A Study of ARRY-371797 in Patients With LMNA-Related Dilated Cardiomyopathy

This is a Phase 2 pilot study, involving a 48-week treatment period, designed to test the effectiveness of investigational study drug ARRY-371797 in treating patients with symptomatic genetic dilated cardiomyopathy due to a lamin A/C gene mutation, and to further evaluate the drug's safety. Approximately 12 patients from the US will be enrolled in this study.

Study Overview

• Status: Completed
• Conditions: LMNA-Related Dilated Cardiomyopathy
• Intervention / Treatment: Drug: ARRY-371797, p38 inhibitor; oral

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Wisconsin
    • Madison, Wisconsin, United States, 53713
      • Meriter Wisconsin Heart

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Patients with idiopathic dilated cardiomyopathy and stable New York Heart Association (NYHA) Class II - IIIa congestive heart failure (CHF).
• Stable, guidelines-based medical and device therapy, without any CHF hospitalizations or change in heart failure drug dose with ≥ 50% reduction in dose or ≥ 100% increase in dose in the past 3 months.
• Left ventricular (LV) end diastolic diameter by trans-thoracic echocardiography of > 3.3 cm/m2 (for females) or 3.4 cm/m2 (for males) and/or LV ejection fraction ≤ 45%.
• Gene positive for a pathogenic mutation in the LMNA gene, as determined by a CLIA-certified clinical laboratory (mutations including but not limited to: splice-site, non-sense, deletion mutations, a mis-sense mutation in a highly conserved codon, a mis-sense mutation involving a major charge change, a mis-sense mutation previously associated with genetic dilated cardiomyopathy).
• Within 3 weeks prior to first dose of study drug, completed distance during six minute walk test of ≥ 100 m and ≤ 350 m AND/OR ≥ 100 m and ≤ 450 m AND ≤ 60% predicted distance AND patient is symptomatic for dilated cardiomyopathy per Investigator judgment.
• On the day before and day of first dose of study drug, completed distance during six minute walk test of ≥ 100 m and ≤ 400 m (with the greater value within 10% of the lesser value) AND/OR ≥ 100 m and ≤ 475 m (with the greater value within 10% of the lesser value) AND patient is symptomatic for dilated cardiomyopathy per Investigator judgment.
• Acceptable hematology, hepatic and renal function laboratory values within 3 weeks prior to first dose of study drug.
• Additional criteria exist.

Key Exclusion Criteria:

• Unstable clinical cardiac symptoms requiring unscheduled hospitalization within 60 days prior to study start.
• Clinically significant coronary artery disease, as per Investigator judgment.
• Currently receiving continuous intravenous (IV) inotrope infusion, or presence of a ventricular assist device, or history of prior heart transplantation.
• Any of the following within 60 days prior to study start: Myocardial infarction, cardiac surgical procedures, acute coronary syndrome, hemodynamically destabilizing cardiac arrhythmia, serious systemic infection with evidence of septicemia, any major surgical procedure requiring general anesthesia.
• Uncorrected, hemodynamically significant primary valvular disease.
• Initiation of cardiac resynchronization therapy within 180 days prior to study start.
• Likelihood, in the Investigator's opinion, of undergoing cardiac transplantation, left ventricular assist device or other device implantation, or other cardiac surgery within the next 6 months; or of requiring continuous IV inotropic treatment, or referral for hospice or end-of-life treatment.
• Active malignancy (except surgically-curative basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma).
• Receiving chronic immunosuppressant therapy.
• Known positive serology for the human immunodeficiency virus (HIV), active hepatitis B and/or hepatitis C.
• Participation in any other investigational study of drugs or devices within 30 days prior to study start.
• Additional criteria exist.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ARRY-371797 (Dose 1)	Drug: ARRY-371797, p38 inhibitor; oral; multiple dose, single schedule
EXPERIMENTAL: ARRY-371797 (Dose 2)	Drug: ARRY-371797, p38 inhibitor; oral; multiple dose, single schedule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Assess the efficacy of the study drug in terms of change from Baseline in 6-minute walk test.	12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Assess the efficacy of study drug in terms of left ventricular function.	48 weeks
Assess the efficacy of study drug in terms of right ventricular function.	48 weeks
Assess the safety of study drug in terms of adverse events, clinical laboratory tests and electrocardiograms.	48 weeks
Characterize the pharmacokinetics (PK) of study drug and metabolites in terms of plasma concentration-time profiles and model-based PK parameters.	48 weeks

Collaborators and Investigators

• Sponsor: Pfizer

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (ACTUAL): May 1, 2016
• Study Completion (ACTUAL): May 1, 2016

Study Registration Dates

• First Submitted: February 5, 2014
• First Submitted That Met QC Criteria: February 5, 2014
• First Posted (ESTIMATE): February 7, 2014

Study Record Updates

• Last Update Posted (ACTUAL): October 14, 2020
• Last Update Submitted That Met QC Criteria: October 6, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: laminopathy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Cardiomegaly; Laminopathies; Cardiomyopathies; Cardiomyopathy, Dilated
• Other Study ID Numbers: ARRAY-797-231; C4411004 (OTHER: Pfizer)