A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Ubenimex in Patients with Pulmonary Arterial Hypertension (WHO Group 1)
- Clements University Hospital
Sonja Bartolome, M.D.
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study comparing ubenimex (150 mg TiD) with placebo in patients with PaH. at Screening and baseline eligible patients will undergo standard laboratory tests, electrocardiogram (eCG) and vital sign evaluations, and physical examination. Baseline cardiopulmonary hemodynamics will be measured during right heart catheterization (RHC) and baseline exercise capacity will be measured by the 6-minute walk test (6MWT) and Borg dyspnea score. The study will consist of three periods- Screening period (Day -28 to Day 0), Treatment period (Day 1 through Week 24) and Follow-up Period (Week 28- 4 weeks after last dose). The maximum anticipated time an individual patient will participate in the study will be 32 weeks.
Patients will be randomized in a 2:1 ratio to receive one of the following treatments, which will be administered orally for a total of 24 weeks: ubenimex 150 mg TiD (total daily dose of 450 mg, 30 patients) or matched placebo TiD (15 patients). eligible patients will be stratified by PaH etiology (PaH associated with
CTD vs PaH not associated with CTD) and by number of PaH therapies at baseline (one vs two or more). a dynamic balancing randomization will be used in an attempt to maintain balance across treatment groups with respect to the stratification factors.
Steady-state PK characteristics of ubenimex will be determined and biomarkers will be measured at selected sites. an ex vivo stimulated LTB4 assay will be used as a PD measure, in order to measure the degree of inhibition of LTa4H achieved in plasma; due to requirement for specialized equipment and the complexity of the procedure, this will be conducted at selected sites. urinary LTe4 levels will also be measured to ensure that ubenimex does not result in
shunting of intermediates and increases in levels of cysteinyl leukotrienes.
on completion of the 24-week Treatment Period, patients may be eligible to enter an open-label extension study, eiG-uBX-002 and the Week 24 visit will also be the first visit for the extension study. a patient who is not eligible for or declines to enroll in eiG-uBX-002 will enter the Follow-up Period in eiG-uBX-001.
The primary endpoint for clinical efficacy is change from baseline in pulmonary vascular resistance (PVR) at 24 weeks as assessed by cardiopulmonary hemodynamic measurements obtained via RHC at Week 24. Secondary efficacy endpoints include 6-minute walk distance (6MWD) and Borg dyspnea score assessments. Changes in WHo/nYHa-FC status and in disease severity (clinical worsening) will be recorded. Quality of life will be assessed at Baseline and Weeks 4, 12, and 24.
1. Provide a personally signed and dated informed consent form (ICF) indicating that the patient has been informed of all pertinent aspects of the study.
2. Male or female, 18x75 years old (inclusive).
3. Has a diagnosis of WHO Group 1 PAH classified by one of the following (Simonneau 2013):
a. Idiopathic PAH (IPAH).
b. Heritable PAH (HPAH).
c. Drug- and toxin-induced, based on prior exposure to legal drugs, chemicals, and toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil, L-tryptophan.A patient with PAH associated with illegal drug use, such as methamphetamine, may beincluded if the patient has been abstinent and under the care of a physician for at least 1 year immediately before Screening and, in the Investigator[Single Quote]s opinion, is compliant with his or her current medication regimen and overall PAH care.
d. Associated with PAH (APAH), specifically:
iii. Congenital heart disease, only if associated with a simple, congenital systemic-topulmonary
shunt (atrial septal defect, ventricular septal defect, or patent ductus
arteriosus). The defect must have been surgically corrected at least 1 year before
4. Right heart catheterization (RHC) performed at Screening with results that are consistent with the diagnosis of PAH meeting all of the following criteria:
a. Mean pulmonary arterial pressure (mPAP) >=25 mmHg (at rest) and
b. Pulmonary venous hypertension (measured as pulmonary capillary wedge pressure [PCWP]) <=15 mmHg. If PCWP is not available, then mean left atrial pressure (mLAP) or left ventricular enddiastolic pressure (LVEDP) <=15 mmHg in the absence of left atrial obstruction. and
c. Pulmonary vascular resistance (PVR) >=300 dyn
* s/cm5 (3.75 Wood units)
Note: Patients who have had a RHC performed within 30 days of the start of Screening under standardized conditions that capture all of the required data points and with results that are consistent with the diagnosis of PAH as outlined above are not required to have a repeat Screening RHC.
5. Has WHO/NYHA-FC of II or III
6. Be on stable dose of at least one of the following PAH-specific PAH: endothelin receptor antagonist (ERA), an agent acting on the nitric oxide pathway (phosphodiesterase type 5 [PDE-5] inhibitor or soluble guanylate cyclase [sGC] stimulator), and/or a prostacyclin or prostacyclin analog. Stable dose is defined as no change in dose within 3 months of start of Screening and for the duration of the study. Prostacyclin/prostacyclin analog may be oral, inhaled, or parenteral.
7. Has a 6-minute walk distance (6MWD) that is >=150 and <=550 meters confirmed by a second 6MWD that is within 15% of the first, with both tests performed during Screening. Each test must be performed on a separate day, preferably a few days apart. If the second 6MWD is not within 15% of the first, a third test may be performed on a different day. The third 6MWD must be within 15% of the first 6MWD in order for the patient to be eligible.
8. Have a ventilationxperfusion (V/Q) scan that rules out thromboembolic disease (ie, should be [?]normal[Single Quote] or [?]low probability[Single Quote] for pulmonary embolism) at Screening, if a scan is not available within 3 years of Screening. V/Q scanning is preferred, but if unavailable, spiral/helical/electron-beam computed tomography (CT) or pulmonary angiogram within 3 years of Screening that shows no evidence of thromboembolic disease (ie, should be normal or low probability for pulmonary embolism) is acceptable. If a V/Q scan is abnormal (ie, is not normal or low probability), then a selective pulmonary angiography must exclude chronic thromboembolic disease.
9. Agrees to use a medically acceptable method of contraception (both male and female patients) throughout the entire study period from informed consent through the follow-up visit if the possibility of conception exists.
10. If the patient is taking the following concomitant medications that may affect PAH, the patient must be on a stable dose for at least 1 month before the start of Screening: vasodilators (including calcium channel blockers), anticoagulants, oral diuretics, digoxin, or L-arginine. The dose of vasodilators, anticoagulants, digoxin or L-arginine should be maintained for the duration of the study; changes in oral diuretic doses are allowed during the study.
11. Body weight of at least 40 kg at Screening.