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

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

5 Apr 2022 → 19 Feb 2025

Decision date (initial)

2024-08-28

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

External identifiers

EU CT number

2023-509140-10-00

EudraCT number

2021-001498-21

WHO UTN

U1111-1309-6376

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacodynamic, Efficacy, Pharmacokinetic, Safety

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.

Conditions and MedDRA coding

Pulmonary Arterial Hypertension (PAH)

Study design 3 periods

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 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

Exclusion criteria 1

1. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 2

1. Overall survival Transplant-free survival Proportion of participants with mortality event at EOS Change from BL in REVEAL Lite 2.0 risk score -Wk 24 Proportion of participants achieved REVEAL Lite 2.0 risk score ≤ 7-Wk 24 Change from BL in NT-proBNP levels -Wk 24 Change from BL in mPAP -Wk 24 Change from BL in PVR -Wk 24
2. Proportion of participants improved in WHO FC at end of DBPC Tx Period Change from BL in 6MWD -Wk 24 Change from BL in CO -Wk 24 Change from BL in EQ-5D-5L index score -Wk 24

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

Maria Jose Loureiro

Public contact point

Organisation

Acceleron Pharma Inc.

Contact name

Maria Jose Loureiro

Third parties 12

Locations

6 EU/EEA countries · 23 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 56 files

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

Application history

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