Ranirestat for the management of diabetic sensorimotor polyneuropathy

Vera Bril, Toshiyuki Hirose, Sasagu Tomioka, Robert Buchanan, Ranirestat Study Group, R Bedlack, A Belanger, T Brannagan, D Brunet, P Dandona, J Ervin, R Freeman, I Grant, P Hollander, L Klaff, D Lau, M Liebowitz, J Liljenquist, D Lorber, T Lyons, M Mollen, P Raskin, M Rendell, S Schwartz, J Selam, A Shaibani, A Vinik, R Weinstein, J Wymer, Vera Bril, Toshiyuki Hirose, Sasagu Tomioka, Robert Buchanan, Ranirestat Study Group, R Bedlack, A Belanger, T Brannagan, D Brunet, P Dandona, J Ervin, R Freeman, I Grant, P Hollander, L Klaff, D Lau, M Liebowitz, J Liljenquist, D Lorber, T Lyons, M Mollen, P Raskin, M Rendell, S Schwartz, J Selam, A Shaibani, A Vinik, R Weinstein, J Wymer

Abstract

Objective: Aldose reductase inhibitors (ARIs) are potential disease modifiers for diabetes complications. We aimed to determine whether ranirestat, an ARI, could slow or reverse the course of diabetic sensorimotor polyneuropathy (DSP).

Research design and methods: A total of 549 patients with DSP were randomly assigned to treatment with placebo or 10, 20, or 40 mg/day ranirestat for 52 weeks in this multicenter, double-blind study. Efficacy was evaluated by nerve conduction studies, the modified Toronto Clinical Neuropathy Score (mTCNS), and quantitative sensory tests (QSTs).

Results: At week 52, the summed sensory (bilateral sural plus proximal median sensory) nerve conduction velocity (NCV) did not show significant changes from baseline (2.0 m/s for placebo compared with 3.2-3.8 m/s for ranirestat). Significant improvement in the summed motor (peroneal, tibial, and median) NCV was observed with 20 and 40 mg/day ranirestat treatment at week 12 (P <or= 0.05) and at weeks 24 and 36 and in peroneal motor NCV at weeks 36 and 52 (P <or= 0.05) for the 20 mg/day ranirestat group. The mTCNS and QST results did not differ among the groups during the study. Ranirestat was well tolerated with no pertinent differences in drug-related adverse events or in effects on clinical laboratory parameters, vital signs, or electrocardiograms among the four groups.

Conclusions: Treatment with ranirestat appears to have an effect on motor nerve function in mild to moderate DSP, but the results of this study failed to show a statistically significant difference in sensory nerve function relative to placebo.

Trial registration: ClinicalTrials.gov NCT00101426.

Figures

Figure 1
Figure 1
Changes from baseline in the summed sensory NCV. Summed sensory NCV includes bilateral sural and proximal median sensory nerves. Data shown are LSM ± SEM change from baseline for last observation carried forward. Adjusted P values: placebo vs. 10 mg (P = 0.962), 20 mg (P = 0.246), and 40 mg (P = 0.369) at week 52.
Figure 2
Figure 2
Changes from baseline in the summed motor NCV. The summed motor NCV includes the median, peroneal, and tibial nerves. Data shown are LSM ± SEM change from baseline for last observation carried forward. Adjusted P values: placebo vs. 10 mg (P = 0.247), 20 mg (P = 0.028), and 40 mg (P = 0.002) at week 12; placebo vs. 10 mg (P = 0.296), 20 mg (P = 0.152), and 40 mg (P = 0.036) at week 24; placebo vs. 10 mg (P = 0.188), 20 mg (P = 0.029), and 40 mg (P = 0.013) at week 36; placebo vs. 10 mg (P = 0.913), 20 mg (P = 0.123), and 40 mg (P = 0.162) at week 52.
Figure 3
Figure 3
Changes from baseline in peroneal motor NCV. *P < 0.05; **P < 0.01. Data shown are LSM ± SEM change from baseline for last observation carried forward. Adjusted P values: placebo versus ranirestat all doses at week 36 (P ≤ 0.035); placebo vs. 10 mg (P = 0.014), 20 mg (P = 0.015), and 40 mg (P = 0.108) at week 52.

References

    1. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein JM, Pach D, Wilson DM, O'Brien PC, Melton LJ, III. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993; 43: 817– 824
    1. De Wytt C, Jackson RV, Hockings GI, Joyner JM, Strakosch CR. Polyneuropathy in Australian outpatients with type II diabetes mellitus. J Diabetes Complications 1999; 13: 74– 78
    1. Oates PJ. Polyol pathway and diabetic peripheral neuropathy. Int Rev Neurobiol 2002; 50: 325– 392
    1. Greene DA, Arezzo JC, Brown MB. Zenarestat Study Group. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Neurology 1999; 53: 580– 591
    1. Pfeifer MA, Schumer MP. Clinical trials of diabetic neuropathy: past, present, and future. Diabetes 1995; 44: 1355– 1361
    1. Pfeifer MA, Schumer MP, Gelber DA. Aldose reductase inhibitors: the end of an era or the need for different trial designs? Diabetes 1997; 46: S82– S89
    1. Bril V, Buchanan RA. AS-3201 Study Group. Aldose reductase inhibition by AS-3201 in sural nerve from patients with diabetic sensorimotor polyneuropathy. Diabetes Care 2004; 27: 2369– 2375
    1. Bril V, Buchanan RA. Ranirestat Study Group. Long-term effects of ranirestat (AS-3201) on peripheral nerve function in patients with diabetic sensorimotor polyneuropathy. Diabetes Care 2006; 29: 68– 72
    1. Report and recommendations of the San Antonio Conference on Diabetic Neuropathy. Diabetes 1988; 37: 1000– 1004
    1. Bril V, Ellison R, Ngo M, Bergstrom B, Raynard D, Gin H. Roche Neuropathy Study Group. Electrophysiological monitoring in clinical trials. Muscle Nerve 1998; 21: 1368– 1373
    1. Bril V, Perkins BA. Validation of the Toronto Clinical Scoring System for Diabetic Polyneuropathy. Diabetes Care 2002; 25: 2048– 2052
    1. Bril V, Tomioka S, Buchanan RA, Perkins BA. mTCNS Study Group. Reliability and validity of the modified Toronto Clinical Neuropathy Score in diabetic sensorimotor polyneuropathy. Diabet Med 2009; 26: 240– 246
    1. Niwa T, Tohyama K, Kato Y. Analysis of polyols in uremic serum by liquid chromatography combined with atmospheric pressure chemical ionization mass spectrometry. J Chromatogr 1993; 613: 9– 14
    1. Vinik AI, Bril V, Kempler P, Litchy WJ, Tesfaye S, Price KL, Bastyr EJ, 3rd, MBBQ Study Group. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C β-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin Ther 2005; 27: 1164– 1180
    1. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R. Oral treatment with α-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 2006; 29: 2365– 2370
    1. Carrington AL, Shaw JE, Van Schie CHM, Abbott CA, Vileikyte L, Boulton AJM. Can motor nerve conduction velocity predict foot problems in diabetic subjects over a 6-year outcome period? Diabetes Care 2002; 25: 2010– 2015
    1. Abbott CA, Carrington AL, Ashe H, Bath S, Every LC, Griffiths J, Hann AW, Hussein A, Jackson N, Johnson KE, Ryder CH, Torkington R, Van Ross ERE, Whalley AM, Widdows P, Williamson S, Boulton AJM. The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 2002; 19: 377– 384

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