Proof-of-concept Study of LymphMonitor 1.0 to Assess the Lymphatic Vessel Function

Study Overview
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Brief Summary
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Lymphedema is the consequence of injured lymphatic system and is characterized by chronic, often disabling swelling of am affected body part, often arm or leg. In the western world secondary lymphedema arises most commonly after removal lymph nodes in an operation as a part of cancer treatment (for example from the armpits or the groin region), however it may also develop as a result of radiation, any other operation, infection or injury that destroys a part of lymphatic system. The disease often develops even years after the event. While there is no cure for lymphedema at present, early detection would ensure timely physiotherapy and application of compression garments that significantly slow down or stop the progression of the disease. However, presently used methods of that are used for diagnosis and evaluating the stage of the disease, are either invasive and expensive or inaccurate and can only be performed at specialized medical centres. Therefore, we developed a simple, affordable and accurate technology, LymphMonitor 1.0 that can allow for testing how efficiently the lymphatic system is functioning. The test can be performed at the local medical centre or potentially even at home. In this study, we investigate whether LymphMonitor 1.0 technology can distinguish between a healthy and a diseased lymphatic system (in lymphedema). This method may allow early diagnosis of lymphedema so that the development of the disease can be detected and prevented early enough. By participating in the study the lymphedema patients are making an important contribution to increasing the quality of life of lymphedema patients. In LymphMonitor 1.0 method method, a solution of a safe fluorescent dye, indocyanine green, is injected painlessly using tiny microneedles, MicronJet600TM, directly into the skin of the arm or leg. After injection, this dye is removed from the skin only through the lymphatic vessels. The intensity of the fluorescence signal corresponds to the amount of dye left in the skin. The decrease in the fluorescence signal after the injection is measured on the surface on the skin using a new device, LymphMeter 1.0. The faster the dye (and that fluorescence signal) disappears from the surface of the skin, the better the lymphatic system works. Therefore in the arm or leg affected by lymphedema the fluorescence signal will decrease much slower compared to the healthy one.

Official Title
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Proof-of-concept Interventional Study to Evaluate the Feasibility of the New Method, LymphMonitor 1.0, to Assess Lymphatic Function, Consisting of Indocyanine Green-based Lymphatic Specific Tracer. and a Custom Fluorescence Measuring Investigational Device LymphMeter 1.0.

Conditions
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Lymphedema, Secondary Lymphedema

Intervention / Treatment
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* Combination Product: Lymphatic clearance measurement


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: informed consent as documented by signature females and males 18 - 75 years old, established (stage 2 or higher) unilateral secondary arm or leg lymphedema resulting from lymphadectonomy, radiation or any other surgical treatment, infection or injury. good general health status. Exclusion criteria: critical illness (active cancer, renal failure, hepatic dysfunction) active infection blood vascular malformations or diseases scleroderma primary lymphedema patients who underwent any surgical procedures for treatment of lymphedema (e.g. lymphovenous anastomosis, liposuction, lymph node transfer). contraindications to use ICG (VERDYE), i.e. patients with hypersensitivity to ICG or to sodium iodide patients with hypersensitivity to iodine, patients with hyper-thyroidism, patients with autonomic thyroid adenomas patients in which the injection of VERDYE was poorly tolerated in the past it must not be used again, since severe anaphylactic reactions might occur. hypersensitivity to albumin or its excipients women, who are pregnant (pregnancy test will be performed in case of women who did not undergo menopause), women who are breast feeding , enrolment of the investigator, his/her family members, employees and other dependent persons, known or suspected non-compliance, drug or alcohol abuse, inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant, participation in another study with investigational drug within the 30 days preceding and during the present study, previous enrolment into the current study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with unilateral arm or leg lymphedema<br> | Combination Product: Lymphatic clearance measurement<br>* The indocyanine green in 5% human albumin solution (tracer) (50 μL) will be injected intradermally in both forearms or both lower legs using MicronJet600 microneedles paying attention to the contralateral symmetry of the injections. The signal at the injection sites will be measured over time using a hand-held portable device LymphMeter 1.0 for the total duration of 3 h. In the first hour, the signal will be measured every 15 minutes followed by measurements every half an hour. Immediately after injection (t=0 h), 1.5 h and 3 h after injection the skin area occupied by the tracer will be measured using a standard near-infrared camera, Fluobeam. The dermal reaction at the injection site will be assessed by observations for presence of redness/erythema and measuring its extent according to the needs. The patient will be constantly observed for the signs of allergic reactions, skin irritations or intolerances.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Areas under the normalized clearance curves (AUCs) | Areas under the normalized clearance curves (AUCs) in healthy and lymphedema limbs measured over 3 hours after injection. To obtain the clearance curve, the fluorescence intensity values at the injection sites in healthy and lymphedema extremities at pre-determined timepoints | Fluorescence values measured immediately after injection and 1 hour, 1.5 hours, 2 hours, 2.5 hours and 3 hours after injection. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| other clearance parameters: clearance constant (k) and half-life of clearance (t1/2); (healthy versus diseased). |  | Fluorescence values measured immediately after injection and 1 hour, 1.5 hours, 2 hours, 2.5 hours and 3 hours after injection. | 
| Correlation/no correlation of clearance parameters with the extent of the swelling (limb volume) in lymphedema patients. |  | 3 hours | 
| dimensions of the injected dye depot measured by FluoBeam | Images of the injection site over time will be recorded using Fluobeam at different and analysed. | Dimensions will be measured immediately after injection and 1.5 hours and 3 hours after injection. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lymphedema, secondary lymphedema, fluorescence, indocyanine green