Conditions: Lymphedema
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

Brief summary:
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:
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

Arms:
arm 1: ubenimex capsules 150 mg three times a day (TID), administered orally for a total of 24 weeks. arm 2: matched placebo capsules TID, administered orally for a total of 24 weeks

Interventions: intervention 1: ubenimex intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 6 
 
 
 
 
 
 
 
Title: 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) 
 
 
NCT02700529 
 
 
 
Document date: 03/31/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol:  
Objectives  
The primary objectives of the study are to evaluate the efficacy and the safety and 
tolerability of ubenimex in patients with leg lymphedema.  
Methodology 
This Phase 2, randomized, double-blind, placebo-controlled, proof-of-concept study 
compared ubenimex 150 mg 3 times daily (TID) with matching placebo in patients with 
leg lymphedema. Eligible patients had a diagnosis of secondary lymphedema or a 
diagnosis of primary lymphedema not of congenital onset, based on a positive 
lymphoscintigraphy (LSG) of the affected leg. In addition, all patients had International 
Society of Lymphology (ISL) Stage ≥ II lymphedema and swelling of at least 1 leg that 
was not completely reversed by leg elevation or compression. The number of patients 
planned for the study is approximately 45. 
The study consisted of 3 periods:  
• 
Screening Period: Day –49 to Day 1 (maximum 7 weeks) 
• 
Treatment Period: Day 1 (first day of treatment) through Week 24 (6 months) 
• 
Follow-up Period: Week 25 through Week 28 (1 month) 
Patients were randomized equally to receive 1 of the following treatments: ubenimex 
150 mg TID or matching placebo TID, which were administered orally for a total of 6 
months:  
Efficacy assessments included skin thickness (measured by skinfold calipers; primary 
efficacy measure), PRELYM-Leg results, leg volume, bioimpedance measures, and skin 
biopsy results. Blood concentrations of ubenimex were measured to characterize the 
steady-state PK of ubenimex. Blood concentrations of the metabolite (2S, 3R)-3-amino-
2-hydroxy-4-phenylbutyric acid [abbreviated as (2S,3R)-AHPA] were also measured. Ex 
vivo A23187 stimulated plasma LTB4 concentrations were assessed to gauge the 
degree of peripheral inhibition of LTA4H at selected study sites. Safety measures 
included AEs, clinical laboratory test results (blood and urine analyte concentrations), 
vital signs, concomitant medications, electrocardiogram (ECG) findings, and urinary 
leukotriene E4 (LTE4) concentrations. 
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. 


Page 3 of 6 
 
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. 


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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 
Dose and Mode of Administration  
150 mg administered orally three times a day (at 8 ± 2 hr intervals), with or without food. 
Duration of Treatment 
Duration of treatment was 6 months. Total study participation lasted up to 8.5 months 
(up to 1.5 months of screening, 6 months of treatment, and 1 month of follow-up). 
Criteria for Evaluation 


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All comparisons were made with placebo. The primary efficacy endpoints are changes 
from baseline to Week 24 in skin thickness of the calf of the most affected leg, 
measured by skinfold calipers. The secondary endpoints include change from baseline 
to Week 24 in lymphedema-specific patient-reported outcome measures (Patient-
Reported Evaluation of Lymphedema [Leg]; PRELYM-Leg), change from baseline to 
Week 24 in leg volume of the most affected leg, change from baseline to Week 24 in 
bioimpedance measures, and change from baseline to Week 24 in biopsy results.  
The safety endpoints include treatment-emergent adverse events (TEAEs), serious 
adverse events (SAEs), treatment-related AEs, treatment-related SAEs, AEs leading to 
early discontinuation of study treatment, AEs leading to dose reduction.  
 
Statistical Analysis Plan 
Analysis Populations  
• Intended to treat (ITT) population: all randomized patients. Patients were 
analyzed according to the treatment group to which they were randomized with 
no imputation of missing data. 
• Skin thickness (ST-ITT) population: The ST-ITT population comprised the subset 
of the ITT population with baseline calf thickness (worse leg) ≥ 10 mm. All 
primary analyses of skin thickness endpoints were conducted on the ST-ITT 
population. 
• Safety population (Safety Set): all patients who received at least 1 dose of study 
drug. Patients were analyzed according to treatment received. 
Efficacy Analyses 
Primary endpoint—The change from Baseline to Week 24 in skin thickness of the calf of 
the most affected leg was analyzed using the ST-ITT population. The Shapiro-Wilk test 
was performed to test for normality of the residuals from the analysis of covariance 
(ANCOVA) model. In the event of departure from normality, the data were log-
transformed. If this corrected departures from normality the result was to be the primary 
analysis. The p-value for difference was calculated using treatment as a factor and the 
baseline value as a covariate. The treatment effect with its 95% confidence interval and 
p-value was presented. In addition, the number and percentage of patients with change 
from baseline ≤ -10 mm vs. > -10 mm at each visit were presented. 
A non-parametric analysis (ANCOVA on ranked change scores with factors for 
treatment and median-split baseline skin thickness) was conducted. In the event of 
departure from normality, even after log-transformation, this analysis was to be the 
primary analysis. 
Secondary endpoints—Change in PRELYM-Leg—total score and domain scores 
analyzed using ANCOVA with treatment as a factor and the baseline value as a 


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covariate. Patient Global Impression of Lymphedema Symptoms (P-GILS) analyzed 
using a logistic regression model with treatment and baseline response as independent 
variables. Change in leg volume of the most affected leg and bioimpedance measures 
are analyzed using ANCOVA with treatment as a factor and the baseline value as a 
covariate. Change in biopsy results—listed only. 
Pharmacokinetic Analyses 
Steady-state PK parameters (Cmax, Cmin, tmax, t1/2, AUC0–8) of ubenimex and the 
metabolite (2S,3R)-AHPA were determined using plasma concentrations measured 
from serial blood samples at Week 4.  
Safety Analyses 
AEs, deaths, concomitant medications, vital signs, electrocardiogram data, and clinical 
laboratory data for each patient and summarized by treatment group. Adverse events 
were coded using the Medical Dictionary for Regulatory Activities (MedDRA)version 
18.1.