Efficacy and Safety of Pregabalin and Alpha-Lipoic Acid Combination in Patients with Painful Diabetic Peripheral Neuropathy: A Randomized, Open-Label, Non-Inferiority, Phase IV Clinical Trial and Subgroup Analysis (OPTIMUM Study)

AIMS:To assess the efficacy and safety of alpha-lipoic acid (ALA) and pregabalin, both as mono and combination therapy, for treating painful diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus, with the hypothesis that pregabalin monotherapy is non-inferior to combination therapy. MATERIALS AND METHODS:A phase 4 randomized, active-controlled, open-label, multicentre trial was conducted over 12 weeks to investigate changes in visual analogue scale (VAS) pain scores from baseline as a primary efficacy endpoint. A total of 151 eligible subjects were randomly assigned to ALA (480 mg/day), pregabalin (150 mg/day), and combination groups in a 1:1:1 ratio. RESULTS:The pregabalin monotherapy group showed a VAS change of -19.73 ± 18.94 mm, while the combination group showed -23.28 ± 18.15 mm at Week 12. The least square mean (LSM) difference between the two groups was 3.46 mm (95% CI: [-4.94, 11.87]), demonstrating that pregabalin monotherapy is non-inferior to combination therapy. Safety analysis revealed no significant differences across treatment groups. Cluster analysis revealed statistically significant differences in VAS scores between the pregabalin monotherapy and combination therapy groups at 12 weeks in cluster 1, characterized by a relatively shorter duration of DPN, and the LSM difference between both groups was 14.79 mm [4.59, 24.99] (p = 0.0055). CONCLUSIONS:The pregabalin monotherapy demonstrated non-inferiority compared to the combination therapy in alleviating DPN pain. Cluster analysis supported the identification of patient groups where combination therapy could be more effective, but future comprehensive studies are required for further verification. TRIAL REGISTRATION:ClinicalTrials.gov, NCT04846673.