title: Safety and efficacy of ranirestat in patients with mild-to-moderate diabetic sensorimotor polyneuropathy.
abstract: We examined the efficacy and safety of ranirestat in patients with diabetic sensorimotor polyneuropathy (DSPN). Patients (18-75 years) with stable type 1/2 diabetes mellitus and DSPN were eligible for this global, double-blind, phase II/III study (ClinicalTrials.gov NCT00927914). Patients (n = 800) were randomized 1 : 1 : 1 to placebo, ranirestat 40 mg/day or 80 mg/day (265 : 264 : 271). Change in peroneal motor nerve conduction velocity (PMNCV) from baseline to 24 months was the primary endpoint with a goal improvement vs. placebo ≥1.2 m/s. Other endpoints included symptoms, quality-of-life, and safety. Six hundred thirty-three patients completed the study. The PMNCV difference from placebo was significant at 6, 12, and 18 months in both ranirestat groups, but <1.2 m/s. The mean improvement from baseline at 24 months was +0.49, +0.95, and +0.90 m/s for placebo, ranirestat 40 mg and 80 mg, respectively (NS). The treatment difference vs. placebo reached significance when ranirestat groups were combined in a post hoc analysis (+0.44 m/s; p = 0.0237). There was no effect of ranirestat on safety assessments, secondary or exploratory endpoints vs. placebo. Ranirestat was well tolerated and improved PMNCV, but did not achieve any efficacy endpoints. The absence of PMNCV worsening in the placebo group underscores the challenges of DSPN studies in patients with well-controlled diabetes.
authors: Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
authors: Michael
authors: M
authors: Polydefkis
authors: Departments of Neuroscience and Neurology, Albert Einstein College of Medicine, New York, NY, USA.
authors: Joseph
authors: J
authors: Arezzo
authors: NeuroStudies.net, LLC, Decatur, GA, USA.
authors: Marshall
authors: M
authors: Nash
authors: Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada.
authors: Vera
authors: V
authors: Bril
authors: Nerve & Muscle Center of Texas, Houston, TX, USA.
authors: Aziz
authors: A
authors: Shaibani
authors: Eisai Ltd, Hatfield, UK.
authors: Robert J
authors: RJ
authors: Gordon
authors: Eisai Ltd, Hatfield, UK.
authors: Kate L
authors: KL
authors: Bradshaw
authors: Eisai Ltd, Hatfield, UK.
authors: Roderick W J
authors: RW
authors: Junor
mesh_terms: D000368:Aged; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D011115:Polyneuropathies / Q000188:drug therapy* / Q000503:physiopathology; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011788:Quality of Life; D013141:Spiro Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D011719:Pyrazines; D013141:Spiro Compounds; C115070:ranirestat
keywords: aldose reductase; clinical trial; diabetic neuropathy; neuropathy progression