A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
Condition: Dilated Cardiomyopathy; Lamin A/C Gene Mutation
MeSH terms: Cardiomyopathies; Cardiomyopathy, Dilated
Intervention: ARRY-371797 (PF-07265803); Placebo
Intervention description: 400 mg twice daily (BID); BID
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: The study will be conducted in 2 parts: a randomized, double-blind treatment period for at least 24 weeks, followed by an ARRY-371797 (PF-07265803) open-label treatment period.
Masking: Double (Participant, Investigator)
Masking description: During the randomized, double-blind period, patients, Investigators, site personnel and the sponsor personnel directly involved with the conduct of the study will remain blinded to assigned treatment, except for regulatory reporting requirements.
Enrollment: 77.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: cardiomyopathy; Lamin Type A; heart failure; ARRY-797; C4411002

Summary:

      This is a randomized, double-blind, placebo-controlled study in patients with dilated
      cardiomyopathy (DCM) due to a mutation of the gene encoding the lamin A/C protein (LMNA). The
      study will further evaluate a dose level of study drug (ARRY-371797) that has shown
      preliminary efficacy and safety in this patient population. After the primary analysis has
      been performed, eligible patients may receive open-label treatment with ARRY-371797.
    

Eligibility 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

          -  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.

        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 (eg, 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.