E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Dilated Cardiomyopathy (DCM) with Lamin A/C protein (LMNA) Mutation |
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E.1.1.1 | Medical condition in easily understood language |
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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 | LLT |
E.1.2 | Classification code | 10056419 |
E.1.2 | Term | Dilated cardiomyopathy |
E.1.2 | System Organ Class | 100000004849 |
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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 |
NYHA Class II/III patients only: Evaluate the effect of ARRY-371797 (PF-07265803) on functional capacity (as measured by the
6-minute walk test [6MWT]) compared to placebo |
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E.2.2 | Secondary objectives of the trial |
- NYHA Class II/III patients only: Evaluate additional measures
of efficacy of ARRY-371797 (PF-07265803) compared to placebo in the randomized period
- Characterize the plasma pharmacokinetics (PK) of ARRY-371797 (PF-07265803) and metabolites
- Evaluate the impact of ARRY-371797 (PF-07265803) on hospitalization-free survival
(HFS) and overall survival (OS)
- Evaluate the safety of ARRY-371797 (PF-07265803) compared to placebo |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Selected Key Inclusion Criteria:
• Provide a signed and dated informed consent document prior to
initiation of any study-related procedures. Patients under guardianship
or partial guardianship will be eligible unless prohibited by local laws or
by local/central ethic committees
• Age ≥ 18 years at time of informed consent
• Patients with symptomatic lamin A/C protein (LMNA)-related cardiomyopathy Class II/III/ or Class IV defined as:
o Gene positive for a deleterious mutation in the LMNA gene as
determined by the study central laboratory or by initial laboratory
testing (central confirmation of initial laboratory results is required prior
to randomization
o Evidence of cardiac impairment as determined by EF ≤ 50%
• Patient will have an implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator (ICD/CRT-D). ICD implanted at least 4 weeks prior to initiation of study treatment or CRT-D initiated at least 6 months prior to initiation of study treatment. Devices must include pacing capabilities or a separate pacemaker must be present.
• Class II/III patients must have objective functional impairment evidenced by a reduction in 6-minute walk test (6MWT);
• Stable medical and/or device therapy consistent with American Heart Association (AHA) / American College of Cardiology (ACC) or European Society of Cardiology (ESC) guidelines
• Patients must meet acceptable hematology, hepatic and renal laboratory values as specified within 35 days prior Day 1
• Affiliated to a social security system, or is a beneficiary (if applicable in
the national regulation)
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E.4 | Principal exclusion criteria |
Selected Key Exclusion Criteria:
• Presence of other form(s) of cardiomyopathy contributing to HF (e.g., inflammatory or infiltrative cardiomyopathy) or clinically significant cardiac anatomic abnormality (e.g., LV aneurysm).
• Clinically significant coronary artery disease (e.g., coronary revascularization, exercise-induced angina) per Investigator judgment.
• Uncorrected, hemodynamically significant (i.e., moderatesevere) primary structural valvular disease not due to HF.
• Currently receiving or deemed at high risk of requiring chronic renal replacement therapy (e.g., hemodialysis or peritoneal dialysis) within 6 months.
• Treatment with any investigational agent(s) for HF within 35 days prior to Day 1. Any treatment with an investigational agent(s) requires approval from the Medical Monitor.
• Malignancy that is active or has been diagnosed within 3 years prior to screening, except surgically curatively resected in situ malignancies or surgically cured early breast cancer, prostate cancer, skin cancer (basal cell carcinoma, squamous cell carcinoma), thyroid cancer or cervical
cancer, or, with prior approval from the Medical Monitor, other early stage surgically curatively resected malignancies with less than a 20% expected 2-year recurrence rate.
• Non-cardiac condition that limits lifespan to < 1 year.
• Serum positive for hepatitis B surface antigen, viremic hepatitis C, or human immunodeficiency virus (HIV) at screening.
• Pregnancy or breastfeeding, or patients who plan to become pregnant
during the duration of the trial
• Patients with an underlying condition that may impact the ability of the
6MWT to reflect changes in cardiovascular function such as: an
orthopedic condition that limits walking abilities (e.g., severe arthritis),
significant musculoskeletal pathology, significant chronic obstructive
pulmonary disease (COPD) that limits exercise tolerance or any other
condition that according to the Investigator's assessment significantly
limits a patient's performance on the 6MWT independently from the
patient's cardiomyopathy.
• Documented hypersensitivity/allergy or clinically significant
intolerance to any component of drug product. |
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E.5 End points |
E.5.1 | Primary end point(s) |
NYHA Class II/III patients only: Change from baseline in
6MWT at Week 12 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. NYHA Class II/III patients only: Change from baseline in 6MWT at Weeks 4 and 24
2. NYHA Class II/III patients only: Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) and Total Symptom Score (TSS) domains at Weeks 12 and 24
3. NYHA Class II/III patients only: Change from baseline in Patient Global Impression (PGI) scores at Weeks 12 and 24
- Patient Global Impression of Severity (PGI-S)
- Patient Global Impression of Change (PGI-C)
4. NYHA Class II/III patients only: Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) at Weeks 4, 12 and 24
5. Plasma concentrations of ARRY-371797 and metabolites (AR00420643, AR00428028 and AR00486705) predose and at a single time point postdose on specified visit days
6. HFS: Defined as the time from randomization to heart failure (HF) -
related hospitalization or death due to any cause
7: OS
8: Safety as determined by:
- Incidence and severity of adverse events (AEs)
- Changes in clinical safety laboratory tests, vital signs and 12-lead
electrocardiograms (ECGs)
- Incidence and severity of ventricular or atrial arrhythmias detected
clinically using existing implantable cardioverter defibrillator
(ICD)/cardiac resynchronization therapy defibrillator (CRT-D) or other
applicable device interrogations at Weeks 12 and 24, if applicable |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Weeks 4 and 24
2. Weeks 12 and 24
3. Weeks 12 and 24
4. Weeks 4, 12 and 24
5. Predose and at a single time point postdose on specified visit days
6. Throughout the duration of the study
7. Throughout the duration of the study
8. Safety endpoints throughout the duration of the study |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 |
Randomized, double-blind treatment period followed by open-label treatment period |
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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
| 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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Argentina |
Belgium |
Canada |
France |
Germany |
Italy |
Mexico |
Netherlands |
Norway |
Spain |
United Kingdom |
United States |
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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
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The end of the study is reached when all patients enrolled into the
randomized portion of the study have had the opportunity to be followed for at least 24 weeks in the open-label or have discontinued from the study, whichever comes first
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
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 |