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

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

Tracking Information
First Submitted Date  ICMJE February 1, 2018
First Posted Date  ICMJE February 20, 2018
Last Update Posted Date April 13, 2021
Actual Study Start Date  ICMJE April 17, 2018
Estimated Primary Completion Date November 10, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (submitted: February 13, 2018)
Change from baseline in 6-minute walk test (6MWT) [ Time Frame: at Week 12 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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  ICMJE
  • Dilated Cardiomyopathy
  • Lamin A/C Gene Mutation
Intervention  ICMJE
  • Drug: ARRY-371797 (PF-07265803)
    400 mg twice daily (BID)
  • Other: Placebo
    BID
Study Arms  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 13, 2018)
160
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 23, 2024
Estimated Primary Completion Date November 10, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pfizer Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com
Listed Location Countries  ICMJE Argentina,   Belgium,   Canada,   Italy,   Mexico,   Netherlands,   Norway,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03439514
Other Study ID Numbers  ICMJE 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  ICMJE
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  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP