This study has been transitioned to CTIS with ID 2022-502858-14-00 check the CTIS register for the current data. primary objective:To assess the long-term safety and tolerability of mavacamten in participants with hypertrophic cardiomyopathy (HCM)…
ID
Source
Brief title
Condition
- Cardiac and vascular disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety
• Incidence of major adverse cardiac events (death, stroke, acute myocardial
infarction)
• Incidence of hospitalizations (both cardiovascular [CV] and non-CV)
• Incidence of heart failure (HF) events (includes HF hospitalizations and
urgent emergency room/outpatient visits for HF)
• Incidence of atrial fibrillation/flutter (new from Screening Visit)
• Incidence of ICD discharges and resuscitated cardiac arrest
• Incidence of ventricular tachyarrhythmias (includes ventricular tachycardia,
ventricular fibrillation)
• Incidence of any AE potentially linked to QT prolongation (Torsade de
pointes, CV or sudden death, sustained ventricular tachycardia, ventricular
fibrillation and flutter, syncope, and seizures)
• Frequency and severity of treatment-emergent AEs, treatmentemergent serious
AEs, and laboratory abnormalities (including trends in NT-proBNP)
Secondary outcome
Efficacy and Pharmacodynamics
• Change from baseline in echocardiographic parameters of systolic function
(eg, LVEF) and diastolic function (eg, peak velocity of early diastolic septal
and lateral mitral annular motion [e*], ratio of peak velocity of early
diastolic transmitral flow [E] to e* [E/e*], ratio of E to peak velocity of late
transmitral flow [A] [E/A], pulmonary artery systolic pressure, left atrium
size) over time
• Change from baseline in resting and post-Valsalva LVOT gradient (EXPLORER-HCM
participants only)
• Change from baseline in New York Heart Association (NYHA) functional class
over time
• Change from baseline in NT-proBNP over time
• Frequency of cardiac transplantation
Background summary
MyoKardia is developing mavacamten, a cardiac myosin modulator, for the
treatment of patients with
symptomatic HCM, a condition with significant unmet medical need, with the
goals to reduce ventricular filling pressures, improve symptoms, and increase
exercise capacity. MyoKardia has designed the current study to generate
long-term data in participants with symptomatic nHCM and oHCM.
Study objective
This study has been transitioned to CTIS with ID 2022-502858-14-00 check the CTIS register for the current data.
primary objective:
To assess the long-term safety and tolerability of mavacamten in participants
with hypertrophic cardiomyopathy (HCM) previously enrolled in 1 of 2
placebo-controlled trials: MAVERICK-HCM (MYK-461-006) for non-obstructive HCM
(nHCM) and EXPLORERHCM (MYK-461-005) for obstructive HCM (oHCM).
Secondary objectives:
• To assess the long-term effects of mavacamten on symptoms and
echocardiographic measures of cardiac function
• To assess left ventricular outflow tract (LVOT) obstruction as determined by
Doppler echocardiography in the EXPLORER-LTE cohort
Study design
This is a multicenter study to evaluate the long-term safety and tolerability
of mavacamten in 2 cohorts:
• Up to 60 participants with nHCM who complete MAVERICK-HCM study through Week
24 and begin Screening for this study within 90 days from
the MAVERICK end of study (EOS) Visit
•Up to 250 participants with oHCM who complete EXPLORER-HCM study through Week
38 and begin Screening for this study within 90 days from the EXPLORER-HCM EOS
Visit
All participants will receive active study drug (mavacamten) once daily (QD)
but their status (active or placebo) in the Parent Study will remain blinded as
the studies will be enrolling in parallel. All participants will undergo the
same assessments and visit schedule (per cohort) to preserve the blind of study
drug assignment in the Parent Study.
Screening Period (Day -28 to Day -1)
Participants in this study will be screened to ensure they continue to meet
eligibility criteria. Results of assessments from the Parent Study
EOS Visit may be used as screening values to confirm eligibility for this study
if the participant signs the Informed Consent Form (ICF) within 28 days of the
Parent Study EOS Visit.
If more than 28 days but less than 90 days has elapsed since the Parent Study
EOS Visit, participants will require a full Screening Visit per
protocol prior to enrollment. Once a participant signs the ICF, the screening
window opens, and participants must complete the Baseline
Visit (Day 1) within 28 days.
For both cohorts, the 90 day interval to begin screening may be extended if
needed under special circumstances and with written approval from the MyoKardia
Medical Monitor.
Participants who fail to meet all enrollment criteria may be re-screened. The
MyoKardia Medical Monitor should be contacted to discuss the specific situation.
Treatment Period (Day 1 to Week 252/End of Treatment)
Participants who meet all Eligibility Criteria will undergo baseline (Day 1)
assessments followed by scheduled visits through Week 104/End of Treatment
(EOT). Clinic visits will include but not be limited to clinical evaluation
symptoms, adverse event (AE)/serious adverse event (SAE)
assessment, electrocardiograms (ECGs), PK samples, transthoracic
echocardiography (TTE), and laboratory assessments including N-terminal pro
b-type natriuretic peptide (NT-proBNP).
For MAVERICK-LTE Cohort Only
• Arterial pulse wave morphology will also be performed.
• This cohort will undergo one additional visit, Week 6 for dose adjustment
based on assessments made at Week 4.
For EXPLORER-LTE Cohort Only
• Dose adjustments will occur based on data from the site-read echocardiogram
at Week 4, Week 8, and Week 12. Study site Investigators will not be blinded to
the site-read echocardiography results from these visits. Echocardiograms will
also be sent to a core laboratory for future assessment during data analysis.
• A site-read stress echocardiogram will be administered at Week 24 to evaluate
the post-exercise LVOT gradient and determine whether further dose adjustment
may be needed (to be discussed with the MyoKardia Medical Monitor).
Participants undergoing dose adjustment at Week 24 will be asked to return 28
days later (+/- 7 days) for echocardiographic assessment of their LVOT
gradient. Repeat of a subsequent post-exercise echocardiographic assessment of
LVOT gradient will be at the Investigator*s discretion.
• At any visit after Week 24, if the site-read LVOT gradient with Valsalva
maneuver is > 30 mm Hg and LVEF is >= 50%, then a dose increase may be
considered after discussion with the MyoKardia Medical Monitor.
• PRO assessments will be performed on-site
Intervention
MAVERICK-LTE Participants
All participants will receive mavacamten immediate-release capsules to achieve
1 of 2 target drug concentrations (Group 1: ~200 ng/mL;
Group 2: ~500 ng/mL). Study drug will be administered as 1 capsule QD by mouth.
Group assignment and dose strength from previous
study will be blinded.
Beginning on Day 1, participants who received active study drug in MAVERICK-HCM
will begin receiving mavacamten at the same dose
level they received at the EOT (Week 16) visit. These participants will undergo
the same assessments and visit schedule as participants who
received placebo in MAVERICK-HCM to preserve the blind (eg, study visits at
Week 4 and Week 6).
If in the MAVERICK-HCM study at Week 16 (EOT), a participant
has PK >= 1000 ng/ml, then the starting dose in this study will be:
• 5 mg if dose at EOT was 15 mg or 10 mg
• 2.5 mg if dose at EOT was 5 mg
Participants who received placebo in MAVERICK-HCM will be randomized in a 1:1
ratio to either Group 1 or Group 2. Randomization will be stratified according
to current treatment with beta blocker (yes or no). They will receive a
starting dose of 5 mg and undergo blinded dose adjustment through an
interactive response system (IXRS) at Week 6 based on assessments made at Week
4.
EXPLORER-LTE Participants
Participants will receive mavacamten immediate-release capsules at a starting
dose of 5 mg QD, for 4 weeks. Dose adjustments will occur on the day of the
visit, based on results of the site-read TTE assessment. All dose adjustments
will occur through IXRS, based on TTE data entered by the study site.
Study burden and risks
The following information about adverse events was obtained from studies of
mavacamten in patients with HCM as of October 30, 2020.
As of 30 October 2020, more than 300 subjects with cardiomyopathy have been
enrolled across completed and ongoing studies and treated with mavacamten.
Side effects that are considered to be related to taking mavacamten:
In a clinical study of subjects with obstructive HCM
• Dizziness (very common, mild or moderate, not serious)
o In the main clinical study, dizziness occurred during the treatment period in
17% of subjects treated with*mavacamten and 12% of subjects who took placebo.
• Heart failure due to systolic dysfunction (common, severe, serious)*
o Heart failure occurred during the treatment period in 2% of subjects treated
with mavacamten and 2% of subjects who took placebo in the main clinical
study.*
o Systolic dysfunction (measured as left ventricular ejection fraction (LVEF)
<50% on echocardiography) occurred during the treatment period in 6% of
subjects treated with mavacamten and 2% of subjects who took placebo in the
main clinical study.*
o In clinical studies overall, heart failure and systolic dysfunction related
to mavacamten have been reversible after stopping mavacamten.*
In a clinical study of subjects with nonobstructive HCM, short-lived ejection
fraction reductions, or a decline in the heart*s ability to pump blood,
occurred in 5 subjects (12.5%) on mavacamten and led to study drug
discontinuation. All 5 subjects recovered following discontinuation of
mavacamten.
Other potential risks under evaluation:
Changes in electrical activity in the heart (Prolonged QT Interval):
In studies conducted in healthy subjects, small changes in the electrical
activity of the heart have been observed at higher doses of mavacamten tested.
However, other laboratory studies and other studies in animals have shown that
these changes in electrical activity of the heart are not expected to result in
irregular heartbeat. In addition, in patients with HCM, such changes in
electrical activity (prolonged QTc interval) have not been more frequent in
patients treated with Mavacamten compared to those on placebo. There has been
no increase in dangerous disruption of heart rhythms associated with prolonged
QTc interval in patients with HCM treated with Mavacamten. There is no
information on QTc prolongation in patients with other types of heart failure.
Sierra Point Parkway 1000
Brisbane CA 94005
US
Sierra Point Parkway 1000
Brisbane CA 94005
US
Listed location countries
Age
Inclusion criteria
1. Has completed the Parent Study through to the EOS Visit within
90 days of signing consent. (Participants who are beyond the 90
day window from EOS Visit may be included in this study
pending MyoKardia Medical Monitor approval). Participants who prematurely
discontinued
from the Parent Study or the MAVA LTE study may be considered for
inclusion.
2. Is able to understand and comply with the study procedures,
understand the risks involved in the study, and provide informed
consent according to federal, local, and institutional guidelines
before the first study-specific procedure
3. Body weight is greater than 45 kg at the Screening Visit or Day 1
(Day 1 weight must be verified prior to dosing)
4. Has adequate acoustic windows to enable accurate TTEs (refer to
Echocardiography Site Instruction Manual)
5. Has documented LVEF >= 50% by echocardiography core
laboratory read of screening TTE at rest
6. Has safety laboratory parameters within normal limits (according
to the central laboratory reference range); however, a participant
with safety laboratory parameters outside normal limits may be
included if he or she meets all of the following criteria:
• The safety laboratory parameter outside normal limits is
considered by the Investigator to be clinically unimportant
• If there is an alanine aminotransferase or aspartate
aminotransferase result, the value must be < 3× the upper limit
of the laboratory reference range
• The body size-adjusted estimated glomerular filtration rate is
>= 30 mL/min/1.73 m2
7. Female participants must not be pregnant or lactating and, if
sexually active, must use one of the following highly effective
birth control methods from the Screening Visit through 90 days
after the last dose of investigational medicinal product (IMP).
• combined (estrogen- and progestogen-containing) hormonal
contraception associated with inhibition of ovulation or
progestogen-only hormonal contraception associated with inhibition of ovulation
by oral, implantable, or injectable route
of administration
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• Female is surgically sterile for 6 months or postmenopausal
for 1 year. Permanent sterilization includes hysterectomy,
bilateral oophorectomy, bilateral salpingectomy, and/or
documented bilateral tubal occlusion at least 6 months prior to
Screening. Females are considered postmenopausal if they
have had amenorrhea for at least 1 year or more following
cessation of all exogenous hormonal treatments and follicle
stimulating hormone (FSH) levels are in the postmenopausal
range.
• In addition to the above contraceptive requirements for female
participants, male partners must also use a contraceptive (eg,
barrier, condom, or vasectomy)
Exclusion criteria
1. Has persistent or permanent atrial fibrillation not on
anticoagulation for at least 4 weeks prior and/or is not adequately
rate-controlled
(Note: participants with persistent or permanent atrial fibrillation
who are anticoagulated and adequately rate-controlled are
allowed)
2. Is currently taking, or has taken within 14 days of Screening, a
prohibited medication such as a cytochrome P450 (CYP) 2C19
inhibitor (eg, omeprazole), a strong CYP 3A4 inhibitor, or St.
John*s Wort (see APPENDIX 2 for more details)
3. Has QTcF > 500 ms at Screening or any other ECG abnormality
considered by the Investigator to pose a risk to participant safety
(eg, second degree atrioventricular block type II)
4. Has documented obstructive coronary artery disease (> 70%
stenosis in one or more epicardial coronary arteries) or history of
myocardial infarction
5. Has known moderate or severe (as per Investigator*s judgment)
aortic valve stenosis at Screening Visit
6. Has hypersensitivity to any of the components of the mavacamten
formulation
7. Has participated in a clinical trial in which the participant received
any investigational drug (or is currently using an investigational device)
within 30 days prior to Screening, or at least 5 times the respective
elimination half life (whichever is longer), except for participation in
MAVERICK-HCM or EXPLORER-HCM. Prior participation in a noninterventional
observational study is
allowed.
8. Has a history of syncope or a history of sustained ventricular
tachyarrhythmia with exercise between Parent Study EOS Visit and
Screening
Visit.
9. Has a history of resuscitated sudden cardiac arrest or known history
of appropriate implantable cardioverter-defibrillator (ICD) discharge for
life-threatening ventricular arrhythmia between Parent Study EOS Visit
and Screening
Visit.
(Note: history of anti-tachycardia pacing (ATP) is
allowed)
10. Currently treated with disopyramide or ranolazine (within 14 days
prior to Screening Visit) or treatment with disopyramide or ranolazine is
planned during the
study
11. Currently treated or planned treatment during the study with a
combination of beta blocker and verapamil or a combination of beta
blocker and
diltiazem
12. Has any acute or serious comorbid condition (eg, major infection or
hematologic, renal, metabolic, gastrointestinal, or endocrine
dysfunction) that, in the judgment of the Investigator, could lead to
premature termination of study participation or interfere with the
measurement or interpretation of the efficacy and safety assessments in
the
study
13. History of clinically significant malignant disease that developed
since enrollment in the Parent
Study
• Participants who have been successfully treated for nonmetastatic
cutaneous squamous cell or basal cell carcinoma or have been
adequately treated for cervical carcinoma in situ or breast ductal
carcinoma in situ (DCIS) can be included in the
study
14. Is unable to comply with the study requirements, including the
number of required visits to the clinical site
15. Is employed by or is a relative of someone employed by MyoKardia,
the Investigator, or his/her staff or family
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 | CTIS2022-502858-14-00 |
| EudraCT | EUCTR2018-004039-64-NL |
| CCMO | NL70105.028.19 |
| Other | nog niet bekend |