CADENCE: A Study of Sotatercept for the Treatment of Cpc-PH Due to HFpEF
Study Details
Study Description
Brief Summary
This is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of sotatercept versus placebo in adults with Cpc-PH due to HFpEF.
The objective of this study is to evaluate the efficacy, safety and tolerability of sotatercept versus placebo in adults with Cpc-PH due to HFpEF. Efficacy is measured by change from baseline in pulmonary vascular resistance (PVR, primary endpoint) and 6-minute walk distance (6MWD, key secondary endpoint).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Participants enrolled in the study will have a diagnosis of Cpc-PH due to HFpEF with New York Heart Association (NYHA) functional class (FC) II or III. Participants will be randomly assigned in a 1:1:1 ratio to 1 of the 3 treatment groups (placebo, 0.3mg/kg sotatercept and 0.7mg/kg sotatercept) during the placebo-controlled Treatment Period. In the extension phase, sotatercept-treated participants will continue on their current dose. Placebo participants will be re-randomized in a 1:1 ratio to one of the two sotatercept treatment groups utilized in the placebo-controlled Treatment Period. Each participant will be enrolled in the study for up to 114 weeks, including a 28-day Screening Period, a 24-week, double-blind, placebo-controlled Treatment Period, an 18-month Extension Period, and an 8-week Follow-up Period.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo Delivered subcutaneously (SC) every 3 weeks (Q3W) for 24 weeks. |
Drug: Placebo
Placebo
|
| Experimental: Sotatercept 0.3 mg/kg Sotatercept SC at a dose level of 0.3 mg/kg Q3W for 24 weeks. |
Drug: Sotatercept
Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1.
Other Names:
|
| Experimental: Sotatercept 0.3 mg/kg, escalating to 0.7 mg.kg Sotatercept SC at a starting dose level of 0.3 mg/kg for 3 dosing visits (Q3W), then escalating to 0.7 mg/kg SC on the fourth dosing visit and Q3W for the remainder of the 24-week Treatment Period. |
Drug: Sotatercept
Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in Pulmonary Vascular Resistance (PVR) at 24 weeks from baseline [From screening to Week 24.]
PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization (RHC).
Secondary Outcome Measures
- Change in 6MWD (6 minute walk distance) [24 weeks from baseline.]
This tests the distance walked in 6 minutes, to assess functional capacity.
- Number of Clinical Worsening events. [From initiation of treatment to 24 weeks.]
Clinical Worsening events are defined as any of the following: Hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to Pulmonary Hypertension and/or Heart Failure) Administration of intravenous diuretics Death (all causes) Decrease in 6 minute walk distance (6MWD) by ≥ 15% from baseline confirmed by 2 tests at least 4 hours, but no more than 1 week, apart
- Number of Clinical Worsening events at 48 weeks [From initiation of treatment to 48 weeks.]
Clinical Worsening events, defined as above, is measured at 48 weeks.
- Number of participants with first Clinical Worsening event at 24 weeks [From initiation of treatment to 24 weeks.]
Number of patients with Clinical Worsening events, defined as above, is measured at 24 weeks.
- Number of participants with first Clinical Worsening event at 48 weeks [From initiation of treatment to 48 weeks.]
Number of patients with Clinical Worsening events, defined as above, is measured at 48 weeks.
- Time to Clinical Worsening [From initiation of treatment to the time of Clinical Worsening event, up to 110 weeks.]
Time to Clinical Worsening events, defined as above, is measured.
- Change in Dyspnea Score (assessed by Borg Category Ratio 10 scale®) [From initiation of treatment to Week 24 .]
This scale assesses subject's perceived severity of shortness of breath. The scale is from 0-10, higher number indicate more severe dyspnea.
- Change in mean pulmonary arterial pressure (mPAP) at 24 weeks from baseline [24 weeks from baseline.]
mPAP is calculated from systolic and diastolic pulmonary artery pressure measured by right heart catheterization.
- Change in pulmonary capillary wedge pressure (PCWP) at 24 weeks from baseline [24 weeks from baseline.]
PCWP is indirect estimate of left atrial pressure measured in right heart catheterization.
- Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) [24 weeks from baseline.]
TAPSE is an echocardiographic measurement of tricuspid valve annulus movement, as an indicator of right heart function.
- Change in right ventricular fractional area change (RVFAC) at 24 weeks from baseline [24 weeks from baseline.]
RVFAC is an echocardiographic measurement of percent change between right ventricular area during diastole and systole, as an indicator of right heart function.
- Change in left ventricular ejection fraction (LVEF) at 24 weeks from baseline [24 weeks from baseline.]
LVEF is an echocardiographic measurement of percent change between left ventricular volume during diastole and systole, as an indicator of left heart function.
- Change in isovolumic relaxation time (IVRT) at 24 weeks from baseline [24 weeks from baseline.]
IVRT is an echocardiographic measurement of the interval between closure of the aortic valve, to onset of filling by opening of the mitral valve. It is used as an indicator of diastolic dysfunction.
- Change in E/e' (early mitral inflow velocity E and mitral annular early diastolic velocity e') ratio at 24 weeks from baseline. [24 weeks from baseline.]
E/e' is a ratio measured in echocardiography as an indicator of diastolic function
- Change in ratio of the peak velocity flow of the E wave in early diastole to peak velocity flow of the A wave in late diastole (E/A ratio) weeks from baseline [24 weeks from baseline.]
E/A is a ratio measured in echocardiography as an indicator of diastolic function
- Change in N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) at 24 weeks from baseline [24 weeks from baseline.]
NT-proBNP is a circulating biomarker that reflects myocardial stretch
- Change in New York Heart Association Functional Class (NYHA FC) at 24 weeks from baseline [24 weeks from baseline.]
NYHA FC classifies the extent of heart failure
- Change in 6MWD at 48 weeks from baseline [48 weeks from baseline.]
- Change in Pulmonary Vascular Resistance (PVR) at 48 weeks from baseline [48 weeks from baseline.]
- Change in mean pulmonary arterial pressure (mPAP) at 48 weeks from baseline [48 weeks from baseline.]
- Change in pulmonary capillary wedge pressure (PCWP) at 48 weeks from baseline [48 weeks from baseline.]
- Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 48 weeks from baseline [48 weeks from baseline.]
- Change in right ventricular fractional area change (RVFAC) at 48 weeks from baseline [48 weeks from baseline.]
- Change in left ventricular ejection fraction (LVEF) at 48 weeks from baseline [48 weeks from baseline.]
- Change in isovolumic relaxation time (IVRT) at 48 weeks from baseline [48 weeks from baseline.]
- Change in E/e' (early mitral inflow velocity E and mitral annular early diastolic velocity e') ratio at 48 weeks from baseline [48 weeks from baseline.]
- Change in A wave in late diastole (E/A) ratio at 48 weeks from baseline [48 weeks from baseline.]
- Change in N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) at 48 weeks from baseline [48 weeks from baseline.]
- Change in New York Heart Association Functional Class (NYHA FC) at 48 weeks from baseline [48 weeks from baseline.]
- Change in Pulmonary Vascular Resistance (PVR) in the placebo crossed Treatment Group [Week 48 from baseline in the Extension Period]
- Change in 6MWD (6 minute walk distance) in the placebo crossed Treatment Group [Week 48 from baseline in the Extension Period]
- Change in New York Heart Association Functional Class (NYHA FC) [Week 48 from baseline in the Extension Period.]
- Change in Pulmonary Vascular Resistance (PVR) in the placebo crossed Treatment Group [Week 24 to Week 48 in the Extension Period.]
- Change in 6MWD (6 minute walk distance) in the placebo crossed Treatment Group [Week 24 to Week 48 in the Extension Period.]
- Change in New York Heart Association Functional Class (NYHA FC) in the placebo crossed Treatment Group [Week 24 to Week 48 in the Extension Period.]
Eligibility Criteria
Criteria
Inclusion Criteria:
Participants must meet the following criteria to be enrolled in this proof-of-concept study:
-
Age 18 to 85 years
-
Clinical diagnosis of HFpEF:
• Left ventricular ejection fraction ≥ 50%, with no history of LVEF below 45%
- Demonstrated Cpc-PH by all of the following:
-
Baseline RHC performed within 10 days prior to Visit 1 (during the Screening Period) documenting a minimum PVR of ≥ 320 dyn•sec/cm5 (4 wood units)
-
Mean pulmonary arterial pressure (mPAP) of > 20 mmHg
-
Pulmonary capillary wedge pressure (PCWP) > 15 mmHg but < 30 mmHg
-
New York Heart Association FC of II or III
-
Six-Minute Walk Distance ≥ 100 m repeated twice during Screening and both values within 15% of each other, calculated from the highest value
-
Chronic medication for HF or for any underlying condition, administered at a stable (per investigator) dose for ≥ 30 days prior to Visit 1. Diuretics and/or anticoagulants are excepted from this rule but should not be newly started or stopped within 30 days of Visit 1, and a prescribed dose change should not occur within 7 days of Visit 1. Anticoagulation may be suspended for RHC if necessary.
-
Women of childbearing potential must:
-
Have a negative pregnancy test 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 continue 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 drug
-
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 drug See Appendix 2 for additional contraceptive information.
- 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 16 weeks (112 days) after the last dose of study drug
-
Ability to adhere to the study visit schedule and understand and comply with all protocol requirements
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Agreement to not participate in any other trials of investigational drugs/devices while enrolled in the A011-16 study
-
Ability to understand and provide written informed consent for participation
Exclusion Criteria:
Participants will be excluded from the study if any of the following criteria are met:
-
A diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5
-
Significant parenchymal lung disease (e.g., chronic obstructive pulmonary disease with Global Initiative for Obstructive Lung Disease (GOLD) criteria III and IV, moderate or severe restrictive lung disease, diffuse interstitial fibrosis or alveolitis, pulmonary thromboembolism)
-
Cardiovascular co-morbidities, which include any of the following:
-
Any history of greater than mild mitral regurgitation or aortic regurgitation valvular disease or greater than mild aortic or mitral stenosis
-
Acute coronary syndrome, coronary artery bypass graft or percutaneous coronary intervention within 180 days of Visit 1
-
Uncontrolled heart rate (> 100 bpm) from atrial fibrillation or atrial flutter
-
History of serious life-threatening or hemodynamically significant arrhythmia
-
History of or anticipated heart transplant or ventricular assist device implantation
-
History of or anticipated implantation of pacemaker or implantable cardioverter defibrillator
-
Occurrence of myocardial infarction within 90 days of Visit 1
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History of known pericardial constriction, hypertrophic cardiomyopathy, sarcoidosis, or amyloid cardiomyopathy
-
Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 mmHg or sitting diastolic blood pressure > 110 mmHg during Screening after a period of rest
-
Systemic hypotension as evidenced by sitting systolic blood pressure < 90 mmHg or sitting diastolic blood pressure < 50 mmHg during Screening
-
Resting heart rate of < 45 bpm or > 115 bpm
-
Cerebrovascular accident within 90 days of Visit 1
-
Acutely decompensated HF within 45 days prior to Visit 1, as per investigator assessment
-
Electrocardiogram (ECG) during Screening Period with Fridericia's corrected QT interval (QTcF) > 480 msec or > 500 msec if a ventricular conduction defect (right bundle branch block; left bundle branch block; or interventricular conduction delay) is present
-
Personal or family history of long corrected QT syndrome or sudden cardiac death in first-degree relative
-
Hospitalization for any indication within 30 days of Visit 1
-
Received any approved PAH-specific therapies (i.e., endothelin receptor antagonists, prostacyclin analogs, phosphodiesterase-5 inhibitors, or soluble guanylate cyclase stimulators) within 30 days prior to Visit 1
-
Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to Visit 1
-
Received erythropoietin within 6 months prior to Visit 1
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Known history of chronic liver disease, including untreated 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 through C)
-
Prior exposure to sotatercept or luspatercept
-
Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent
-
Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to Visit 1 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)
-
Any of the following clinical laboratory values prior to Visit 1 as specified:
-
Hemoglobin (Hgb) above the gender-specific upper limit of normal (ULN) per local laboratory test within 28 days of Visit 1or < 10 g/dL per local laboratory within 28 days of Visit 1
-
Serum alanine aminotransferase or aspartate aminotransferase levels > 3× ULN or total bilirubin > 1.5× ULN within 28 days of Visit 1
-
Estimated glomerular filtration rate < 30 ml/min/1.73 m2 (4-variable Modification of Diet in Renal Disease equation) within 28 days of Visit 1 or required renal replacement therapy within 90 days of Visit 1
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Glycated hemoglobin (HbA1c) > 10% within 28 days of Visit 1
-
Platelet count < 75,000/mm3 within 28 days of Visit 1
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History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product
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Major surgery within 60 days prior to Visit 1. Participants must have completely recovered from any previous surgery prior to Visit 1
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Prior heart-lung transplants or life expectancy of < 12 months
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Pregnancy or breastfeeding in females
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History of active malignancy, with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in situ, or ≤ 2 squamous cell carcinomas of the skin
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History of clinically significant (as determined by the investigator) endocrine, hematologic, hepatic, (auto)immune, metabolic, urologic, pulmonary, neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or another disease that may limit participation in the study
-
Body mass index ≥ 45 kg/m2
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Arizona ( Site 1006) | Tucson | Arizona | United States | 85724 |
| 2 | Cedars Sinai Medical Center ( Site 1082) | Los Angeles | California | United States | 90048 |
| 3 | Stanford University ( Site 1024) | Stanford | California | United States | 94305 |
| 4 | University Of Colorado ( Site 1013) | Aurora | Colorado | United States | 80045 |
| 5 | South Denver Cardiology Associates ( Site 1091) | Littleton | Colorado | United States | 80120 |
| 6 | The George Washington University Medical Faculty Associates ( Site 1025) | Washington | District of Columbia | United States | 20037 |
| 7 | Bay Area Cardiology ( Site 1071) | Brandon | Florida | United States | 33511 |
| 8 | AdventHealth Orlando ( Site 1058) | Orlando | Florida | United States | 32803 |
| 9 | University of South Florida ( Site 1043) | Tampa | Florida | United States | 33606 |
| 10 | IU Health Advanced Heart and Lung Care ( Site 1092) | Indianapolis | Indiana | United States | 46202-1218 |
| 11 | Ascension Medical Group St. Vincent ( Site 1076) | Indianapolis | Indiana | United States | 46260 |
| 12 | University of Iowa Hospital and Clinics ( Site 1050) | Iowa City | Iowa | United States | 52242 |
| 13 | University of Kansas Medical Center ( Site 1020) | Kansas City | Kansas | United States | 66160 |
| 14 | Norton Pulmonary Specialists ( Site 1066) | Louisville | Kentucky | United States | 40202 |
| 15 | Brigham and Women's Hospital [Boston, MA] ( Site 1014) | Boston | Massachusetts | United States | 02115 |
| 16 | University of Minnesota Hospitals ( Site 1062) | Minneapolis | Minnesota | United States | 55455 |
| 17 | Washington University School of Medicine [Saint Louis, MO] ( Site 1022) | Saint Louis | Missouri | United States | 63110 |
| 18 | University of Nebraska Medical Center ( Site 1053) | Omaha | Nebraska | United States | 68198 |
| 19 | Weill Cornell Medical College ( Site 1046) | New York | New York | United States | 10021 |
| 20 | University of Toledo Medical Center ( Site 1070) | Toledo | Ohio | United States | 43614 |
| 21 | Rhode Island Hospital ( Site 1033) | Providence | Rhode Island | United States | 02903 |
| 22 | Medical University of South Carolina - PPDS ( Site 1003) | Charleston | South Carolina | United States | 29425-0001 |
| 23 | Statcare Pulmonary Consultants - Knoxville ( Site 1031) | Knoxville | Tennessee | United States | 37919 |
| 24 | Intermountain Medical Center ( Site 1079) | Salt Lake City | Utah | United States | 84107 |
| 25 | Pulmonary Associates of Richmond Inc. ( Site 1069) | Richmond | Virginia | United States | 23230 |
| 26 | West Virginia University ( Site 1081) | Morgantown | West Virginia | United States | 26506 |
| 27 | Medical College of Wisconsin Inc CRS ( Site 1051) | Milwaukee | Wisconsin | United States | 53226 |
| 28 | Hôpital Erasme ( Site 1402) | Anderlecht | Bruxelles-Capitale, Region De | Belgium | 1070 |
| 29 | UZ Gasthuisberg ( Site 1401) | Leuven | Vlaams-Brabant | Belgium | 3000 |
| 30 | Institut Universitaire de Cardiologie et de Pneumologie ( Site 2107) | Sainte Foy | Quebec | Canada | G1V 4G5 |
| 31 | Hôpital Pasteur - CHU Nice ( Site 1311) | Nice | Alpes-Maritimes | France | 06000 |
| 32 | Centre Hospitalier Universitaire de Grenoble ( Site 1303) | Grenoble cedex 09 | Isere | France | 38043 |
| 33 | CHU de Nantes - Hôptal Nord Laennec ( Site 1309) | Nantes | Loire-Atlantique | France | 44000 |
| 34 | CHU Angers ( Site 1313) | Angers | Maine-et-Loire | France | 49100 |
| 35 | CHRU de Nancy Hopitaux de Brabois ( Site 1308) | Vandœuvre-lès-Nancy | Meurthe-et-Moselle | France | 54500 |
| 36 | CHRU Lille ( Site 1306) | Lille | Nord | France | 59037 |
| 37 | CHU de Rouen ( Site 1323) | Rouen | Seine-Maritime | France | 76000 |
| 38 | Centre Hospitalier Universitaire de Bicetre ( Site 1304) | Le Kremlin Bicêtre | Val-de-Marne | France | 94270 |
| 39 | Thoraxklinik-Heidelberg gGmbH ( Site 1509) | Heidelberg | Baden-Wurttemberg | Germany | 69126 |
| 40 | Krankenhaus Neuwittelsbach ( Site 1510) | München | Bayern | Germany | 80639 |
| 41 | Shamir Medical Center Assaf Harofeh ( Site 1713) | Be'er Ya'akov | Israel | 7030001 | |
| 42 | Kaplan Medical Center ( Site 1712) | Rehovot | Israel | 7610001 | |
| 43 | Hospital Universitario Puerta de Hierro (Majadahonda) ( Site 1604) | Majadahonda | Madrid | Spain | 28222 |
| 44 | Hospital Clinic de Barcelona ( Site 1602) | Barcelona | Spain | 08036 | |
| 45 | Hospital Universitario 12 de Octubre ( Site 1603) | Madrid | Spain | 28041 | |
| 46 | Hospital Universitario Virgen Macarena ( Site 1612) | Sevilla | Spain | 41009 | |
| 47 | Imperial College Healthcare NHS Trust ( Site 1203) | London | London, City Of | United Kingdom | W2 1NY |
Sponsors and Collaborators
- Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 7962-007
- A011-16
- 2021-003020-32