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

Study Overview
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Brief Summary
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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.

Conditions
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LMNA-Related Dilated Cardiomyopathy

Intervention / Treatment
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* Drug: ARRY-371797, p38 inhibitor; oral


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARRY-371797 (Dose 1)<br> | Drug: ARRY-371797, p38 inhibitor; oral<br>* multiple dose, single schedule<br>|
| Experimental: ARRY-371797 (Dose 2)<br> | Drug: ARRY-371797, p38 inhibitor; oral<br>* multiple dose, single schedule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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laminopathy