Ubenimex in Adult Patients With Lymphedema of The Lower Limb (ULTRA)

Study Overview
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Brief Summary
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This proof-of-concept study is designed as a randomized, double-blind, placebo-controlled study comparing ubenimex at 150 mg, 3 times daily (total daily dose of 450 mg) with placebo for 6 months treatment period in patients with leg lymphedema.

Detailed Description
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Leukotriene B4 (LTB4) inhibits lymphangiogenesis in the mouse tail model of lymphedema and is elevated in tissue in patients with lymphedema. Ubenimex is an inhibitor of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for LTB4. This proof-of-concept study is designed as a randomized, double-blind, placebo-controlled study comparing ubenimex at 150 mg, 3 times daily (total daily dose of 450 mg) with placebo for 6 months treatment period in patients with leg lymphedema. The primary objectives for the study are: To evaluate the efficacy of ubenimex in patients with leg lymphedema To evaluate the safety and tolerability of ubenimex in patients with leg lymphedema

Official Title
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Ubenimex in Adult Patients With Lymphedema of The Lower Limb: a Phase 2, RAndomized, Double-blind, Placebo-controlled Study of Efficacy, Safety, and Pharmacokinetics (ULTRA)

Conditions
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Lymphedema

Intervention / Treatment
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* Drug: ubenimex
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of secondary leg lymphedema, based on a positive lymphoscintigraphy (LSG) study of the affected leg OR has a diagnosis of primary lymphedema not of congenital onset affecting one or both lower limbs, based on positive LSG. Swelling of at least 1 leg not completely reversed by leg elevation or compression. Stage II or greater lymphedema, based on the International Society of Lymphology (ISL) staging system. Completion of a full course of complete decongestive therapy (CDT). Stable limb volume (within 10% during screening for worse/affected leg) . If patient has had a lymphatic vascularization procedure (lymphovenous bypass or lymph node transfer) or liposuction for lymphedema in the affected limb, then procedure must have been performed at least 1 year (12 months) prior to Screening AND affected limb must be clinically stable over the 3 months prior to Screening AND significant residual disease must be present. Ambulatory status (use of a walking aid is permitted). Agree to use a medically acceptable method of contraception, if the possibility of conception exists. Exclusion Criteria: Exclusions Based on Lymphedema: A diagnosis of primary lymphedema with congenital onset. Primary lymphedema is defined as lymphedema with onset prior to or without an inciting event (e.g, surgery, trauma, radiation) Occurrence of significant lymphedema of another body part that is not the lower limb (e.g, upper extremity, trunk, head and neck, genitalia). Lymphedema involving all four limbs Recent initiation of, or intention to initiate CDT or maintenance physiotherapy for lymphedema. Exclusions Based on Other Medical Conditions Deep venous thrombosis in either lower limb or systemic anticoagulation within 6 months Other medical condition that could lead to acute or chronic leg edema. Other medical condition that could result in symptoms overlapping those of lymphedema in the affected leg. History of clotting disorder (hypercoagulable state). Chronic (persistent) infection in either lower limb. Cellulitis or other infection in either lower limb or use of antibiotics for cellulitis within 3 months prior to screening. Other unstable or severe medical condition requiring active management and/or likely to decompensate/require active management within the next year Current evidence of malignancy. History of malignancy within the previous 3 years, except for nonmelanoma skin cancer or cervical carcinoma in situ treated with curative intent. Currently receiving chemotherapy or radiation therapy. Life expectancy < 2 years for any reason. Pregnancy or nursing. Substance abuse (such as alcohol or drug abuse) within 6 months prior to screening. Exclusions Based on Concurrent Medication Use Regular concurrent use or regular use within 6 months before screening of another leukotriene pathway inhibitor. Concurrent antibiotic use. Concurrent use of any agent active on the sphingosine-1-phosphate (S1P) pathway. Concurrent use of unapproved (including herbal) treatments for lymphedema. Exclusions Based on Laboratory Values Significant or chronic renal insufficiency or requires dialytic support. Hepatic dysfunction. Absolute neutrophil count <1500 mm3 at screening. Hemoglobin concentration <9 g/dL at screening.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ubenimex<br>ubenimex capsules 150 mg three times a day (TID), administered orally for a total of 24 weeks. | Drug: ubenimex<br> <br> * Other names: UBX;|
| Placebo Comparator: placebo<br>matched placebo capsules TID, administered orally for a total of 24 weeks | Other: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Skin Thickness of the Calf of the Most Affected Leg, Measured by Skinfold Calipers | Change from baseline to Week 24 in skin thickness of the calf of the most affected leg, measured by skinfold calipers in the Skin-Thickness Intent-to-Treat (ST-ITT) population (patients with skin thickness >/= 10 mm at baseline) which comprised of 36 patients (16 ubenimex, 20 placebo). | Baseline through Week 24 |