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A Phase 3, Multinational, Randomized, Placebo-controlled Study of ARRY-371797 in Patients with Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutations

Study category: Heart and Blood Conditions

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Description

This multinational Phase 3 study will evaluate the efficacy, safety and PK following treatment with ARRY-371797 compared with placebo (1:1 randomization) in at least 120 patients with NYHA functional Class II and III DCM secondary to LMNA mutations. NYHA functional Class IV patients (up to approximately 40) will ARRY-371797 (p38 MAP Kinase Inhibitor) Array BioPharma Inc. Clinical Study ARRAY-797-301 Protocol Version 2 7 Confidential 23 October 2017 also be enrolled (1:1 randomization) and will be assessed for overall safety and time from randomization to HF-related hospitalization or death due to any cause, in addition to PK and efficacy, if feasible. For the Class IV patients, some assessments (i.e., 6MWT, triplicate ECGs, echocardiograms (ECHO), arrhythmia, PK assessment and PD assessment) are considered optional based on whether the patient is ambulatory or not.

Details
Age

Adult

Eligibility

1. Age ≥ 18 years at time of informed consent. 2. Patients with symptomatic LMNA-related cardiomyopathy defined as all of the following: a. Gene positive for a deleterious mutation in the LMNA gene as determined by the study central laboratory or by local laboratory testing b. NYHA functional Class II or III that has been stable for at least 3 months; c. Evidence of cardiac impairment as determined by: i. Serum NT-proBNP (by local laboratory) > 400 pg/mL; AND ii. EF ≤ 50% (by ECHO local read). 3. Patient will have an ICD/CRT-D. 4. Objective functional impairment evidenced by a reduction in 6MWT; patients must meet all of the following 6MWT criteria: a. Screening: 6MWT distance >100 m but ≤ 450 m AND ≤ 70% predicted (by Troosters et al 1999); AND b. Day -1 and Baseline Visit (Day 1): 6MWT distance >100 m but ≤ 485 m AND ≤ 75% predicted (by Troosters et al 1999).

Detailed Eligibility: Inclusion Criteria for NYHA Functional Class II/III Patients: Patients of NYHA functional Class II or III must meet all of the following criteria at screening to be eligible for randomization into the study: 1. Provide a signed and dated informed consent document prior to initiation of any study-related procedures. 2. Age ≥ 18 years at time of informed consent. 3. Patients with symptomatic LMNA-related cardiomyopathy defined as all of the following: a. Gene positive for a deleterious mutation in the LMNA gene as determined by the study central laboratory or by local laboratory testing (central confirmation of local laboratory results is required either during screening or within 30 days of initiating study treatment); b. NYHA functional Class II or III that has been stable for at least 3 months; c. Evidence of cardiac impairment as determined by: i. Serum NT-proBNP (by local laboratory) > 400 pg/mL; AND ii. EF ≤ 50% (by ECHO local read). 4. Patient will have an ICD/CRT-D. 5. Patient will have a history of a reduced EF and at least one of the following: a. Atrioventricular conduction block of at least first degree, i.e., PR interval ≥ 220 msec during sinus rhythm; b. Family history of early onset HF/arrhythmia consistent with a diagnosis of idiopathic DCM. 6. Objective functional impairment evidenced by a reduction in 6MWT; patients must meet all of the following 6MWT criteria: a. Screening: 6MWT distance >100 m but ≤ 450 m AND ≤ 70% predicted (by Troosters et al 1999); AND b. Day -1 and Baseline Visit (Day 1): 6MWT distance >100 m but ≤ 485 m AND ≤ 75% predicted (by Troosters et al 1999). 7. In the judgment of the Investigator, the patient has impaired function due to symptomatic DCM rather than any noncardiac comorbidity that can significantly impair function. 8. Stable medical and/or device therapy consistent with American Heart Association (AHA) / American College of Cardiology (ACC) or European Society of Cardiology (ESC) guidelines, without change in HF failure drug(s) dose in the past 1 month. 9. Acceptable hematology laboratory values within 3 weeks prior to Day 1: a. Hemoglobin > 9.5 g/dL; b. White blood cell (WBC) count > 2,500/μL; c. Platelet count > 100,000/μL. 10. Acceptable hepatic and renal function laboratory values within 3 weeks prior to Day 1: a. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 4.0 ? the upper limit of normal (ULN); b. Total bilirubin ≤ 1.5? ULN; Contact study team for additional inclusion/exclusion criteris

Phase

III - Research Studies that gather more information about a drug's safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. These studies typically involve more participants.

Type of Study

Treatment

Locations

CTRC-adult
University of Colorado Hospital

Principal Investigator
Matthew Taylor,  MD

Matthew Taylor, MD

Study ID

Protocol Number: 17-2345

ClinicalTrials.gov: NCT03439514

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