E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Arterial Hypertension (PAH) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objectives of this study are to evaluate the efficacy and safety of sotatercept treatment (plus background PAH therapy) versus placebo (plus background PAH therapy) at 24 weeks in adults with PAH. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Documented diagnostic right heart catheterization (RHC) at any time 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 pulmonary hypertension classified as WHO FC II or III
4. Baseline RHC performed during the Screening Period documenting a minimum PVR of ≥ 5 WU and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure of ≤ 15 mmHg.
5. At stable doses of background PAH therapy and diuretics (i.e., patientspecific dose goal for each therapy already achieved) for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical practice.
6. 6MWD ≥ 150 and ≤ 500 m repeated twice at screening (measured at least 4 hours apart, but no longer than 1 week), and both values are within 15% of each other (calculated from the highest value)
7. Females of childbearing potential must:
• Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study drug administration; she must agree to ongoing pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
• If sexually active, have used, and agree to use, highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, 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:
• Agree to use a condom, defined as a male latex condom or non-latex 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 112 days (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 |
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E.4 | Principal exclusion criteria |
1. Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension. Exclusions in PAH Group I should also include schistosomiasis associated PAH and pulmonary veno-occlusive disease
3. Hemoglobin (Hgb) at screening above gender-specific upper limit of normal, per local laboratory test
4. Baseline platelet count < 50,000/mm3 (< 50.0 × 109/L) at screening.
5. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mmHg or sitting diastolic blood pressure > 100 mmHg during screening visit after a period of rest
6. Baseline systolic blood pressure < 90 mmHg at screening
7. Pregnant or breastfeeding women
8. Any of the following clinical laboratory values at the screening visit:
• eGFR < 30 mL/min/m2 (as defined by the Modification of Diet in Renal Disease [MDRD] equation)
• Serum alanine aminotransferase, aspartate aminotransferase levels or total bilirubin levels > 3 × ULN (bilirubin criterion waived if there is a
documented history of Gilbert's syndrome)
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 (ACE-011) or luspatercept (ACE-536) or known allergic reaction to either one
11. History of full pneumonectomy
12. Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at the screening visit or within 6 months prior to the screening visit. If PFT is not available, a chest CT scan showing more than mild interstitial lung disease (ILD) at the screening visit or 1 years prior to it
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. History of more than mild obstructive sleep apnea that is untreated
15. 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).
16. History of restrictive, constrictive or congestive cardiomyopathy
17. History of atrial septostomy within 180 days prior to the screening visit
18. Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 500 ms during Screening Period
19. Personal or family history of long QT syndrome (LQTS) or sudden cardiac death
20. Left ventricular ejection fraction (LVEF) < 45% on historical ECHO
within 6 months prior to the screening visit
21. Any symptomatic coronary disease events (prior myocardial
infarction, percutaneous coronary intervention, coronary artery bypass
graft surgery, or cardiac anginal chest pain) within 6 months prior to the screening visit. Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions
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, vasopressin) within 30 days prior to the screening visit.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change from baseline in 6MWD at
Week 24 versus baseline. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Multicomponent improvement endpoint measured by the proportion of participants achieving all of the following:
• Improvement in NT-proBNP (decrease in NT-proBNP ≥ 30%) or maintenance/achievement of NT-proBNP level < 300 ng/L
• Improvement in WHO FC or maintenance of WHO FC II
2. Change from baseline in PVR
3. Change from baseline in NT-proBNP levels
4. Proportion of participants who improve in WHO FC
5. Time to death or the first occurrence of any of the following clinical worsening events
• Worsening-related listing for lung and/or heart transplant
• Need to initiate rescue therapy with an approved background PAH therapy or the need to increase the dose of infusion prostacyclin by 10% or more
• Need for atrial septostomy
• Hospitalization for worsening of PAH (≥ 24 hours)
• Deterioration of PAH, defined by both of the following events occurring at any time, even if they began at different times, as compared to their baseline values:
− Worsened WHO FC
− Decrease in 6MWD by ≥ 15% confirmed by 2 tests at least 4 hours apart, but no more than 1 week
6. Proportion of participants who maintain or achieve a low risk score (Section 5.3.6) at Week 24 versus baseline using the simplified French Risk score calculator
7. Change from baseline in the Physical Impacts domain score of Pulmonary Arterial
Hypertension-Symptoms and Impact (PAH-SYMPACT®) at Week 24
8. Change from baseline in the Cardiopulmonary Symptoms domain score
of PAH-SYMPACT® at Week 24
9. Change from baseline in the Cognitive/Emotional Impacts domain score of PAH-SYMPACT® at Week 24 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 83 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
Israel |
Korea, Republic of |
Mexico |
New Zealand |
United States |
Austria |
France |
Poland |
Sweden |
Netherlands |
Spain |
Switzerland |
Czechia |
Germany |
Italy |
Belgium |
Ireland |
Serbia |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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A participant is considered to have completed the study if he/she has completed all phases of the study, including the EOT and/or EOS visits. The EOS visits are only required for participants who discontinue the study early or decline transition to a future sotatercept LTFU study. The EOS is defined as when the last participant completes the last visit |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |