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A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy (VALOR-HCM)

Primary Purpose

HOCM, Hypertrophic Obstructive Cardiomyopathy

Status
Active
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Mavacamten
Placebo
Sponsored by
Bristol-Myers Squibb
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HOCM, Hypertrophic Obstructive Cardiomyopathy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

  • At least 18 years old at screening and body weight > 45 kg at screening
  • Diagnosed with oHCM consistent with current ACCF/AHA 2011 and/or ESC 2014 guidelines and meet their recommendations for invasive therapies
  • Referred or under active consideration within the past 12 months for SRT procedure and willing to have SRT procedure
  • Has documented left ventricular ejection fraction (LVEF) ≥ 60% at Screening
  • Has documented oxygen saturation at rest ≥ 90% at Screening

Key Exclusion Criteria:

  • Persistent or permanent atrial fibrillation and subject not on anticoagulation for ≥ 4 weeks prior to screening and/or not adequately rate controlled ≤ 6 months prior to screening
  • Previously treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation [ASA])
  • For individuals on beta blockers, calcium channel blockers, or disopyramide, any dose adjustment of these medications < 14 days prior to screening or an anticipated change in regimen during the first 16 weeks of the study
  • Any medical condition that precludes upright exercise stress testing
  • Paroxysmal, intermittent atrial fibrillation with atrial fibrillation present at screening
  • Prior treatment with cardiotoxic agents, such as doxorubicin or similar
  • Has a history or evidence of any other clinically significant disorder, condition, or disease that would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion

Sites / Locations

  • Local Institution - 0009
  • Local Institution - 0011
  • Local Institution - 0001
  • Cleveland Clinic Florida
  • Local Institution - 0016
  • Local Institution - 0007
  • Local Institution - 0006
  • Local Institution - 0013
  • Local Institution - 0015
  • Local Institution - 0005
  • Local Institution - 0010
  • Local Institution - 0017
  • Local Institution - 0004
  • Local Institution - 0020
  • Local Institution - 0002
  • Local Institution - 0003
  • Local Institution - 0019
  • Local Institution - 0014
  • Local Institution - 0018
  • Local Institution
  • Local Institution - 0012

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Drug: Mavacamten

Drug: Placebo

Arm Description

Mavacamten Capsules Other names: MYK-461

Matching Placebo Capsules

Outcomes

Primary Outcome Measures

Composite of Decision to Proceed With Septal Reduction Therapy (SRT) and SRT Guideline Eligible at Week 16
Participants who decided to proceed with SRT or were eligible for SRT at week 16. Participants with missing assessments were classified as meeting the primary endpoint (did not improve). SRT eligibility using the New York Heart Association Functional Class (NYHA) and left ventricular outflow tract (LVOT) assessments per the 2011 ACCF/AHA guideline clinical and hemodynamic criterion are below: NYHA Class III or IV/ NYHA Class II with exertion-induced syncope/near syncope, AND Dynamic LVOT gradient at rest or with provocation >= 50 mmHg. NYHA Class II at week 16, the following rules will be applied: NYHA Class II with history of exertional syncope/ syncope at baseline and at W16 is still NYHA Class II, they remain SRT eligible IF their maximal LVOT gradient is ≥ 50mmHg NYHA Class III/IV at baseline and at W16 has improved to Class II, they are no longer SRT eligible UNLESS they have AE of exertional syncope or pre-syncope during the 16 weeks.

Secondary Outcome Measures

Number of Participants With at Least One Class Improvement From Baseline in New York Heart Association (NYHA) Class at Week 16
The NYHA functional classification of heart failure assigns participants to 1 of 4 categories based on the participants symptoms. Baseline values are defined generally as the last available value before the first administration of study drug of analysis interest. Participants with missing NYHA class assessments are treated as no improvement. Class 1: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). Class 2: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class 3: Marked limitation of physical activity. Comfortable at rest. Less-than ordinary-activity causes fatigue, palpitation, or dyspnea. Class 4: Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
Change From Baseline to Week 16 in Kansas City Cardiomyopathy Questionnaire 23-item Version, Clinical Summary Score (KCCQ-23, CSS)
The KCCQ-23 is a 23-item, self-administered questionnaire that measures the impact of a participant's cardiovascular disease or its treatment on 6 distinct domains using a 2-week recall period: symptoms/signs, physical limitation, quality of life (QoL), social limitations, self-efficacy, and symptom stability. The KCCQ 23 Clinical Summary Score (CSS) is derived from the Total Symptom Score (TSS) and the Physical Limitations (PL) score of the KCCQ 23. The CSS, TSS, and the PL score range from 0 to 100 with higher scores representing less severe symptoms and/or physical limitations. The CSS is a mean of the TSS and the PL score.
Change From Baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP)
A geometric mean ratio was used to assess the change from baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP). Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise.
Change From Baseline to Week 16 in Cardiac Troponin
A geometric mean ratio was used to assess the change from baseline to week 16 in cardiac troponin. Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise.
Change From Baseline to Week 16 in Post-Exercise Left Ventricular Outflow Tract (LVOT) Gradient
Change from baseline to week 16 in post-exercise left ventricular outflow tract (LVOT) gradient. Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise.

Full Information

First Posted
April 7, 2020
Last Updated
May 17, 2023
Sponsor
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT04349072
Brief Title
A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy
Acronym
VALOR-HCM
Official Title
A Randomized, Double-blind, Placebo-controlled Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 6, 2020 (Actual)
Primary Completion Date
February 7, 2022 (Actual)
Study Completion Date
June 11, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a randomized, double-blind, placebo-controlled, multi-center study in the United States (U.S.) that will evaluate the effect of mavacamten treatment on reducing the number of septal reduction therapy (SRT) procedures performed in subjects with symptomatic obstructive hypertrophic cardiomyopathy (oHCM [also known as HOCM]) who are eligible for SRT based on ACCF/AHA 2011 and/or ESC 2014 guidelines.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HOCM, Hypertrophic Obstructive Cardiomyopathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
This is a parallel group treatment study with 2 treatment groups; subjects and investigators are blinded to treatment and dose for the first 16 weeks of treatment. Mavacamten dose is blinded throughout the study.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
112 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Drug: Mavacamten
Arm Type
Experimental
Arm Description
Mavacamten Capsules Other names: MYK-461
Arm Title
Drug: Placebo
Arm Type
Placebo Comparator
Arm Description
Matching Placebo Capsules
Intervention Type
Drug
Intervention Name(s)
Mavacamten
Intervention Description
Mavacamten Capsules Other names: MYK-461
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Composite of Decision to Proceed With Septal Reduction Therapy (SRT) and SRT Guideline Eligible at Week 16
Description
Participants who decided to proceed with SRT or were eligible for SRT at week 16. Participants with missing assessments were classified as meeting the primary endpoint (did not improve). SRT eligibility using the New York Heart Association Functional Class (NYHA) and left ventricular outflow tract (LVOT) assessments per the 2011 ACCF/AHA guideline clinical and hemodynamic criterion are below: NYHA Class III or IV/ NYHA Class II with exertion-induced syncope/near syncope, AND Dynamic LVOT gradient at rest or with provocation >= 50 mmHg. NYHA Class II at week 16, the following rules will be applied: NYHA Class II with history of exertional syncope/ syncope at baseline and at W16 is still NYHA Class II, they remain SRT eligible IF their maximal LVOT gradient is ≥ 50mmHg NYHA Class III/IV at baseline and at W16 has improved to Class II, they are no longer SRT eligible UNLESS they have AE of exertional syncope or pre-syncope during the 16 weeks.
Time Frame
Week 16
Secondary Outcome Measure Information:
Title
Number of Participants With at Least One Class Improvement From Baseline in New York Heart Association (NYHA) Class at Week 16
Description
The NYHA functional classification of heart failure assigns participants to 1 of 4 categories based on the participants symptoms. Baseline values are defined generally as the last available value before the first administration of study drug of analysis interest. Participants with missing NYHA class assessments are treated as no improvement. Class 1: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). Class 2: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class 3: Marked limitation of physical activity. Comfortable at rest. Less-than ordinary-activity causes fatigue, palpitation, or dyspnea. Class 4: Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.
Time Frame
Baseline and week 16
Title
Change From Baseline to Week 16 in Kansas City Cardiomyopathy Questionnaire 23-item Version, Clinical Summary Score (KCCQ-23, CSS)
Description
The KCCQ-23 is a 23-item, self-administered questionnaire that measures the impact of a participant's cardiovascular disease or its treatment on 6 distinct domains using a 2-week recall period: symptoms/signs, physical limitation, quality of life (QoL), social limitations, self-efficacy, and symptom stability. The KCCQ 23 Clinical Summary Score (CSS) is derived from the Total Symptom Score (TSS) and the Physical Limitations (PL) score of the KCCQ 23. The CSS, TSS, and the PL score range from 0 to 100 with higher scores representing less severe symptoms and/or physical limitations. The CSS is a mean of the TSS and the PL score.
Time Frame
Baseline and week 16
Title
Change From Baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP)
Description
A geometric mean ratio was used to assess the change from baseline to Week 16 in N-Terminal Pro-b-Type Natriuretic Peptide (NT-proBNP). Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise.
Time Frame
Baseline and week 16
Title
Change From Baseline to Week 16 in Cardiac Troponin
Description
A geometric mean ratio was used to assess the change from baseline to week 16 in cardiac troponin. Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise.
Time Frame
Baseline and week 16
Title
Change From Baseline to Week 16 in Post-Exercise Left Ventricular Outflow Tract (LVOT) Gradient
Description
Change from baseline to week 16 in post-exercise left ventricular outflow tract (LVOT) gradient. Baseline values are defined as the last non-missing value prior to the first dose of study drug unless specified otherwise.
Time Frame
Baseline and week 16

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria: At least 18 years old at screening and body weight > 45 kg at screening Diagnosed with oHCM consistent with current ACCF/AHA 2011 and meet their recommendations for invasive therapies Referred or under active consideration within the past 12 months for SRT procedure and willing to have SRT procedure Has documented left ventricular ejection fraction (LVEF) ≥ 60% at Screening Has documented oxygen saturation at rest ≥ 90% at Screening Key Exclusion Criteria: Persistent or permanent atrial fibrillation and subject not on anticoagulation for ≥ 4 weeks prior to screening and/or not adequately rate controlled ≤ 6 months prior to screening Previously treated with invasive septal reduction (surgical myectomy or percutaneous alcohol septal ablation [ASA]) For individuals on beta blockers, calcium channel blockers, or disopyramide, any dose adjustment of these medications < 14 days prior to screening or an anticipated change in regimen during the first 16 weeks of the study Any medical condition that precludes upright exercise stress testing Paroxysmal, intermittent atrial fibrillation with atrial fibrillation present at screening Prior treatment with cardiotoxic agents, such as doxorubicin or similar Has a history or evidence of any other clinically significant disorder, condition, or disease that would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bristol-Myers Squibb
Organizational Affiliation
Bristol-Myers Squibb
Official's Role
Study Director
Facility Information:
Facility Name
Local Institution - 0009
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Local Institution - 0011
City
Stanford
State/Province
California
ZIP/Postal Code
94305 5406
Country
United States
Facility Name
Local Institution - 0001
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Facility Name
Cleveland Clinic Florida
City
Weston
State/Province
Florida
ZIP/Postal Code
33331
Country
United States
Facility Name
Local Institution - 0016
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114-2696
Country
United States
Facility Name
Local Institution - 0007
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Local Institution - 0006
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Local Institution - 0013
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49503
Country
United States
Facility Name
Local Institution - 0015
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Local Institution - 0005
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Local Institution - 0010
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Local Institution - 0017
City
Valhalla
State/Province
New York
ZIP/Postal Code
10595
Country
United States
Facility Name
Local Institution - 0004
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Local Institution - 0020
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Local Institution - 0002
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Local Institution - 0003
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Local Institution - 0019
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15212
Country
United States
Facility Name
Local Institution - 0014
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37205
Country
United States
Facility Name
Local Institution - 0018
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37235
Country
United States
Facility Name
Local Institution
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Local Institution - 0012
City
Murray
State/Province
Utah
ZIP/Postal Code
84107-5701
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
36335531
Citation
Desai MY, Owens A, Geske JB, Wolski K, Saberi S, Wang A, Sherrid M, Cremer PC, Naidu SS, Smedira NG, Schaff H, McErlean E, Sewell C, Balasubramanyam A, Lampl K, Sehnert AJ, Nissen SE. Dose-Blinded Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy: Outcomes Through 32 Weeks. Circulation. 2023 Mar 14;147(11):850-863. doi: 10.1161/CIRCULATIONAHA.122.062534. Epub 2022 Nov 6.
Results Reference
derived
PubMed Identifier
35798455
Citation
Desai MY, Owens A, Geske JB, Wolski K, Naidu SS, Smedira NG, Cremer PC, Schaff H, McErlean E, Sewell C, Li W, Sterling L, Lampl K, Edelberg JM, Sehnert AJ, Nissen SE. Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. J Am Coll Cardiol. 2022 Jul 12;80(2):95-108. doi: 10.1016/j.jacc.2022.04.048.
Results Reference
derived
PubMed Identifier
34081217
Citation
Zampieri M, Argiro A, Marchi A, Berteotti M, Targetti M, Fornaro A, Tomberli A, Stefano P, Marchionni N, Olivotto I. Mavacamten, a Novel Therapeutic Strategy for Obstructive Hypertrophic Cardiomyopathy. Curr Cardiol Rep. 2021 Jun 3;23(7):79. doi: 10.1007/s11886-021-01508-0.
Results Reference
derived
PubMed Identifier
34038706
Citation
Desai MY, Wolski K, Owens A, Naidu SS, Geske JB, Smedira NG, Schaff H, Lampl K, McErlean E, Sewell C, Zhang D, Edelberg JM, Sehnert AJ, Nissen SE. Study design and rationale of VALOR-HCM: evaluation of mavacamten in adults with symptomatic obstructive hypertrophic cardiomyopathy who are eligible for septal reduction therapy. Am Heart J. 2021 Sep;239:80-89. doi: 10.1016/j.ahj.2021.05.007. Epub 2021 May 24.
Results Reference
derived
Links:
URL
https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html
Description
BMS Clinical Trial Information
URL
https://www.bmsstudyconnect.com/s/US/English/USenHome
Description
BMS Clinical Trial Patient Recruiting
URL
https://www.fda.gov/Safety/MedWatch/SafetyInformation/default.htm
Description
FDA Safety Alerts and Recalls
URL
https://www.bms.com/researchers-and-partners/clinical-trials-and-research.html
Description
Investigator Inquiry Form

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A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy

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