Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary, Hypertension, Sotatercept
Brief summary
The objective of this study is to evaluate the effects of sotatercept (MK-7962, formerly called ACE-011) treatment (plus background pulmonary arterial hypertension \[PAH\] therapy) versus placebo (plus background PAH therapy) on time to clinical worsening (TTCW) in participants who are newly diagnosed with PAH and are at intermediate or high-risk of disease progression.
Detailed description
This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate sotatercept when added to background PAH therapy in newly diagnosed intermediate- or high risk PAH participants. Participants enrolled in the study will have a diagnosis within 12 months of study screening of symptomatic PAH (World Health Organization \[WHO\] Group 1, classified as functional class \[FC\] II or III) and presentation of idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug- or toxin- induced PAH, post shunt correction PAH, or PAH presenting at least 1 year following the correction of congenital heart defects. As of Amendment 11, this study will be closed so that all eligible participants can receive sotatercept either on the MK-7962-004 extension study (SOTERIA, NCT04796337) or by commercial access, if available. All eligible participants will complete the end of treatment visit before enrollment in the extension study or initiation of commercial product. Participants not enrolling into the extension study or initiating commercial product will complete the end of study visit.
Interventions
DRUGSotatercept
SC injection
OTHERPlacebo
Placebo-matched SC injection
Sponsors
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blind
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion criteria include but are not limited to: * Documented diagnostic right heart catheterization (RHC) within 12 months of screening documenting a minimum pulmonary vascular resistance (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 connective tissue disease * PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair * Symptomatic PAH classified as World Health Organization (WHO) Functional Class (FC) II or III * Either Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) Lite 2 Risk Score ≥ 6 or Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 2.0 risk score ≥2 (intermediate to-low-risk or above) * 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 * Six-minute walk distance ≥ 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) * Females of childbearing potential must meet the following criteria: * Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study drug administration; she must agree to ongoing urine or serum pregnancy testing 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, have 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Clinical Worsening | Up to ~35 months | Time to clinical worsening (TTCW) is defined as time from randomization to the first confirmed morbidity event or death. Clinical worsening events are defined as all-cause death, non-planned PAH-related hospitalization of ≥ 24 hours in duration, atrial septostomy, lung transplant, and/or deterioration in performance in 6-minute walk test from baseline combined with one of the following conditions: worsening of WHO FC from baseline, signs/symptoms of increased right heart failure, addition of a background PAH therapy or change in the background PAH therapy delivery route to parenteral. All events were adjudicated by a blinded, independent committee of clinical experts. The median TTCW is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving the Multicomponent Improvement Endpoint of 6-Minute Walk Distance (6MWD), N-terminal Prohormone B-type Natriuretic Peptide (NT-ProBNP) WHO FC | Baseline and Week 24 | The multicomponent improvement outcome measure is determined by the percentage of participants achieving all of the following at Week 24 relative to baseline: * Improvement in 6MWD (increase ≥30 m) * Improvement or maintenance/achievement of 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 (indicated by maintaining the same WHO FC or a lower WHO FC by Week 24 relative to baseline) The percentage of participants achieving the multicomponent improvement endpoint is presented. |
| Percentage of Participants Who Maintained or Achieved a Low Registry to Evaluate Early and Long Term PAH Disease Management (REVEAL) Lite 2 Risk Score | Baseline and Week 24 | REVEAL Lite 2.0 risk scoring is used to guide PAH treatment decisions. Total score uses 6 variables with each assessed based on contribution to mortality risk. Variables and sub-score ranges: estimated glomerular filtration rate \[eGFR\] (0, +1), WHO FC (-1, 0, +1, +2), SBP (0, +1), heart rate (0, +1), 6MWD (-2, -1, 0, +1), and NT-proBNP (-2, 0, +2). Sub-scores are added to a base score of +6 and a total score of 1 to 14 is obtained (≤5=low risk; 6,7=intermediate risk; ≥8=high risk). A higher score = higher risk. Per SAP, participants who did not have a REVEAL risk score at Week 24 were considered as non-responders and multiple imputation was not conducted for this endpoint. Comparisons between this analysis reporting non-imputed data should not be made to other REVEAL analyses which included imputation of missing Week 24 data. The percentage of participants who maintained or achieved a low REVEAL Lite 2.0 score at Week 24 is reported. |
| Percentage of Participants Who Maintained or Achieved a Low Simplified French Risk Score | Baseline and Week 24 | The simplified French Risk Score uses WHO FC, 6MWD, and NT-proBNP to determine the total risk score. A low risk score can be defined as attaining or maintaining all three low-risk criteria: WHO FC I or II, 6MWD \> 440m, and NT-proBNP \< 300 ng/L. The percentage of participants who maintained or achieved a low risk score at Week 24 versus baseline using the simplified French Risk score calculator is presented. |
| Median Change From Baseline in NT-proBNP Levels at Week 24 | Baseline and Week 24 | NT-proBNP is a circulating biomarker that reflects myocardial stretch and is an established biomarker used to determine the ventricular dysfunction in participants with PAH. NT-proBNP was measured at Day 1 (baseline) and at Week 24. The median change from baseline in NT-proBNP at Week 24 is presented. |
| Percentage of Participants Who Improved in WHO FC or Maintained WHO FC II at 24 Weeks From Baseline | Baseline and Week 24 | The severity of an individual's PAH symptoms was graded using the WHO FC system. WHO functional classification for PAH range 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). The change from baseline in WHO FC is classified into "Improved", "No change" and "Worsened". Improvement = reduction in FC, worsened = increase in FC and no change = no change in FC. The percentage of participants who improved in WHO FC or maintained WHO FC II at 24 Weeks from Baseline is presented. |
| Median Change From Baseline in Six-Minute Walk Distance (6MWD) | Baseline and Week 24 | The 6-minute walk distance (6MWD) was measured using the 6-Minute Walk Test (6MWT). The 6MWT measures the distance covered in 6 minutes and is intended to measure changes in functional exercise capacity. Each participant's 6MWD was measured at baseline and at 24 weeks. An increase in the distance walked during the 6MWT indicated improvement in functional exercise capacity. Median change from baseline in 6MWD at Week 24 is reported. |
| Overall Survival (OS) | Up to ~35 Months | Overall survival is defined as the time from randomization to date of death due to any cause. OS is presented. |
| Mean Change From Baseline in the Physical Impacts Domain Score of Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT)® | Baseline and Week 24 | The PAH SYMPACT is a 23-item questionnaire to measure pulmonary arterial hypertension (PAH)-related symptoms and impact of PAH on daily life. The physical impact domain consists of walking slowly on a flat surface, walking quickly on a flat surface, walking uphill, carrying things, doing light indoor household chores, washing, or dressing oneself, and needing help from others. Participants were asked to recall and report on each item experienced in past 7 days. Score for each item ranges from 0 (not difficult at all) to 4 (extremely difficult). A domain score was calculated by summing the individual responses for each item and dividing by the number of impact items (range: 0=no physical impact to 4=severe physical impact). A higher score indicated more severe physical impact. Mean change from baseline in responses in physical symptoms of the PAH-SYMPACT questionnaire at Week 24 is reported. |
| Mean Change From Baseline in the Cardiopulmonary Symptoms Domain Score of PAH-SYMPACT® | Baseline and Week 24 | The PAH SYMPACT is a 23-item questionnaire to measure PAH-related symptoms and impact of PAH on daily life. The cardiopulmonary symptoms consist of shortness of breath, fatigue, lack of energy, swelling in the ankles or legs, swelling in the stomach area, and cough. Participants were asked to recall and report on each item experienced in past 7 days. Score for each item ranges from 0 (no symptom at all) to 4 (very severe symptoms). The mean individual symptom item score was determined for each of the 6 items and a domain score was calculated by summing the mean individual symptom item scores and dividing by the number of items (range: 0=no cardiopulmonary symptoms to 4=severe cardiopulmonary symptoms). A higher score indicated more severe symptoms experienced. Mean change from baseline in cardiopulmonary symptoms of the PAH-SYMPACT questionnaire at Week 24 is reported. |
| Mean Change From Baseline in the Cognitive/Emotional Impacts Domain Score of PAH-SYMPACT® | Baseline and Week 24 | The PAH SYMPACT is a 23-item questionnaire to measure PAH-related symptoms and impact of PAH on daily life. The Cognitive/Emotional Impact domain consists of thinking clearly, feeling sad, feeling worried, and feeling frustrated. Participants were asked to recall and report on each item experienced in past 7 days. Score for each item ranges from 0 (not difficult at all) to 4 (extremely difficult). A domain score was calculated by summing the individual responses for each item and dividing by the number of impact items (range: 0=no cognitive/emotional impact to 4=severe cognitive/emotional impact). A higher score indicated more severe cognitive/emotional impact. Mean change from baseline in responses in the Cognitive/Emotional Impacts Domain Score of the PAH-SYMPACT questionnaire at Week 24 is reported. |
| Percentage of Participants Who Experience an Adverse Event (AE) | Up to ~35 Months | An AE is any untoward medical occurrence in a clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The percentage of participants who experienced an AE are presented. |
| Percentage of Participants Who Discontinued Study Treatment Due to AEs | Up to ~35 months | An AE is any untoward medical occurrence in a clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The percentage of participants who discontinued study treatment due to an AE are presented. |
| Number of Participants Who Had Anti-drug Antibodies (ADAs) to Sotatercept | Up to ~35 Months | Blood samples collected at designated timepoints were used to determine the ADA response to sotatercept. The number of participants who had ADAs to sotatercept over time is presented. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Colombia, Croatia, Czechia, Denmark, France, Germany, Greece, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Serbia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
Of the 321 participants who were randomized, one participant was randomized but withdrew from study before receiving study intervention. This participant, who was randomized to the sotatercept group, had no data collected for study specific baseline characteristics or outcome measures and was excluded from all analysis populations.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 56.1 Years STANDARD_DEVIATION 16.4 |
| Background PAH therapy (double or triple therapy) Double | 115 Count of Participants |
| Background PAH therapy (double or triple therapy) Triple | 44 Count of Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 51 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 246 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 24 Participants |
| PAH World Health Organization Functional Class (WHO FC) (Class II or III) WHO FC II | 36 Count of Participants |
| PAH World Health Organization Functional Class (WHO FC) (Class II or III) WHO FC III | 128 Count of Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 8 Participants |
| Race (NIH/OMB) Black or African American | 5 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 | 13 Participants |
| Race (NIH/OMB) White | 136 Participants |
| Sex: Female, Male Female | 112 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 161 | 13 / 160 |
| other Total, other adverse events | 127 / 160 | 128 / 160 |
| serious Total, serious adverse events | 39 / 160 | 45 / 160 |
Outcome results
None listed