Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial.

OBJECTIVE: To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]-Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). RESULTS: Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). CONCLUSIONS: Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.

Dose escalating safety study of CNS 5161 HCl, a new neuronal glutamate receptor antagonist (NMDA) for the treatment of neuropathic pain.

AIMS: The purpose of the current study was to establish the safety and maximal tolerated dose of CNS 5161 HCl. METHODS: Forty patients with chronic neuropathic pain (23 male, 17 female) were treated with escalating dosages of CNS 5161. All adverse events to study drug, blood pressure, heart rate, ECG, drug level and clinical laboratory values were monitored. Actual pain was measured on a 100-mm visual analogue scale (VAS) and ordinal verbal pain scores. RESULTS: The most commonly occurring nervous system disorder was headache, which was found more often during placebo than during CNS 5161 HCl treatment. Visual disturbances were experienced by 16.7% of patients receiving 250 microg and by 33.3% receiving 500 microg CNS 5161 HCl, but not during placebo treatment. An increase in blood pressure was observed in 8.3% of patients receiving 250 microg and in 50% of patients receiving 500 microg CNS 5161 HCl, compared with 15.4% during placebo treatment. The study was abandoned after two patients entered the 750 microg cohort due to a sustained systolic blood pressure response. Although this study was underpowered for the confirmation of efficacy, some indications of greater pain relief after 500 microg CNS 5161 compared with placebo could be observed (change in VAS between baseline and 12 h 10 +/- 22 mm vs. 2 +/- 19 mm; P = 0.11). CONCLUSIONS: CNS 5161 HCl was reasonably well tolerated up to 500 microg. The most common adverse events were hypertension, headache and mild visual disorders.