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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 : May 18, 2022
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Description
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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.

Condition or disease Intervention/treatment Phase
Dilated Cardiomyopathy Lamin A/C Gene Mutation Drug: ARRY-371797 (PF-07265803) Other: Placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
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
Official Title: A Phase 3, Multinational, Randomized, Placebo-controlled Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation (REALM-DCM)
Actual Study Start Date : April 17, 2018
Estimated Primary Completion Date : April 2, 2024
Estimated Study Completion Date : February 17, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Part 1 Double-blind Treatment
ARRY-371797 (PF-07265803) tablet orally OR matching placebo tablet orally
 Drug: ARRY-371797 (PF-07265803)
400 mg twice daily (BID)

Other: Placebo
BID
Experimental: Part 2 Open-label Treatment
ARRY-371797 (PF-07265803) tablet orally
 Drug: ARRY-371797 (PF-07265803)
400 mg twice daily (BID)


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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)

  5. 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).

  6. Change from baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [ Time Frame: at Weeks 4, 12 and 24 ]
  7. 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 80 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).

  8. Evaluate the impact of ARRY-371797 (PF-07265803) on overall survival (OS). [ Time Frame: From randomization up to 80 months. ]
    Defined as the time from randomization until death due to any cause.

  9. Evaluate the safety of ARRY-371797 (PF-07265803). [ Time Frame: From randomization up to 80 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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); a. Screening: 6MWT distance >100 m but ≤450 m, AND b. Day -1 visit: 6MWT distance >100 m but ≤485 m, AND c. Baseline visit (Day 1): 6MWT distance >100 m but ≤485
  • 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 at the investigator discretion, without change in heart failure drug(s) dose in the past 1 month.
  • Patients must meet acceptable hematology, hepatic and renal laboratory values within 35 days prior to Day 1 as specified in the protocol.

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, or history of prior heart transplantation. Participants listed for cardiac transplantation may be enrolled provided transplantation is not likely to occur in the next 6 months.
  • Myocardial infarction, cardiac surgical procedures (other than for pacemaker/ICD/CRT-D implantation or replacement), acute coronary syndrome, serious systemic infection with evidence of septicemia, or any major surgical procedure requiring general anesthesia within 3 months prior to screening.
  • Currently receiving or deemed at high risk of requiring chronic renal replacement therapy (eg, hemodialysis or peritoneal dialysis) within 6 months.
  • Initiation of CRT within 6 months prior to screening.
  • Treatment with any investigational agent(s) for HF within 35 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), thyroid cancer, or cervical cancer, or, with prior review by the medical monitor, other early stage surgically curatively resected malignancies with less than a 20% expected 2 year recurrence rate.
  • 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03439514


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

Locations
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Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer Pfizer CT.gov Call Center Pfizer
More Information
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Additional Information:

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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03439514    
Other Study ID Numbers: ARRAY-797-301
C4411002 ( Other Identifier: Alias Study Number )
2017-004310-25 ( EudraCT Number )
First Posted: February 20, 2018    Key Record Dates
Last Update Posted: May 18, 2022
Last Verified: May 2022
Individual Participant Data (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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
cardiomyopathy
Lamin Type A
heart failure
ARRY-797
C4411002
Additional relevant MeSH terms:
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Cardiomyopathies
Cardiomyopathy, Dilated
Heart Diseases
Cardiovascular Diseases
 Cardiomegaly
Laminopathies
Genetic Diseases, Inborn