Lymphedema Study for Arm or Leg Lymphedema

Study Overview
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Brief Summary
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This study compares the effectiveness of a study drug versus placebo in the treatment of lymphedema.

Detailed Description
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Part 1 is feasibility, exploratory, open-label study of ketoprofen, to document effects. Part 2, is open-label trial of ketoprofen to document histological response. Part 3 is double-blind randomized trial of receive placebo or ketoprofen to evaluate safety and efficacy. We will try to determine how the study drug affects the body tissue by obtaining tissue biopsies (small pieces of skin from the arm or leg) before treatment and after treatment.

Official Title
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Placebo-controlled, Case-controlled, Open Label Therapeutic Trial for Unilateral or Bilateral Lymphedema of Arm or Leg.

Conditions
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Lymphedema

Intervention / Treatment
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* Drug: Ketoprofen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: a history of lymphedema of one or more limbs (unilateral or bilateral), with a duration of > 6 months. Exclusion Criteria: Patients with active cancer, infection or bleeding tendency will be excluded. We will also exclude patients with medical contraindications to NSAIDs, including history of allergies, know gastrointestinal intolerance, or other serious systemic illness (e.g., renal failure, hepatic dysfunction, congestive heart failure, neurological or psychological impairment) that would impair the patients' ability to participate. Minors (<18 years of age) *>90 years of age

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Exploratory Group<br>Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months | Drug: Ketoprofen<br> <br> |
| Experimental: Part 2: Open-label Group<br>Ketoprofen 225 mg daily, taken orally Open-label group: 75 mgs, three times daily, for four months | Drug: Ketoprofen<br> <br> |
| Placebo Comparator: Part 3: Placebo Group<br>Participants randomized to receive placebo: placebo, three times daily, taken orally Placebo: 1 capsule, three times daily, for four months | Drug: Placebo<br>* Placebo to match ketoprofen.<br>|
| Active Comparator: Part 3: Ketoprofen Group<br>Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally Ketoprofen: 1 capsule, three times daily, for four months | Drug: Ketoprofen<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Count of Participants Able to Complete Ketoprofen Treatment | Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events. | Baseline to month 6 | 
| Part 2: Change From Baseline in Cutaneous Histological Architecture | Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology. | Baseline; Month 4 | 
| Part 3: Measurement of Skin Thickness | Caliper-measured skin thickness (mm) was serially assessed and pre-to-post paired analysis was performed for both arms (Placebo and Ketoprofen) of the study. | Baseline and 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Measurement of Skin Thickness | Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed. | Baseline and 4 months | 
| Part 3: Change From Baseline in Cutaneous Histological Architecture | Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen or placebo, respectively. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. For the analysis, the 4-month post-minus-pre change in this score for ketoprofen- and placebo-recipients, respectively, was compared. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology. | Baseline; 4 months | 
| Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy | A four-electrode configuration was used to non-invasively assess the extracellular and intracellular fluid contents of the limb. Data were analyzed according to Cole theory, using the manufacturer's software (Impedimed Ltd.), to provide values for a bioimpedance ratio (Ro), the resistance of the extracellular fluid including lymph, R∞ the resistance of total tissue fluid and Ri, the resistance of the intracellular fluid. For the purposes of these investigations, in patients with unilateral lymphedema, the ratio of Ro in the affected:unaffected limbs was analyzed in each patient, as a measure of the bioimpedance attributable to the extracellular fluid content. An Ro level of 1.034 was considered normal; values ≥1.034 were considered abnormal. | Baseline; 4 months | 
| Part 2/Part 3: Change in Limb Volume | Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values. | Baseline; 4 months | 
| Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF) | The systemic inflammatory response of G-CSF, in the two treatment groups, Ketoprofen and Placebo, will be assessed with Luminex-bead inflammasome analysis of pre- and post-treatment plasma samples. G-CSF, a glycoprotein, is an inflammatory cytokine produced by endothelium and immune cells. Ketoprofen is a unique NSAID possessing dual pathways of inflammatory inhibition, blocking cyclooxygenase (COX) and 5-LO. Measurement using median fluorescence intensity (MFI) was employed. | Baseline; 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphedema, edema, swelling