| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| obstructive hypertrophic cardiomyopathy (oHCM) |
| miocardiopatía hipertrófica obstructiva (MHO) |
|
| E.1.1.1 | Medical condition in easily understood language |
| heart disease with thickening of the heart muscle |
| Cardiopatía con engrosamiento del miocardio. |
|
| 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 oHCM |
| Determinar la seguridad y la tolerabilidad de CK3773274 en pacientes con MHO sintomática |
|
| E.2.2 | Secondary objectives of the trial |
To assess long-term effects of CK-3773274 on left ventricular outflow tract gradient (LVOT-G)
To assess steady-state PK during long-term administration of CK-3773274 |
Evaluar los efectos a largo plazo de CK3773274 en el gradiente del infundíbulo del ventrículo izquierdo (G-IVI)
Evaluar la FC en estado de equilibrio durante la administración a largo plazo de CK3773274 CK3773274 |
|
| 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.
Patients with eGFR <30 mL/min/1.73 m2 or an allergy to gadolinium may only be given non-contrast CMR.
Subsequent CMR studies will be performed at the Q12W visit corresponding to Weeks 48, 144 and 240. |
Un subestudio de imágenes de resonancia magnética cardíaca (RMC) evaluará los efectos de la administración a largo plazo de CK-3773274 sobre la morfología cardíaca, la función y la fibrosis en los pacientes con MHo que sean elegidos para participar en el estudio y cumplan los criterios pertinentes. Se realizará una RMC en el periodo inicial.
En el caso de los pacientes con una TFGe <30 ml/min/1,73 m2 o alergia al gadolinio, es posible que solo se realice una RMC sin contraste. Los estudios de RMC posteriores se realizarán en las visitas programadas cada 12 semanas correspondientes a las semanas 48, 144 y 240. |
|
| 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 trial 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 ≥ 55%.
4. Male patients are eligible to participate if they agree to the following during the study and for at least 10 weeks after the last dose of IP:
a. Refrain from donating sperm
Plus either:
b. Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
Must agree to use a male condom and, when his female partner is a woman of childbearing potential, 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 or breastfeeding, 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]) 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) within 3 days before the first dose of study intervention.
Note: The Principal Investigator 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. |
En el estudio solo podrán participar los pacientes que cumplan todos los criterios enumerados a continuación:
1. Pacientes con capacidad de comprensión y que estén dispuestos a firmar un FCI y a cumplir todas las restricciones y procedimientos del estudio durante el intervalo de tiempo especificado en el calendario de actividades.
2. Finalización de un ensayo de Cytokinetics en el que se investigue CK-3773274. En caso de que no se pueda finalizar el ensayo debido a circunstancias no relacionadas con el cumplimiento o la seguridad, el supervisor médico podrá revisar y determinar la elegibilidad.
3. Fracción de eyección ventricular izquierda ≥55 %.
4. Los pacientes varones podrán participar si aceptan cumplir con lo siguiente a lo largo del estudio y durante como mínimo las diez semanas posteriores a haber recibido la última dosis del PEI:
a. Abstenerse de donar semen.
Más una de las siguientes:
b. Abstenerse de tener relaciones heterosexuales de acuerdo con su estilo de vida preferido y habitual (abstinencia a largo plazo y de forma persistente) y aceptar mantener dicha abstinencia;
O BIEN,
comprometerse a usar un preservativo masculino y, en caso de que su pareja femenina sea una mujer potencialmente fértil, pedir a su pareja femenina que use un método anticonceptivo muy eficaz (tal y como se describe en el Apéndice 3 [Apartado 10.3] del protocolo).
5. Una paciente femenina podrá participar si no está embarazada ni en fase de lactancia, y además cumple una de las siguientes condiciones:
a. No ser una mujer potencialmente fértil (MPF, tal y como se describe en el Apéndice 3 [Apartado 10.3] del protocolo);
O BIEN,
ser una MPF y usar un método anticonceptivo muy eficaz (tal y como se describe en el Apéndice 3 [Apartado 10.3]) durante el estudio y, como mínimo, durante las cuatro semanas siguientes a haber recibido la última dosis del PEI.
b. Las MPF deben obtener un resultado negativo en una prueba de embarazo (orina o suero según lo requiera la normativa local) en el plazo de los tres días anteriores a recibir la primera dosis de la intervención del estudio.
Nota: El investigador principal tendrá la responsabilidad de revisar los antecedentes médicos, el historial menstrual y la actividad sexual reciente para reducir el riesgo de incluir a una mujer con un embarazo precoz no detectado.
El uso de anticonceptivos por parte de los hombres y las MPF debe ser conforme con las pautas del Apéndice 3 (Apartado 10.3) y la normativa local relativa a los métodos anticonceptivos en participantes en estudios clínicos.
6. Pacientes dispuestos a completar todos los procedimientos de selección. |
|
| E.4 | Principal exclusion criteria |
• Has taken any investigational study drug other than CK-3773274 within 30 days prior to screening.
• Since completion of a previous trial of CK-3773274 has:
− Developed new-onset paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-current cardioversion, ablation procedure, or antiarrhythmic therapy) <30 days prior to screening. Patient may re-screen for CY 6022 after 30 days if heart rate (HR) <100 bpm and/or rhythm is stable >30 days.
− Undergone septal reduction therapy (surgical myectomy or transcatheter alcohol ablation).
• Has current obstructive coronary artery disease (>70% stenosis documented in one or more arteries).
• Has moderate or severe aortic valve stenosis.
• Had a confirmed LVEF <40% with an associated dose interruption during CY 6021. If data from the participant's cohort has been unblinded, the patient may be considered for entry into CY 6022 (see Section 6.6.1 of the protocol).
• Has been treated with drugs that have negative inotropic activity within 30 days prior to screening.
• History of syncope or sustained ventricular tachyarrhythmia with exercise within 30 days prior to screening.
• History of appropriate ICD shock within 30 days prior to screening.
• Has received treatment with mavacamten within 3 months prior to screening.
Exclusion Criteria for CMR sub-study:
• Inability to tolerate CMR.
• Has an implantable cardioverter-defibrillator (ICD).
• Has a cardiac pacemaker. |
•Has taken any investigational study drug other than CK3773274 within 30 days prior to screening.
•Since completion of a previous trial of CK3773274 has:
Developed new-onset paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-current cardioversion, ablation procedure, or antiarrhythmic therapy) <30 days prior to screening. Patient may re-screen for CY 6022 after 30 days if heart rate (HR) <100 bpm and/or rhythm is stable >30 days.
Undergone septal reduction therapy (surgical myectomy or transcatheter alcohol ablation).
•Has current obstructive coronary artery disease (>70% stenosis documented in one or more arteries)
•Has moderate or severe aortic valve stenosis
•Had a confirmed LVEF <40% with an associated dose interruption during CY 6021. If data from the participant's cohort has been unblinded, the patient may be considered for entry into CY 6022 (see Section 6.6.1).
•Has been treated with drugs that have negative inotropic activity within 30 days prior to screening.
•History of syncope or sustained ventricular tachyarrhythmia with exercise within 30 days prior to screening.
•History of appropriate ICD shock within 30 days prior to screening.
•Has received treatment with mavacamten within 3 months prior to screening.
Exclusion Criteria for CMR sub-study
•Inability to tolerate CMR
•Has an implantable cardioverter-defibrillator (ICD)
•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% |
• Incidencia en los pacientes de los acontecimientos adversos (AA) notificados
• Incidencia en los pacientes de los acontecimientos adversos graves (AAG) notificados
• Incidencia en los pacientes de una fracción de expulsión del ventrículo izquierdo (FEVI) <50 % |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of participation |
| Fin de participación |
|
| 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
3. C^trough at 12-week intervals through end of participation |
1. Cambio desde los valores basales, a intervalos de 12 semanas y hasta el final de la participación, de:
Valor máximo del G-IVI en reposo y con provocación de Valsalva
Proporción de pacientes con G-IVI <50 mmHg en reposo
Proporción de pacientes con G-IVI <30 mmHg en reposo
Proporción de pacientes con G-IVI <50 mmHg tras la maniobra de Valsalva
Proporción de pacientes con G-IVI <30 mmHg tras la maniobra de Valsalva
Proporción de pacientes con FEVI ≥50 %, G-IVI <30 mmHg en reposo y G-IVI <50 mmHg tras la maniobra de Valsalva
2. Tiempo transcurrido hasta el siguiente acontecimiento desde el último seguimiento
Primer G-IVI <50 mmHg en reposo
Primer G-IVI <30 mmHg en reposo
Primer G-IVI <50 mmHg tras la maniobra de Valsalva
Primer G-IVI <30 mmHg tras la maniobra de Valsalva
Primer FEVI ≥50 %, G-IVI <30 mmHg en reposo y G-IVI <50 mmHg tras la maniobra de Valsalva |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of participation |
| Fin de participación |
|
| 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
| 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 | 2 |
| 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 |
| Italy |
| 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
|
| LVLS |
| Ultima visita del ultimo participante |
|
| 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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