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The N-LVA Study: RCT Comparing LVA vs. Sham Surgery in Cancer-related Lymphedema

Primary Purpose

Lymphedema, Secondary, Lymphedema of Upper Limb, Lymphedema, Lower Limb

Status
Not yet recruiting
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Lymphaticovenous anastomosis
Sham surgery
Sponsored by
Maastricht University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphedema, Secondary focused on measuring Lymphaticovenous anastomosis, Sham surgery, Microsurgery, LVA

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Treated for cancer and underwent treatment of either axillary or inguinal lymph nodes or radiotherapy; Early stage lymphedema (ISL I-II) in the upper or lower extremity, and diagnosed by lymphoscintigraphy for the lower extremity; Unilateral lymphedema; Viable lymphatic vessels as determined by indocyanine green (ICG)Lymphography (stage II-III); Refractory lymphedema that underwent at least three months of conservative treatment; Informed consent. Exclusion Criteria: History of lymphatic reconstruction in the past 10 years; Late-stage lymphedema of the extremity (ISL classification ≥ II lymphedema) with evident fat deposition and/or fibrosis; Patients with active distant metastases, treated with palliative intent; Patients with the active treatment of primary cancer, i.e. surgery, radiotherapy, and/or chemotherapy. Note: patients receiving adjuvant targeted and/or endocrine treatment are eligible; Edema due to venous insufficiency, evaluated by venous duplex ultrasound of the deep and superficial venous system; Active infection in the lymphedematous extremity; Bilateral lymphedema; Lymphedema present in genital or breast area only; Primary lymphedema; Non-viable lymphatic system as determined by ICG Lymphography (stages IV and V).

Sites / Locations

  • Radboud University Medical Center
  • Maastricht University Medical Center
  • Erasmus University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Lymphaticovenous anastomosis (LVA)

Sham surgery

Arm Description

Patients in this group will undergo lymphaticovenous anastomosis at one or more locations on the affected limb, and the procedure will be performed under local anesthesia. During the operation, patients will be blinded using a noise-canceling headphone and blindfolds. Incisions will be made at the sites where lymphatic vessels are obstructed, ensuring no harm to the viable part of the lympahtic system. The locations will be determined prior to the surgery using ICG lymphography. The LVA(s) will be made in the subdermal plane with the aid of a surgical microscope. Generally, 1 to 4 LVAs are made. The LVA(s) is made using a surgical microscope and the operation will take approximately 60 to 90 minutes.

Patients in this group will undergo sham surgery at one location on the affected limb, and the procedure will be performed under local anesthesia. During the operation, patients will be blinded using a noise-canceling headphone and blindfolds. The locations for LVA surgery will be determined prior to the surgery using ICG lymphography. However, the incision for the sham procedure will be made 2 centimeters medial or lateral to the predetermined site. This is done in order to avoid damage to the lymph vessels as to allow for future LVA surgery. After the incision, no LVA is made. Rather than performing the actual operation, the plastic surgeon will simulate the procedure by applying pressure in the surgical area. To mimic the approximate duration of a regular LVA procedure, the sham operation will take approximately 60 to 90 minutes.

Outcomes

Primary Outcome Measures

Change from Baseline in the Lymph-ICF Score at 12 and 24 months
The Dutch version of the 'Lymphedema Functioning, Disability, and Health" (Lymph-ICF) questionnaire is used. There are two versions of the Lymph-ICF; one for the upper extremity and one for the lower extremity. The questionnaires assess the impairments in function, activity limitations, and participation restrictions of patients with lymphedema. It is a validated, disease-specific questionnaire, consisting of items across 5 domains. Each item is scored on a VAS, ranging from 0 to 100.

Secondary Outcome Measures

Change from baseline in excess limb volume
The excess limb volume will be measured with BioImpedance Spectroscopy (BIS). With a bioimpedance device, the volume of the extremities can be measured together with the fluid in different compartments of the extremities.
Change from baseline in extremity circumference measured by the Upper and Lower Extremity Lymphedema (UEL and LEL) indices
The extremity circumference will be measured using measuring tape according to the fixed measuring points of the UEL- and LEL-indices. The UEL- and LEL-indices are corrected for BMI.
Change from baseline in the use of conservative treatment
Discontinuation of conservative treatment, being complex decongestive therapy, will be assessed with a patient diary to record the frequency of treatments received (i.e. skin therapy visits, number of compression garments, etc.).
Postoperative complications
All postoperative complications for both treatment groups will be recorded to monitor safety. SAEs will be directly reported to the sponsor.
Patency of the LVA
The patency of the LVAs will be measured with ICG lymphography
Patient costs, QALYs, and incremental cost-effectiveness
Patients costs are registered by the patient in the patient diary. The QALY will be calculated using the EQ-5D-5L questionnaire. The EQ-5D is a questionnaire responsive to changes in health in cancer-patients after the conclusion of treatment.

Full Information

First Posted
October 3, 2023
Last Updated
October 9, 2023
Sponsor
Maastricht University Medical Center
Collaborators
Radboud University Medical Center, Erasmus Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT06082349
Brief Title
The N-LVA Study: RCT Comparing LVA vs. Sham Surgery in Cancer-related Lymphedema
Official Title
Effectiveness and Cost-effectiveness of Lymphaticovenous Anastomosis for Cancer Patients Who Suffer From Chronic Peripheral Lymphedema: a Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 24, 2023 (Anticipated)
Primary Completion Date
October 24, 2026 (Anticipated)
Study Completion Date
October 24, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Maastricht University Medical Center
Collaborators
Radboud University Medical Center, Erasmus Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this randomized controlled trial is to compare the effectiveness and cost-effectiveness of lymphaticovenous anastomosis (LVA) with sham surgery for patients suffering from unilateral cancer-related lymphedema in either the upper or lower extremity. It aims to answer whether LVA is more effective than sham surgery in terms of improvement in Lymph-ICF score. A total of 110 participants will be allocated randomly into two groups at a 1:1 ratio. The first group will receive lymphaticovenous anastomosis (LVA), while the second group will undergo sham surgery.
Detailed Description
One of the most debilitating side effects of cancer treatment is cancer-related lymphedema (CRL), with an overall incidence of 15.5%. To date, there is no definite cure for lymphedema. Conservative therapy, namely complex decongestive therapy is the golden standard for the treatment. Lymphaticovenous anastomosis (LVA) might be a promising treatment modality for patients with CRL, but available studies are small and the quality is lacking. No large-scale prospective or randomized studies have been published on the efficacy of LVA. The main objective of this randomized controlled trial is to assess whether LVA is more effective than sham surgery in terms of improvement in Lymph-ICF score, volume reduction, reduction of complex decongestive therapy, and cost-effectiveness. The study will take place in three centers in the Netherlands: Maastricht University Medical Center, Radboud University Medical Center, and Erasmus University Medical Center. The patients will be randomly distributed into two groups: the LVA group or the Sham group. Both procedures are performed under local anesthesia. Patients in both groups are subject to minor surgical complications (wound infection, bleeding, wound dehiscence). Special care will be taken to prevent damage to lymphatic vessels in the Sham group, to allow a future LVA operation once the study ends. The follow-up moments will be at 3, 6, 12, 18, and 24 months. Additionally, a subset of patients will partake in an annual extended follow-up, ongoing until the start of the analysis. Each follow-up moment will last 45 minutes in total. The patient also receives two digital questionnaires at each follow-up moment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphedema, Secondary, Lymphedema of Upper Limb, Lymphedema, Lower Limb, Lymphedema Arm, Lymphedema of Leg
Keywords
Lymphaticovenous anastomosis, Sham surgery, Microsurgery, LVA

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Multicenter, double-blind, randomized sham-controlled trial
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
The researcher, research nurse and patients will be blinded. The blinded researcher and research nurse will perform the measurements during follow-up, as well as the assessment of the outcomes. Due to the nature of the study, the surgeon performing both procedures cannot be blinded.
Allocation
Randomized
Enrollment
110 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Lymphaticovenous anastomosis (LVA)
Arm Type
Experimental
Arm Description
Patients in this group will undergo lymphaticovenous anastomosis at one or more locations on the affected limb, and the procedure will be performed under local anesthesia. During the operation, patients will be blinded using a noise-canceling headphone and blindfolds. Incisions will be made at the sites where lymphatic vessels are obstructed, ensuring no harm to the viable part of the lympahtic system. The locations will be determined prior to the surgery using ICG lymphography. The LVA(s) will be made in the subdermal plane with the aid of a surgical microscope. Generally, 1 to 4 LVAs are made. The LVA(s) is made using a surgical microscope and the operation will take approximately 60 to 90 minutes.
Arm Title
Sham surgery
Arm Type
Sham Comparator
Arm Description
Patients in this group will undergo sham surgery at one location on the affected limb, and the procedure will be performed under local anesthesia. During the operation, patients will be blinded using a noise-canceling headphone and blindfolds. The locations for LVA surgery will be determined prior to the surgery using ICG lymphography. However, the incision for the sham procedure will be made 2 centimeters medial or lateral to the predetermined site. This is done in order to avoid damage to the lymph vessels as to allow for future LVA surgery. After the incision, no LVA is made. Rather than performing the actual operation, the plastic surgeon will simulate the procedure by applying pressure in the surgical area. To mimic the approximate duration of a regular LVA procedure, the sham operation will take approximately 60 to 90 minutes.
Intervention Type
Procedure
Intervention Name(s)
Lymphaticovenous anastomosis
Other Intervention Name(s)
LVA, Lymphaticovenular anastomosis, Lymphovenous bypass, Lymphatic-venous shunt
Intervention Description
Lymphaticovenous anastomosis (LVA) involves connecting a lymphatic vessel to a adjacent vein of similar size, thereby facilitating the ouflow of lymphatic fluid in patients suffering from secondary lymphedema
Intervention Type
Procedure
Intervention Name(s)
Sham surgery
Other Intervention Name(s)
Placebo surgery, Simulated surgery, Surgical placebo
Intervention Description
Sham surgery involves the process of surgery, including local anesthesia and incisions, but no LVA is made.
Primary Outcome Measure Information:
Title
Change from Baseline in the Lymph-ICF Score at 12 and 24 months
Description
The Dutch version of the 'Lymphedema Functioning, Disability, and Health" (Lymph-ICF) questionnaire is used. There are two versions of the Lymph-ICF; one for the upper extremity and one for the lower extremity. The questionnaires assess the impairments in function, activity limitations, and participation restrictions of patients with lymphedema. It is a validated, disease-specific questionnaire, consisting of items across 5 domains. Each item is scored on a VAS, ranging from 0 to 100.
Time Frame
Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits).
Secondary Outcome Measure Information:
Title
Change from baseline in excess limb volume
Description
The excess limb volume will be measured with BioImpedance Spectroscopy (BIS). With a bioimpedance device, the volume of the extremities can be measured together with the fluid in different compartments of the extremities.
Time Frame
Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits).
Title
Change from baseline in extremity circumference measured by the Upper and Lower Extremity Lymphedema (UEL and LEL) indices
Description
The extremity circumference will be measured using measuring tape according to the fixed measuring points of the UEL- and LEL-indices. The UEL- and LEL-indices are corrected for BMI.
Time Frame
Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits).
Title
Change from baseline in the use of conservative treatment
Description
Discontinuation of conservative treatment, being complex decongestive therapy, will be assessed with a patient diary to record the frequency of treatments received (i.e. skin therapy visits, number of compression garments, etc.).
Time Frame
Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits).
Title
Postoperative complications
Description
All postoperative complications for both treatment groups will be recorded to monitor safety. SAEs will be directly reported to the sponsor.
Time Frame
Baseline, 3, 6, 12, 18 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits).
Title
Patency of the LVA
Description
The patency of the LVAs will be measured with ICG lymphography
Time Frame
12 and 24 months post-operatively and afterwards annualy during the extended follow-up, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits).
Title
Patient costs, QALYs, and incremental cost-effectiveness
Description
Patients costs are registered by the patient in the patient diary. The QALY will be calculated using the EQ-5D-5L questionnaire. The EQ-5D is a questionnaire responsive to changes in health in cancer-patients after the conclusion of treatment.
Time Frame
, lasting up to the start of the first analysis (maximally 3 years extra or 3 additional visits).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Treated for cancer and underwent treatment of either axillary or inguinal lymph nodes or radiotherapy; Early stage lymphedema (ISL I-II) in the upper or lower extremity, and diagnosed by lymphoscintigraphy for the lower extremity; Unilateral lymphedema; Viable lymphatic vessels as determined by indocyanine green (ICG)Lymphography (stage II-III); Refractory lymphedema that underwent at least three months of conservative treatment; Informed consent. Exclusion Criteria: History of lymphatic reconstruction in the past 10 years; Late-stage lymphedema of the extremity (ISL classification ≥ II lymphedema) with evident fat deposition and/or fibrosis; Patients with active distant metastases, treated with palliative intent; Patients with the active treatment of primary cancer, i.e. surgery, radiotherapy, and/or chemotherapy. Note: patients receiving adjuvant targeted and/or endocrine treatment are eligible; Edema due to venous insufficiency, evaluated by venous duplex ultrasound of the deep and superficial venous system; Active infection in the lymphedematous extremity; Bilateral lymphedema; Lymphedema present in genital or breast area only; Primary lymphedema; Non-viable lymphatic system as determined by ICG Lymphography (stages IV and V).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Alieske Kleeven, MSc
Phone
+31628416378
Email
alieske.kleeven@mumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shan Shan Qiu Shao, MSc, PhD
Organizational Affiliation
Maastricht University Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Stefan Hummelink, MSc, PhD
Organizational Affiliation
Radboud University Medical Center
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Dalibor Vasilic, MSc, PhD
Organizational Affiliation
Erasmus Medical Center
Official's Role
Study Chair
Facility Information:
Facility Name
Radboud University Medical Center
City
Nijmegen
State/Province
Gelderland
ZIP/Postal Code
6525GA
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alieske Kleeven, MSc
Phone
+31(6)28416378
Email
alieske.kleeven@mumc.nl
First Name & Middle Initial & Last Name & Degree
Stefan Hummelink, MSc, PhD
First Name & Middle Initial & Last Name & Degree
Alieske Kleeven, MSc
First Name & Middle Initial & Last Name & Degree
Yasmine Jonis, MSc
Facility Name
Maastricht University Medical Center
City
Maastricht
State/Province
Limburg
ZIP/Postal Code
6229HX
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alieske Kleeven, MSc
Phone
+31(6)28416378
Email
alieske.kleeven@mumc.nl
First Name & Middle Initial & Last Name & Degree
Shan Shan Qiu Shao, MSc, PhD
First Name & Middle Initial & Last Name & Degree
Alieske Kleeven, MSc
Facility Name
Erasmus University Medical Center
City
Rotterdam
State/Province
Zuid-Holland
ZIP/Postal Code
3015GD
Country
Netherlands
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alieske Kleeven, MSc
Phone
+31(6)28416378
Email
alieske.kleeven@mumc.nl
First Name & Middle Initial & Last Name & Degree
Dalibor Vasilic, MSc, PhD
First Name & Middle Initial & Last Name & Degree
Alieske Kleeven, MSc

12. IPD Sharing Statement

Learn more about this trial

The N-LVA Study: RCT Comparing LVA vs. Sham Surgery in Cancer-related Lymphedema

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