A Phase 2 Study of Sotatercept for the Treatment of PAH
- Conditions
- Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]Pulmonary Arterial Hypertension (PAH)MedDRA version: 20.0Level: LLTClassification code 10077739Term: Pulmonary arterial hypertension WHO functional class ISystem Organ Class: 100000004855
- Registration Number
- EUCTR2017-004738-27-ES
- Lead Sponsor
- Acceleron Pharma Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 106
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:
Idiopathic or Heritable PAH
Drug- or toxin-induced PAH
PAH associated with connective tissue disease
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.Screening RHC documenting a minimum PVR of = 400 dyn·sec/cm5 (5 Wood units)
5.Pulmonary function tests (PFTs) within 6 months prior to Screening as follows:
a.Total lung capacity (TLC) > 70% predicted; or if between 60-70% predicted, confirmatory high-resolution computed tomography indicating no more than mild interstitial lung disease (ILD)
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), any time prior to Screening with normal or low probability result
7.No contraindication per investigator for RHC during the study
8.6MWD = 150 and = 450 meters repeated twice at Screening and both values within 15% of each other, calculated from the highest value (see Appendix 4)
9.PAH therapy at stable (per investigator) dose levels of SOC therapies as defined in Section 4.1 for at least 90 days prior to C1D1.
10.Females of childbearing potential, defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 months), must:
a.Have two negative pregnancy tests as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of C1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment.
b.If sexually active, agree to use, and be able to comply with, highly effective contraception** without interruption, 5 weeks prior to starting investigational product during the study therapy (including dose interruptions), and for 16 weeks after discontinuation of study treatment.
c.Refrain from breastfeeding a child, donating blood, eggs, or ovum for the duration of the study and for at least 112 days after the last dose of study treatment.
** Highly effective contraception is defined in this protocol as the following (information will also appear in the ICF): Hormonal contraception (for example, birth control pills,injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation (having your tubes tied); or a partner with a vasectomy who has completed follow-up to confirm a successful procedure (see Appendix 6 for additional contraceptive information)
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 12 weeks following investigational product discontinuation, even if he
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 30days prior to C1D1
3. History of atrial septostomy within 180days prior to Screening;
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 90days 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) >160mm Hg or sitting diastolic blood pressure >100mm Hg during Screening after a period of rest
10. Systolic BP <90mmHg during Screening or at baseline;
11. History of known pericardial constriction;
12. ECG with QTcF >480 sec during Screening Period or C1D1;
13. History of personal or family history of long QTc syndrome or sudden cardiac death;
14. History of recent cerebrovascular accident (CVA) within 3months 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 or pulmonary capillary wedge pressure (PCWP) >15mmHg on right heart catheterization during baseline evaluation;
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);
18. Acutely decompensated heart failure within 30days 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 >15.0g/dL for women; >16.0g/dL for men within 28 days of C1D1;
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 6months prior to Screening; serious local infection (e.g.,cellulitis, abscess) or systemic infection (e.g.,septicemia) within 3months prior to Screening;
22. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in investigational product;
23. Major surgery within 8weeks prior to randomization. Participants must have completely recovered from any previous surgery prior to randomization;
24. Prior heart or heart-lung transplants, active on the lung transplant list, or life expectancy of <12months
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: Treatment Period<br>-To evaluate the effect on PVR in WHO functional class II-III PAH patients treated with sotatercept plus SOC compared with placebo plus SOC<br>Extension Period<br>-To evaluate the long-term safety of sotatercept in WHO functional class II-III PAH patients;Secondary Objective: To assess the effects of sotatercept plus SOC on functional and pharmacodynamic endpoints in patients with PAH compared with placebo plus SOC;Primary end point(s): Treatment Period<br>-Change in PVR<br>Extension Period<br>-Presence and nature of AEs and changes in clinical laboratory parameters;Timepoint(s) of evaluation of this end point: Treatment Period<br>-At 24 weeks vs baseline<br>Extension Period<br>-During the extension period
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Key Secondary Endpoint<br>-Change in 6MWD <br>Other Secondary Endpoints:<br>-Change in NT-proBNP <br>-Change in TAPSE;Timepoint(s) of evaluation of this end point: Key Secondary Endpoint<br>-At 24 weeks vs baseline<br>Other Secondary Endpoints:<br>-At 24 weeks vs baseline<br>-At 24 weeks vs baseline