Clinical trial NCT02664558: A Study of Ubenimex in Patients With Pulmonary Arterial Hypertension (WHO Group 1)
Official title: A Phase 2, Randomized, Double-BLInd, Placebo- Controlled Study of UBEnimex in Patients With Pulmonary ARTerial HYpertension (WHO Group 1) (LIBERTY)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: Eiger BioPharmaceuticals
Sponsor class: INDUSTRY
First posted: 2016-01-27
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This proof-of-concept study is designed as a Phase 2, multicenter, randomized, double-blind, placebo controlled study comparing ubenimex with placebo in patients with pulmonary arterial hypertension (PAH) (World Health Organization \[WHO\] Group 1) and have a WHO/New York Heart Association (NYHA) Functional Classification (WHO/NYHA-FC) of II or III.

Detailed description: Ubenimex is being developed for the treatment of PAH (WHO Group 1) to improve exercise capacity and delay clinical worsening. This proof-of-concept study is designed as a Phase 2, multicenter, randomized, double-blind, placebo controlled study comparing ubenimex with placebo in patients with PAH (WHO Group 1) and have a WHO/NYHA Functional Classification (WHO/NYHA-FC) of II or III. The Primary Objectives for the study are:

* To evaluate the efficacy of ubenimex in patients with PAH (WHO Group 1).
* To evaluate the safety and tolerability of ubenimex in patients with WHO Group 1 PAH.

Eligibility criteria: Inclusion Criteria:

1. Male or female, 18-75 years old.
2. Has a diagnosis of WHO Group 1 PAH.
3. Right heart catheterization performed at Screening with results that are:

   1. Mean pulmonary arterial pressure ≥25 mmHg (at rest) and
   2. Pulmonary venous hypertension (measured as pulmonary capillary wedge pressure (PCWP) ≤15 mmHg. If PCWP is not available, then mean left atrial pressure or left ventricular end-diastolic pressure ≤15 mmHg in the absence of left atrial obstruction. and
   3. Pulmonary vascular resistance (PVR) ≥300 dyn•s/cm5 (3.75 Wood units)
4. Has WHO/NYHA-FC of II or III.
5. Be on stable dose of at least one of the following PAH-specific therapies: endothelin receptor antagonist, an agent acting on the nitric oxide pathway (phosphodiesterase type 5 inhibitor or soluble guanylate cyclase stimulator), and/or a prostacyclin or prostacyclin analog.
6. Has a 6-minute walk distance that is ≥150 and ≤500 meters.
7. Have a ventilation-perfusion scan that rules out thromboembolic disease.

Exclusion Criteria:

Exclusions Related to Cardiovascular Disease

1. History of uncontrolled hypertension
2. Persistent hypotension at Screening.
3. Evidence or history of left-sided heart disease and/or clinically significant cardiac disease in which pulmonary hypertension is more likely WHO Group 2.
4. Acute decompensated heart failure within 1 month of Screening.
5. Recent initiation (\<8 weeks from Screening) or planned initiation of cardiopulmonary rehabilitation exercise program.

   Exclusions Related to Pulmonary Disease
6. Newly diagnosed with PAH and not on PAH-specific therapy.
7. Pulmonary hypertension due to:

   1. Uncorrected congenital systemic-to-pulmonary shunt.
   2. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
   3. Persistent pulmonary hypertension of the newborn
   4. WHO clinical classification Groups 2-5
8. Evidence of significant airway and/or parenchymal lung disease.
9. Chronic infection related to tuberculosis or fungal or mycobacterial disease.

   Exclusions Based on Other Medical Conditions
10. Chronic infections including, but not limited to tuberculosis (TB), hepatitis B virus (HBV) or hepatitis C virus (HCV).
11. History of portal hypertension or chronic liver disease, including positive serology for infection with HCV and/or HBV.
12. Evidence of active infection requiring intravenous or oral antibiotics within 4 weeks of Screening.
13. Body mass index ≥35.0 at Screening.
14. History of obstructive sleep apnea.
15. History of malignancy within the last 5 years, except nonmelanoma skin cancer and cervical carcinoma in situ treated with curative intent.
16. Neuropsychiatric disorders/symptoms or psychological conditions.
17. Pregnancy or breast-feeding
18. Prior treatment with B cell or lymphocyte-depleting agents (eg, rituximab, Campath)

    Exclusions Based on Concomitant Medication Use
19. Concurrent regular use of another leukotriene pathway inhibitor, including over-the-counter medications or herbal remedies.

    Exclusions Based on Laboratory Values
20. Significant/chronic renal insufficiency.
21. Transaminases (alanine transaminase, aspartate transaminase) levels \>3 × upper limit of normal (ULN) and/or bilirubin level \>2 × ULN.
22. Absolute neutrophil count \<1500 mm3.
23. Hemoglobin concentration \<9 g/dL at Screening.
24. Hepatic dysfunction as defined by Child-Pugh Class B or C

Primary outcomes:
measure: Change in Pulmonary Vascular Resistance (PVR)
timeFrame: Baseline to Week 24
Secondary outcomes:
measure: Change in 6-minute Walk Distance (6MWD)
timeFrame: Baseline to Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Beverly Hills
country: United States
facility: California Heart Center Foundation, An Affiliate of Cedars-Sinai Heart Institute, Cedars-Sinai Medical Care Foundation
state: California
city: La Jolla
country: United States
facility: UCSD Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic, Florida
state: Florida
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Associates
state: Kentucky
city: South Portland
country: United States
facility: Chest Medicine Associates
state: Maine
city: Baltimore
country: United States
facility: Johns Hopkins University, Pulmonary and Critical Care Medicine
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic College of Medicine
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Respiratory Institute
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pennsylvania Medical Center
state: Pennsylvania
city: Providence
country: United States
facility: Alpert Medical School of Brown University Rhode Island Hospital
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: San Antonio
country: United States
facility: University Texas Health Science Center
state: Texas
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
Study officials:
References:
citation: Tian W, Jiang X, Tamosiuniene R, Sung YK, Qian J, Dhillon G, Gera L, Farkas L, Rabinovitch M, Zamanian RT, Inayathullah M, Fridlib M, Rajadas J, Peters-Golden M, Voelkel NF, Nicolls MR. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med. 2013 Aug 28;5(200):200ra117. doi: 10.1126/scitranslmed.3006674.
citation: Qian J, Tian W, Jiang X, Tamosiuniene R, Sung YK, Shuffle EM, Tu AB, Valenzuela A, Jiang S, Zamanian RT, Fiorentino DF, Voelkel NF, Peters-Golden M, Stenmark KR, Chung L, Rabinovitch M, Nicolls MR. Leukotriene B4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension. Hypertension. 2015 Dec;66(6):1227-1239. doi: 10.1161/HYPERTENSIONAHA.115.06370. Epub 2015 Oct 5.