A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (SPECTRA)

• ClinicalTrials.gov Identifier: NCT03738150
• Recruitment Status: Completed
• First Posted: November 13, 2018
• Last Update Posted: August 16, 2022
• Sponsor: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Information provided by (Responsible Party): Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Study Description

Brief Summary:

This study evaluates the effect of sotatercept (ACE-011) in adults with Pulmonary Arterial Hypertension. 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.

Condition or disease	Intervention/treatment	Phase
Pulmonary Arterial Hypertension	Biological: Sotatercept	Phase 2

Detailed Description:

This is a Phase 2a, single arm, open-label, multi center exploratory study to determine the effects of sotatercept (ACE-011) plus standard of care (SOC) in adults with WHO functional class III pulmonary arterial hypertension (PAH).

All eligible participants will receive standard of care (SOC) plus sotatercept (ACE-011) at a starting dose level of 0.3 mg/kg SC 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: April 19, 2019
• Actual Primary Completion Date: December 21, 2021
• Actual Study Completion Date: March 22, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sotatercept; Each participant will receive standard of care (SOC) plus sotatercept at a dose of 0.3 mg/kg SC for Cycle 1. Dose will escalate to 0.7 mg/kg SC at Cycle 2 through the remainder of the treatment period. Dosing will be every three weeks during the 24 weeks Treatment Period and every three weeks during the 18 month Extension Period.	Biological: Sotatercept; Sotatercept injection; Other Name: ACE-011

Outcome Measures

Primary Outcome Measures :

1. Change from baseline in peak oxygen uptake (VO2 max) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]

Secondary Outcome Measures :

1. Change from baseline in ventilatory efficiency (VE/VCO2 slope) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
2. Change from baseline in cardiac index (L/min/m2) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
3. Change from baseline in mean pulmonary arterial pressure [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
4. Change from baseline in arteriovenous O2 content difference (Ca-vO2) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
5. Change from baseline in right ventricular stroke volume (RV SV) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
6. Change from baseline in right ventricular end-systolic volume (RV ESV) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
7. Change from baseline in right ventricular end-diastolic volume (RV EDV) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
8. Change from baseline in right ventricular ejection fraction (RV EF) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
9. Change from baseline in right ventricular stroke volume index (RV SVI) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
10. Change from baseline in right ventricular (RV) mass [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
11. Change from baseline in pulmonary vascular resistance (PVR) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
12. Measurement of serum concentration of sotatercept [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
13. Measurement of individual maximum sotatercept concentration (Cmax ) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
14. Measurement of individual minimum sotatercept concentration(Cmin) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
15. Measurement of individual average sotatercept concentration(Cavg) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
16. Measurement of area under the concentration (AUC) versus time curve [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
17. Measurement of apparent terminal half-life (t1/2 ) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
18. Measurement of apparent serum clearance (CL) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
19. Measurement of apparent volume of distribution (Vd) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
20. Measurement of absorption rate constant (Ka) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
21. Change from baseline in 6MWD [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
22. Change from baseline in concentration of amino-terminal brain natriuretic propeptide (NT-proBNP) [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
23. Change from baseline in WHO (World Health Organization) functional class [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]
24. Number of patients experiencing one or more events indicative of clinical worsening of PAH [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 34 (each cycle is 21 days) ]
    Events that indicate clinical worsening of PAH include death, need for and/or worsening-related listing for lung and/or heart transplant, need to initiate an approved PAH SOC rescue therapy, PAH-specific hospitalization, or functional deterioration (worsened WHO Functional Class AND 15% decrease in 6MWD)
25. Measurement of the number of adverse events (AEs) in subjects [ Time Frame: From initiation of treatment Cycle 1 Day 1 to the end of Cycle 9 (each cycle is 21 days). ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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

Contacts and Locations

Locations

United States, Arizona

The University of Arizona

Tucson, Arizona, United States, 85724

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, Pennsylvania

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States, 15213

Sponsors and Collaborators

Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

More Information

• Responsible Party: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• ClinicalTrials.gov Identifier: NCT03738150
• Other Study ID Numbers: A011-10; 7962-002 ( Other Identifier: Merck )
• First Posted: November 13, 2018
• Last Update Posted: August 16, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.):

PAH

Additional relevant MeSH terms:

Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Vascular Diseases; Cardiovascular Diseases; Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases