A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation

JRCT ID: jRCT2051210191

Registered date:09/03/2022

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: *Dilated Cardiomyopathy *Lamin A/C Gene Mutation
• Date of first enrollment: 27/07/2022
• Target sample size: 200
• Countries of recruitment: Argentina,Japan,Belgium,Japan,Canada,Japan,Italy,Japan,Mexico,Japan,Netherlands,Japan,Norway,Japan,Spain,Japan,United Kingdom,Japan,United States,Japan
• Study type: Interventional

Intervention(s)

Drug: ARRY-371797 (PF-07265803)
400 mg twice daily (BID)
Other: Placebo
BID

Drug: ARRY-371797 (PF-07265803)
400 mg twice daily (BID)

Outcome(s)

Primary Outcome

Primary Outcome Measures :
1.Change from baseline in 6-minute walk test (6MWT) [ Time Frame: at Week 24 ]
The 6 MWT measures the distance walked over a total of six minutes on a hard, and flat surface.

Secondary Outcome

Secondary Outcome Measures :
1.Change from baseline in 6-minute walk test (6MWT) [ Time Frame: at Weeks 4 and 12 ]
The 6 MWT measures the distance walked over a total of six minutes on a hard, and flat surface.
2.Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) domain [ Time Frame: at Weeks 12 and 24 ]
The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The PL is a single domain consisting of 7 items scored using a range of 0 - 100, in which higher scores reflect better physical functioning status.
3.Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) as measured by Total Symptom Score (TSS) domain [ Time Frame: at Weeks 12 and 24 ]
The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The TSS is a combined score based upon the symptom burden, symptom frequency and symptom severity domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
4.Change from baseline in Patient Global Impression score of Severity(PGI-S) of heart failure symptoms and physical activity limitations [ Time Frame: at Weeks 12 and 24 ]
Measured by the scale of: none, mild, moderate, severe or very severe (listed from better to worse)
5.Change from baseline in Patient Global Impression score of Change (PGI-C) in heart failure symptoms and physical activity limitations [ Time Frame: at Weeks 12 and 24 ]
Measured by the scale of: very much better, moderately better, a little better, no change, a little worse, moderately worse, very much worse (listed from better to worse).
6.Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [ Time Frame: at Weeks 4, 12 and 24 ]
7.Evaluate the impact of ARRY-371797 (PF-07265803) on composite endpoint of all-cause mortality, or worsening heart failure (WHF). [ Time Frame: From randomization up to 80 months. ]
Defined as the time from randomization to the first occurrence of any event of death due to any cause, or worsening heart failure (HF-related hospitalization or HF-related urgent care visit).
8.Evaluate the impact of ARRY-371797 (PF-07265803) on overall survival (OS). [ Time Frame: From randomization up to 80 months. ]
Defined as the time from randomization until death due to any cause.
9.Evaluate the safety of ARRY-371797 (PF-07265803). [ Time Frame: From randomization up to 80 months. ]
Incidence and severity of adverse events. Changes in clinical safety laboratory tests, vital signs, and 12 lead ECGs, and incidence and severity of ventricular or atrial arrhythmias detected.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

Selected Key Inclusion Criteria:
*Patients with symptomatic lamin A/C protein (LMNA)-related cardiomyopathy Class II/III/ or Class IV defined as:
*Gene positive for a pathogenic, likely pathogenic, or VUS mutation in the LMNA gene as determined by an accredited clinical laboratory.
*Evidence of cardiac impairment in LVEF <= 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 and defibrillation function activated at least 4 weeks prior to initiation of study treatment.
*Class II/III patients must have objective functional impairment evidenced by a reduction in 6-minute walk test (6MWT);a. Screening: 6MWT distance >100 m but <=450 m, AND b. Day -1 visit: 6MWT distance >100 m but <=485 m, AND c. Baseline visit (Day 1): 6MWT distance >100 m but <=485 m
*Class II/III patients must be stable for at least 3 months
*Stable medical and/or device therapy consistent with regional American Heart Association (AHA) / American College of Cardiology (ACC) or European Society of Cardiology (ESC) guidelines at the investigator discretion, without change in heart failure drug(s) dose in the past 1 month.
*Patients must meet acceptable hematology, hepatic and renal laboratory values within 35 days prior to Day 1 as specified in the protocol

Exclude criteria

Selected Key Exclusion Criteria:
*Presence of other form(s) of cardiomyopathy contributing to HF (eg, inflammatory or infiltrative cardiomyopathy), clinically significant cardiac anatomic abnormality (eg,LV aneurysm), clinically significant coronary artery disease (eg, coronary revascularization, exercise induced angina) or uncorrected, hemodynamically significant (ie, moderate-severe) primary structural valvular disease not due to HF, per investigator judgment.
*Currently receiving intermittent or continuous IV inotrope infusion, or presence of a ventricular assist device, or history of prior heart transplantation. Participants listed for cardiac transplantation may be enrolled provided transplantation is not likely to occur in the next 6 months.
*Myocardial infarction, cardiac surgical procedures (other than for pacemaker/ICD/CRT-D implantation or replacement), acute coronary syndrome, serious systemic infection with evidence of septicemia, or any major surgical procedure requiring general anesthesia within 3 months prior to screening.
*Currently receiving or deemed at high risk of requiring chronic renal replacement therapy (e.g., hemodialysis or peritoneal dialysis) within 6 months.
*Initiation of CRT within 6 months prior to screening.
*Treatment with any investigational agent(s) for HF within 35 days prior to Day 1.
*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 review by 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.

Related Information

• Primary Sponsor: Kawai Norisuke
• Secondary ID(s): NCT03439514