| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Obstructive hypertrophic cardiomyopathy (oHCM) |
| Cardiomiopatia ipertrofica ostruttiva (oHCM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Heart disease with thickening of the heart muscle |
| Malattia cardiaca con ispessimento del muscolo cardiaco |
|
| 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 oHCM |
| Determinare la sicurezza e la tollerabilità di CK3773274 in pazienti con oHCM sintomatica |
|
| 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.
To describe the dose response relationship of CK3773274 in patients with symptomatic oHCM.
To evaluate the plasma concentrations of CK3773274 in patients with oHCM. |
Descrivere la relazione concentrazione-risposta di CK3773274 all’elettrocardiogramma di LVOT-G a riposo e post-Valsalva nelle 10 settimane di trattamento.
Descrivere la relazione dose-risposta di CK3773274 in pazienti con oHCM sintomatica.
Valutare le concentrazioni plasmatiche di CK3773274 in pazienti con oHCM. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 (SoA). Males and females between 18 and 70 years of age at Screening.
Body weight is =45 kg at Screening. Diagnosed with oHCM per the following criteria:
• Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease.
• Has minimal wall thickness =15 mm at time of initial diagnosis (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.
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. |
In grado di comprendere e acconsente a firmare l’ICF e acconsente a aderire a tutte le procedure e le restrizioni dello studio per la durata specificata nel Programma delle attività (SoA).
Pazienti di sesso maschile o femminile di età compresa tra 18 e 70 anni allo Screening.
Peso corporeo =45 kg allo screening.
Con diagnosi di oHCM in base ai seguenti criteri:
• Con ipertrofia LV e camera LV non dilatata in assenza di altra malattia cardiaca.
• Con spessore minimo della parete =15 mm al momento della diagnosi iniziale (uno spessore minimo della parete =13 mm è accettabile con una anamnesi familiare positiva di HCM o con una mutazione genica causativa nota).
Finestre acustiche adeguate per l’ecocardiografia.
Con LVOT-G durante lo screening come segue:
• Gradiente a riposo =50 mmHg
OPPURE
• Gradiente a riposo =30 mmHg e <50 mmHg con LVOT-G post-Valsalva =50 mmHg
LVEF =60% allo screening.
Classe II o III della New York Heart Association (NYHA) allo screening.
Pazienti che assumono beta-bloccanti, verapamil, diltiazem o ranolazina devono essere stati a dosi stabili per > 4 settimane prima della Randomizzazione e prevedere di rimanere allo stesso regime di trattamento durante lo studio. |
|
| E.4 | Principal exclusion criteria |
Aortic stenosis or fixed subaortic obstruction.
Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM (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. Has been treated with disopyramide or antiarrhythmic drugs that have negative inotropic activity within 4 weeks prior to screening.
Documented atrial fibrillation during the Screening period.
Paroxysmal atrial fibrillation or flutter requiring treatment (eg, anticoagulation or antiarrhythmic therapy including disopyramide) documented within the 6 months prior to Screening.
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. |
Stenosi aortica o ostruzione subaortica fissa.
Malattia infiltrativa o da accumulo nota che provoca ipertrofia cardiaca che mimica oHCM (ad es. sindrome di Noonan, malattia di Fabry, amiloidosi).
Anamnesi di disfunzione sistolica LV (LVEF <45%) in qualsiasi momento durante il decorso clinico.
Anamnesi documentata di attuale coronaropatia ostruttiva (>70% stenosi in una o più arterie coronarie epicardiche) o anamnesi documentata di infarto del miocardio.
Ha ricevuto un trattamento con terapia di riduzione del setto (miectomia chirurgica o ablazione percutanea alcolica del setto) o prevede di sottoporsi a uno dei due trattamenti durante lo studio.
È stato/a trattato/a con disopiramide o farmaci antiaritmici che hanno una attività inotropica negativa entro 4 settimane prima dello screening.
Fibrillazione atriale documentata durante il periodo di screening.
Fibrillazione atriale parossistica o flutter che necessita di trattamento (ad es. terapia con anticoagulante o antiaritmica compreso disopiramide) documentata entro 6 mesi prima dello screening.
Anamnesi di sincope o tachiaritmia ventricolare sotto sforzo sostenuta entro 6 mesi prima dello screening.
Ha ricevuto un precedente trattamento con CK3773274 o sta attualmente ricevendo mavacamten. |
|
| 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% |
• Incidenza degli AE segnalati nei pazienti
• Incidenza degli SAE segnalati nei pazienti
• Incidenza di LVEF < 50% nei pazienti |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• 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
• Observed maximum plasma concentration (Cmax) and trough plasma concentration (Ctrough) for CK-3773274 |
• Curva del rapporto della concentrazione plasmatica di CK3773274 rispetto al cambiamento dal basale nel LVOT-G a riposo
• Curva del rapporto della concentrazione plasmatica di CK3773274 rispetto al cambiamento dal basale nel LVOT-G post-Valsalva
• Cambiamento dal basale nel LVOT-G a riposo e post-Valsalva nel tempo in funzione della dose
• Cambiamento dal basale nel LVOT-G a riposo e post-Valsalva fino alla Settimana 10
• Concentrazione plasmatica massima (Cmax) e concentrazione plasmatica minima (Ctrough) osservate per CK-3773274 |
|
| 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 | 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 | No |
| 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 | 1 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 | Information not present in EudraCT |
| 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 |
| Netherlands |
| Spain |
| United Kingdom |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 24 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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