A Rollover 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 rollover study designed to investigate the safety and effectiveness of investigational study drug ARRY-371797 in patients who previously received ARRY-371797 in a study for patients with LMNA-related dilated cardiomyopathy sponsored by Array BioPharma and may, in the Investigator's opinion, derive benefit from continued treatment.

Official Title
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An Open-label Rollover Study of ARRY-371797 in Patients With Symptomatic Genetic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation

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: Received ARRY-371797 as treatment for a genetic dilated cardiomyopathy secondary to LMNA mutations in a clinical study sponsored by Array BioPharma. May, in the opinion of the Investigator, benefit from continued ARRY-371797 treatment. Additional criteria exist. Key Exclusion Criteria: Discontinued treatment in the parent study for any reason other than study completion or Sponsor termination of the study. 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARRY-371797<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 |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both serious and non-serious adverse events. | Baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks) | 
| Number of Participants With Change From Baseline Value in Clinical Laboratory Hematology Test Results to Worst Value | In this outcome measure, number of participants with baseline laboratory hematology values as per National Cancer Institute Common Terminology Criteria (NCI-CTC) grade (Grade 0= within normal limits, Grade 1=Mild, Grade 2=Moderate, Grade 3= Severe, Grade 4= Life-threatening) and corresponding changes/shift to the worst CTC grades post baseline were presented. Shift data have been reported for hematology parameters: hemoglobin (g/L), platelets (10^9/L), leukocytes (10^9/L), neutrophils (10^9/L), lymphocytes (10^9/L) and eosinophils (10^9/L). Baseline was defined as last non-missing value before the initial administration of study treatment in parent study and worst post-baseline value defined as worst value between first dose of study drug up to the maximum of 282 weeks. Only those categories in which at least 1 participant had data were reported. | Baseline, Post-Baseline (anytime from first dose of study drug to maximum duration of up to 282 weeks) | 
| Number of Participants With Change From Baseline Value in Clinical Laboratory Chemistry Test Results to Worst Value | In this outcome measure, number of participants with baseline laboratory chemistry values as per NCI-CTC grade (Grade 0= within normal limits, Grade 1=Mild, Grade 2=Moderate, Grade 3= Severe, Grade 4= Life-threatening) and corresponding changes/shift to the worst CTC grades post baseline were presented. Shift data have been reported for laboratory parameters: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, international unit per liter (IU/L), albumin, bilirubin, urea nitrogen, calcium, creatinine, glucose, magnesium, protein and phosphate grams per deciliter (g/dL), potassium and sodium, millimol per liter (mmol/L). Baseline was defined as last non-missing value before the initial administration of study treatment in parent study and worst post-baseline value defined as worst value between first dose of study drug up to the maximum of 282 weeks. Only those categories in which at least 1 participant had data were reported. | Baseline, Post-Baseline (anytime from first dose of study drug to maximum duration of up to 282 weeks) | 
| Number of Participants With Abnormal Physical Examination Findings | Physical examination included the assessment of skin, head, ears, eyes, nose, throat, cardiovascular system, abdomen and lungs. Abnormality in physical examination were based on investigator's discretion. | Baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks) | 
| Number of Participants With Abnormalities in Vital Signs | Following vital signs parameters were analyzed using prespecified range of results for signs of clinical significance: systolic blood pressure in millimeters of mercury (mmHg): <90 mmHg and ≥160 mmHg, diastolic blood pressure: <60 mmHg and ≥100 mmHg, heart rate in beats per minute (bpm): <40bpm and >120 bpm, temperature in degree Celsius (C): <36.1 and > 37.2 degree C. | Baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks) | 
| Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings | Following ECG parameters were analyzed using prespecified range of results for signs of clinical significance: heart rate: <40bpm and >120 bpm; QT/QTcF (QT interval corrected using Fridericia's formula) criteria: QT interval >500 ms; QTcF interval >450 ms; or change from baseline in QTcF >30 ms. | Baseline up to 30 days after last dose of study drug (i.e., maximum up to 282 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Six Minute Walk Test (6MWT) Distance at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit | 6MWT was the distance that a participant could quickly walk on a flat, hard surface in a period of 6 minutes. Participants were asked to walk a set course of 30 meters for 6 minutes (timed), and the distance walked (in meters) was recorded. Change from baseline in 6MWT distance at specified time points were reported. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study. | Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks) | 
| Change From Baseline in Left Ventricular End Systolic Index (LVESVI) and Left Ventricular End Diastolic Volume Index (LVEDVI) at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit | LVESVI and LVEDVI were echocardiographic assessment of left ventricular remodeling. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study. | Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks) | 
| Change From Baseline in Left Ventricular Mass (LVM) at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit | LVM is the weight of the left ventricle in grams estimated by echocardiography. For this outcome measure, Baseline is the pre-dose baseline of parent study. | Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks) | 
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit | LVEF was the fraction of the end-diastolic volume (EDV) that was ejected out of left ventricle with each contraction, estimated by echocardiography. EDV was the volume of blood within a ventricle immediately before a contraction. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study. | Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks) | 
| Change From Baseline in Left Ventricular Mass (LVM) to Volume Ratio at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit | LVM divided by the end diastolic volume, estimated by echocardiography. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study. | Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks) | 
| Change From Baseline in Right Ventricular End Diastolic Diameter at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit | The internal diameter of the right ventricle at the end of diastole, measured by echocardiography. Baseline was defined as last non-missing value before the initial administration of study treatment in parent study. | Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks) | 
| Change From Baseline in Right Ventricular Fractional Area at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit | Right ventricular fractional area change is a measure of global right ventricular systolic function estimated by echocardiography. For this outcome measure, Baseline is the pre-dose baseline of parent study. | Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks) | 
| Change From Baseline in 36-Item Short-Form (SF-36) Health Survey Score at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit | The SF-36 health survey is a participant-reported survey to measure participant's health. It is a 36-item questionnaire used to measure 8 various aspects of health (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health). The score range for each of the 8 aspects was from 0 (maximum disability) to 100 (no disability), higher scores indicating good health condition. For this analysis, baseline was defined as last non-missing value before the initial administration of study treatment in parent study. | Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks) | 
| Change From Baseline in Quality of Life by Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Day 1, Weeks 24, 48, 72, 96 and Early Termination Visit | KCCQ was a 23-item heart failure specific questionnaire quantified into following 10 summary scores: physical limitation score, symptom frequency score, symptom severity score, symptom stability score, total symptoms score, quality of life score, social interference score, self-efficacy score, overall summary score and clinical summary score. These scores ranged from 0 to 100, where higher scores indicated better functioning, fewer symptoms, and better disease specific quality of life. For this analysis, baseline was defined as last non-missing value before the initial administration of study treatment in parent study. | Baseline, Day 1, Weeks 24, 48, 72, 96 and early termination visit (anytime within the maximum duration of up to 282 weeks) | 
| Mean Plasma Concentration of ARRY-371797 and Metabolites (AR00420643, AR00428028, AR00486705) | Plasma concentrations of ARRY-371797 and its metabolites (AR00420643, AR00428028 and AR00486705) was summarized on Day 1, Weeks 12 and 24 at both pre and post dose. | Pre dose and post dose on Day 1, Weeks 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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laminopathy, ARRY-797