Condition médicale (spécialité visée)
Choix aire thérapeutique
Cardiologie et maladies vasculaires
Stades de cancer
Non applicable
Profil des participants
Sexe(s) des participants
Hommes
Femmes
Aptitude des participants
Majeurs aptes
Critères de sélection
Critères d'inclusion
1) Signed Written Informed Consent
a) Participants must have signed and dated an Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written informed consent form (ICF) in accordance with regulatory, local, and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal patient care.
2) Age of Participant
a) Participant must be 18 years of age (or local age of majority) inclusive at the time of signing the ICF.
3) Type of Participant and Target Disease Characteristics
a) Able to understand and comply with study procedures, understand the risks involved in the study, and provide written informed consent before the first study-specific procedure.
b) Body weight > 45 kg at screening.
c) Adequate acoustic windows to enable accurate TTEs.
d) Diagnosed with oHCM, in accordance with current American College of Cardiology Foundation/American Heart Association and European Society of Cardiology guidelines (ie, satisfy both criteria below):
i) Unexplained LV hypertrophy with nondilated ventricular chambers in the absence of other cardiac (eg, hypertension, aortic stenosis) or systemic disease, which can produce the required magnitude of hypertrophy, and with maximal LV wall thickness ≥ 15 mm (or ≥ 13 mm with positive family history of HCM), as determined by site interpretation,
AND
ii) LVOT peak gradient ≥ 30 mm Hg during the screening period, as assessed by echocardiography at rest, and ≥ 50 mm Hg after Valsalva or after exercise, as determined by echocardiography site interpretation.
e) Documented LVEF ≥ 55% at rest, as determined by site interpretation of screening TTE.
f) NYHA Functional Class II or III symptoms at screening.
g) Documented oxygen saturation ≥ 90% at rest at screening and baseline.
4) Reproductive Status
• Investigators shall counsel WOCBP (as defined in APPENDIX 4) participants on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
• The investigator shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
• Local laws and regulations may require the use of alternative and/or additional contraception methods.
a) Female Participants:
i) Women who are not of childbearing potential (as defined in APPENDIX 4) are exempt from contraceptive requirements.
ii) WOCBP must have a negative highly sensitive serum pregnancy test at the screening visit and a negative highly sensitive urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 24 hours prior to the start of study
intervention.
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must
be excluded from participation if the serum pregnancy result is positive.
• Additional requirements for pregnancy testing during and after study intervention are located in the SOA (Section 2).
• The investigator is responsible for review of medical history and menstrual history to potentially decrease the risk for inclusion of a woman with an
undetected pregnancy.
iii) WOCBP must agree to follow instructions for methods of contraception (as described in APPENDIX 4 and also below) and included in the ICF.
• WOCBP are permitted to use hormonal contraception methods (as described in APPENDIX 4).
iv) A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
(1) Is not a WOCBP
OR
(2) Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), preferably, with low user dependency,
as described in APPENDIX 4, during the study period until 4 months after the last dose of study intervention
b) Male Participants:
i) Male participants should maintain their usual practice with regard to contraception (if any); however, there are no specific requirements.
Critères d'exclusion
1) Medical Conditions
a) A known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM (eg, Fabry disease, glycogen storage disorder, or amyloidosis), or multiorgan system disease with LV hypertrophy (eg, Noonan syndrome).
b) Any medical condition whereby, in the judgment of the investigator, the participant is unable to perform stress echocardiography if needed.
c) A history of syncope or history of sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
d) A history of resuscitated sudden cardiac arrest (at any time) or life-threatening ventricular arrhythmia within 6 months prior to screening.
e) AF (paroxysmal, persistent, or permanent) without adequate heart rate control (≤ 100 bpm) within 2 months prior to screening (rescreening is allowed if criterion subsequently met).
f) AF not on current guideline-recommended anticoagulation for at least 4 weeks prior to screening (rescreening is allowed after meeting the 4-week criterion).
g) An implantable cardioverter defibrillator (ICD) or pacemaker, or another contraindication for CMR.
h) Any severe or hemodynamically significant (as per the investigator’s judgment) fixed LV outflow (eg, aortic valve stenosis) obstruction or regurgitation.
i) Documented obstructive coronary artery disease (> 70% stenosis in one or more epicardial coronary arteries) or history of myocardial infarction.
j) 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.
k) Pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation. Condition may be chronic (eg, chronic obstructive pulmonary disease) or acute (eg, pneumonia).
l) A history of malignant disease within 5 years of screening:
i) 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 as well as low risk prostate cancer can be included in the study.
ii) Participants with other malignancies who are cancer-free for more than 5 years before screening can be included in the study.
m) A positive serologic test at screening for infection with human deficiency virus (HIV), hepatitis C virus, or hepatitis B viru
2) Reproductive Status
a) Women who are pregnant.
b) Women with a positive pregnancy test.
c) Women who are breastfeeding.
d) Women who are lactating.
e) Women who are planning pregnancy during the study period.
f) WOCBP who are not using appropriate contraception methods
3) Prior/Concomitant Therapy
a) Has been successfully treated with invasive septal reduction (surgical myectomy or
percutaneous alcohol septal ablation [ASA]) within 6 months prior to screening or plans to
have either of these treatments during the study period. (Note: Participants with myectomy
or percutaneous ASA performed > 6 months prior to screening may be enrolled if study
eligibility criteria for Valsalva LVOT gradient are met.)
b) Is currently taking or has taken within 14 days prior to screening a prohibited medication,
such as a strong CYP 2C19 inhibitor (rescreening ×1 is allowed).
c) Prior treatment with cardiotoxic agents, such as doxorubicin or similar.
d) Prior history of any myosin inhibitor use.
4) Physical and Laboratory Test Findings
a) Has safety laboratory parameters (chemistry, hematology, and urinalysis) outside normal
limits (according to the central laboratory reference range) at screening, as assessed by the
central laboratory interpretation; however, a participant with safety laboratory parameters
outside normal limits may be included if he or she meets all of the following criteria
(rescreening ×1 is allowed, as applicable):
i) The safety laboratory parameter outside normal limits is considered to be clinically not significant by the investigator.
ii) Elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is < 3× upper limit of normal (ULN).
iii) The body size-adjusted estimated glomerular filtration rate (eGFR) is ≥ 30 mL/min/1.73 m2
5) Allergies and Adverse Drug Reactions
a) History of allergy to mavacamten or related compounds.
b) History of hypersensitivity to any of the components of the mavacamten formulation.
c) History of any significant drug allergy, such as anaphylaxis or hepatotoxicity.
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated.
b) Previously participated in a clinical study 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).
c) Is unable to comply with the study requirements, including number of required visits to the study site, per the investigator’s discretion.
d) Is a first-degree relative of personnel directly affiliated with the study at the study site, any study vendor, or the Sponsor.