Lymphedema Study for Arm or Leg Lymphedema

Phase 4

Completed

Conditions: Lymphedema

Interventions: Drug: Ketoprofen
Drug: Placebo

Registration Number: NCT02257970

Lead Sponsor: Stanford University

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

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 117

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 2: Open-label Group	Ketoprofen	Ketoprofen 225 mg daily, taken orally Open-label group: 75 mgs, three times daily, for four months
Part 1: Exploratory Group	Ketoprofen	Ketoprofen 225-300 mgs daily, taken orally Ketoprofen-exploratory group: 225-300 mgs daily for four to six months
Part 3: Ketoprofen Group	Ketoprofen	Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally Ketoprofen: 1 capsule, three times daily, for four months
Part 3: Placebo Group	Placebo	Participants randomized to receive placebo: placebo, three times daily, taken orally Placebo: 1 capsule, three times daily, for four months

Primary Outcome Measures

Name	Time	Method
Part 3: Measurement of Skin Thickness	Baseline and 4 months	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.
Part 1: Count of Participants Able to Complete Ketoprofen Treatment	Baseline to month 6	Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events.
Part 2: Change From Baseline in Cutaneous Histological Architecture	Baseline; Month 4	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.

Secondary Outcome Measures

Name	Time	Method
Part 3: Change From Baseline in Cutaneous Histological Architecture	Baseline; 4 months	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.
Part 2: Measurement of Skin Thickness	Baseline and 4 months	Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed.
Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy	Baseline; 4 months	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.
Part 2/Part 3: Change in Limb Volume	Baseline; 4 months	Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values.
Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF)	Baseline; 4 months	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.