Lymphovenous Bypass as an Adjunct to Standard Care for Diabetic Peripheral Neuropathy: Protocol for a Randomized, Assessor-Blinded Superiority Trial (Preprint)

BACKGROUND Diabetic peripheral neuropathy (DPN) is a length-dependent, symmetric sensorimotor polyneuropathy with substantial global and regional burden. Current pharmacologic options are largely symptomatic and do not modify disease. Lymphovenous bypass (LVB), a supermicrosurgical procedure established for lymphedema, may modulate lymphatic-immune-microvascular dysfunction relevant to DPN OBJECTIVE The primary objective is to determine whether lymphovenous bypass (LVB) combined with standard of care (SOC) improves small-fiber and autonomic function compared with SOC alone at 6 months. Secondary objectives are to evaluate the effects of LVB on large-fiber function, neuropathic pain, ulcer healing, quality of life, and relevant biomarkers, as well as to characterize its safety profile. METHODS SPIRIT-aligned, single-center, randomized, controlled, parallel-group superiority trial with 2:1 allocation (LVB+SOC:SOC), stratified by ulcer status. Outcome assessors and statisticians are blinded. Primary endpoint is change in pain (DN4) and DPN burden (MNSI), at 6 and 12 months. Key secondary endpoints include foot electrochemical skin conductance (ESC, µS; Sudoscan), nerve conduction studies (NCS), and ulcer outcomes (time to epithelialization; proportion healed by 20 weeks; infection; reoperation; amputation). Exploratory endpoints include oxidative stress/antioxidant indices, inflammatory cytokines, and intraepidermal nerve fiber density (IENFD). N = 60 (LVB n = 40; SOC n = 20) provides 80% power (α = 0.05) to detect a conservative between-group ESC effect (Cohen’s d ≈ 0.70). RESULTS Recruitment is planned for September 1, 2025–July 31, 2026; follow-up through July 31, 2027. No outcome data are included. CONCLUSIONS This trial tests a mechanism-based, non-pharmacologic adjunct targeting lymphatic-immune-microvascular dysfunction in DPN. If effective, LVB could inform phenotype-directed treatment algorithms and motivate multicenter evaluation and health-economic analyses. CLINICALTRIAL NCT07126197