| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| hypertrophic cardiomyopathy (HCM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| heart disease with thickening of the heart muscle |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020871 |
| E.1.2 | Term | Hypertrophic cardiomyopathy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the safety and tolerability of CK3773274 in patients with symptomatic HCM |
|
| E.2.2 | Secondary objectives of the trial |
To describe the concentration-response relationship of CK3773274 on the resting and post-Valsalva LVOT-G on echocardiogram over 10 weeks of treatment in patients with oHCM (Cohorts 1, 2, 3 only).
To describe the dose response relationship on LVOT-G (resting and Valsalva) of CK3773274 in patients with symptomatic oHCM (cohorts 1, 2 and 3 only).
To evaluate the concentration-response relationship of CK3773274 on resting left ventricular ejection fraction (LVEF) over 10 weeks of treatment in patients with HCM.
To evaluate the plasma concentrations of CK-3773274 in patients with HCM. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Males and females between 18 and 85 years of age at Screening.
Body weight is ≥45 kg at Screening.
Diagnosed with HCM per the following criteria:
• Has LV hypertrophy with non-dilated LV chamber in the absence of other cardiac disease.
• Has minimal wall thickness ≥15 mm (minimal wall thickness ≥13 mm is acceptable with a positive family history of HCM or with a known disease-causing gene mutation).
Adequate acoustic windows for echocardiography.
For Cohorts 1,2 and 3 has LVOT-G during screening as follows:
• Resting gradient ≥50 mmHg
OR
• Resting gradient ≥30 mmHg and <50 mmHg with post-Valsalva LVOT G ≥50 mmHg
LVEF ≥60% at screening.
New York Heart Association (NYHA) Class II or III at Screening.
Patients on beta-blockers, verapamil, diltiazem, or ranolazine should have been on stable doses for >4 weeks prior to Randomization and anticipate remaining on the same medication regimen during the study.
For Cohort 3: Patients must be taking disopyramide. Patients should have been on stable disopyramide doses for >4 weeks prior to screening and anticipate remaining on the same medication regimen during the study.
For Cohort 4 has resting and post-Valsalva LVOT-G <30 mmHg at the time of screening.
For Cohort 4 has elevated NT-proBNP >300 pg/mL at the time of screening.
|
|
| E.4 | Principal exclusion criteria |
- Aortic stenosis or fixed subaortic obstruction.
- Known infiltrative or storage disorder causing cardiac hypertrophy that mimics HCM (eg, Noonan syndrome, Fabry disease, amyloidosis).
- History of LV systolic dysfunction (LVEF <45%) at any time during their clinical course.
- Documented history of current obstructive coronary artery disease (>70% stenosis in one or more epicardial coronary arteries) or documented history of myocardial infarction.
- Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the study period (Cohorts 1, 2, and 3 only). Patients having undergone septal reduction therapy > 12 months prior to screening who remain symptomatic from nHCM, and who meet all other criteria for inclusion, may be enrolled in Cohort 4.
- For Cohorts 1, 2 and 4: Has been treated with disopyramide or antiarrhythmic drugs that have negative inotropic activity within 4 weeks prior to screening. For Cohort 3, use of disopyramide is required.
- Paroxysmal atrial fibrillation or flutter documented during the Screening period.
- Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-current cardioversion, ablation procedure, or antiarrhythmic therapy) ≤6 months prior to screening. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequately rate-controlled for >6 months.)
- History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to Screening.
- Has received prior treatment with CK3773274 or is currently receiving mavacamten.
- For Cohort 4: has any documented history of LVOT-G ≥ 30 mmHg at rest, with Valsalva, or with exercise (for subjects who have had prior septal reduction therapy, this exclusion criteria only applies to gradients detected following septal reduction therapy). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Patient incidence of reported AEs
• Patient incidence of reported SAEs
• Patient incidence of LVEF < 50%
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Cohorts 1, 2 and 3 only:
• The slope of the relationship of the plasma concentration of CK3773274 to the change from baseline in the resting LVOT-G
• The slope of the relationship of the plasma concentration of CK3773274 to the change from baseline in the post-Valsalva LVOT-G
• The change from baseline in resting and post-Valsalva LVOT-G over time as a function of dose
• The change from baseline in resting and post-Valsalva LVOT-G to Week 10
All Cohorts:
• Slope of the relationship of the plasma concentration of CK-3773274 to the change from baseline in the resting LVEF
• Observed maximum plasma concentration (Cmax) and trough plasma concentration (Ctrough) for CK-3773274 during dosing |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Cohorts 1 & 2 are randomized and placebo-controlled. Cohorts 3 & 4 all participants are assigned IMP |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Netherlands |
| Spain |
| Italy |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 20 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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