This study has been transitioned to CTIS with ID 2023-506352-24-00 check the CTIS register for the current data. Primary Objectives: • To assess the efficacy of a 48-week course of mavacamten compared to placebo on patient- reported health status (…
ID
Source
Brief title
Condition
- Congenital cardiac disorders
- Cardiac and vascular disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
• Change from baseline in KCCQ-23 CSS at Week 48
• Change from baseline in pVO2 at Week 48
Secondary outcome
Secundary endpoints:
• Change from baseline in VE/VCO2 slope to Week 48
• Proportion of participants with at least 1 class of NYHA improvement from
baseline to Week 48
• Proportion of participants with (1) pVO2 >= 1.5 mL/kg/min and NYHA
improvement >= 1; or (2) pVO2 >= 3 mL/kg/min and NYHA no worsening, from
baseline to Week 48
• Change from baseline in NT-proBNP to Week 48
• Change from baseline in cTn-T to Week 48
• Change from baseline in HCMSQ-SoB domain to Week 48
• Time to first MACE-plus events defined as any CV death, non-fatal myocardial
infarction, non-fatal stroke, hospitalization for heart failure, or
hospitalization for arrhythmias or appropriate ICF therapy
Background summary
The efficacy of medications commonly used to treat symptomatic patients with
nHCM (beta blockers, verapamil, and diltiazem) can be limited by side effects
and bradycardia. Accordingly, safer and more effective treatments to reduce
symptoms and increase functional capacity for patients with nHCM have been
identified as unmet medical needs by the recent American College of
Cardiology/American Heart Association (ACC/AHA) Joint Committee on Clinical
Practice Guidelines. The Sponsor believes mavacamten has the potential to meet
this unmet need. In contrast to currently available therapies, mavacamten is a
first-in-class, selective, and reversible modulator of cardiac myosin that
targets the underlying pathophysiology of the disease.
Dyspnea and fatigue are the most common symptoms reported by patients with
nHCM. Dyspnea associated with nHCM can be attributed to reduced LV compliance
characteristic of HCM. The formation of an excessive number of myosin-actin
crossbridges that persist during diastole in patients with HCM decreases
diastolic compliance. Reduced LV compliance increases left ventricular filling
pressure (LVFP) which increases LA pressure causing exudation of fluid into
pulmonary tissue. The accumulated pulmonary fluid causes dyspnea, especially
with exertion. Mavacamten can reduce dyspnea by increasing LV compliance
through reducing the number of crossbridges that persist during diastole.
Increased LV compliance reduces the increased LVFP that causes dyspnea.
Beta blockers and non-dihydropyridine calcium channel blockers are often used
to treat patients with symptomatic nHCM but unlike mavacamten, neither targets
the abnormal crossbridge formation that underlies the disease. Therapy with
these drugs can be limited by adverse reactions.
Data from clinical studies with mavacamten suggest that mavacamten could
provide a safe potential treatment option to reduce symptoms and improve
exercise capacity in patients with nHCM.
Study objective
This study has been transitioned to CTIS with ID 2023-506352-24-00 check the CTIS register for the current data.
Primary Objectives:
• To assess the efficacy of a 48-week course of mavacamten compared to placebo
on patient- reported health status (symptoms and physical limitations)
• To assess the efficacy of a 48-week course of mavacamten compared to placebo
on exercise capacity
Secundary Objectives:
• Evaluate the effects of mavacamten on exercise capacity as measured by
VE/VCO2
• Evaluate the effects of mavacamten on NYHA classification
• Evaluate the effects of mavacamten on the composite of NYHA and
pVO2
• Evaluate the effects of mavacamten on cardiac biomarkers of wall stress
• Evaluate the effects of mavacamten on cardiac biomarkers of myocardial
injury
• Evaluate the effects of mavacamten on patient- reported shortness of
breath
• Evaluate the effects of mavacamten on composite of cardiovascular events
Study design
CV027031 is a Phase 3, double-blind, randomized, placebo-controlled,
multicenter, international, parallel-group study to evaluate the safety,
tolerability, and efficacy of mavacamten compared with placebo in participants
with symptomatic nHCM. The study will randomize approximately 420 participants
at 180 sites in a 1:1 ratio to mavacamten and placebo. Randomization will be
stratified by New York Heart Association (NYHA) class (II or III), type of
exercise (treadmill or exercise bicycle), region (Asia, North America, Europe,
and Rest of the World), and beta blocker use at baseline (Yes/No). All
participants are planned to be on double-blind study treatment from the time
the first participant is randomized until the last randomized participant
completes 48 weeks of study treatment. To participate in the study,
participants must have: 1) New York Heart Association (NYHA) Functional
Classification II or III and Kansas City Cardiomyopathy Questionnaire-23
Clinical Summary Score (KCCQ-23 CSS) <= 80 2) Increased cardiac wall stress
(increased N-terminal pro B-type natriuretic peptide/B-type natriuretic peptide
according to thresholds specified in the protocol) 3) Cardiac wall thickness >=
15 mm (or >= 13 mm if family history) 4) Left ventricular ejection fraction
(LVEF) >= 60% 5) Left ventricular diastolic dysfunction (E/e* > 14 OR left
atrial volume index > 34 mL/m2) OR myocardial damage as indicated by elevated
cardiac troponin > 99th percentile of the upper limit of normal of the assay
used by the analyzing laboratory 6) Left ventricular outflow tract gradient <
30 mm Hg at rest and < 50 mm Hg after provocation (Valsalva and post exercise).
Cardiac medications cannot be initiated, discontinued, or dose adjusted within
2 weeks prior to screening and up to the day of randomization. At Week 48 after
study treatment, the effects of mavacamten compared to placebo on health status
(symptoms and physical limitations) will be assessed by change from baseline in
KCCQ-23 CSS and the effect on exercise capacity by change from baseline in peak
oxygen consumption (pVO2). The 2 primary endpoints were selected to assess the
symptoms and functional limitation reported most frequently as troublesome by
participants with nHCM: exertional dyspnea, fatigue, and limited exercise
capacity.
Intervention
Study Intervention for CV027031
Medication
Potency IP/Non-IP/AxMP
Mavacamten 1 mg, 2.5 mg, 5 mg, 10 mg, and
15
mg IP
PBO matching mavacamten oral capsule
NA IP
Study burden and risks
Overall, the benefit/risk profile of mavacamten is positive and warrants
further evaluation in the population of nHCM that carries a high unmet medical
need. This study has been designed with appropriate measures in place to
monitor and minimize any potential health risks to participating patients.
Taking into account the clinical experience with mavacamten to date and the
extent of monitoring and precautions included in the study protocol,
participation in this study should represent an acceptable risk to patients who
meet the inclusion/exclusion criteria and consent to participate in the study.
An independent Data Monitoring Committee (DMC) will be responsible for
safeguarding the interests of the study participants by reviewing safety data
throughout the study. The DMC and Sponsor will evaluate the risk/benefit
profile of the study on an ongoing basis. This evaluation will be based on all
available data, with particular attention to: (i) AEs or other safety trends in
this or any other clinical study of BMS-986427 whose character, severity,
and/or frequency suggest that participants would be exposed to an unreasonable
and significant risk of illness or injury; (ii) new data suggesting
unreasonable and significant risk of illness or injury.
If such evaluation suggests that the risk/benefit profile of the study has
become unfavorable to participants, the Sponsor will pause enrollment and/or
treatment until further evaluation of data, and interaction with the
appropriate Health Authority(ies) can take place on potential actions. Such
actions may include (but are not limited to) study continuation, substantial
amendment, or termination of the study.
Sierra Point Parkway 1000
Brisbane, CA 94005
US
Sierra Point Parkway 1000
Brisbane, CA 94005
US
Listed location countries
Age
Inclusion criteria
1. Participants must be at least 18 years old or local age of majority at the
time of signing the informed consent 2. Female participants must adhere to
highly effective contraceptive methods or have documented proof that they are
not of childbearing potential 3. No additional contraceptive measures are
required to be used for male participants 4. Diagnosis of HCM consistent with
current American College of Cardiology Foundation/American Heart Association
and European Society of Cardiology guidelines. 5. Peak LVOT pressure gradient <
30 mmHg at rest and < 50 mmHg with provocation (Valsalva maneuver and stress
echocardiography) 6. CPET: Documented oxygen saturation at rest >90% at
Screening. Able to perform an upright cardiopulmonary stress test (CPET) and
has a respiratory exchange ratio (RER) >= 1.0 at Screening per central reading.
If the RER is between 0.91 and 1.0, the participant may be enrolled if the
central CPET laboratory determines that peak exercise has been achieved.
Participants with subpeak performance may not be enrolled as described in the
CPET Laboratory Manual. 7. New York Heart Association (NYHA) Class II or III 8.
NT-proBNP>=200 pg/mL or BNP>=70 pg/mL 9. LVEF >=60 % as determined by the
echocardiography central laboratory 10. KCCQ-23 CSS Score <= 85 at screening
Exclusion criteria
Medical Conditions - Known infiltrative or storage disorder causing cardiac
hypertrophy that mimics nHCM such as Fabry disease, amyloidosis, or Noonan
syndrome with LV hypertrophy
Note: Investigators should not screen participants who have comprehensive Echo
features suggestive of amyloidosis, including
abnormal global longitudinal strain in the setting of an appropriate clinical
picture which could include low voltage on ECG and severely elevated NT-proBNP
or BNP
- History of unexplained syncope within 6 months prior to screening - History
of sustained ventricular tachyarrhythmia (> 30 seconds) within 6 months prior
to Screening - Paroxysmal or persistent (non-permanent) AF detected at the time
of screening. Permanent AF is allowed if the participant is anticoagulated and
the investigator considers the heart rate adequately controlled - CV diseases
or treatments that in the opinion of the investigator increase the
unpredictability of or change the participants' clinical course. - Acute heart
failure from 4 weeks prior to screening up to randomization - Coronary artery
disease requiring intervention, including myocardial infarction (increase in
cardiac enzymes in combination with symptoms of ischemia or new ischemic ECG
changes), coronary artery bypass graft surgery, or other major CV surgery,
stroke, or transient ischemic attack in the past 90 days - Women who are
breastfeeding or pregnant. Prior/Concomitant Therapy - Any adjustments of
beta-blockers, verapamil, or diltiazem within 2 weeks prior to Screening and up
to the day of randomization - Concomitant use of strong inhibitors of
cytochrome P450 (CYP) 2C19 Note: Use should be discontinued for a minimum of 5
elimination half-lives prior to first dose of study intervention. Other
Exclusion Criteria - Any other serious condition that in the opinion of the
investigator could prevent participation in the study and follow-up, including
active infection with COVID-19 from 4 weeks prior to screening up to
randomization - Completed a study with an investigational device < 30 days
prior to screening or an investigational drug <5 half-lives prior to screening
- Participants who have completed a study with mavacamten or aficamten
--Enrolled in another study and receiving any investigational treatment (device
or drug) other than the study intervention given in this study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-506352-24-00 |
| EudraCT | EUCTR2021-005329-26-NL |
| ClinicalTrials.gov | NCT05582395 |
| CCMO | NL82368.091.22 |