A study to evaluate Sotatercept in Participants with PAH WHO FC III or FC IV at High Risk of Mortality

• Register: EUCTR
• Last refreshed on: 2 September 2024
• Main ID: EUCTR2021-001498-21-DE
• Date of registration: 24/09/2021
• Prospective Registration: Yes
• Primary sponsor: Acceleron Pharma Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA
• Public title: A study to evaluate Sotatercept in Participants with PAH WHO FC III or FC IV at High Risk of Mortality
• Scientific title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Sotatercept When Added to Maximum Tolerated Background Therapy in Participants With Pulmonary Arterial Hypertension (PAH) World Health Organization (WHO) Functional Class (FC) III or FC IV at High Risk of Mortality - A Phase3 Study of Sotatercept in Participants with PAH WHO FC III or FC IV at High Risk of Mortality
• Date of first enrolment: 01/02/2022
• Target sample size: 166
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-001498-21
• 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

Australia, Belgium, Canada, France, Germany, Israel, Italy, Mexico, Netherlands, Spain, United Kingdom, United States

Contacts

• Name: Maria J Loureiro
• Affiliation: Acceleron Pharma Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA

• Name: Maria J Loureiro
• Affiliation: Acceleron Pharma Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA

Key inclusion & exclusion criteria

Inclusion criteria:
Eligible participants must meet all of the following inclusion criteria to be enrolled in the study:
1. Age 18 to 75 years, inclusive
2. Documented diagnostic right heart catheterization prior to screening confirming the diagnosis of WHO PAH Group 1 in any of the following subtypes:
• Idiopathic PAH
• Heritable PAH
• Drug/toxin-induced PAH
• PAH associated with CTD
• PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair
3. Symptomatic PAH classified as WHO FC III or IV
4. REVEAL Lite 2.0 risk score of = 9
5. Right heart catheterization performed during screening (or within 2 weeks prior to screening, if done at the clinical study site) documenting a minimum PVR of = 5 Wood units and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of = 15 mmHg
6. Clinically stable and on stable doses of maximum tolerated (per
investigator’s judgment) double or triple background PAH therapies for at least 30 days prior to screening
7. Females of childbearing potential must:
• Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; 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
- Agree 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
8. Male participants must:
• 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 146
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

Exclusion criteria:
1. Diagnosis of PH WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus-associated PAH and PAH associated
with portal hypertension
3. Diagnosis of pulmonary veno-occlusive diseases or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement
4. Hemoglobin at screening above gender-specific upper limit of
normal (ULN), per local laboratory test
5. Baseline platelet count < 50,000/mm3 (< 50.0 x 109/L) at
screening
6. Baseline systolic blood pressure < 85 mmHg at screening
7. Pregnant or breastfeeding women
8. Serum alanine aminotransferase, aspartate aminotransferase, or total bilirubin levels > 3.0 × ULN
9. 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
10.Prior exposure to sotatercept or known allergic reaction to sotatercept, its excipients, or luspatercept
11. History of pneumonectomy
12.This criterion has been removed
13.Untreated more than mild obstructive sleep apnea
14.History of known pericardial constriction
15.History of restrictive or congestive cardiomyopathy
16.Electrocardiogram (ECG) with Fridericia's corrected QT interval
(QTcF) > 500 ms during the Screening Period
17. Personal or family history of long QT syndrome or sudden cardiac death
18. Left ventricular ejection fraction < 45% on historical echocardiogram within 1 year prior to the Screening Visit
19. 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
20. Cerebrovascular accident within 3 months prior to the Screening Visit
21. Significant (= 2+ regurgitation) mitral regurgitation or aortic
regurgitation valvular disease
22.Currently on dialysis or anticipated need for dialysis within the next 12 months


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/ MK-7962
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: SOTATERCEPT
CAS Number: 1001080-50-7
Current Sponsor code: ACE-011 / MK-7962
Other descriptive name: ActRIIA-IgG1Fc
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Lyophilisate and solvent for solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Primary end point(s): The primary efficacy endpoint is the time to first event of all-cause
death, lung transplantation, or PAH worsening-related hospitalization
of = 24 hours.

Secondary Objective: Not Applicable

Main Objective: The objective of this study is to evaluate the effects of sotatercept
treatment (plus maximum tolerated background PAH therapy) versus
placebo (plus maximum tolerated background PAH therapy) on time to
first event of all-cause death, lung transplantation, or PAH worsening related hospitalization of = 24 hours, in participants with WHO FC III
or FC IV PAH at high risk of mortality.

Timepoint(s) of evaluation of this end point: An IA of the primary efficacy endpoint is planned to occur when approximately 59 participants have experienced a primary endpoint event (roughly 50% of the required number of events) have occurred.

Secondary Outcome(s)

Secondary end point(s): The secondary endpoints are ranked as follows:
1. Overall survival
2. Transplant-free survival
3. Proportion of participants who experienced a mortality event at
EOS
4. Change from baseline in REVEAL Lite 2.0 risk score at Week 24
5. Proportion of participants achieving a low or intermediate (= 7)
REVEAL Lite 2.0 risk score at Week 24
6. Change from baseline in NT-proBNP levels at Week 24
7. Change from baseline in mean pulmonary artery pressure (mPAP) at Week 24
8. Change from baseline in PVR at Week 24
9. Proportion of participants who improve in WHO FC at the end
of the DBPC Treatment Period
10. Change from baseline in 6MWD at Week 24
11. Change from baseline in cardiac output (CO) at Week 24
12. Change from baseline in EuroQoL-5 dimensions scale 5 levels
(EQ-5D-5L) index score at Week 24

Timepoint(s) of evaluation of this end point: If the efficacy boundary is crossed for the primary endpoint at the IA, then analyses of secondary endpoints will be performed using a
gatekeeping method. The 1-sided Type 1 error rate for the evaluation of secondary endpoints should be 0.025.

Secondary ID(s)

2021-001498-21-ES

136150

A011-14

Source(s) of Monetary Support

Acceleron Pharma Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA

Ethics review

Status: Approved
Approval date: 01/02/2022
Contact: