OPTIMUM
(2026)Objective
Determine whether pregabalin monotherapy is non-inferior to pregabalin + alpha-lipoic acid (ALA) combination therapy for pain relief in painful diabetic peripheral neuropathy (DPN).
Study Summary
• Mean VAS change: pregabalin -19.73 mm vs combination -23.28 mm vs ALA -18.33 mm (no significant differences across groups in FAS).
• ≥30% VAS responders: 51.2% pregabalin, 63.0% combination, 50.0% ALA (NS).
• Safety comparable across arms (TEAEs 25-33%, p=0.67); dizziness most common with pregabalin (~8%).
• Exploratory cluster analysis: combination therapy superior in patients with shorter DPN duration (LSM diff pregabalin vs combination 14.79 mm, p=0.0055).
Intervention
Pregabalin 150 mg/day (up-titratable to 300 mg at Week 6) vs alpha-lipoic acid (ALA) 480 mg/day vs pregabalin + ALA combination, for 12 weeks.
Inclusion Criteria
Adults 19-75 years with type 2 diabetes, HbA1c ≤ 10%, painful DPN with baseline VAS ≥ 40 mm and DN4 ≥ 4 or objective evidence of neuropathy (abnormal peroneal NCS or CPT).
Study Design
Arms: ALA 480 mg/day (n=50) vs Pregabalin 150-300 mg/day (n=51) vs Combination (n=50); 1:1:1 randomization.
Patients per Arm: ~50 per arm (151 total; FAS 46/43/46)
Outcome
• Secondary: BPI-K, TSS, PD-Q, EQ-5D-3L not significantly different across groups; BPI-K pain severity favored combination over ALA at 6 wk.
• Cluster 1 (shorter DPN duration): combination significantly better than pregabalin (LSM diff 14.79 mm, p=0.0055) and ALA (LSM diff -10.83 mm, p=0.0405).
• Safety: TEAEs 32.65% ALA, 25.53% pregabalin, 33.33% combination (p=0.67); no new safety signals.
Clinical Question
In adults with painful diabetic peripheral neuropathy, is pregabalin monotherapy non-inferior to pregabalin + alpha-lipoic acid combination therapy for 12-week pain relief?
Bottom Line
Pregabalin monotherapy is non-inferior to pregabalin + ALA combination for pain relief in painful DPN over 12 weeks, with comparable safety; combination therapy may offer added benefit only in patients with shorter DPN duration (exploratory).
Major Points
- Phase 4 open-label, non-inferiority RCT of 151 patients with painful DPN randomized 1:1:1 to ALA 480 mg/day, pregabalin 150-300 mg/day, or combination for 12 weeks.
- Primary endpoint (VAS change from baseline to Week 12, PPS): pregabalin -19.73 mm vs combination -23.28 mm; LSM difference 3.46 mm (95% CI -4.94 to 11.87), upper bound below the pre-specified non-inferiority margin of 12.20 mm.
- In FAS, all three arms showed similar VAS reductions (ALA -18.33, pregabalin -19.81, combination -22.78 mm) with no statistically significant differences.
- Cluster analysis using DPN duration and DN4 score revealed that in cluster 1 (short DPN duration, ~9 months), combination therapy was significantly better than pregabalin (LSM diff 14.79 mm, p=0.0055) and ALA (LSM diff -10.83 mm, p=0.0405).
- Safety profile was comparable across the three arms; dizziness was the most common AE in pregabalin-containing arms (~8%).
Study Design
- Study Type
- Randomized Controlled Trial (Phase 4, non-inferiority)
- Randomization
- Yes
- Blinding
- Open-label
- Sample Size
- 151
- Follow-up
- 12 weeks
- Centers
- 15
- Countries
- South Korea
Primary Outcome
Definition: Change in visual analogue scale (VAS) pain score from baseline to Week 12 (PPS): pregabalin monotherapy vs combination therapy
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -23.28 ± 18.15 mm (combination) | -19.73 ± 18.94 mm (pregabalin) | - (LSM difference 3.46 mm (95% CI -4.94 to 11.87 mm); NI margin 12.20 mm) | Non-inferiority established (upper bound of 95% CI below NI margin) |
Limitations & Criticisms
- Open-label design introduces expectancy bias for subjective outcomes such as VAS pain scores.
- Only 12-week treatment duration – likely insufficient to detect disease-modifying effects of ALA that may require longer exposure.
- Conservative dosing regimen (pregabalin max 300 mg/day, ALA 480 mg/day) chosen for Asian population may not reflect Western clinical practice.
- Cluster analysis was exploratory with small subgroup sample sizes, no multiple-comparison correction, and risk of overfitting – findings are hypothesis-generating only.
- Site-based outcome assessment with no blinded/centralized adjudication may amplify subjective outcome variability.
- Study conducted entirely in South Korea, limiting generalizability across populations.
- No depression/anxiety questionnaires or sleep assessments, though these are highly relevant in chronic pain.
- Industry-funded by Yuhan Corporation (manufacturer of pregabalin used in the study).
Citation
Diabetes Obes Metab 2026;28(7):6172-6183