A Study of Sotatercept for the Treatment of Cpc-PH Due to HFpEF (CADENCE)

• ClinicalTrials.gov Identifier: NCT04945460
• Recruitment Status: Not yet recruiting
• First Posted: June 30, 2021
• Last Update Posted: October 26, 2021
• Sponsor: Acceleron Pharma Inc.
• Information provided by (Responsible Party): Acceleron Pharma Inc.

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
Cpc-PH Due to HFpEF (Combined Post-capillary and Pre-capillary Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction)	Drug: Sotatercept; Drug: Placebo	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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Each eligible participant will be randomly assigned in a 1:1:1 ratio to 1 of the 3 treatment groups during the Treatment Period:

Arm 1: Treatment Group 1: Placebo delivered subcutaneously (SC) every 3 weeks (Q3W) for 24 weeks

Arm 2: Treatment Group 2: Sotatercept SC at a dose level of 0.3 mg/kg Q3W for 24 weeks

Arm 3: Treatment Group 3: 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

• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effects of Sotatercept Versus Placebo for the Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) Due to Heart Failure With Preserved Ejection Fraction (HFpEF)
• Estimated Study Start Date: October 2021
• Estimated Primary Completion Date: August 2023
• Estimated Study Completion Date: March 2025

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 Name: ACE-011
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 Name: ACE-011

Outcome Measures

Primary Outcome Measures :

1. Change in Pulmonary Vascular Resistance (PVR) at 24 weeks from baseline [ Time Frame: From screening to Week 24. ]
   PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization (RHC).

Secondary Outcome Measures :

1. Change in 6MWD (6 minute walk distance) [ Time Frame: 24 weeks from baseline. ]
   This tests the distance walked in 6 minutes, to assess functional capacity.
2. Number of Clinical Worsening events. [ Time Frame: 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
3. Number of Clinical Worsening events at 48 weeks [ Time Frame: From initiation of treatment to 48 weeks. ]
   Clinical Worsening events, defined as above, is measured at 48 weeks.
4. Number of participants with first Clinical Worsening event at 24 weeks [ Time Frame: From initiation of treatment to 24 weeks. ]
   Number of patients with Clinical Worsening events, defined as above, is measured at 24 weeks.
5. Number of participants with first Clinical Worsening event at 48 weeks [ Time Frame: From initiation of treatment to 48 weeks. ]
   Number of patients with Clinical Worsening events, defined as above, is measured at 48 weeks.
6. Time to Clinical Worsening [ Time Frame: 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.
7. Change in Dyspnea Score (assessed by Borg Category Ratio 10 scale®) [ Time Frame: 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.
8. Change in mean pulmonary arterial pressure (mPAP) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
   mPAP is calculated from systolic and diastolic pulmonary artery pressure measured by right heart catheterization.
9. Change in pulmonary capillary wedge pressure (PCWP) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
   PCWP is indirect estimate of left atrial pressure measured in right heart catheterization.
10. Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) [ Time Frame: 24 weeks from baseline. ]
    TAPSE is an echocardiographic measurement of tricuspid valve annulus movement, as an indicator of right heart function.
11. Change in right ventricular fractional area change (RVFAC) at 24 weeks from baseline [ Time Frame: 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.
12. Change in left ventricular ejection fraction (LVEF) at 24 weeks from baseline [ Time Frame: 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.
13. Change in isovolumic relaxation time (IVRT) at 24 weeks from baseline [ Time Frame: 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.
14. Change in E/e' (early mitral inflow velocity E and mitral annular early diastolic velocity e') ratio at 24 weeks from baseline. [ Time Frame: 24 weeks from baseline. ]
    E/e' is a ratio measured in echocardiography as an indicator of diastolic function
15. 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 [ Time Frame: 24 weeks from baseline. ]
    E/A is a ratio measured in echocardiography as an indicator of diastolic function
16. Change in N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
    NT-proBNP is a circulating biomarker that reflects myocardial stretch
17. Change in New York Heart Association Functional Class (NYHA FC) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
    NYHA FC classifies the extent of heart failure
18. Change in 6MWD at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
19. Change in Pulmonary Vascular Resistance (PVR) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
20. Change in mean pulmonary arterial pressure (mPAP) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
21. Change in pulmonary capillary wedge pressure (PCWP) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
22. Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
23. Change in right ventricular fractional area change (RVFAC) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
24. Change in left ventricular ejection fraction (LVEF) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
25. Change in isovolumic relaxation time (IVRT) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
26. Change in E/e' (early mitral inflow velocity E and mitral annular early diastolic velocity e') ratio at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
27. Change in A wave in late diastole (E/A) ratio at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
28. Change in N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
29. Change in New York Heart Association Functional Class (NYHA FC) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
30. Change in Pulmonary Vascular Resistance (PVR) in the placebo crossed Treatment Group [ Time Frame: Week 48 from baseline in the Extension Period ]
31. Change in 6MWD (6 minute walk distance) in the placebo crossed Treatment Group [ Time Frame: Week 48 from baseline in the Extension Period ]
32. Change in New York Heart Association Functional Class (NYHA FC) [ Time Frame: Week 48 from baseline in the Extension Period. ]
33. Change in Pulmonary Vascular Resistance (PVR) in the placebo crossed Treatment Group [ Time Frame: Week 24 to Week 48 in the Extension Period. ]
34. Change in 6MWD (6 minute walk distance) in the placebo crossed Treatment Group [ Time Frame: Week 24 to Week 48 in the Extension Period. ]
35. Change in New York Heart Association Functional Class (NYHA FC) in the placebo crossed Treatment Group [ Time Frame: Week 24 to Week 48 in the Extension Period. ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Participants must meet the following criteria to be enrolled in this proof-of-concept study:

1. Age 18 to 85 years

2. Clinical diagnosis of HFpEF:

   • Left ventricular ejection fraction ≥ 50%, with no history of LVEF below 45%

3. 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
4. New York Heart Association FC of II or III
5. Six-Minute Walk Distance ≥ 100 m repeated twice during Screening and both values within 15% of each other, calculated from the highest value
6. 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.

7. 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.

8. 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
9. Ability to adhere to the study visit schedule and understand and comply with all protocol requirements
10. Agreement to not participate in any other trials of investigational drugs/devices while enrolled in the A011-16 study
11. 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:

1. A diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5
2. 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)

3. 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
   • 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
4. Hospitalization for any indication within 30 days of Visit 1
5. 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
6. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to Visit 1
7. Received erythropoietin within 6 months prior to Visit 1
8. 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)
9. Prior exposure to sotatercept or luspatercept
10. 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
11. 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)

12. 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
    • Glycated hemoglobin (HbA1c) > 10% within 28 days of Visit 1
    • Platelet count < 75,000/mm3 within 28 days of Visit 1
13. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product
14. Major surgery within 60 days prior to Visit 1. Participants must have completely recovered from any previous surgery prior to Visit 1
15. Prior heart-lung transplants or life expectancy of < 12 months
16. Pregnancy or breastfeeding in females
17. 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
18. 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
19. Body mass index ≥ 45 kg/m2

Contacts and Locations

Contacts

Contact: Clinical Trial Manager; 617-649-9200; Clinicaltrials011@acceleronpharma.com

Sponsors and Collaborators

Acceleron Pharma Inc.

Investigators

• Study Director: Jonathan Lu, MD, PhD; Acceleron Pharma Inc.

More Information

• Responsible Party: Acceleron Pharma Inc.
• ClinicalTrials.gov Identifier: NCT04945460
• Other Study ID Numbers: A011-16
• First Posted: June 30, 2021
• Last Update Posted: October 26, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Acceleron is committed to sharing clinical trial data following completion of a clinical study. All data provided are de-identified to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Data will be shared after the primary publication or 2 years after the study has ended for market authorized products and indications.
• Access Criteria: Data from eligible studies will be shared according to the criteria and process to be posted on Acceleron's website
• URL: https://acceleronpharma.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Acceleron Pharma Inc.:

Pulmonary, hypertension, Cpc PH, HFpEF, sotatercept

Additional relevant MeSH terms:

Hypertension, Pulmonary; Hypertension; Heart Failure; Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Lung Diseases; Respiratory Tract Diseases