E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypertension |
|
E.1.1.1 | Medical condition in easily understood language |
Pulmonary arterial hypertension (PAH) is a rare, progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10037403 |
E.1.2 | Term | Pulmonary hypertension NOS |
E.1.2 | System Organ Class | 100000004855 |
|
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 |
1. To evaluate the safety and tolerability of sotatercept over 24 weeks of treatment 2. To evaluate the PK of sotatercept over 24 weeks of treatment |
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate the pharmacodynamics of sotatercept over 24 weeks of treatment |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female participants ≥1 to <18 years of age at the time of providing documented informed consent/assent 2. Documented, historic diagnostic RHC any time before Screening confirming the diagnosis of PAH WHO Group 1 in any of the following subtypes (for participants with a history of cardiac intervention for shunt closure, the RHC confirmation must have been performed more than 6 months after the cardiac intervention): - IPAH - Heritable PAH - Drug/toxin-induced PAH - PAH associated with CTD - PAH-CHD with shunt closure >6 months before Screening and subsequently confirmed by RHC before Screening - PAH with coincidental shunt 3. For the above-mentioned historical RHC, diagnostic criteria will be mean pulmonary artery pressure ≥20 mmHg at rest, pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤15 mmHg, and PVR >240 dynes•sec•cm-5 4. PAH classified as WHO FC I or symptomatic PAH classified as WHO FC II to IV 5. Participants must be on a stable dose(s) of background PAH therapy: - WHO FC I to III: single, double, or triple background PAH therapy for at least 12 weeks before Screening - WHO FC IV: must be clinically stable and on stable doses of maximum tolerated double or triple background PAH therapy for at least 30 days before Screening 6. Arterial BP at Screening within normal range for the age, gender, and height percentiles as follows: - Cohort 1: systolic BP <120 mmHg and diastolic BP <80 mmHg - Cohorts 2, 3, and 4: systolic and diastolic BP <90th percentile based on the corresponding age ranges as outlined in National High Blood Pressure Education Program, 2004 7. Left ventricular ejection fraction ≥50% on the ECHO at Screening 8. If male, agrees to the following during the intervention period and for at least 16 weeks after the last dose of study intervention: • Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent OR • Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) as detailed below: - Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant - Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies 9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: • Not a WOCBP OR • A WOCBP and: - Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least 16 weeks after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies - Has a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive - Abstains from breastfeeding during the study intervention period and for at least 16 weeks after study intervention - Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy 10. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR 11. If male, agrees to refrain from donating blood or sperm for the duration of the study and for 16 weeks after the last dose of study intervention 12. If female, agrees to refrain from donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks after the last dose of study intervention Optional Long-term Extension Treatment Period 13. Completes Visit 9 of the Primary Treatment Period on study intervention 14. The participant (or legally acceptable representative) has provided documented informed consent/assent for the Long-term Extension Treatment Period |
|
E.4 | Principal exclusion criteria |
1. History of left-sided heart disease, including valvular disease (eg, moderate or greater mitral or aortic regurgitation or stenosis), left ventricular outflow tract obstruction, and/or left heart failure (eg, restrictive or dilated cardiomyopathy) 2. Severe (as based on the opinion of the investigator) congenital abnormalities of the lung, thorax, and/or diaphragm 3. History of Eisenmenger syndrome 4. Unrepaired or residual cardiac shunt with Qp/Qs >1.5 5. Diagnosis of pulmonary veno-occlusive diseases, pulmonary capillary hemangiomatosis, or overt signs of capillary and/or venous involvement 6. PAH associated with portal hypertension 7. Known visceral (lung, liver, or brain) arteriovenous malformation(s) 8. History of full or partial pneumonectomy 9. Untreated more than mild obstructive sleep apnea 10. History of known pericardial constriction 11. Family history of sudden cardiac death or long QT syndrome 12. Any current or prior history of symptomatic coronary disease (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months before Screening 13. Cerebrovascular accident within 3 months before Screening 14. Prior exposure to sotatercept or luspatercept or has had an allergic reaction to any of their excipients 15. Currently enrolled in or has completed a study with any other investigational product within 30 days before Screening for small molecule drugs or within 5 half-lives before Screening for biologics 16. Screening platelet count <50,000/mm3 17. Screening Hgb value above gender-specific ULN (per local laboratory) 18. Screening eGFR <30 mL/min/m2 (as defined by the Bedside Schwartz equation) and/or a urine protein:creatinine ratio >1 g/g 19. Screening AST and/or ALT >3X ULN 20. Screening ECG with Fridericia’s corrected QT interval (QTcF) >500 ms (or >550 ms, if right bundle branch block is present) 21. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Serum Trough Concentration (Ctrough) of Sotatercept 2. Area Under the Curve at Steady State (AUCss) of Sotatercept 3. Area Under the Curve from 0 to 3 weeks (AUC0-3 weeks) of Sotatercept 4. Percentage of Participants Who Experience at Least 1 Adverse Event (AE) 5. Percentage of Participants Who Discontinue Study Drug Due to an AE 6. Laboratory Parameter (Hematology): Concentration of Hemoglobin on Days 21, 42, 63, 84, 105, and 126 7. Laboratory Parameter (Hematology): Hematocrit on Days 21, 42, 63, 84, 105, and 126 8. Laboratory Parameter (Hematology): RBC Count on Days 21, 42, 63, 84, 105, and 126 9. Laboratory Parameter (Hematology): Reticulocyte Count on Days 21, 42, 63, 84, 105, and 126 10. Laboratory Parameter (Hematology): Platelet Count on Days 21, 42, 63, 84, 105, and 126 11. Blood Pressure (BP) at Days 21, 42, 63, 84, 105 and 126 12. Titer of Anti-drug Antibody (ADA) to Sotatercept |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Predose Day 1, Day 7, Day 14, Predose Day 21, Day 22, Day 28, Day 35, Predose Days 42, 63, 84 and 105 2. Predose Day 1, Day 7, Day 14, Predose Day 21, Day 22, Day 28, Day 35, Predose Days 42, 63, 84 and 105 3. Predose Day 1, Day 7, Day 14, and Predose Day 21 4. Up to 24 weeks 5. Up to 24 weeks 6. Up to 24 weeks 7. Up to 24 weeks 8. Up to 24 weeks 9. Up to 24 weeks 10. Up to 24 weeks 11. Up to 24 weeks 12. Up to 24 weeks |
|
E.5.2 | Secondary end point(s) |
1. Mean Change from Baseline in 6-Minute Walk Distance (6MWD) (Cohorts 1 and 2) 2. Mean Change from Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) 3. Mean Change from Baseline in Pulmonary Artery Systolic Pressure (PASP) 4. Mean Change from Baseline in Right Ventricular Fractional Area Change (RVFAC) 5. Mean Change from Baseline in Eccentricity Index 6. Mean Change from Baseline in Right Ventricular (RV) Function (Cohort 1 Only) 7. Mean Change from Baseline on Cardiac Output (Cohort 1 Only) 8. Mean Change from Baseline in Pulmonary Arterial Pressure (PAP) (Cohort 1 Only) 9. Mean Change from Baseline in Pediatric Quality of Life (PedsQL) Generic Score 10. Mean Change from Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) 11. Percentage of Participants who Either Improved or Maintained Their World Health Organization Functional Class (WHO FC) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline and Week 24 2. Baseline and Week 24 3. Baseline and Week 24 4. Baseline and Week 24 5. Baseline and Week 24 6. Baseline and Week 24 7. Baseline and Week 24 8. Baseline and Week 24 9. Baseline and Week 24 10. Baseline and Week 24 11. Baseline and Week 24 |
|
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 14 |
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 |
Australia |
Colombia |
Israel |
Mexico |
South Africa |
United States |
France |
Poland |
Netherlands |
Spain |
Germany |
Turkey |
United Kingdom |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |