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

Dilated Cardiomyopathy Clinical Trial

— REALM-DCM  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03439514
• Other study ID #: ARRAY-797-301
• Secondary ID: C44110022017-004
• Status: Terminated
• Phase: Phase 3
• Start date: April 17, 2018
• Est. completion date: October 13, 2022

Study information

• Verified date: December 2023
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 77
• Est. completion date: October 13, 2022
• Est. primary completion date: October 13, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Dilated Cardiomyopathy
• Lamin A/C Gene Mutation

Intervention

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

Other:
• Placebo
BID

Locations

Country	Name	City	State
Argentina	Fundacion Favaloro para la Docencia e Investigacion Medica	Buenos Aires	Ciudad Autónoma DE Buenos Aires
Argentina	Hospital Británico de Buenos Aires	Buenos Aires
Argentina	Hospital Provincial Del Centenario	Rosario	Santa FE
Argentina	Instituto CAICI	Rosario	Santa FE
Argentina	Hospital Provincial Dr Jose Maria Cullen	Santa Fe
Belgium	Onze-Lieve-Vrouwziekenhuis	Aalst	Oost-vlaanderen
Belgium	UZ Leuven	Leuven
Canada	Nova Scotia Health Authority (Capital District Health Authority)	Halifax	Nova Scotia
Canada	NSHA QEII Health Sciences Halifax Infirmary	Halifax	Nova Scotia
Canada	Clinical Laboratories of Montreal Heart Institute	Montreal	Quebec
Canada	University of Ottawa Heart Institute	Ottawa	Ontario
Canada	Kawartha Cardiology Clinical Trials	Peterborough	Ontario
Canada	Centre Intégré Universitaire de santé et de services sociaux de l'Estrie Centre hospitalier	Sherbrooke	Quebec
Canada	St. Paul's Hospital	Vancouver	British Columbia
Italy	AO Ospedale Policlinico Consorziale di Bari	Bari
Italy	Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari	Bari
Italy	Azienda Ospedaliera Spedali Civili di Brescia	Brescia
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze	Toscana
Italy	Lacopo Olivotto, Azienda Ospedaliera Universitaria Careggi	Florence	Tuscany
Italy	Fondazione IRCCS Policlinico San Matteo di Pavia	Pavia	PV
Italy	IRCCS Pavia - Istituti Clinici Scientifici Maugeri Spa ? Società Benefit	Pavia
Italy	A.O.U. di Perugia Ospedale Santa Maria Della Misericordia	Perugia
Italy	A.O.U. di Perugia Ospedale Santa Maria della Misericordia	Perugia
Italy	A.O.U. di Perugia Ospedale Santa Maria della Misericordia	Perugia	Umbria
Italy	Ospedale Santa Maria Della Misericordia Perugia	Perugia - Località S. Andrea Delle Fratte	Perugia
Italy	Azienda Ospedaliera Sant'Andrea	Roma	Lazio
Italy	Presidio Ospedaliero Madonna del Soccorso	San Benedetto del Tronto
Italy	Ospedale Di Cattinara	Trieste
Italy	Ospedale Di Cattinara	Trieste	Friuli-venezia Giulia
Mexico	Hospital Boutique Riobamba	Ciudad de Mexico	Distrito Federal
Mexico	Fundación de Atención e Investigación Médica Lindavista S.C.	Ciudad de México
Mexico	Cardiolink Clin Trials S.C.	Monterrey	Nuevo LEÓN
Mexico	Christus Muguerza Hospital Alta Especialidad	Monterrey	Nuevo LEÓN
Netherlands	Amsterdam UMC, Location Academic Medical Center	Amsterdam	Noord-holland
Norway	Sykehuset Innlandet HF Hamar	Hamar
Norway	Oslo University Hospital, Rikshospitalet	Oslo
Spain	Complexo Hospitalario Universitario A Coruña	A Coruna
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebrón - PPDS	Barcelona
Spain	Hospital General Universitario Reina Sofia	Cordoba
Spain	C.H. Regional Reina Sofia - PPDS	Córdoba
Spain	Hospital Universitario Virgen de la Arrixaca	El Palmar	Murcia
Spain	Hospital Universitario Puerta de Hierro - Majadahonda	Majadahonda
Spain	Hospital Universitario Puerta de Hierro de Majadahonda	Majadahonda	Madrid
Spain	Hospital Universitario Son Llatzer	Palma de Mallorca
Spain	Centro de Farmacovigilancia de Galicia	Santiago de Compostela	A Coruña
Spain	Complejo Hospitalario Universitario de Vigo - H. Alvaro Cunqueiro	Vigo	Pontevedra
United Kingdom	Queen Elizabeth University Hospital - PPDS	Glasgow	Glasgow CITY
United Kingdom	Royal Brompton Hospital	London
United Kingdom	St Bartholomew's Hospital	London
United States	Centers for Heart Failure Therapy	Atlanta	Georgia
United States	Emory University Hospital	Atlanta	Georgia
United States	University of Colorado Academic Offices Building	Aurora	Colorado
United States	University of Colorado Clinical and Translational Research Center	Aurora	Colorado
United States	University of Colorado Hospital	Aurora	Colorado
United States	Cardiovascular Clinical Trials Unit	Birmingham	Alabama
United States	IDS Pharmacy at UAB Hospital	Birmingham	Alabama
United States	University of Alabama at Birmingham Hospital	Birmingham	Alabama
United States	University of Alabama at Birmingham the Kirklin Clinic	Birmingham	Alabama
United States	Saint Luke's Idaho Cardiology Associates	Boise	Idaho
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Chandler Regional Medical Center	Chandler	Arizona
United States	Valley Heart Rhythm Specialists, PLLC	Chandler	Arizona
United States	Medical University of South Carolina - PPDS	Charleston	South Carolina
United States	Medical University of South Carolina - PPDS	Charleston	South Carolina
United States	Innovative Research of West Florida	Clearwater	Florida
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	Columbus Cardiology Associates Research - Centricity Research - HyperCore - PPDS	Columbus	Georgia
United States	Columbus Cardiology Associates Research - IACT - HyperCore - PPDS	Columbus	Georgia
United States	Columbus Regional Research Institute	Columbus	Georgia
United States	Columbus Regional Research Institute at Talbotton - Centricity Research - HyperCore - PPDS	Columbus	Georgia
United States	Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Baylor Annette C and Harold C Simmons Transplant Institute	Dallas	Texas
United States	Baylor Scott and White Heart and Vascular Hospital	Dallas	Texas
United States	Stern Cardiovascular Foundation Inc	Germantown	Tennessee
United States	Cardiovascular and Stem Cell Consultants	Gilbert	Arizona
United States	Cardiovascular Research Clinic	Gilbert	Arizona
United States	Dignity Health, Mercy Gilbert Medical Center	Gilbert	Arizona
United States	Mercy Gilbert Medical Center	Gilbert	Arizona
United States	Ahmanson Cardiomyopathy Center Cardiovascular Genetics	Los Angeles	California
United States	Meriter Hospital	Madison	Wisconsin
United States	MyMichigan Medical Center Midland	Midland	Michigan
United States	CB Flock Research Corporation	Mobile	Alabama
United States	Intermountain Medical Center	Murray	Utah
United States	Columbia University Irving Medical Center	New York	New York
United States	Columbia University/Presbyterian Hospital - Vivian & Seymour Milstein Family Heart Center	New York	New York
United States	NYU School of Medicine / NYU Langone Health	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Rutgers New Jersey Medical School - Doctors Office Center	Newark	New Jersey
United States	University of Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Washington University Center For Advanced Medicine	Saint Louis	Missouri
United States	Washington University Center for Outpatient Health	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Washington Medical Center	Seattle	Washington
United States	Stanford Hospital and Clinics	Stanford	California
United States	Florida Cardiovascular Institute PA	Tampa	Florida
United States	University of South Florida	Tampa	Florida
United States	USF Health	Tampa	Florida
United States	Banner - Banner University Medical Center South	Tucson	Arizona
United States	Banner - University Medical Center Tucson	Tucson	Arizona
United States	Banner University Medical Center Tuscon	Tucson	Arizona
United States	Banner University Medicine North	Tucson	Arizona
United States	Children's Clinic	Tucson	Arizona
United States	University of Arizona Sarver Heart Center	Tucson	Arizona
United States	Tennessee Center for Clinical Trials	Tullahoma	Tennessee
United States	Medstar Washington Hospital Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Canada,  Italy,  Mexico,  Netherlands,  Norway,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Six-Minute Walk Test (6 MWT) at Week 24	The 6 MWT was an assessment where the distance that a participant could walk on a flat and hard surface in 6 minutes was measured. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed, and under supervision of a qualified professional. Study discontinuation & death were incorporated into endpoint definition through ranking in hypothesis testing of treatment difference. Missing data resulting from study discontinuation were imputed using control-based multiple imputation method to estimate treatment effect.	Baseline, Week 24
Secondary	Change From Baseline in 6 MWT at Weeks 4 and 12	The 6 MWT was an assessment where the distance that a participant could walk on a flat and hard surface in 6 minutes was measured. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed, and under supervision of a qualified professional.	Baseline, Week 4, Week 12
Secondary	Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) and Total Symptom Score (TSS) Domain Scores at Weeks 12 and 24	The KCCQ measured the effects of symptoms, functional (physical) limitations, and psychological distress on an individual's health-related quality of life. It contains 23 items, which assessed the ability to perform activities of daily living, frequency and severity of symptoms, the impact of these symptoms, and health-related quality of life. PL was a single questionnaire with score range of 0 to 100, where higher scores reflected better physical functioning status. TSS included frequency and severity of symptoms, and the impact of these symptoms. TSS scores were transformed to a range of 0 to 100, where higher scores reflected better health status.	Baseline, Week 12, Week 24
Secondary	Number of Participants With Improvement From Baseline in Patient Global Impression of Severity (PGI-S) Score at Weeks 12 and 24	PGI-S is a global index that rate the severity of the disease using a 5-point scale. In this outcome the number of participants with improvements in PGI-S the severity of their heart failure symptoms and in the severity of their PL were reported. Measured by the scale of: none, mild, moderate, severe or very severe (listed from better to worse).	Week 12, Week 24
Secondary	Number of Participants With Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Weeks 12 and 24	PGI-C is a global index that rate the severity of the disease using a 7-point scale. In this outcome the number participants with improvements in their heart failure symptoms and "in their physical activity limitations?", were reported. 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).	Week 12, Week 24
Secondary	Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) at Weeks 4, 12, and 24	NT pro-BNP is a cardiac biomarker that is released in the blood in response to changes in the pressure inside of the heart. Levels go up when heart failure develops or gets worse, and levels go down when heart failure is stable or improves. This biomarker helps to measure the changes in the severity of heart failure over time in response to therapy.	Baseline, Week 4, Week 12, Week 24
Secondary	Composite Time to First Occurrence of All-Cause Mortality or Worsening Heart Failure (WHF)	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). Kaplan-Meier method and cox regression model were used for analysis.	Maximum up to 212.28 weeks (maximum exposure was 208 weeks)
Secondary	Overall Survival (OS)	OS was defined as time from randomization to death due to any cause. Participants who did not have a death date were censored for OS at their last contact date. Kaplan-Meier method and cox regression model were used for analysis.	From randomization up to death due to any cause or censored date, maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
Secondary	Number of Participants With Treatment Emergent Adverse Events (AEs) and by Severity	An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. Treatment-emergent AEs were events that occurred between first dose of study drug and up to 30 days after last dose. Serious adverse event (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. AEs included both SAEs and all Non-SAEs. Grade >=3 AEs meant severe AEs.	Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
Secondary	Number of Participants With Laboratory Test Abnormalities	Following parameters were analyzed for laboratory examination: hematology (eosinophils, erythrocytes, hemoglobin, hematocrit, granulocytes, leukocytes, lymphocytes, monocytes, platelets, neutrophils, nucleated erythrocytes); blood chemistry (alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bicarbonate, bilirubin, blood urea nitrogen, C-reactive protein, calcium, chloride, creatinine, creatine kinase, epidermal growth factor receptor, follicle stimulating hormone, gamma glutamyl transferase, glucose, magnesium, N-Terminal ProB-type natriuretic peptide, phosphate, potassium, protein, sodium, potassium, thyrotropin, troponin I, troponin T, urate).	Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
Secondary	Number of Participants According to Categorization of Abnormal Vital Signs	Following vital sign parameters were assessed: diastolic blood pressure, systolic blood pressure, heart rate, and body weight. Vital sign abnormalities criteria included: a) systolic blood pressure (mmHg): decrease (change <= -20, or value <90) and increase (change >=20, or value >140); b) diastolic blood pressure (mmHg): decrease (change <= -15, or value <60) and increase (change >=15, or value >90); c) heart Rate (bpm) decrease: (change <= -15, or value <50) and increase (change >=15, or value >100); d) weight: (kg) decrease (Change <= -7%) and increase (Change > =7%).	Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
Secondary	Number of Participants According to Categorization of Electrocardiogram (ECG) Data	Following parameters were analyzed: heart rate, QT interval, corrected QT (QTc) interval, Bazett's correction QT (QTcB) interval, and Fridericia's correction (QTcF) interval. Criteria for notable ECG values were as follows: QT interval (in millisecond [msec]) new (newly occurring post-baseline value) greater than (>) 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Fredericia formula (QTcF) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; corrected QT interval by Bazett's formula (QTcB) in msec new (newly occurring post-baseline value) > 450, 480, 500, increase from baseline >30, increase from baseline >60; heart rate in bpm new (newly occurring post-baseline value) <60 and >100.	Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
Secondary	Number of Participants With a New Clinically Significant Ventricular or Atrial Arrhythmias	Arrhythmia assessment: incidence of new and clinically significant ventricular or atrial arrhythmias was assessed by an implantable cardioverter defibrillator (ICD) or CRT defibrillator (CRT-D) applicable device interrogations.	Baseline, Week 12, Week 24

External Links

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