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Long-Term Effects of Ranirestat (AS-3201) on Peripheral Nerve Function in Patients With Diabetic Sensorimotor Polyneuropathy

¹ Department of Medicine, University of Toronto, Toronto, Canada
² Dainippon Pharmaceuticals, Teaneck, New Jersey

Address correspondence and reprint requests to Vera Bril, EN11-209, Toronto General Hospital, University Health Network, 200 Elizabeth St., Toronto, Ontario, Canada, M5G 2C4. E-mail: vera.bril{at}utoronto.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS Appendix References

 
OBJECTIVES—We aimed to determine whether ranirestat, an aldose reductase inhibitor, maintains the improved nerve function observed in patients with diabetic sensorimotor polyneuropathy (DSP) after completing a 12-week nerve biopsy study.

RESEARCH DESIGN AND METHODS—Patients with mild to moderate DSP, as determined by the presence of sural nerve responses, were enrolled in a double-blind, placebo-controlled biopsy trial and randomized to placebo or 5 or 20 mg/day ranirestat for 12 weeks. Patients completing this biopsy study were offered a 48-week extension at the same ranirestat dose or at 5 mg/day ranirestat if they were originally treated with placebo. Electrophysiological tests, the Toronto Clinical Neuropathy Score, and vibration perception thresholds (VPTs) were performed at entry and at 12 (end of the biopsy study) and 60 (end of the 48-week extension) weeks.

RESULTS—Peroneal motor nerve conduction velocity (NCV) improved in the 20-mg/day group following 60 weeks of treatment. Sural and median sensory NCV improved after both 12 and 60 weeks of treatment with 20 mg/day. VPT improved after 60 weeks of treatment with 20 mg/day. Ranirestat was well tolerated with no difference in adverse events between the 5- and 20-mg/day groups.

CONCLUSIONS—Twenty milligrams ranirestat per day improves NCV and VPT following 60 weeks of administration. The improved sensory nerve function observed after 12 weeks of therapy was maintained at 60 weeks, and improved motor nerve function was observed at 60 weeks.

Abbreviations: ARI, aldose reductase inhibitor • DSP, diabetic sensorimotor polyneuropathy • NCS, nerve conduction studies • NCV, nerve conduction velocity • TCNS, Toronto Clinical Neuropathy Score • VPT, vibration perception threshold

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS Appendix References

 
In spite of advances in the management of diabetes, diabetic sensorimotor polyneuropathy (DSP) continues to be a frequent and potentially serious complication, leading to foot ulceration and amputation (1). A fundamental pathophysiological mechanism in DSP is aberrant activity of the polyol pathway, in which hyperglycemia increases aldose reductase enzyme activity (2). This activation then results in an increased conversion of glucose to sorbitol, leading to accumulation of sorbitol and fructose in nerves. If the aldose reductase enzyme system could be pharmacologically inhibited by an aldose reductase inhibitor (ARI) with decreases in nerve sorbitol and fructose, nerve damage might be prevented and possibly reversed.

Ranirestat (AS-3201), a novel ARI developed by Dainippon Pharmaceutical (Osaka, Japan) demonstrated potent inhibition of the polyol pathway after 12 weeks of treatment (3). In this phase 2 trial, patients were randomized to one of three groups: placebo or 5 or 20 mg/day ranirestat in a double-blind fashion for 12 weeks. The placebo-treated patients had a mean nerve sorbitol concentration of 3.14 x 10^–2 nmol/mg wet nerve, similar to other reports from studies (4). This was reduced by 65.2% in those patients who received 5 mg/day ranirestat and by 83.5% in those who received 20 mg/day ranirestat. Concomitant with inhibition of the polyol pathway, patients had improved sensory nerve conduction velocities (NCVs), particularly those receiving the higher dose. On completion of the 12-week sural nerve biopsy study, patients were offered a 48-week extension phase and treated with either 5 or 20 mg/day ranirestat. We aimed to determine whether the improved nerve function observed in the biopsy study was maintained after 60 weeks of treatment with ranirestat.

	RESEARCH DESIGN AND METHODS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS Appendix References

 
The extension study was a multicenter, double-blind, randomized, efficacy study in which patients previously randomized to placebo in the original 12-week phase 2 biopsy study received 5 mg/day ranirestat. Those previously randomized to either 5 or 20 mg/day ranirestat continued their same dose. The double blind was maintained for all patients, investigators, technicians, and research staff. The efficacy procedures including nerve conduction studies (NCS), vibration perception threshold (VPT), and the Toronto Clinical Neuropathy Score (TCNS) were performed as previously described at entry into the 12-week biopsy study, at the end of the biopsy study, which was entry into the 48-week extension for each patient, and at the end of the extension, i.e., 60 weeks of treatment (3). Those patients who switched from placebo to 5 mg daily were not included in the efficacy analyses due to the different duration of treatment with ranirestat. The TCNS evaluates the signs and symptoms of DSP (5). The maximum TCNS has a value of 19 points by which the severity of DSP is categorized, i.e., 0–5: no neuropathy, 6–8: mild neuropathy, 9–11: moderate neuropathy, and 12: severe neuropathy.

The study inclusion criteria for the biopsy study have been previously described (3). Only patients completing the 12-week biopsy study were offered the 48-week extension study. The central core laboratory (University of Toronto) continued to review all NCS, VPT, and TCNS results for each patient to ensure the consistency of study procedures and high quality data (6). The extension study was approved by the institutional review boards at each of the six participating centers. All study patients provided separate written informed consent for the extension study.

Study end points
Baseline values for NCS, VPT, and TCNS were taken from the entry values into the 12-week biopsy study, as were the plasma ranirestat levels. The efficacy end points were changes in NCS, VPT, and the TCNS at the end of the extension, which is a full 60 weeks of treatment compared with entry into the biopsy study, and also changes compared with entry into the extension. Plasma ranirestat levels were measured at weeks 14, 16, 20, 24, and 36 from entry into the biopsy study.

Adverse events were carefully documented during the study. Clinical laboratory tests were periodically performed with an electrocardiogram at entry into the extension then at weeks 36 and 60. Neurological and physical examinations were performed at entry and at the end of the extension study.

Analytic procedures
Electrophysiologic measurements.
The same standardized procedures were used in the extension study as described for the 12-week biopsy study (3). The only difference was that unilateral sural nerve testing was done at week 60 from entry into the biopsy study as a sural nerve had been biopsied and no response would be expected.

Biochemical measurements
Plasma ranirestat levels were measured as previously described (3).

VPT
VPT was measured at the first toe by the method of limits using a neurothesiometer (Horwell Scientific, London, U.K.).

Statistical analyses
The results are based on the modified intent-to-treat patient population, i.e., those patients with at least one postdose efficacy assessment (NCS and/or TCNS). Baseline refers to predose data for patients treated with 5 and 20 mg/day ranirestat from entry into the biopsy study (week 0). Demographic and baseline characteristics were analyzed for homogeneity using the Wilcoxon’s rank-sum test for continuous variables or the ² test for categorical variables. TCNS severity scores were analyzed using the Cochran-Mantel-Haenszel test, controlling for center effect. Within-group comparisons between the baseline value and postdose value were assessed using the paired t test. Intergroup comparisons for the 5 and 20 mg/day groups were assessed using an ANCOVA model, including baseline values and site as covariates. Predefined medically meaningful covariates were not included in the model if they were found to be homogeneous at baseline. Statistical tests were declared statistically significant if the calculated P value was <0.050, except for baseline homogeneity, which were declared statistically significant if the P value was <0.100. Since this was an extension study, the number of patients per group was determined from the biopsy study, which was powered to show changes in sural nerve polyol levels, not for changes in NCS or the TCNS.

	RESULTS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS Appendix References

 
Demographics
Ninety-two of 94 eligible patients entered the double-blind extension phase: 34 were given placebo to 5 mg/day ranirestat, 31 were given 5 mg/day ranirestat, and 27 were given 20 mg/day ranirestat; 82.6% of patients completed the extension study (30 at placebo to 5 mg/day, 31 at 5 mg/day, and 25 at 20 mg/day). The demographic information has previously been described for entry into the biopsy study, where the three groups were shown to be comparable (3). The demographic information is presented in Table 1 for those who continued into the extension study. The treatment groups remain comparable. Most of the patients had type 2 diabetes for 14 years and DSP for 5 years at study entry. Glycemic control as indicated by the mean HbA_1c was similar.

View larger version (34K): [in this window] [in a new window]   Figure 1— Changes in NCV during the biopsy and extension studies for placebo (week 12), 5 mg/day ranirestat (weeks 12 and 60), and 20 mg/day ranirestat (weeks 12 and 60). Proximal median sensory NCV improved in the 20-mg group by 1.8 m/s at week 12 and 3.4 m/s at week 60. Peroneal motor NCV improved by 1 m/s at week 60 for both the 5- and 20-mg groups. The improvement in sural NCV at week 12 was maintained at week 60. P value; paired t test within-group comparison from entry into the biopsy study to week 60. P < 0.100; *P < 0.050;**P < 0.010 vs. baseline.

The right sural NCV slightly deteriorated in the placebo group in the 12-week biopsy study. The 5-mg/day group improved by 0.7 m/s (P = 0.42) at week 60. The 20-mg/day group showed an improvement of 1.3 m/s (P = 0.07) after 60 weeks of treatment. The left sural nerve was biopsied at the end of the previous 12-week biopsy study in most patients, so NCS results were not available.

The proximal median sensory NCV was unchanged in the placebo group in the 12-week biopsy study and showed some improvement for the 5-mg/day group at week 60, by 0.5 m/s (P = 0.31). The 20-mg/day group improved in the 12-week biopsy study and then improved further by 3.4 m/s (P = 0.01) at week 60. There was a trend of difference (P = 0.05) between the 5- and 20-mg/day groups following 60 weeks of treatment, indicating that 20 mg/day had a greater treatment effect. The lack of improvement in the distal median sensory NCV is likely due to mechanical factors at the carpal tunnel in patients with diabetes (7).

VPT
VPT did not change significantly in the placebo or 5-mg/day groups in the 12-week biopsy study or in the extension study at 60 weeks. VPT tended to improve in both toes in those treated with 20 mg/day ranirestat, but there was some asymmetry in the changes. The left side decreased by 1.9 volts (P = 0.09) compared with 0.8 volts (P = 0.50) for the right side.

TCNS
Mean changes in the symptom, sensory test, reflex, and total scores from entry are shown in Fig. 2 by treatment group. A decrease in score indicates fewer clinical features of DSP. The symptom score (0–6) decreased by –1.0 for the 5-mg/day treatment group (P < 0.001) and by –0.6 for the 20-mg/day group (P = 0.01) from weeks 0 to 60. The sensory test score (0–5) decreased by –0.2 for the 5-mg/day treatment group (P = 0.08) and –0.4 for the 20-mg/day group (P = 0.08). The combined symptom and sensory scores (0–11) decreased by –1.2 for the 5-mg/day group (P < 0.001) and by –1.0 for the 20-mg/day group (P = 0.009) from weeks 0 to 60.

View larger version (31K): [in this window] [in a new window]   Figure 2— TCNS improves in patients treated with ranirestat. A decrease in score indicates fewer symptoms and signs of DSP. P values; paired t test within-group comparison from entry to end of the biopsy study then to the end of the extension. *P < 0.050; **P < 0.010; ***P < 0.001 vs. baseline.

Pharmacokinetics
Plasma ranirestat levels are proportional to dose with no evidence of drug accumulation (data not shown).

Safety
Ranirestat was well tolerated for up to 60 weeks of administration. The prevalence of treatment-emergent adverse events was similar between the 5- and 20-mg groups. No clinically significant changes were observed for the other safety parameters.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS Appendix References

 
The results of the extension study demonstrate that effective inhibition of the polyol pathway by the ARI, ranirestat, is maintained with long-term treatment. The unexpected improvements in nerve function and clinical features of DSP after 12 weeks of treatment with 20 mg/day rantirestat were not lost but became even more evident after 60 weeks of therapy, as shown by the current findings, although the extension study was not powered to show changes in NCS or the TCNS.

The magnitude of NCV improvement after ranirestat therapy for 60 weeks is an indicator of the strong efficacy of this ARI in polyol pathway inhibition. In population studies, Arezzo (8) reported that motor NCV decreased by 0.5 m/s per year in patients with diabetes. Greene et al. (9) reported a decline in peroneal motor NCV and median and sural sensory NCV of >0.25 m/s in the placebo-treated patients in a zenarestat study. Brown et al. (10) reported more detail on these same patients, indicating a decline of median forearm sensory NCV of –0.05 m/s (n = 360), of peroneal motor NCV of –0.2 m/s (n = 359), and of sural CV of –0.65 m/s (n = 359) in 12 months. Other authors (11,12) have reported deterioration in NCV in patients with DSP. In this slowly progressive chronic disorder, ARI therapy would be expected to slow or halt the progression of NCV deterioration. Thus, the small deteriorations in motor and sensory NCV found in the placebo patients after 12 weeks are as expected, and greater decline would be predicted after 60 weeks. However, the improved NCV of 1 m/s for lower-limb motor and sensory nerves and of >3 m/s in the forearm median sensory nerve following 60 weeks of treatment with 20 mg/day ranirestat are completely unexpected and indicate the strong efficacy of ranirestat. The lack of change for median distal sensory NCV is likely due to mechanical factors at the carpal tunnel in patients with diabetes (6,7).

The magnitude of change in NCV is greater at 60 weeks than at 12 weeks. Also, improved VPT were first evident at 60 weeks, although the changes in VPT were not statistically significant. These findings suggest that ARIs have sustained and increasing effects on nerve function and clinical sensory activity that can be observed after 12 months of therapy.

Finally, the improvement in the TCNS scores and the shift in DSP severity on a simple clinical grading scale after 60 weeks of therapy confirm the clinical relevance of the improvements in NCS and VPT testing (5). Together with improved nerve function and sensation, more patients were classified as having no neuropathy and fewer as having severe DSP at 60 weeks.

The improvement in nerve function, VPT, and DSP severity observed with 20 mg/day ranirestat in this study as well as the 83.5% inhibition of nerve sorbitol levels found in the biopsy study suggest that 20 mg/day ranirestat would be clinically effective for the management of DSP. The findings in the current study are in keeping with a previous study of zenarestat, another ARI, that showed that dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by a signficiant improvement in NCV (9). In particular, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter sural nerve myelinated fibers. Given the lack of a placebo group and statistical power in the current study, the results need to be confirmed in a placebo-controlled trial of comparable duration, i.e., 12 months. Nonetheless, the current findings support the polyol pathway as being a major pathophysiological mechanism underlying DSP (2).

	Appendix

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS Appendix References

 
Ranirestat Study Group members
Andre Belanger, Centre de Recherche Clinique de Laval, Laval, Canada; V.B., University Health Network, Toronto, Canada; Denis Brunet, Enfant-Jesus du Centre Hospitalier Affilie Universitaire de Quebec, Quebec, Canada; Ian Grant, New Halifax Infirmary, Halifax, Canada; Aaron Vinik, Diabetes Research Institute, Norfolk, VA; and Sherwyn Schwartz, Diabetes and Glandular Disease, San Antonio, TX.

	Acknowledgments

 
We thank Dainippon Pharmaceuticals, Osaka, Japan, for grant support.

We also thank David Liang for assistance with table and figure preparation and MyLan Ngo for assistance in core laboratory management.

	Footnotes

 
*A list of the members of the Renirestat Study Group can be found in the APPENDIX.

V.B. is on an advisory panel for, has received honoraria/consulting fees from, and has received grant/research support from Dainippon Pharmaceuticals.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Received for publication August 2, 2005. Accepted for publication September 22, 2005.

	References

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS Appendix References

 

1. Oates PJ: Polyol pathway and diabetic peripheral neuropathy. Int Rev Neurobiol 50:325–392, 2002[Medline]
   
2. Gabbay KH, O’Sullivan JB: The sorbitol pathway: enzyme localization and content in normal and diabetic nerve and cord. Diabetes 17:239–243, 1968[Medline]
   
3. Bril V, Buchanan RA, the AS-3201 Study Group: Aldose reductase inhibition by AS-3201 in sural nerve from patients with diabetic sensorimotor polyneuropathy. Diabetes Care 27:2369–2375, 2004[Abstract/Free Full Text]
   
4. Bril V, Ono Y, Buchanan RA: Sural nerve sorbitol in patients with diabetic sensorimotor polyneuropathy. Diabetes Care 27:1160–1163, 2004[Abstract/Free Full Text]
   
5. Bril V, Perkins BA: Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy. Diabetes Care 25:2048–2052, 2002[Abstract/Free Full Text]
   
6. Bril V, Ellison R, Ngo M, Bergstrom B, Raynard D, Gin H: Electrophysiological monitoring in clinical trials: Roche Neuropathy Study Group. Muscle Nerve 21:1368–1373, 1998[Medline]
   
7. Perkins BA, Olaleye D, Bril V: Carpal tunnel syndrome in patients with diabetic polyneuropathy. Diabetes Care 25:565–569, 2002[Abstract/Free Full Text]
   
8. Arezzo JC: The use of electrophysiology for the assessment of diabetic neuropathy. Neurosci Res Commun 21:13–23, 1997
   
9. Greene DA, Arezzo JC, Brown MB, the Zenarestat Study Group: Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy: Zenarestat Study Group. Neurology 53:580–591, 1999[Abstract/Free Full Text]
   
10. Brown MJ, Bird SJ, Watling S, Kaleta H, Hayes L, Eckert S, Foyt HL: Natural progression of diabetic peripheral neuropathy in the zenarestat study population. Diabetes Care 27:1153–1159, 2004[Abstract/Free Full Text]
    
11. Laudadio C, Sima AAF: Progression rates of diabetic neuropathy in placebo patients in an 18-month clinical trial: Ponalrestat Study Group. J Diabetes Complications 12:121–127, 1998[Medline]
    
12. Diabetes Control and Complications Trial Research Group: Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 38:869–880, 1995[Medline]
    

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