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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Acceleron Pharma Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

13 May 2022 → 3 Apr 2025

Decision date (initial)

2024-09-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

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

External identifiers

EU CT number

2023-509139-16-00

EudraCT number

2021-000199-12

WHO UTN

U1111-1309-6312

ClinicalTrials.gov

NCT04811092

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Safety, Efficacy, Therapy

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.

Secondary objectives 1

1. Not applicable

Conditions and MedDRA coding

Therapeutic confirmatory (phase III)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. "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 enddiastolic 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 CTD - 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. Either REVEAL Lite 2 risk score ≥ 6 or COMPERA 2.0 risk score ≥ 2 (intermediate-low-risk or above) 5. Diagnosis of PAH within 12 months of screening and on stable doses of a double or triple combination of background PAH therapies and diuretics (if any) for at least 90 days prior to screening. Background PAH therapy and diuretics are further defined in Section 7.2. 6. 6MWD≥ 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). 7. Females of childbearing potential (as defined in Appendix 4) must meet the following criteria: •Have 2 negative urine or serum pregnancy tests as verified by the investigator during the Screening Period; •Agree to ongoing pregnancy testing (either urine or serum) 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 documented informed consent "

Exclusion criteria 3

1. 1.Diagnosis of pulmonary hypertension (PH) 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.Hgb 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) > 180 mmHg or sitting diastolic BP > 110 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 (eGFR) < 30 mL/min/1.73 m2 (as defined by MDRD equation) •Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels > 3 × ULN (For United Kingdom [UK], refer to the specific requirement in Appendix 6) •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 halflives for investigational biologics prior to the date of documented 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 PH 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 cardiomyopathy 17.History of atrial septostomy within 180 days prior to the Screening Visit 18.Electrocardiogram (ECG) with Fridericia's corrected QT interval > 500 ms during the Screening Period (For UK and South Korea, refer to the specific requirements in Appendix 6). 19.Personal or family history of long QT syndrome or sudden cardiac death 20.Left ventricular ejection fraction < 50% documented by a historical echocardiograph (ECHO) or cardiac magnetic resonance imaging (MRI) within the last 12 months prior to screening (if there is more than 1 assessment of left ventricular ejection fraction (LVEF), the value from the most recent measurement should be used in assessing eligibility) 21.Coronary artery disease (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 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 26.Active malignancy with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or prostate cancer that is not currently or expected, during the study, to be treated with radiation therapy, chemotherapy, and/or surgical intervention, or hormonal treatment.
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Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. The primary efficacy endpoint is TTCW.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,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 in the background PAH therapy delivery route to parenteral
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Secondary endpoints 6

1. Multicomponent improvement endpoint: Measure of participants achieving improvement in 6MWD, NT-proBNP, and WHO FC at Week 24. achieving low-risk category in REVEAL Lite 2 risk score; using simplified French Risk score calculator; change in NT-proBNP levels; maintaining or improving WHO FC at 24 weeks; change in 6MWD; and changes in the Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores of PAH-SYMPACT® at Week 24 versus baseline.
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Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Acceleron Pharma Inc.

Sponsor organisation

Acceleron Pharma Inc.

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Acceleron Pharma Inc.

Contact name

Michela Brambatti

Public contact point

Organisation

Acceleron Pharma Inc.

Contact name

Michela Brambatti

Third parties 14

Locations

13 EU/EEA countries · 59 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 146 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications