A Phase 2, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effects of Sotatercept Versus Placebo for the Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) Due to Heart Failure With Preserved Ejection Fraction (HFpEF)
Overview
- Phase
- Phase 2
- Intervention
- Placebo
- Conditions
- Hypertension, Pulmonary
- Sponsor
- Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
- Enrollment
- 164
- Locations
- 238
- Primary Endpoint
- Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24
- Status
- Completed
- Last Updated
- 17 days ago
Overview
Brief Summary
This is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of sotatercept versus placebo in adults with Cpc-PH due to HFpEF.
The objective of this study is to evaluate the efficacy, safety and tolerability of sotatercept versus placebo in adults with Cpc-PH due to HFpEF. Efficacy is measured by change from baseline in pulmonary vascular resistance (PVR, primary endpoint) and 6-minute walk distance (6MWD, key secondary endpoint).
Detailed Description
Participants enrolled in the study will have a diagnosis of Cpc-PH due to HFpEF with New York Heart Association (NYHA) functional class (FC) II or III. Participants will be randomly assigned in a 1:1:1 ratio to 1 of the 3 treatment groups (placebo, 0.3mg/kg sotatercept and 0.7mg/kg sotatercept) during the placebo-controlled Treatment Period. In the extension phase, sotatercept-treated participants will continue on their current dose. Placebo participants will be re-randomized in a 1:1 ratio to one of the two sotatercept treatment groups utilized in the placebo-controlled Treatment Period. Each participant will be enrolled in the study for up to 114 weeks, including a 28-day Screening Period, a 24-week, double-blind, placebo-controlled Treatment Period, an 18-month Extension Period, and an 8-week Follow-up Period. As of protocol amendment 6, the 18-month Extension Period is being removed. Participants who have completed at least the 24-week placebo controlled treatment period and the end of study visit, and who have not discontinued study treatment early, may be eligible to participate in an extension study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants must meet the following criteria to be enrolled in this proof-of-concept study:
- •Age 18 to 85 years
- •Clinical diagnosis of HFpEF:
- •Left ventricular ejection fraction ≥50%, with no history of LVEF below 45% in more than two consecutive measurements under stable conditions
- •Demonstrated Cpc-PH by all of the following:
- •Baseline RHC performed within 28 days of randomization documenting a minimum PVR of ≥320 dyn•sec/cm5 (4 wood units)
- •Mean pulmonary arterial pressure (mPAP) of \>20 mmHg
- •Pulmonary capillary wedge pressure (PCWP) \>15 mmHg but \< 30 mmHg
- •New York Heart Association FC of II or III
- •Six-minute Walk Distance ≥100 m repeated twice during Screening and both values within 15% of each other, calculated from the highest value
Exclusion Criteria
- •Participants will be excluded from the study if any of the following criteria are met:
- •A diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5
- •Clinically significant and active lung disease:
- •Chronic obstructive pulmonary disease with post-bronchodilator forced expiratory volume in the first second (FEV1) \<60% predicted
- •Restrictive lung disease with total lung capacity \<70% predicted
- •More than mild interstitial lung disease (ILD), with FVC\<70% or FEV1\<60% predicted (still appropriate if absence of more than mild ILD, fibrosis, or COPD on computed tomography \[CT\] imaging)
- •Cardiovascular co-morbidities, which include any of the following:
- •History of more than mild mitral or aortic stenosis
- •Ongoing more than mild mitral or aortic regurgitation
- •More than one valve replacement or repair (mechanical or biomechanical) or anticipation of any valve replacement or repair
Arms & Interventions
Placebo
Delivered subcutaneously (SC) every 3 weeks (Q3W) for 24 weeks in the placebo-controlled treatment period.
Intervention: Placebo
Sotatercept 0.3 mg/kg, escalating to 0.7 mg.kg
Sotatercept SC at a starting dose level of 0.3 mg/kg for 3 dosing visits (Q3W), then escalating to 0.7 mg/kg SC on the fourth dosing visit and Q3W for the remainder of the 24-week treatment Period.
Intervention: Sotatercept 0.3 mg/kg escalating to 0.7 mg/kg
Sotatercept 0.3 mg/kg
Participants will receive sotatercept SC at a dose level of 0.3 mg/kg Q3W for 24 weeks in the placebo-controlled treatment period.
Intervention: Sotatercept 0.3 mg/kg
Outcomes
Primary Outcomes
Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24
Time Frame: Baseline and Week 24
PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization (RHC).
Secondary Outcomes
- Percentage of Participants with One or More Adverse Events (AEs)(Week 24)
- Percentage of Participants who Discontinue Study Treatment Due to an AE(Week 24)
- Change From Baseline in the 6-Minute Walk Distance (6MWD) at Week 24(Baseline and Week 24)
- Time to First Clinical Worsening Event (TTCW) at Weeks 24(Week 24)
- Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Week 24(Baseline and Week 24)
- Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 24(Baseline and Week 24)
- Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 24(Baseline and Week 24)
- Change From Baseline in Right Ventricular Fractional Area Change (RVFAC) at Week 24(Baseline and Week 24)
- Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 24(Baseline and Week 24)
- Change From Baseline in Isovolumic Relaxation Time (IVRT) at Week 24(Baseline and Week 24)
- Change From Baseline in ratio of mitral inflow velocity I to mitral annular velocity'(e') (E/e' ratio) at Week 24(Baseline and Week 24)
- Change From Baseline in the Ratio of the Peak Velocity Flow of the E Wave in Early Diastole to Peak Velocity Flow of the A Wave in Late Diastole (E/A Ratio) at Week 24(Baseline and Week 24)
- Change From Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide (NT-proBNP) at Week 24(Baseline and Week 24)
- Change From Baseline in New York Heart Association Functional Class (NYHA FC) at Week 24(Baseline and Week 24)
- Change From Baseline in Myocardial Contraction Fraction (MCF) at Week 24(Baseline and Week 24)