A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation (REALM-DCM)

• ClinicalTrials.gov Identifier: NCT03439514
• Recruitment Status: Recruiting
• First Posted: February 20, 2018
• Last Update Posted: April 13, 2021
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: February 1, 2018
• First Posted Date: February 20, 2018
• Last Update Posted Date: April 13, 2021
• Actual Study Start Date: April 17, 2018
• Estimated Primary Completion Date: November 10, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 7, 2021)

Change from baseline in 6-minute walk test (6MWT) [ Time Frame: at Week 24 ]

The 6 MWT measures the distance walked over a total of six minutes on a hard, and flat surface.

• Original Primary Outcome Measures (submitted: February 13, 2018): Change from baseline in 6-minute walk test (6MWT) [ Time Frame: at Week 12 ]

Current Secondary Outcome Measures (submitted: April 7, 2021)

• Change from baseline in 6-minute walk test (6MWT) [ Time Frame: at Weeks 4 and 12 ]
  The 6 MWT measures the distance walked over a total of six minutes on a hard, and flat surface.
• Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) domain [ Time Frame: at Weeks 12 and 24 ]
  The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The PL is a single domain consisting of 7 items scored using a range of 0 - 100, in which higher scores reflect better physical functioning status.
• Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) as measured by Total Symptom Score (TSS) domain [ Time Frame: at Weeks 12 and 24 ]
  The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The TSS is a combined score based upon the symptom burden, symptom frequency and symptom severity domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
• Change from baseline in Patient Global Impression score of Severity(PGI-S) of heart failure symptoms and physical activity limitations [ Time Frame: at Weeks 12 and 24 ]
  Measured by the scale of: none, mild, moderate, severe or very severe (listed from better to worse)
• Change from baseline in Patient Global Impression score of Change (PGI-C) in heart failure symptoms and physical activity limitations [ Time Frame: at Weeks 12 and 24 ]
  Measured by the scale of: very much better, moderately better, a little better, no change, a little worse, moderately worse, very much worse (listed from better to worse).
• Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [ Time Frame: at Weeks 4, 12 and 24 ]
• Evaluate the impact of ARRY-371797 (PF-07265803) on composite endpoint of all-cause mortality, or worsening heart failure (WHF). [ Time Frame: From randomization up to 60 months. ]
  Defined as the time from randomization to the first occurrence of any event of death due to any cause, or worsening heart failure (HF-related hospitalization or HF-related urgent care visit).
• Evaluate the impact of ARRY-371797 (PF-07265803) on overall survival (OS). [ Time Frame: From randomization up to 60 months. ]
  Defined as the time from randomization until death due to any cause.
• Evaluate the safety of ARRY-371797 (PF-07265803). [ Time Frame: From randomization up to 60 months. ]
  Incidence and severity of adverse events. Changes in clinical safety laboratory tests, vital signs, and 12 lead ECGs, and incidence and severity of ventricular or atrial arrhythmias detected.

Original Secondary Outcome Measures (submitted: February 13, 2018)

• Change from baseline in 6-minute walk test (6MWT) [ Time Frame: at Weeks 4 and 24 ]
• Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) domain [ Time Frame: at Weeks 12 and 24 ]
  The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The PL is a single domain consisting of 7 items scored using a range of 0 - 100, in which higher scores reflect better physical functioning status.
• Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) as measured by Total Symptom Score (TSS) domain [ Time Frame: at Weeks 12 and 24 ]
  The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The TSS is a combined score based upon the symptom burden, symptom frequency and symptom severity domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
• Change from baseline in Patient Global Impression score of Severity(PGI-S) of heart failure symptoms and physical activity limitations [ Time Frame: at Weeks 12 and 24 ]
  Measured by the scale of: none, mild, moderate, severe or very severe (listed from better to worse)
• Change from baseline in Patient Global Impression score of Change (PGI-C) in heart failure symptoms and physical activity limitations [ Time Frame: at Weeks 12 and 24 ]
  Measured by the scale of: very much better, moderately better, a little better, no change, a little worse, moderately worse, very much worse (listed from better to worse).
• Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [ Time Frame: at Weeks 12 and 24 ]
• Plasma concentrations of ARRY-371797 and metabolites predose and at a single time point post dose on specified visit days [ Time Frame: Duration of treatment cycle, 24 weeks ]
• Hospitalization-free survival (HFS) [ Time Frame: From randomization up to 24 months ]
  Defined as the time from randomization until the earliest of hospitalization for heart-failure related reasons or death due to any cause.
• Overall survival (OS) [ Time Frame: From randomization up to 24 months ]
  Defined as the time from randomization until death due to any cause.
• Number of participants with Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (SAEs) [ Time Frame: From randomization until approximately 18 months ]
  Severity of AEs will be graded using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (April 2005), as appropriate

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
• Official Title: A Phase 3, Multinational, Randomized, Placebo-controlled Study of ARRY-371797 in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
• Brief 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

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.

Primary Purpose: Treatment

Condition

• Dilated Cardiomyopathy
• Lamin A/C Gene Mutation

Intervention

• Drug: ARRY-371797 (PF-07265803)
  400 mg twice daily (BID)
• Other: Placebo
  BID

Study Arms

• Experimental: Part 1 Double-blind Treatment
  ARRY-371797 (PF-07265803) tablet orally OR matching placebo tablet orally
  Interventions:

  • Drug: ARRY-371797 (PF-07265803)
  • Other: Placebo
• Experimental: Part 2 Open-label Treatment
  ARRY-371797 (PF-07265803) tablet orally
  Intervention: Drug: ARRY-371797 (PF-07265803)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 13, 2018): 160
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 23, 2024
• Estimated Primary Completion Date: November 10, 2023 (Final data collection date for primary outcome measure)

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);
• 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.
• Patients must meet acceptable hematology, hepatic and renal laboratory values as specified

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. Patients listed for cardiac transplantation may be enrolled provided transplantation is not likely to occur in the next 6 months.
• Currently receiving or deemed at high risk of requiring chronic renal replacement therapy (e.g., hemodialysis or peritoneal dialysis) within 6 months.
• Treatment with any investigational agent(s) for HF within 28 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) or cervical cancer.
• 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Pfizer Pfizer CT.gov Call Center; 1-800-718-1021; ClinicalTrials.gov_Inquiries@pfizer.com

• Listed Location Countries: Argentina, Belgium, Canada, Italy, Mexico, Netherlands, Norway, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03439514
• Other Study ID Numbers: ARRAY-797-301; C4411002 ( Other Identifier: Alias Study Number ); 2017-004310-25 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: April 2021