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

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 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). Randomization is stratified based on the presence or absence of active diabetic foot ulcers-defined by IWGDF and IDSA criteria. Sixty adults aged 20-80 years with confirmed DPN will be enrolled. LVB involves lymphatic-venous anastomosis to venules ≤0.8 mm. SOC consists of guideline-based glycemic and risk-factor management, pain control, and standardized wound care. Outcome assessors and statisticians are blinded. The primary outcomes are the changes in clinical neuropathy burden and pain severity at 6 and 12 months. Secondary outcomes comprise objective measures of somatic and autonomic physiology, alongside histopathological nerve fiber density, biological serum markers, and longitudinal ulcer epithelialization parameters. Data analysis will utilize a mixed-effects model for repeated measures (MMRM) with N = 60 providing 80% power to detect a conservative between-group effect size of Cohen's d ≈ 0.70. RESULTS: Recruitment commenced in February 2026 and is planned to continue through July 31, 2027; follow-up through July 31, 2028. As of May 2026, the first participant has been treated, and a second is scheduled. Data analysis and reporting are anticipated between late 2027 and early 2028. 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.