| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| symptomatic 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 CK-3773274 in patients with symptomatic HCM |
|
| E.2.2 | Secondary objectives of the trial |
To assess long-term effects of CK-3773274 on left ventricular outflow tract gradient (LVOT-G) in patients with oHCM
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A cardiac magnetic resonance (CMR) imaging sub-study will assess the effects of long-term administration of CK-3773274 dosing on cardiac morphology, function and fibrosis in those oHCM patients who are eligible and elect to participate. CMR will be performed at baseline any time during the screening period and may be performed within 8 weeks prior to the first dose of IP given on Day 1. Patients that screen fail and rescreen do not need a repeat baseline CMR.
NOTE: Baseline CMR does not need to be repeated if subject has enrolled in the CY-6031 CMR sub-study.
Patients with eGFR <30 mL/min/1.73 m^2 or an allergy to gadolinium may only be given non-contrast CMR. Patients may also choose only non-contrast CMR evaluations for any other reason.
Subsequent CMR studies will be performed ± 30 days of the Week 48 and Week 144 visits, or within 60 days prior to the Week 240 or end of treatment (EOT) visit. |
|
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if all the following criteria apply:
1. Able to comprehend and willing to sign an ICF and willing to comply with all study procedures and restrictions for the duration specified in the Schedule of Activities.
2. Completion of a Cytokinetics study investigating CK-3773274. If unable to complete due to circumstances not related to compliance or safety, Medical Monitor may review and determine eligibility.
3. Left ventricular ejection fraction (LVEF) ≥ 55%.
4. Male patients are eligible to participate if they agree to the following:
a. Refrain from donating sperm during the trial plus at least 10 weeks after the last dose of IP
AND
b. During the trial plus 4 weeks after the last dose of IP either:
− Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent in writing
OR
Must agree to use a male condom when his female partner is a woman of childbearing potential, and have his female partner use a highly effective method of contraception (as described in Appendix 3 [Section 10.3] of the protocol)
5. A female patient is eligible to participate if she is not pregnant, breastfeeding or planning to donate eggs, and at least one of the following conditions applies:
a. Is not a woman of childbearing potential (WOCBP; as described in Appendix 3 [Section 10.3] of the protocol)
OR
Is a WOCBP and using a highly effective method of contraceptive (as described in Appendix 3 [Section 10.3]) and male partner agrees to use a condom during the study and for at least 4 weeks after the last dose of IP.
b. A WOCBP must have a negative pregnancy test (urine or serum as required by local regulations) before the first dose of study IP.
Note: The Principal Investigator or designee is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Contraceptive use by men or WOCBPs should be consistent with the guidance in Appendix 3 (Section 10.3) and local regulations regarding the methods of contraception for those participating in clinical studies.
6. Willing and able to complete all screening procedures.
|
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if any of the following criteria apply:
1. Has received treatment with mavacamten:
(a) within 56 days prior to dosing and
(b) has not received approval for participation from the Medical Monitor.
2. Has participated in another investigational device or drug study or received an investigational device or drug <1 month (or 5 half-lives for drugs, whichever is longer) prior to screening. Other investigational procedures while participating in this study are not permitted.
3. Has any acute or serious comorbid condition (e.g., major infection or hematologic, oncologic, cardiac, renal, metabolic, gastrointestinal, or endocrine dysfunction) that, in the opinion of the site Principal Investigator/designee or Medical Monitor, would pose a risk to patient safety or interfere with the study evaluation, procedures, or completion
4. Since completion of a previous study of CK-3773274, has developed new-onset paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (e.g., direct-current cardioversion, ablation procedure, or antiarrhythmic therapy) within 30 days prior to screening. Patient may re-screen for CY 6022 after 30 days if rate (heart rate <100 bpm) and/or rhythm is stable >30 days. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequately rate-controlled for ≥14 days.)
5. Since completion of a previous study of CK-3773274, has undergone septal reduction therapy (surgical myectomy or transcatheter alcohol ablation) since the completion of a prior study of CK-3773274.
6. Had a confirmed LVEF <40% with an associated dose interruption during participation in a prior study with CK-3773274. If data from the patient's cohort has been unblinded, the patient may be considered for entry into CY 6022 after the patient’s unblinded data have been reviewed by Cytokinetics and discussion between the Principal Investigator (or designee) and Medical Monitor.
7. History of implantable cardioverter-defibrillator (ICD) placement within 30 days prior to screening.
8. Hypersensitivity to excipients in CK-3773274 Tablets, Film-Coated
Criteria for CMR sub-study
1. Does not consent to participate in CMR sub-study
2. Inability to tolerate CMR
3. Has an ICD.
4. Has a cardiac pacemaker. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Patient incidence of reported adverse events (AEs)
• Patient incidence of reported serious adverse events (SAEs)
• Patient incidence of left ventricular ejection fraction (LVEF) <50% |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Change from baseline values at 12-week intervals through end of participation in:
− Peak LVOT-G at rest and with Valsalva provocation
− Proportion of patients with resting LVOT-G <50 mmHg
− Proportion of patients with resting LVOT-G <30 mmHg
− Proportion of patients with post-Valsalva LVOT-G <50 mmHg
− Proportion of patients with post-Valsalva LVOT-G <30 mmHg
− Proportion of patients with LVEF ≥50%, resting LVOT-G <30 mmHg, and post-Valsalva LVOT-G <50 mmHg
2. Time to the following event through last follow-up
− First resting LVOT-G <50 mmHg
− First resting LVOT-G <30 mmHg
− First post-Valsalva LVOT-G <50 mmHg
− First post-Valsalva LVOT-G <30 mmHg
− First LVEF ≥50%, resting LVOT-G <30 mmHg, and post-Valsalva LVOT-G <50 mmHg
|
|
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Israel |
| United Kingdom |
| United States |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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