A Study of Ubenimex in Patients With Pulmonary Arterial Hypertension (WHO Group 1)

Study Overview
=================
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.

Official Title
-----------------
A Phase 2, Randomized, Double-BLInd, Placebo- Controlled Study of UBEnimex in Patients With Pulmonary ARTerial HYpertension (WHO Group 1) (LIBERTY)

Conditions
-----------------
Pulmonary Arterial Hypertension

Intervention / Treatment
-----------------
* Drug: ubenimex
* Other: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, 18-75 years old. Has a diagnosis of WHO Group 1 PAH. Right heart catheterization performed at Screening with results that are: Mean pulmonary arterial pressure ≥25 mmHg (at rest) and 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 Pulmonary vascular resistance (PVR) ≥300 dyn•s/cm5 (3.75 Wood units) Has WHO/NYHA-FC of II or III. 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. Has a 6-minute walk distance that is ≥150 and ≤500 meters. Have a ventilation-perfusion scan that rules out thromboembolic disease. Exclusion Criteria: Exclusions Related to Cardiovascular Disease History of uncontrolled hypertension Persistent hypotension at Screening. Evidence or history of left-sided heart disease and/or clinically significant cardiac disease in which pulmonary hypertension is more likely WHO Group 2. Acute decompensated heart failure within 1 month of Screening. Recent initiation (<8 weeks from Screening) or planned initiation of cardiopulmonary rehabilitation exercise program. Exclusions Related to Pulmonary Disease Newly diagnosed with PAH and not on PAH-specific therapy. Pulmonary hypertension due to: Uncorrected congenital systemic-to-pulmonary shunt. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis Persistent pulmonary hypertension of the newborn WHO clinical classification Groups 2-5 Evidence of significant airway and/or parenchymal lung disease. Chronic infection related to tuberculosis or fungal or mycobacterial disease. Exclusions Based on Other Medical Conditions Chronic infections including, but not limited to tuberculosis (TB), hepatitis B virus (HBV) or hepatitis C virus (HCV). History of portal hypertension or chronic liver disease, including positive serology for infection with HCV and/or HBV. Evidence of active infection requiring intravenous or oral antibiotics within 4 weeks of Screening. Body mass index ≥35.0 at Screening. History of obstructive sleep apnea. History of malignancy within the last 5 years, except nonmelanoma skin cancer and cervical carcinoma in situ treated with curative intent. Neuropsychiatric disorders/symptoms or psychological conditions. Pregnancy or breast-feeding Prior treatment with B cell or lymphocyte-depleting agents (eg, rituximab, Campath) Exclusions Based on Concomitant Medication Use Concurrent regular use of another leukotriene pathway inhibitor, including over-the-counter medications or herbal remedies. Exclusions Based on Laboratory Values Significant/chronic renal insufficiency. Transaminases (alanine transaminase, aspartate transaminase) levels >3 × upper limit of normal (ULN) and/or bilirubin level >2 × ULN. Absolute neutrophil count <1500 mm3. Hemoglobin concentration <9 g/dL at Screening. Hepatic dysfunction as defined by Child-Pugh Class B or C

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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>placebo capsules TID, administered orally for a total of 24 weeks | Other: placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pulmonary Vascular Resistance (PVR) | Change from Baseline at End of Treatment in PVR Using Worst Case Imputation in the Modified Intent to Treat Population. PVR was assessed by hemodynamic measurements obtained via right heart catheterization. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6-minute Walk Distance (6MWD) | Change in exercise capacity from baseline to Week 24 as determined by the 6MWD | Baseline to Week 24 |