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

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)

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.

Study Overview

• Status: Completed
• Conditions: Lymphedema
• Intervention / Treatment: Other: placebo; Drug: ubenimex

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2109
      • Macquarie University Hospital (MUH)
• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University
  • Florida
    • Orlando, Florida, United States, 32806
      • Orlando Health, Inc.
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center James Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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.
2. Swelling of at least 1 leg not completely reversed by leg elevation or compression.
3. Stage II or greater lymphedema, based on the International Society of Lymphology (ISL) staging system.
4. Completion of a full course of complete decongestive therapy (CDT).
5. Stable limb volume (within 10% during screening for worse/affected leg) .
6. 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.
7. Ambulatory status (use of a walking aid is permitted).
8. Agree to use a medically acceptable method of contraception, if the possibility of conception exists.

Exclusion Criteria:

Exclusions Based on Lymphedema:

1. 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)
2. Occurrence of significant lymphedema of another body part that is not the lower limb (e.g, upper extremity, trunk, head and neck, genitalia).
3. Lymphedema involving all four limbs

4. Recent initiation of, or intention to initiate CDT or maintenance physiotherapy for lymphedema.

   Exclusions Based on Other Medical Conditions

5. Deep venous thrombosis in either lower limb or systemic anticoagulation within 6 months
6. Other medical condition that could lead to acute or chronic leg edema.
7. Other medical condition that could result in symptoms overlapping those of lymphedema in the affected leg.
8. History of clotting disorder (hypercoagulable state).
9. Chronic (persistent) infection in either lower limb.
10. Cellulitis or other infection in either lower limb or use of antibiotics for cellulitis within 3 months prior to screening.
11. Other unstable or severe medical condition requiring active management and/or likely to decompensate/require active management within the next year
12. Current evidence of malignancy.
13. History of malignancy within the previous 3 years, except for nonmelanoma skin cancer or cervical carcinoma in situ treated with curative intent.
14. Currently receiving chemotherapy or radiation therapy.
15. Life expectancy < 2 years for any reason.
16. Pregnancy or nursing.

17. Substance abuse (such as alcohol or drug abuse) within 6 months prior to screening.

    Exclusions Based on Concurrent Medication Use

18. Regular concurrent use or regular use within 6 months before screening of another leukotriene pathway inhibitor.
19. Concurrent antibiotic use.
20. Concurrent use of any agent active on the sphingosine-1-phosphate (S1P) pathway.

21. Concurrent use of unapproved (including herbal) treatments for lymphedema.

    Exclusions Based on Laboratory Values

22. Significant or chronic renal insufficiency or requires dialytic support.
23. Hepatic dysfunction.
24. Absolute neutrophil count <1500 mm3 at screening.
25. Hemoglobin concentration <9 g/dL at screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in lymphedema-specific patient reported outcome measures (Patient-Reported Evaluation of Lymphedema [Leg]) questionnaire results	Week 24
Change in leg volume of the most affected leg	Week 24
Change in extracellular fluid volume of the lower limb, measured by the bioimpedance spectroscopy device.	Week 24
Change in biospy result for dermal thickness	Week 24

Collaborators and Investigators

• Sponsor: Eiger BioPharmaceuticals

Publications and helpful links

General Publications

• Orning L, Krivi G, Fitzpatrick FA. Leukotriene A4 hydrolase. Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes. J Biol Chem. 1991 Jan 25;266(3):1375-8.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): February 1, 2019

Study Registration Dates

• First Submitted: February 26, 2016
• First Submitted That Met QC Criteria: March 2, 2016
• First Posted (Estimate): March 7, 2016

Study Record Updates

• Last Update Posted (Actual): January 18, 2023
• Last Update Submitted That Met QC Criteria: December 22, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Lymphatic Diseases; Lymphedema; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Immunologic Factors; Protease Inhibitors; Anti-Bacterial Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Ubenimex
• Other Study ID Numbers: EIG-UBX-003