Clinical trial NCT03738150: A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension
Official title: A Phase 2a Single-Arm, Open-Label, Multicenter Exploratory Study to Assess the Effects of Sotatercept (ACE-011) for the Treatment of Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Keywords: PAH
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2018-11-13
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study evaluates the effect of sotatercept (ACE-011) in adults with pulmonary arterial hypertension (PAH). Each eligible participant will receive standard of care (SOC) plus sotatercept (ACE-011) for a 24-week treatment period, followed by an 18-month extension period, and an 8-week follow-up period.

Detailed description: This is a Phase 2a, single-arm, open-label, multicenter exploratory study to determine the effects of sotatercept plus SOC in adults with WHO functional class III PAH.

All eligible participants will receive SOC plus sotatercept at a starting dose level of 0.3 mg/kg by subcutaneous (SC) injection for Cycle 1 and escalating to 0.7 mg/kg at Cycle 2 for the remainder of the treatment period. Participants will be required to attend clinic visits once every three weeks for the 24-week treatment period and once every three weeks for the 18-month extension period to perform one or more protocol specified evaluations. Evaluations include hemodynamic measures collected during right heart catheterization (RHC) with invasive cardiopulmonary exercise test (iCPET), and cardiac magnetic resonance imaging (MR), 6-minute walk distance (6MWD), pharmacokinetic parameters, pharmacodynamic parameters, anti-drug antibody testing, and adverse events.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years
2. Documented findings on RHC at any time prior to Screening consistent with a diagnosis of World Health Organization (WHO) pulmonary hypertension Group 1: PAH of any of the following subtypes:

   * Idiopathic PAH
   * Heritable PAH
   * Drug- or toxin-induced PAH
   * PAH associated with connective tissue disease
   * PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following shunt repair
3. Symptomatic pulmonary hypertension classified as WHO functional class III
4. Screening RHC documenting a minimum PVR of ≥ 4 Wood units
5. Pulmonary function tests within 6 months prior to Screening as follows:

   1. Total lung capacity \> 70% predicted; or if between 60% to 70% predicted, or not possible to be determined, confirmatory high-resolution computed tomography (CT) indicating no more than mild interstitial lung disease per investigator interpretation or
   2. Forced expiratory volume (first second) (FEV1)/forced vital capacity (FVC) \> 70% predicted
   3. For subjects with a history of lobectomy or pneumonectomy, and for whom there are no population-based normalization methods, assessment based on residual lung volume will be permitted to assess eligibility.
6. Ventilation-perfusion (VQ) scan (or, if unavailable, a negative CT pulmonary angiogram \[CTPA\] or pulmonary angiography result), any time prior to Screening or conducted during Screening Period with normal or low probability result
7. 6MWD ≥ 100 and ≤ 550 meters repeated twice during Screening Period and both values within 15% of each other, calculated from the highest value
8. Combination PAH therapy at stable (per investigator) dose levels for at least 90 days prior to Cycle 1 Day 1 (C1D1)

Exclusion Criteria:

Participants will be excluded from the study if they meet any of the following criteria:

1. Started or stopped receiving any general supportive therapy for pulmonary hypertension (e.g., diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to C1D1 (Cycle 1 Day 1)
2. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to C1D1
3. History of atrial septostomy within 180 days prior to Screening
4. History of more than mild obstructive sleep apnea that is untreated
5. History of portal hypertension or chronic liver disease, defined as mild to severe hepatic impairment (Child-Pugh Classes A to C)
6. History of human immunodeficiency virus infection-associated PAH
7. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536)
8. Uncontrolled systemic hypertension as evidenced by sitting systolic BP \> 160 mm Hg or sitting diastolic BP \> 100 mm Hg during Screening after a period of rest
9. Systolic BP \< 90 mm Hg during Screening or at baseline
10. History of known pericardial constriction
11. Electrocardiogram (ECG) with QTcF \> 480 msec during Screening or C1D1
12. History of personal or family history of long QTc syndrome or sudden cardiac death
13. History of restrictive or constrictive cardiomyopathy
14. Left ventricular ejection fraction \< 45% on echocardiogram performed within 6 months of Screening OR pulmonary capillary wedge pressure (PCWP) \> 15 mm Hg on RHC during baseline evaluation
15. Any current symptomatic coronary disease (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain in the past 6 months prior to Screening)
16. Acutely decompensated heart failure within 30 days prior to C1D1, as per investigator assessment
17. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease

Primary outcomes:
measure: Change From Baseline in Peak Oxygen Uptake (VO2 Max) at 24 Weeks
timeFrame: Baseline and 24 weeks
Secondary outcomes:
measure: Change From Baseline in Right Ventricular Stroke Volume (RV SV) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in Right Ventricular End-Systolic Volume (RV ESV) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in Right Ventricular End-Diastolic Volume (RV EDV) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Percent Change From Baseline in Right Ventricular Ejection Fraction (RV EF) at 24 Weeks
timeFrame: Baseline and 24 Weeks
measure: Change From Baseline in Right Ventricular Stroke Volume Index (RV SVI) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in Right Ventricular (RV) Mass at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in Ventilatory Efficiency (VE/VCO2 Slope) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in Cardiac Index at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in Mean Pulmonary Arterial Pressure at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in Arteriovenous O2 Content Difference (Ca-vO2) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Change From Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks
timeFrame: Baseline and 24 Weeks
measure: Change From Baseline in WHO (World Health Organization) Functional Class at 24 Weeks
timeFrame: Baseline and 24 Weeks
measure: Number of Participants With One or More Adverse Events (AEs)
timeFrame: Up to 24 weeks
measure: Number of Participants Who Experienced One or More Events Indicative of Clinical Worsening of Pulmonary Arterial Hypertension (PAH)
timeFrame: Up to 102 weeks
measure: Observed Trough Concentration (Ctrough) of Sotatercept at Cycle 9
timeFrame: Day 1 of Cycle 9 (Each cycle was 21 days.)
measure: Maximum Plasma Concentration (Cmax) of Sotatercept at Cycle 9
timeFrame: Day 1 of each 21-day cycle: Cycles 1-9
measure: Minimum Plasma Concentration (Cmin) of Sotatercept at Cycle 9
timeFrame: Day 1 of each 21-day cycle: Cycles 1-9
measure: Average Concentration (Cavg) of Sotatercept at Cycle 9
timeFrame: Day 1 of each 21-day cycle: Cycles 1-9
measure: Area Under the Concentration-Time Curve From 0 to T (AUC0-T) of Sotatercept at Cycle 9
timeFrame: Day 1 of each 21-day cycle: Cycles 1-9
measure: Apparent Terminal Half-life (t1/2 ) of Sotatercept at Cycle 9
timeFrame: Day 1 of each 21-day cycle: Cycles 1-9
measure: Apparent Serum Clearance (CL) of Sotatercept at Cycle 9
timeFrame: Day 1 of each 21-day cycle: Cycles 1-9
measure: Apparent Volume of Distribution (Vz/F) of Sotatercept at Cycle 9
timeFrame: Day 1 of each 21-day cycle: Cycles 1-9
measure: Absorption Rate Constant (Ka) of Sotatercept at Cycle 9
timeFrame: Day 1 of each 21-day cycle: Cycles 1-9
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona
state: Arizona
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
affiliation: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
name: Jonathan Lu, MD
role: STUDY_DIRECTOR
References:
citation: Waxman AB, Systrom DM, Manimaran S, de Oliveira Pena J, Lu J, Rischard FP. SPECTRA Phase 2b Study: Impact of Sotatercept on Exercise Tolerance and Right Ventricular Function in Pulmonary Arterial Hypertension. Circ Heart Fail. 2024 May;17(5):e011227. doi: 10.1161/CIRCHEARTFAILURE.123.011227. Epub 2024 Apr 4.