A Phase 3 Study of Sotatercept for the Treatment of PAH

• Register: EUCTR
• Last refreshed on: 26 April 2021
• Main ID: EUCTR2020-004142-11-SE
• Date of registration: 28/01/2021
• Prospective Registration: Yes
• Primary sponsor: Acceleron Pharma Inc.
• Public title: A Phase 3 Study of Sotatercept for the Treatment of PAH
• Scientific title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Compare the Efficacy and Safety of Sotatercept Versus Placebo When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy for the Treatment of PAH - A Phase 3 Study of Sotatercept for the Treatment of PAH
• Date of first enrolment: 26/03/2021
• Target sample size: 284
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-004142-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Canada, Czechia, France, Germany, Ireland, Israel, Italy, Korea, Republic of, Mexico, Netherlands, New Zealand, Poland, Serbia, Spain, Sweden, Switzerland, United Kingdom, United States

Contacts

• Name: SaraBeth Hahn
• Affiliation: Acceleron Pharma Inc.

• Name: SaraBeth Hahn
• Affiliation: Acceleron Pharma Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age = 18 years
2. Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of WHO pulmonary arterial hypertension (PAH) Group 1 in any of the following subtypes:
• Idiopathic PAH
• Heritable PAH
• Drug/toxin-induced PAH
• PAH associated with connective tissue disease
• PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair
3. Symptomatic pulmonary hypertension classified as WHO Functional Class II or III
4. Baseline RHC performed during the Screening Period documenting a minimum pulmonary vascular resistance (PVR) of = 5 WU
5. At stable doses of background PAH therapy and diuretics (i.e., patientspecific dose goal for each therapy already achieved) for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical practice.
6. 6MWD = 150 and = 500 m repeated twice at screening (measured at least 4 hours apart, but no longer than 1 week), and both values are within 15% of each other (calculated from the highest value)
7. Females of childbearing potential must:
• Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study drug administration; she must agree to ongoing pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
• If sexually active, have used, and agree to use, highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment
• Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment
8. Male participants must:
• Agree to use a condom, defined as a male latex condom or non-latex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
• Refrain from donating blood or sperm for the duration of the study and for 112 days (112 days) after the last dose of study treatment
9. Ability to adhere to study visit schedule and understand and comply with all protocol requirements
10. Ability to understand and provide written informed consent
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 142
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 142

Exclusion criteria:
1. Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension. Exclusions in PAH Group I should also include schistosomiasis APAH and pulmonary veno-occlusive disease
3. Hemoglobin (Hgb) at screening above gender-specific upper limit of normal, per local laboratory test
4. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mmHg or sitting diastolic blood pressure > 100 mmHg during screening visit after a period of rest
5. Baseline systolic BP < 90 mmHg at screening
6. Pregnant or breastfeeding women
7. Any of the following clinical laboratory values at the screening visit:
• eGFR < 30 mL/min/m2 (as defined by MDRD equation)
• Serum alanine aminotransferase or aspartate aminotransferase levels
> 3 × upper limit of normal (ULN) or total bilirubin > 1.5 × ULN
8. Currently enrolled in or have completed any other investigational product study within 30 days for small-molecule drugs or within 5 halflives for biologics prior to the date of signed informed consent
9. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536) or known allergic reaction to either one
10. Have full or partial pneumonectomy
11. Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at the screening visit or within 6 months prior to the screening visit. If PFT is not available, a chest CT scan showing no more than mild interstitial lung disease (ILD) at the screening visit or 1 years prior to it
12. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the screening visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible)
13. History of more than mild obstructive sleep apnea that is untreated
14. Known history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent
infection and/or active virus replication), defined as mild to severe hepatic impairment (Child-Pugh Class A-C).
15. History of restrictive, constrictive or congestive cardiomyopathy
16. History of atrial septostomy within 180 days prior to the screening visit
17. Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 500 ms during screening visit
18. Personal or family history of long QT syndrome (LQTS) or sudden cardiac death
19. Left ventricular ejection fraction (LVEF) < 45% on historical ECHO
within 6 months prior to the screening visit or pulmonary capillary wedge pressure (PCWP) > 15 mmHg as determined in the Screening Period RHC
20. Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) in the past 6 months prior to the screening visit. Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions
21. Cerebrovascular accident within 3 months prior to the screening visit
22. Acutely decompensated heart failure within 30 days prior to the screening visit, as per investigator assessment
23. Significant (= 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease.
24. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Pulmonary Arterial Hypertension (PAH)
MedDRA version: 21.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Product Name: Sotatercept
Product Code: ACE-011
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: SOTATERCEPT
CAS Number: 1001080-50-7
Current Sponsor code: ACE-011
Other descriptive name: ActRIIA-IgG1Fc
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Secondary Objective: Not Applicable

Main Objective: The objectives of this study are to evaluate the efficacy and safety of sotatercept treatment (plus background PAH therapy) versus placebo (plus background PAH therapy) at 24 weeks in adults with PAH.

Timepoint(s) of evaluation of this end point: Week 24

Primary end point(s): The primary efficacy endpoint is the change from baseline in 6MWD

Secondary Outcome(s)

Secondary end point(s): 1. Multicomponent improvement endpoint measured by the proportion of participants achieving all of the following:
• Improvement in NT-proBNP (decrease in NT-proBNP = 30%) or maintenance/achievement of NT-proBNP level < 300 ng/L
• Improvement in WHO FC or maintenance of WHO FC II
2. Change from baseline in PVR
3. Change from baseline in NT-proBNP levels
4. Proportion of participants who improve in WHO FC
5. Time to death or the first occurrence of any of the following clinical worsening events (TTCW)
• Worsening-related listing for lung and/or heart transplant
• Need to initiate rescue therapy with an approved background PAH therapy or the need to increase the dose of infusion prostacyclin by 10% or more
• Need for atrial septostomy
• Hospitalization for worsening of PAH (= 24 hours)
• Deterioration of PAH, defined by both of the following events occurring at any time, even if they began at different times, as compared to their baseline values:
- Worsened WHO FC
- Decrease in 6MWD by = 15% confirmed by 2 tests at least 4 hours apart, but no more than 1 week
6. Proportion of participants who maintain or achieve a low risk score using the simplified French Risk score calculator
7. Change from baseline in EuroQoL - 5 dimensions (EQ-5D-5L) index score
8. Change from baseline in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT®)

Timepoint(s) of evaluation of this end point: Week 24

Secondary ID(s)

A011-11

Source(s) of Monetary Support

Acceleron Pharma Inc.

Ethics review

Status: Approved
Approval date: 24/03/2021
Contact: