12-Month Efficacy and Safety of Diepalrestat in Adults With Diabetic Peripheral Neuropathy, a DB, Placebo-Controlled Study

Twelve-Month Chronic Efficacy and Safety of Diepalrestat in Adult Subjects With Diabetic Peripheral Neuropathy (DPN), A Randomized, Double-Blind, Placebo-Controlled Study

An interventional study to investigate the efficacy and safety of diepalrestat (BNV-222) in diabetic patients with diabetic peripheral neuropathy. Subjects will receive twice daily an oral dose of diepalrestat, an aldose reductase inhibitor, or placebo to investigate the effect on motor nerve conduction velocity (MNCV) and symptomatic clinical responses over 12 months of treatment. Subjects will be assessed at screening and baseline, with office visits every 12 weeks, for a total of 6 visits. The study will explore in a double-blind fashion, the effect of two doses of diepalrestat, 150 and 300 mg, to reduce the loss in nerve conduction velocity that is expected to be demonstrated in the group randomized to placebo treatment for up to 12 months.

This 12 month double-blind, randomized, placebo-controlled, parallel group efficacy and safety study will enroll 400 adult diabetic subjects with diabetic peripheral neuropathy (DPN) to investigate the effect of diepalrestat (BNV-222) 150 mg, 300 mg, or placebo on MNCV and patients' perception of nerve function over 12 months as measured by VAS scales and composite clinical outcome patient reported scales that evaluate numbness, tingling, cramping, paresthesiae, hyperesthesia, coldness, weakness and spontaneous pain perception of upper and lower extremities, and the effects on other measures of nerve motor and sensory conduction. Subjects will be assessed at screening and baseline, with office visits every 12 weeks, for a total of 6 visits. Subjects will be assessed by testing motor nerve conduction velocity and other assessments at each office visit. A subgroup of 24 patients will be selected for pharmacokinetic (PK) testing for up to 48 hours with additional blood draws on Day 7 and 14. This study will investigate the ability of diepalrestat to reduce the ongoing deterioration of nerve function which is a hallmark of the DPN process.

Inclusion Criteria:

• Patients with type 1 or type 2 diabetes mellitus that is controlled by oral or parenteral hypoglycemic agents or diet.
• Patients with diabetes that is stable and controlled (HbA1C ≤ than 10 %) with no new symptoms associated with diabetes within previous 3 months.
• Patients diagnosed with neuropathy who have abnormalities in 2 of 3 categories (signs, symptoms, and objective tests of nerve conduction studies or quantitative sensory threshold testing).
• Patients on pain medication (prescribed analgesics), stable for at least 3 months before study entry or pain treatment naive.
• Patients with at least mild painful symptoms of diabetic neuropathy for at least 1 year duration, but not longer than 10 years duration.
• Able to withstand the fundus evaluation during ophthalmology testing

Exclusion Criteria:

• A condition that would preclude a patient for participation in the study in opinion of investigator, e.g., unstable medical status including glycemic control and blood pressure.
• Any neurological disorder that may confound assessment of diabetic peripheral neuropathy such as radiculopathies. multiple sclerosis, myelopathies.
• Ongoing severe peripheral arterial diseases, skin ulcers, or amputation in the lower extremities.
• Neuropathy findings due to any of the following: alcohol abuse, liver or renal disease, toxic exposure, endocrine, metabolic or nutritional disorders, inflammatory diseases, or monoclonal gammopathies.
• Patients with absent peroneal nerve response.
• Other pain that may confound assessment of neuropathic pain.
• Previous participation in any studies of investigational drugs within 1 month preceding Day 0 (excluding vitamins and minerals