A Phase 2 Study of Sotatercept for the Treatment of PAH

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2017-004738-27-BE
• Date of registration: 31/08/2018
• Prospective Registration: Yes
• Primary sponsor: Acceleron Pharma Inc.
• Public title: A Phase 2 Study of Sotatercept for the Treatment of PAH
• Scientific title: A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study to Compare the Efficacy and Safety of Sotatercept (ACE-011) Versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)
• Date of first enrolment: 04/01/2019
• Target sample size: 100
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004738-27
• 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: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Brazil, France, Germany, Israel, Spain, United Kingdom, United States

Contacts

• Name: Janethe Pena
• Affiliation: Acceleron Pharma Inc

• Name: Janethe Pena
• Affiliation: Acceleron Pharma Inc

Key inclusion & exclusion criteria

Inclusion criteria:
Participants must satisfy all of the following criteria to be enrolled in the study:
1. Age =18 years
2. Documented diagnostic right heart catheterization (RHC) at any time prior to Screening confirming diagnosis of WHO diagnostic pulmonary hypertension Group I: PAH in any of the following subtypes:
o Idiopathic
o Heritable PAH
o Drug- or toxin-induced PAH
o PAH associated with connective tissue disease
o PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following shunt repair
3. Symptomatic pulmonary hypertension classified as WHO functional class II or III
4. Baseline RHC performed within 10 days prior to C1D1 visit during the Screening Period documenting a minimum PVR of = 400 dyn·sec/cm5 (5 Wood units)
5. Pulmonary function tests (PFTs) within 6 months prior to Screening Visit as follows:
a. Total lung capacity (TLC) > 70% predicted; or if between 60 to 70% predicted, or not possible to be determined, confirmatory high-resolution computed tomography (CT) indicating no more than mild interstitial lung disease (ILD), per investigator interpretation or;
b. Forced expiratory volume (first second) (FEV1)/ forced vital capacity (FVC) > 70% predicted
6. Ventilation-perfusion (VQ) scan (or, if unavailable a negative CT pulmonary angiogram [CTPA] result, or pulmonary angiography result), any time prior to Screening Visit or conducted during the Screening Period with normal or low probability result
7. No contraindication per investigator for RHC during the study
8. 6MWD = 150 and = 550 meters repeated twice during Screening Period and both values within 15% of each other, calculated from the highest value
9. PAH therapy at stable (per investigator) dose levels of SOC therapies as defined in the protocol for at least 90 days prior to C1D1.
10. Females of childbearing potential must:
a. Have two negative pregnancy tests as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study and until eight weeks after the last dose of the study drug.
b. If sexually active, have used and agree to continue to use highly effective contraception without interruption, for at least 28 days prior to starting investigational product during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment.
c. Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 112 days after the last dose of study treatment.
Male participants must:
a. Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (for example, 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 112 days following investigational product discontinuation, even if he has undergone a successful vasectomy. (see Appendix 6 for additional contraceptive information).
b. Refrain from donating blood or sperm for the
Exclusion criteria:
Participants will be excluded from the study if they meet any of the following criteria:
1. Stopped receiving any pulmonary hypertension chronic general supportive therapy (e.g, diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to C1D1
2. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to C1D1
3. History of atrial septostomy within 180 days prior to Screening Visit
4. History of more than mild obstructive sleep apnea that is untreated
5. 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)
6. History of human immunodeficiency virus infection-associated PAH
7. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536)
8. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to C1D1 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).
9. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during Screening Visit after a period of rest
10. Systolic BP < 90 mmHg during Screening Visit or at baseline (C1D1)
11. History of known pericardial constriction
12. ECG with QTcF >480 msec during Screening Period or C1D1
13. Personal or family history of long QTc syndrome or sudden cardiac death
14. Cerebrovascular accident (CVA) within 3 months of C1D1
15. History of restrictive or congestive cardiomyopathy
16. Left ventricular ejection fraction (LVEF) < 45% on historical echocardiogram (ECHO) within 6 months prior to Screening Period (or done as a part of the Screening Period) or pulmonary capillary wedge pressure (PCWP) > 15 mmHg as determined in the Screening Period RHC
17. 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 Screening Visit
18. Acutely decompensated heart failure within 30 days prior to C1D1, as per investigator assessment
19. Significant (= 2+ regurgitation) mitral regurgitation (MR) or aortic regurgitation (AR) valvular disease
20. Any of the following clinical laboratory values during the Screening Period prior to C1D1:
a. Baseline Hgb > 16 g/dL
b. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 3X upper limit of normal (ULN) or total bilirubin > 1.5X ULN within 28 days of C1D1
c. White blood cell (WBC) count < 4000/mm3
d. Platelets < 100,000/µL
e. Absolute neutrophil count (ANC) < 1500/mm3
21. History of opportunistic infection (e.g., invasive candidiasis or pneumocystis pneumonia) within 6 months prior to Screening; serious local infection (e.g., cellulitis,

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: 20.0 Level: LLT Classification code 10077739 Term: Pulmonary arterial hypertension WHO functional class I System Organ Class: 100000004855

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)

Main Objective: Placebo-Controlled Treatment Period
-To evaluate the effect on PVR in WHO functional class II-III PAH patients treated with sotatercept plus SOC compared with placebo plus SOC
Extension Period
-To evaluate the long-term safety of sotatercept in WHO functional class II-III PAH patients

Primary end point(s): Placebo-Controlled Treatment Period
-Change in PVR at 24 weeks (C9D1A) vs screening PVR
Extension Period
-Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, vital signs.

Timepoint(s) of evaluation of this end point: Placebo-Controlled Treatment Period
-At 24 weeks vs baseline
Extension Period
-During the extension period

Secondary Objective: To assess the effects of sotatercept plus SOC on functional and pharmacodynamic endpoints in patients with PAH compared with placebo plus SOC

Secondary Outcome(s)

Secondary end point(s): Key Secondary Endpoint
-Change in 6MWD at 24 weeks (C9D1A) vs baseline (screening C1D1)
Other Secondary Endpoints:
-Change in NT-proBNP at 24 weeks (C9D1A) vs C1D1
-Change in TAPSE at 24 weeks (C9D1) vs C1D1

Timepoint(s) of evaluation of this end point: Key Secondary Endpoint
-At 24 weeks vs baseline
Other Secondary Endpoints:
-At 24 weeks vs baseline
-At 24 weeks vs baseline

Secondary ID(s)

2017-004738-27-DE

A011-09

NCT03496207

Source(s) of Monetary Support

Acceleron Pharma Inc.

Ethics review

Status: Approved
Approval date:
Contact: