Effect of Lymphovenous Anastomosis on Lower Limb Lymphedema: Pragmatic Randomized Controlled Trial

Not Applicable

Recruiting

• Conditions: Lymphedema; Lymphoedema; Lymphoedema of Leg; Lymphedema of Leg

• Registration Number: NCT07073586
• Lead Sponsor: Herlev and Gentofte Hospital

Brief Summary

This multicentre pragmatic randomised controlled trial evaluates lymphovenous anastomosis (LVA) for lower-limb lymphedema (LLL) in Denmark. Adults with unilateral or bilateral International Society of Lymphology stage 1-2a LLL who have completed protocol-defined Complete Decongestive Therapy (CDT) are randomised 1:1 to

Intervention arm - LVA surgery plus ongoing compression care

Control arm - Compression care only

Recruitment takes place at the Departments of Plastic Surgery, Herlev-Gentofte Hospital and Odense University Hospital. Outcomes are assessed by independent blinded staff at baseline, 6, 12 and 24 months. A biopsy substudy in ten LVA patients explores inflammatory and fibrotic changes. Primary endpoint is change in L-Dex ratio at 12 months. Secondary endpoints include limb volume, infection rate, lymphoscintigraphy findings, patient-reported outcomes, compression-garment use and anastomosis patency.

The trial follows Good Clinical Practice and GDPR. Patients are covered by the Danish public patient-compensation scheme. Results will be published regardless of outcome, and control participants may opt for LVA after the 12-month visit.

Detailed Description

LLL causes chronic swelling, pain, recurrent infections and impaired quality of life. CDT is standard care, yet many patients have persistent disease. LVA is a super-microsurgical procedure that diverts lymph into the venous system, but robust randomised evidence in LLL is lacking

This multicentre pragmatic randomised trial will test whether lymphovenous anastomosis (LVA) can reduce lower-limb lymphedema and improve life quality in adults who have completed Complete Decongestive Therapy. The study is carried out at two Danish university hospitals that routinely manage complex lymphedema. A computer system assigns participants in a 1:1 ratio to either LVA plus compression care or compression care alone. Surgeons create as many anastomoses as possible under general anaesthesia, using indocyanine green mapping to find suitable lymphatic vessels.

Adults aged 18 years or older with International Society of Lymphology stage 1 or 2a lymphedema of one or both legs can join if they have finished CDT. Key exclusions are stage 2b or 3 disease, body-mass index above 28, active cancer, severe medical illness, or prior lymphedema surgery.

The primary outcome is the change in L-Dex ratio, from baseline to 12 months. Secondary outcomes measured at baseline, 6, 12 and 24 months include limb volume by tape, perometry and dual-energy X-ray absorptiometry, infection frequency, lymphoscintigraphy findings, quality-of-life scores (LYMQOL and EQ-5D-5L) and use of compression garments. At 12 months the patency of the anastomoses is checked with indocyanine green lymphography in the surgical arm. A small substudy in ten surgical participants will compare inflammatory markers and tissue structure in paired skin biopsies collected during surgery and again 6 months later.

Participants attend the clinic for baseline, 6-month and 12-month visits and return at 24 months for long-term follow-up. Conservative measures such as compression garments may continue (but not reduced in 12 months for LVA-group), but no other surgical or medical lymphedema procedures are allowed during the study period.

All data are entered into a secure electronic database and analysed according to Good Clinical Practice, the Danish Code of Conduct for Research Integrity and GDPR. The regional research ethics committee has approved the protocol, and participants are covered by the Danish public patient-compensation scheme. Results will be published in peer reviewed journals no matter whether LVA shows benefit, harm or no difference.

Study Timeline

• Study Start: 2025-05-09
• Status Verified: 2025-07
• Study First Submitted: 2025-07-09
• Study First Submitted QC: 2025-07-09
• Last Update Submitted: 2025-07-09
• Study First Posted: 2025-07-18
• Last Update Posted: 2025-07-18
• Primary Completion: 2027-08
• Study Completion: 2029-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 66

Inclusion Criteria

• LLL International Society of Lymphology (ISL) stage 1-2a (both primary and secondary lymphedema and both unilateral and bilateral)
• Cancer-free with no recurrence for at least one year
• Age 18 or above
• Circumference of the affected leg is at least 1 cm larger than the non-lymphedema leg at the most affected site of lymphedema.
• Proficiency in Danish language, and ability to provide informed consent.
• Dermal Backflow Stage 0-4

Exclusion Criteria

• LLL International Society of Lymphology (ISL) stage 2b-3
• Medical conditions contraindicating surgical intervention or anesthesia, such as severe heart or lung disease
• Allergy to ICG
• Ongoing infections or skin diseases in the affected limb
• Previous surgery or other treatment modalities that could interfere with the study results (previous LVA, liposuction or similar).
• Dermal Backflow Stage 5
• Active cancer
• Heart or kidney conditions that can cause leg swelling
• A BMI above 28 kg/m²
• Current smoker
• Any foreign objects in the lower extremities (e.g., metal implants, prostheses)
• Venous insufficiency Unilateral weakness in the lower extremity (e.g., after a stroke)
• Known iodine allergy (contraindication for ICG injection)
• Leg length discrepancy (anisomelia) > 1.5 cm

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change in L-Dex ratio (bioimpedance spectroscopy) at 12 months.	Baseline to 12 months	Difference in L-Dex ratio of the most affected leg, measured with the SOZO bioimpedance device (ImpediMed). Measurements are performed by blinded assessors after 48 h without compression garments.

Secondary Outcome Measures

Name	Time	Method
Change in Compression Garment Use	Baseline to 24 months	Reduction of compression class, reduce daily use, or discontinue compression garments. Data collected by questionnaire.
Change in LYMQOL	Baseline, 6 months, 12 months, 24 months	Difference in total score of the Lymphoedema Quality of Life Questionnaire for lower limb lymphedema.
Change in EQ-5D-5L Index Value	Baseline, 6 months, 12 months, 24 months	Difference in health utility index calculated from the Danish EQ-5D-5L value set.
Change in Lymphoscintigraphy	Baseline, 6 mo, 12 mo, 24 mo	Change in lymphoscintigraphy transport. Scans read by blinded nuclear-medicine specialists.
Change in Limb Volume by Tape Measurement	Baseline, 6 months, 12 months, 24 months	Difference in limb volume using tape measurements and calculating using formulas.
Change in Limb Volume by Perometry	Baseline, 6 months, 12 months, 24 months	Difference in limb volume obtained with optoelectronic perometry (automatic three-dimensional scan of the leg).
Change in Limb Mass by DXA	Baseline, 6 months, 12 months, 24 months	Difference in limb mass of the affected leg measured with dual-energy X-ray absorptiometry.
Incidence of Erysipelas Infections	Baseline, 6 months, 12 months, 24 months	Number of erysipelas episodes in the affected limb

Trial Locations

Locations (2)

Department of Plastic Surgery, Odense University Hospital; 🇩🇰 Odense, Fyn, Denmark

Department of Plastic Surgery, Herlev and Gentofte Hospital; 🇩🇰 Herlev, Sjaelland, Denmark