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 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. |
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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) within 12 months of screening documenting a minimum PVR of ≥ 4 Wood units and pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic 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 |
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E.4 | Principal exclusion criteria |
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 half-lives 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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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is TTCW, defined as the time from randomization to the first confirmed morbidity event or death. 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, defined as a decrease in 6MWD from baseline (average of screening) on 2 consecutive tests (which must be at least 4 hours apart) 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 PAH background therapy, delivery route to parenteral All events will be adjudicated by a blinded, independent committee of clinical experts. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be analyzed using a stratified log-rank test with randomization stratification factors as strata. The point estimate of the hazard ratio with 95% CI will be estimated by a Cox regression model stratified by the randomization factors. |
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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 at Week 24 relative to baseline: -Improvement in 6MWD (increase ≥ 30 meters [m]) -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. Proportion of participants who maintain or achieve a low-risk category of REVEAL Lite 2 risk score at Week 24 versus baseline 3. Proportion of participants who maintain or achieve a low risk score at Week 24 versus baseline using the simplified French Risk score calculator 4. Change from baseline in NT-proBNP levels at Week 24 5. Proportion of participants who improve in WHO FC or maintain WHO FC II at 24 weeks from baseline 6. Change from baseline in 6MWD at Week 24 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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 59 |
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 |
Colombia |
New Zealand |
Switzerland |
Taiwan |
Australia |
Brazil |
Canada |
Israel |
Korea, Republic of |
Serbia |
United Kingdom |
United States |
Austria |
Belgium |
Croatia |
Czechia |
Denmark |
France |
Germany |
Greece |
Italy |
Netherlands |
Poland |
Portugal |
Spain |
Sweden |
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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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The end of the study 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 | 6 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 9 |