Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid - A 7-month multicenter randomized controlled trial (ALADIN III Study)

OBJECTIVE - To evaluate the efficacy and safety of alpha-lipoic acid given intravenously, followed by oral treatment in type 2 diabetic patients with symptomatic polyneuropathy. RESEARCH DESIGN AND METHODS - In a multicenter randomized double-blind plac ebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy [ALADIN] III Study), 509 outpatients were randomly assigned to sequential treatment wit h 600 mg alpha-lipoic acid once daily intravenously for 3 weeks, followed b y 600 mg alpha-lipoic acid three times a day orally for 6 months (A-A; n = 167); 600 mg or-lipoic acid once daily intravenously for 3 weeks, followed by placebo three times a day orally for 6 months (A-P; n = 174); and placeb o once daily intravenously for 3 weeks, followed by placebo three times a d ay orally for 6 months (P-P; n = 168). Outcome measures included the Total Symptom Score (TSS) for neuropathic symptoms (pain, burning, paresthesias, and numbness) in the feet, and the Neuropathy Impairment Score (NIS). Data analysis was based on the intention to treat. RESULTS - No significant differences between the groups were noted for the demographic variables and the nerve function parameters at baseline. The TS S in the feet decreased from baseline to day 19 (median [range]) by -3.7 (- 12.6 to 5.0) points in the group given alpha-lipoic acid intravenously and by -3.0 (-12.3 to 8.0) points in the placebo group (P = 0.447), but the are a under curve on a daily basis was significantly smaller in the active as c ompared with the placebo group (85.6 [0-219] vs. 95.9 [5.5-220]); P = 0.033 ). After 7 months, the changes in the TSS from baseline were not significan tly different between the three groups studied, which could be due to incre asing intercenter variability in the TSS during the trial. The NIS decrease d after 19 days by -4.34 +/- 0.35 points (mean +/- SEM) in A-A and A-P and -3.49 +/- 0.58 points in P-P (P = 0.02 for alpha-lipoic acid versus placebo ) and after 7 months by -5.82 +/- 0.73 points in A-A, -5.76 +/- 0.69 points in A-P, and -4.37 +/- 0.83 points in P-P (P = 0.09 for A-A vs. P-P). The r ates of adverse events were not different between the groups throughout the study. CONCLUSIONS - These findings indicate that a 3-week intravenous treatment w ith alpha-lipoic acid, followed by a 6-month oral treatment, had no effect on neuropathic symptoms distinguishable from placebo to a clinically meanin gful degree, possibly due to increasing intercenter variability in symptom scoring during the study. However, this treatment was associated with a fav orable effect on neuropathic deficits without causing significant adverse r eactions Long-term trials that focus on neuropathic deficits rather than sy mptoms as the primary criterion of efficacy are needed to see whether oral treatment with alpha-lipoic acid over several years may slow or reverse the progression of diabetic neuropathy.