Pulmonary Arterial Hypertension
Conditions
Brief summary
This local Phase 3 study is planned to confirm the efficacy and safety in Japanese PAH participants. The primary population of this study is Japanese PAH participants with World Health Organization Functional Class (WHO FC) II or III while the study includes PAH participants with WHO FC I or IV as other populations. There are no hypotheses for this study.
Interventions
BIOLOGICALSotatercept
SC injection at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg every 21 days plus background PAH therapy.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of World Health Organization (WHO) pulmonary arterial hypertension (PAH) Group 1 in any of the following subtypes: * Idiopathic PAH * Heritable PAH * Drug/toxin-induced PAH * PAH associated with connective tissue disease * PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair * PAH classified as WHO functional class (FC) I or symptomatic PAH classified as WHO FC II to IV * On stable doses of background PAH therapy and diuretics (if applicable) for at least 90 days prior to screening
Exclusion criteria
* Diagnosis of PH WHO Groups 2, 3, 4, or 5 * Diagnosis of the following PAH Group 1 subtypes: * Human immunodeficiency virus (HIV)-associated PAH * PAH associated with portal hypertension * Schistosomiasis-associated PAH * PAH with features of significant venous/capillary pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH) involvement * Is on the waiting list for lung transplant * Pregnant or breastfeeding women * History of full or partial pneumonectomy * 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. * Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the screening visit or planned initiation during the study. * History of more than mild obstructive sleep apnea that is untreated * 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. * History of restrictive, constrictive, or congestive cardiomyopathy. * History of atrial septostomy within 180 days prior to the screening visit. * Personal or family history of long QT syndrome (LQTS) or sudden cardiac death. * Left ventricular ejection fraction (LVEF) \< 45% on historical Echocardiogram (ECHO) within 6 months prior to the screening visit. * Any symptomatic coronary disease events within 6 months prior to the screening visit. * Cerebrovascular accident within 3 months prior to the screening visit. * Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease, mitral stenosis and more than mild aortic valve stenosis. * Prior exposure to sotatercept or luspatercept or history of allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in investigational product * Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to the screening visit * Currently enrolled in or have completed any other investigational product study within 30 days * Weight at the screening is over 85 kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Pulmonary Vascular Resistance (PVR) From Baseline at Week 24 | Baseline and Week 24 | PVR was the resistance against blood flow from the pulmonary artery to the left atrium. PVR was measured in dyn\*sec/cm\^5 by right heart catheterization (RHC). RHC was performed during the screening period (baseline) and Week 24. Per protocol, the change in PVR from baseline at Week 24 was reported for the primary treatment period. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to ~24 weeks | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, the number of participants who experienced an AE were reported for the primary treatment period. |
| Number of Participants Who Discontinued Study Intervention Due to AEs | Up to ~24 weeks | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, the number of participants who discontinued study treatment due to AEs were reported for the primary treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Six-Minute Walk Distance (6MWD) at Week 24 | Baseline and Week 24 | The 6MWD was the distance walked in 6 minutes as a measure of functional capacity was measured during the screening period (baseline) and at Week 24. This was assessed using the 6-minute walk test (6MWT). Per protocol, the change from baseline in 6MWD at Week 24 was reported for the primary treatment period. |
| Percentage of Participants With Improvement in World Health Organization Functional Class (WHO FC) at Week 24 | Baseline and Week 24 | The severity of participant's pulmonary arterial hypertension (PAH) symptoms will be graded using the WHO FC system. WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). Participants who improve in WHO FC were classified into "Improved", "No change" and "Worsened". Improvement = reduction in FC, worsened = increase in FC and no change = no change in FC. Per protocol, the percentage of participants with improvement in WHO FC at Week 24 were presented for the primary treatment period. |
| Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 24 | Baseline and Week 24 | NT-proBNP is an established marker of ventricular dysfunction in participants with PAH. NT-proBNP was measured at Day 1 (baseline) and at Week 24. The change from baseline in NT-proBNP at Week 24 was reported for the primary treatment period. |
Countries
Japan
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
All allocated participants.
Participants by arm
| Arm | Count |
|---|---|
| Sotatercept Participants on background PAH therapy received sotatercept subcutaneous (SC) injections at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg every 3 weeks up to 24 weeks. Thereafter, participants received sotatercept at the same dose and schedule in the extension treatment period Week 24 to Week 42. | 46 |
| Total | 46 |
Baseline characteristics
| Characteristic | Sotatercept |
|---|---|
| Age, Continuous | 44.7 Years STANDARD_DEVIATION 16.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Pulmonary Vascular Resistance (PVR) at Baseline ≤800 dyn*sec/cm^5 | 43 Participants |
| Pulmonary Vascular Resistance (PVR) at Baseline >800 dyn*sec/cm^5 | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 46 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 45 |
| other Total, other adverse events | 36 / 46 | 12 / 45 |
| serious Total, serious adverse events | 6 / 46 | 2 / 45 |
Outcome results
Primary
Change From Pulmonary Vascular Resistance (PVR) From Baseline at Week 24
PVR was the resistance against blood flow from the pulmonary artery to the left atrium. PVR was measured in dyn\*sec/cm\^5 by right heart catheterization (RHC). RHC was performed during the screening period (baseline) and Week 24. Per protocol, the change in PVR from baseline at Week 24 was reported for the primary treatment period.
Time frame: Baseline and Week 24
Population: All participants who received at least one dose of study intervention in the primary treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sotatercept - Primary Treatment Period | Change From Pulmonary Vascular Resistance (PVR) From Baseline at Week 24 | 417.2 dynes*sec/cm^5 |
95% CI: [-129.6, -68.4]
Primary
Number of Participants Who Discontinued Study Intervention Due to AEs
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, the number of participants who discontinued study treatment due to AEs were reported for the primary treatment period.
Time frame: Up to ~24 weeks
Population: All participants who received at least one dose of study intervention in the primary treatment period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sotatercept - Primary Treatment Period | Number of Participants Who Discontinued Study Intervention Due to AEs | 0 Participants |
Primary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, the number of participants who experienced an AE were reported for the primary treatment period.
Time frame: Up to ~24 weeks
Population: All participants who received at least one dose of study intervention in the primary treatment period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sotatercept - Primary Treatment Period | Number of Participants Who Experienced an Adverse Event (AE) | 43 Participants |
Secondary
Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 24
NT-proBNP is an established marker of ventricular dysfunction in participants with PAH. NT-proBNP was measured at Day 1 (baseline) and at Week 24. The change from baseline in NT-proBNP at Week 24 was reported for the primary treatment period.
Time frame: Baseline and Week 24
Population: All participants who received at least one dose of study intervention in primary treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sotatercept - Primary Treatment Period | Change From Baseline in N-terminal proB-type Natriuretic Peptide (NT-proBNP) at Week 24 | 18.5 pg/mL |
95% CI: [-77, -24.8]
Secondary
Change From Baseline in Six-Minute Walk Distance (6MWD) at Week 24
The 6MWD was the distance walked in 6 minutes as a measure of functional capacity was measured during the screening period (baseline) and at Week 24. This was assessed using the 6-minute walk test (6MWT). Per protocol, the change from baseline in 6MWD at Week 24 was reported for the primary treatment period.
Time frame: Baseline and Week 24
Population: All participants who received at least one dose of study intervention in the primary treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sotatercept - Primary Treatment Period | Change From Baseline in Six-Minute Walk Distance (6MWD) at Week 24 | 462.0 Meter |
95% CI: [27.8, 55.5]
Secondary
Percentage of Participants With Improvement in World Health Organization Functional Class (WHO FC) at Week 24
The severity of participant's pulmonary arterial hypertension (PAH) symptoms will be graded using the WHO FC system. WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). Participants who improve in WHO FC were classified into Improved, No change and Worsened. Improvement = reduction in FC, worsened = increase in FC and no change = no change in FC. Per protocol, the percentage of participants with improvement in WHO FC at Week 24 were presented for the primary treatment period.
Time frame: Baseline and Week 24
Population: All participants who received at least one dose of study intervention in the primary treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotatercept - Primary Treatment Period | Percentage of Participants With Improvement in World Health Organization Functional Class (WHO FC) at Week 24 | 19.6 Percentage of participants |