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

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.

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.