and 7=very much worse. Using Modified BOCF. | Week 15/EOT | 
| Change From Baseline to Week 15/EOT in SF-36 Physical and Mental Component Scores | Short Form 36 Health Survey Questionnaire (SF-36) measuring limitations in Physical Components including physical activities, usual role activities (due to physical problems), measuring bodily pain, general health perceptions, and Mental Components including social activities, usual role activities (due to emotional problems), vitality (energy and fatigue. Each of the 8 domains are described by a score ranging from 0 to 100, for a range of total possible scores of 0-400 for physical and 0-400 for mental. Higher scores reflect better subject status. | Baseline and Week 15/EOT | 
| Change From Baseline to Week 15/EOT in Hospital Anxiety and Depression Scale (HADS) Anxiety and Depression Subscale Scores | HADS anxiety subscale score=sum of scores for 7 anxiety items, each scored on a 4-pt scale (0, 1, 2, or 3), where a higher score indicates worse anxiety. Range of possible HADS anxiety subscale scores, 0 to 21. HADS depression subscale score=sum of scores for 7 depression items, each scored on a 4-pt scale (0, 1, 2, or 3), where a higher score indicates worse depression. Range of possible HADS depression subscale scores, 0 to 21. | Baseline and Week 15/EOT | 
| Withdrawal Due to Treatment Failure During Double-Blind Dosing Period | Based on data reported on the End of Study case report form (CRF): If a subject terminated the study early during the Double-blind Dosing Period due to 'lack of therapeutic efficacy,' the subject was counted as a withdrawal due to treatment failure. | Baseline and Week 15 | 
| Presence or Absence of Allodynia at Week 15/EOT | Investigators rated subjects' allodynia as mild, moderate, severe, or not present. The presence of allodynia (yes/no) at Week 15/EOT was analyzed. | Week 15/EOT | 
| Analysis of Rescue Analgesic Medication Use (Acetaminophen) During Double-Blind Dosing Period | If acetaminophen was not reported on the Pain Therapy CRF or on the Concomitant Medication CRF, it was assumed that the subject did not use rescue analgesic medication. | Baseline to Week 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic neuropathy