A Phase 3 Study of Sotatercept in Newly Diagnosed Intermediate- and High-risk Pulmonary arterial hypertension (PAH) Patients.

• Register: EUCTR
• Last refreshed on: 9 December 2024
• Main ID: EUCTR2021-000199-12-HR
• Date of registration: 03/02/2022
• Prospective Registration: No
• Primary sponsor: Acceleron Pharma Inc.
• Public title: A Phase 3 Study of Sotatercept in Newly Diagnosed Intermediate- and High-risk Pulmonary arterial hypertension (PAH) Patients.
• Scientific title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Sotatercept When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy in Newly Diagnosed Intermediate- and High-risk PAH Patients. - A Phase 3 Study of Sotatercept in Newly Diagnosed Intermediate- and High-risk PAH Patients
• Date of first enrolment: 19/01/2022
• Target sample size: 662
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-000199-12
• 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, Colombia, Croatia, Czech Republic, Czechia, Denmark, France, Germany, Greece, Ireland, Israel, Italy, Korea, Republic of, Netherlands, New Zealand, Poland, Portugal, Serbia, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States

Contacts

• Name: John Butler
• Affiliation: Acceleron Pharma Inc.

• Name: John Butler
• Affiliation: Acceleron Pharma Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age = 18 years
2. Documented diagnostic right heart catheterization (RHC) within 12 months of screening documenting a minimum PVR of = 4 Wood units and pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of = 15 mmHg, with the diagnosis of WHO 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 PAH classified as WHO FC II or III
4. REVEAL Lite 2 risk score = 6
5. Diagnosis of PAH within 12 months of screening and on stable doses of a double or triple combination of background PAH therapies for at least 90 days prior to screening.
6. Six-minute walk distance = 150 m repeated twice at screening at least 4 hours apart, but no longer than 1 week apart, and both values are within 15% of each other (calculated from the highest value).Background PAH therapy is further defined in Section 7.2.
7. Females of childbearing potential must meet the following criteria:
-Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study drug administration; she must agree to ongoing urine or serum pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
-If sexually active, with a male partner:
- Used highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, AND
- Agreed to use the same highly effective contraception in combination with a barrier method 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 meet the following criteria:
-Agree to use a condom, defined as a male latex condom or nonlatex 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 16 weeks (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 497
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 165

Exclusion criteria:
1. Diagnosis of PAH WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH, PAH associated with portal hypertension schistosomiasis-associated PAH, pulmonary veno occlusive disease and pulmonary capillary hemangiomatosis.
3. Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
4. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mmHg or sitting diastolic BP > 100 mmHg during the 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:
-Estimated glomerular filtration rate < 30 mL/min/m2 (as defined by MDRD equation)
-Serum alanine aminotransferase aspartate aminotransferase , or total bilirubin levels > 3 × ULN.
- Platelet count < 50,000/mm3 (< 50.0 × 109/L)
8. Currently enrolled in or have completed any other investigational product study within 30 days for small-molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent
9. Known allergic reaction to sotatercept (ACE-011)), its excipients, or luspatercept
10. History of pneumonectomy
11. Pulmonary function test values of forced vital capacity < 60% predicted within 1 year prior to the Screening Visit
12. Stopped receiving any pulmonary hypertension chronic general supportive therapy (e.g., diuretics, oxygen, anticoagulants, and
digoxin) within 60 days prior to the Screening Visit
13. 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)
14. Untreated more than mild obstructive sleep apnea
15. History of known pericardial constriction
16. History of restrictive or congestive cardiomyopathy
17. History of atrial septostomy within 180 days prior to the Screening Visit
18. Electrocardiogram with Fridericia’s corrected QT interval > 500 ms during the Screening Period
19. Personal or family history of long QT syndrome or sudden cardiac death
20. Left ventricular ejection fraction < 50% on historical echocardiogram within 1 year prior to the Screening Visit or pulmonary capillary wedge pressure > 15 mmHg as determined by historical RHC within 12 months prior to the Screening Visit
21. 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
22. Cerebrovascular accident within 3 months prior to the Screening Visit
23. Acutely decompensated heart failure within 30 days prior to the Screening Visit, as per investigator assessment
24. Significant (= 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
25. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, and vasopressin) within 30 days prior to the Screening Visit


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

Health Condition(s) or Problem(s) studied

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

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

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: Lyophilisate for solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Secondary Objective: not applicable

Timepoint(s) of evaluation of this end point: The primary endpoint will be analyzed using a weighted stratified log-rank test with randomization stratification factors as strata. The Cui-Hung-Wang (CHW) method will be used to control the Type I error rate for the primary endpoint. The point estimate of the hazard ratio with 95% CI will be estimated by a Cox regression model stratified by the randomization factors. If there is no increase in the number of events and sample size following the planned interim analysis, then the CHW method will be the same as a conventional analysis of this data using a log-rank test. The Chen-DeMets-Lan method will be used as a supportive analysis to the CHW method.

Main Objective: The objective of this study is to evaluate the effects of sotatercept treatment (plus background PAH therapy) versus placebo (plus background PAH therapy) on TTCW in participants who are newly diagnosed with PAH and are at intermediate or high risk of PAH disease progression.

Primary end point(s): The primary efficacy endpoint is TTCW, defined as the time from randomization to the first confirmed morbidity event or death. The events that will comprise this endpoint
include the following:
• All-cause death
• Non-planned PAH-related hospitalization of = 24 hours in duration
• Atrial septostomy
• Lung transplant
• Deterioration in performance in exercise testing due to PAH, defined as a decrease in 6MWD from baseline on
2 consecutive tests (which must be at least 4 hours apart) and at least 1 of the following:
- Worsening of WHO FC from baseline
- Signs/symptoms of increased right heart failure
- Addition of a background PAH therapy or change PAH background therapy, delivery route to parenteral
All events will be adjudicated by a blinded, independent committee of clinical experts.

Secondary Outcome(s)

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

Secondary end point(s): 1. Multicomponent improvement endpoint measured by the proportion of participants achieving all of the following at Week 24 relative to baseline:
-Improvement in 6MWD (increase = 30 m)
-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. Proportion of participants who achieve a low REVEAL Lite 2 risk score at Week 24 versus baseline
3. Proportion of participants who maintain or achieve a low risk score at Week 24 versus baseline using the simplified French
Risk score calculator
4. Change from baseline in NT-proBNP levels at Week 24
5. Proportion of participants who improve in WHO FC or maintain WHO FC II at 24 weeks from baseline
6. Change from baseline in 6MWD at Week 24
7. Change from baseline in the Physical Impacts domain score of Pulmonary Arterial Hypertension-Symptoms and Impact (PAH SYMPACT®) at Week 24
8. Change from baseline in the Cardiopulmonary Symptoms (domain score of PAH-SYMPACT)®® at Week 24
9. Change from baseline in the Cognitive/Emotional Impacts domain score of PAH-SYMPACT® at Week 24

Secondary ID(s)

136150

2021-000199-12-BE

A011-13

NCT04811092

Source(s) of Monetary Support

Acceleron Pharma Inc.

Ethics review

Status: Approved
Approval date: 11/11/2021
Contact: