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OBJECTIVE To evaluate the efficacy and safety of actovegin in patients with diabetic polyneuropathy. RESEARCH DESIGN AND METHODS In this multicenter, randomized, double-blind trial, 567 patients with type 2 diabetes received 20 intravenous infusions of actovegin (2,000 mg/day) (n = 281) or placebo (n = 286) once daily followed by three tablets of actovegin (1,800 mg/day) or placebo three times daily for 140 days. Total symptom score (TSS) of the lower limbs and vibration perception threshold (VPT) were used as coprimary outcome measures, computed as the area under the curve (AUC) from repeated scores and divided by duration of exposure. Secondary end points included individual TSS symptoms, neuropathy impairment score of the lower limbs (NIS-LL), and quality of life (short form [SF]-36). RESULTS TSS was significantly improved during actovegin treatment compared with placebo, as assessed by AUC (−0.56 points [95% CI −0.85 to −0.27]; P = 0.0003), and from baseline to 160 days (−0.86 points [−1.22 to −0.50]; P < 0.0001). VPT (five sites per foot) decreased by 3% (95% CI 0–6; P = 0.084) with actovegin than placebo, as assessed by AUC, and by 5% (1–9; P = 0.017) after 160 days. NIS-LL sensory function, as assessed by AUC, was significantly improved with actovegin versus placebo (−0.25 [95% CI −0.46 to −0.04]; P = 0.021), as was the SF-36 mental health domain. There were no differences in the incidence of adverse events between the groups. CONCLUSIONS Sequential intravenous and oral actovegin treatment over 160 days improved neuropathic symptoms, VPT, sensory function, and quality of life in type 2 diabetic patients with symptomatic polyneuropathy.