Clinical trial NCT03439514: 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 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation (REALM-DCM)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Dilated Cardiomyopathy
Lamin A/C Gene Mutation
Keywords: cardiomyopathy
Lamin Type A
heart failure
ARRY-797
C4411002
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2018-02-20
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.


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); 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.

Primary outcomes:
measure: Change From Baseline in Six-Minute Walk Test (6 MWT) at Week 24
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: Change From Baseline in 6 MWT at Weeks 4 and 12
timeFrame: Baseline, Week 4, Week 12
measure: Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) and Total Symptom Score (TSS) Domain Scores at Weeks 12 and 24
timeFrame: Baseline, Week 12, Week 24
measure: Number of Participants With Improvement From Baseline in Patient Global Impression of Severity (PGI-S) Score at Weeks 12 and 24
timeFrame: Week 12, Week 24
measure: Number of Participants With Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Weeks 12 and 24
timeFrame: Week 12, Week 24
measure: Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) at Weeks 4, 12, and 24
timeFrame: Baseline, Week 4, Week 12, Week 24
measure: Composite Time to First Occurrence of All-Cause Mortality or Worsening Heart Failure (WHF)
timeFrame: Maximum up to 212.28 weeks (maximum exposure was 208 weeks)
measure: Overall Survival (OS)
timeFrame: From randomization up to death due to any cause or censored date, maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
measure: Number of Participants With Treatment Emergent Adverse Events (AEs) and by Severity
timeFrame: Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
measure: Number of Participants With Laboratory Test Abnormalities
timeFrame: Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
measure: Number of Participants According to Categorization of Abnormal Vital Signs
timeFrame: Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
measure: Number of Participants According to Categorization of Electrocardiogram (ECG) Data
timeFrame: Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
measure: Number of Participants With a New Clinically Significant Ventricular or Atrial Arrhythmias
timeFrame: Baseline, Week 12, Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Hospital
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham the Kirklin Clinic
state: Alabama
city: Birmingham
country: United States
facility: IDS Pharmacy at UAB Hospital
state: Alabama
city: Birmingham
country: United States
facility: Cardiovascular Clinical Trials Unit
state: Alabama
city: Mobile
country: United States
facility: CB Flock Research Corporation
state: Alabama
city: Chandler
country: United States
facility: Chandler Regional Medical Center
state: Arizona
city: Chandler
country: United States
facility: Valley Heart Rhythm Specialists, PLLC
state: Arizona
city: Gilbert
country: United States
facility: Cardiovascular and Stem Cell Consultants
state: Arizona
city: Gilbert
country: United States
facility: Cardiovascular Research Clinic
state: Arizona
city: Gilbert
country: United States
facility: Dignity Health, Mercy Gilbert Medical Center
state: Arizona
city: Gilbert
country: United States
facility: Mercy Gilbert Medical Center
state: Arizona
city: Tucson
country: United States
facility: Children's Clinic
state: Arizona
city: Tucson
country: United States
facility: Banner - Banner University Medical Center South
state: Arizona
city: Tucson
country: United States
facility: Banner - University Medical Center Tucson
state: Arizona
city: Tucson
country: United States
facility: Banner University Medicine North
state: Arizona
city: Tucson
country: United States
facility: Banner University Medical Center Tuscon
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Sarver Heart Center
state: Arizona
city: Los Angeles
country: United States
facility: Ahmanson Cardiomyopathy Center Cardiovascular Genetics
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Aurora
country: United States
facility: University of Colorado Academic Offices Building
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Clinical and Translational Research Center
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Washington
country: United States
facility: Medstar Washington Hospital Center
state: District of Columbia
city: Clearwater
country: United States
facility: Innovative Research of West Florida
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Tampa
country: United States
facility: USF Health
state: Florida
city: Tampa
country: United States
facility: Florida Cardiovascular Institute PA
state: Florida
city: Atlanta
country: United States
facility: Centers for Heart Failure Therapy
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Columbus
country: United States
facility: Columbus Cardiology Associates Research - Centricity Research - HyperCore - PPDS
state: Georgia
city: Columbus
country: United States
facility: Columbus Cardiology Associates Research - IACT - HyperCore - PPDS
state: Georgia
city: Columbus
country: United States
facility: Columbus Regional Research Institute at Talbotton - Centricity Research - HyperCore - PPDS
state: Georgia
city: Columbus
country: United States
facility: Columbus Regional Research Institute
state: Georgia
city: Boise
country: United States
facility: Saint Luke's Idaho Cardiology Associates
state: Idaho
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Midland
country: United States
facility: MyMichigan Medical Center Midland
state: Michigan
city: Saint Louis
country: United States
facility: Washington University Center For Advanced Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Washington University Center for Outpatient Health
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Newark
country: United States
facility: Rutgers New Jersey Medical School - Doctors Office Center
state: New Jersey
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: New York
country: United States
facility: NYU School of Medicine / NYU Langone Health
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Columbia University/Presbyterian Hospital - Vivian & Seymour Milstein Family Heart Center
state: New York
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina - PPDS
state: South Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina - PPDS
state: South Carolina
city: Germantown
country: United States
facility: Stern Cardiovascular Foundation Inc
state: Tennessee
city: Tullahoma
country: United States
facility: Tennessee Center for Clinical Trials
state: Tennessee
city: Dallas
country: United States
facility: Baylor Scott and White Heart and Vascular Hospital
state: Texas
city: Dallas
country: United States
facility: Baylor Annette C and Harold C Simmons Transplant Institute
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Madison
country: United States
facility: Meriter Hospital
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Fundacion Favaloro para la Docencia e Investigacion Medica
state: Ciudad Autónoma DE Buenos Aires
city: Rosario
country: Argentina
facility: Instituto CAICI
state: Santa FE
city: Rosario
country: Argentina
facility: Hospital Provincial Del Centenario
state: Santa FE
city: Buenos Aires
country: Argentina
facility: Hospital Británico de Buenos Aires
city: Santa Fe
country: Argentina
facility: Hospital Provincial Dr Jose Maria Cullen
city: Aalst
country: Belgium
facility: Onze-Lieve-Vrouwziekenhuis
state: Oost-vlaanderen
city: Leuven
country: Belgium
facility: UZ Leuven
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: Nova Scotia Health Authority (Capital District Health Authority)
state: Nova Scotia
city: Halifax
country: Canada
facility: NSHA QEII Health Sciences Halifax Infirmary
state: Nova Scotia
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute
state: Ontario
city: Peterborough
country: Canada
facility: Kawartha Cardiology Clinical Trials
state: Ontario
city: Montreal
country: Canada
facility: Clinical Laboratories of Montreal Heart Institute
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Intégré Universitaire de santé et de services sociaux de l'Estrie Centre hospitalier
state: Quebec
city: Trieste
country: Italy
facility: Ospedale Di Cattinara
state: Friuli-venezia Giulia
city: Roma
country: Italy
facility: Azienda Ospedaliera Sant'Andrea
state: Lazio
city: Perugia - Località S. Andrea Delle Fratte
country: Italy
facility: Ospedale Santa Maria Della Misericordia Perugia
state: Perugia
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo di Pavia
state: PV
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
state: Toscana
city: Florence
country: Italy
facility: Lacopo Olivotto, Azienda Ospedaliera Universitaria Careggi
state: Tuscany
city: Perugia
country: Italy
facility: A.O.U. di Perugia Ospedale Santa Maria della Misericordia
state: Umbria
city: Bari
country: Italy
facility: AO Ospedale Policlinico Consorziale di Bari
city: Bari
country: Italy
facility: Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
city: Brescia
country: Italy
facility: Azienda Ospedaliera Spedali Civili di Brescia
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Pavia
country: Italy
facility: IRCCS Pavia - Istituti Clinici Scientifici Maugeri Spa ? Società Benefit
city: Perugia
country: Italy
facility: A.O.U. di Perugia Ospedale Santa Maria Della Misericordia
city: Perugia
country: Italy
facility: A.O.U. di Perugia Ospedale Santa Maria della Misericordia
city: San Benedetto del Tronto
country: Italy
facility: Presidio Ospedaliero Madonna del Soccorso
city: Trieste
country: Italy
facility: Ospedale Di Cattinara
city: Ciudad de Mexico
country: Mexico
facility: Hospital Boutique Riobamba
state: Distrito Federal
city: Monterrey
country: Mexico
facility: Cardiolink Clin Trials S.C.
state: Nuevo LEÓN
city: Monterrey
country: Mexico
facility: Christus Muguerza Hospital Alta Especialidad
state: Nuevo LEÓN
city: Ciudad de México
country: Mexico
facility: Fundación de Atención e Investigación Médica Lindavista S.C.
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, Location Academic Medical Center
state: Noord-holland
city: Hamar
country: Norway
facility: Sykehuset Innlandet HF Hamar
city: Oslo
country: Norway
facility: Oslo University Hospital, Rikshospitalet
city: Santiago de Compostela
country: Spain
facility: Centro de Farmacovigilancia de Galicia
state: A Coruña
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro de Majadahonda
state: Madrid
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
state: Murcia
city: Vigo
country: Spain
facility: Complejo Hospitalario Universitario de Vigo - H. Alvaro Cunqueiro
state: Pontevedra
city: A Coruna
country: Spain
facility: Complexo Hospitalario Universitario A Coruña
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón - PPDS
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Cordoba
country: Spain
facility: Hospital General Universitario Reina Sofia
city: Córdoba
country: Spain
facility: C.H. Regional Reina Sofia - PPDS
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro - Majadahonda
city: Palma de Mallorca
country: Spain
facility: Hospital Universitario Son Llatzer
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital - PPDS
state: Glasgow CITY
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: Royal Brompton Hospital
Study officials:
affiliation: Pfizer
name: Pfizer Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: