A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
- Conditions
- Dilated CardiomyopathyLamin A/C Gene Mutation
- Interventions
- Drug: ARRY-371797 (PF-07265803)Other: Placebo
- Registration Number
- NCT03439514
- Lead Sponsor
- Pfizer
- 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 available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 77
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1 Double-blind Treatment ARRY-371797 (PF-07265803) ARRY-371797 (PF-07265803) tablet orally OR matching placebo tablet orally Part 1 Double-blind Treatment Placebo ARRY-371797 (PF-07265803) tablet orally OR matching placebo tablet orally Part 2 Open-label Treatment ARRY-371797 (PF-07265803) ARRY-371797 (PF-07265803) tablet orally
- Primary Outcome Measures
Name Time Method Change From Baseline in Six-Minute Walk Test (6 MWT) at Week 24 Baseline, 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With Treatment Emergent Adverse Events (AEs) and by Severity Maximum up to 212.28 weeks (maximum exposure was of 208 weeks) 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.
Number of Participants With Laboratory Test Abnormalities Maximum up to 212.28 weeks (maximum exposure was of 208 weeks) 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).
Number of Participants With Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Weeks 12 and 24 Week 12, Week 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).
Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) at Weeks 4, 12, and 24 Baseline, Week 4, Week 12, Week 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.
Composite Time to First Occurrence of All-Cause Mortality or Worsening Heart Failure (WHF) Maximum up to 212.28 weeks (maximum exposure was 208 weeks) 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.
Overall Survival (OS) From randomization up to death due to any cause or censored date, maximum up to 212.28 weeks (maximum exposure was of 208 weeks) 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.
Change From Baseline in 6 MWT at Weeks 4 and 12 Baseline, Week 4, Week 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.
Number of Participants With Improvement From Baseline in Patient Global Impression of Severity (PGI-S) Score at Weeks 12 and 24 Week 12, Week 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).
Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) and Total Symptom Score (TSS) Domain Scores at Weeks 12 and 24 Baseline, Week 12, Week 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.
Number of Participants According to Categorization of Abnormal Vital Signs Maximum up to 212.28 weeks (maximum exposure was of 208 weeks) 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%).
Number of Participants According to Categorization of Electrocardiogram (ECG) Data Maximum up to 212.28 weeks (maximum exposure was of 208 weeks) 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.
Number of Participants With a New Clinically Significant Ventricular or Atrial Arrhythmias Baseline, Week 12, Week 24 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.
Trial Locations
- Locations (103)
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
Oslo University Hospital, Rikshospitalet
🇳🇴Oslo, Norway
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
Hospital Boutique Riobamba
🇲🇽Ciudad de Mexico, Distrito Federal, Mexico
Fundación de Atención e Investigación Médica Lindavista S.C.
🇲🇽Ciudad de México, Mexico
Hospital Universitario Virgen de la Arrixaca
🇪🇸El Palmar, Murcia, Spain
Fundacion Favaloro para la Docencia e Investigacion Medica
🇦🇷Buenos Aires, Ciudad Autónoma DE Buenos Aires, Argentina
Centro de Farmacovigilancia de Galicia
🇪🇸Santiago de Compostela, A Coruña, Spain
Ospedale Santa Maria Della Misericordia Perugia
🇮🇹Perugia - Località S. Andrea Delle Fratte, Perugia, Italy
St. Paul's Hospital
🇨🇦Vancouver, British Columbia, Canada
Hospital General Universitario Reina Sofia
🇪🇸Cordoba, Spain
University of Arizona Sarver Heart Center
🇺🇸Tucson, Arizona, United States
Ohio State University Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Centers for Heart Failure Therapy
🇺🇸Atlanta, Georgia, United States
Columbia University/Presbyterian Hospital - Vivian & Seymour Milstein Family Heart Center
🇺🇸New York, New York, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
Columbus Regional Research Institute
🇺🇸Columbus, Georgia, United States
MyMichigan Medical Center Midland
🇺🇸Midland, Michigan, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
Onze-Lieve-Vrouwziekenhuis
🇧🇪Aalst, Oost-vlaanderen, Belgium
Ospedale Di Cattinara
🇮🇹Trieste, Italy
Presidio Ospedaliero Madonna del Soccorso
🇮🇹San Benedetto del Tronto, Italy
Tennessee Center for Clinical Trials
🇺🇸Tullahoma, Tennessee, United States
C.H. Regional Reina Sofia - PPDS
🇪🇸Córdoba, Spain
Complexo Hospitalario Universitario A Coruña
🇪🇸A Coruna, Spain
Nova Scotia Health Authority (Capital District Health Authority)
🇨🇦Halifax, Nova Scotia, Canada
NYU School of Medicine / NYU Langone Health
🇺🇸New York, New York, United States
Baylor Annette C and Harold C Simmons Transplant Institute
🇺🇸Dallas, Texas, United States
Intermountain Medical Center
🇺🇸Murray, Utah, United States
Queen Elizabeth University Hospital - PPDS
🇬🇧Glasgow, Glasgow CITY, United Kingdom
Saint Luke's Idaho Cardiology Associates
🇺🇸Boise, Idaho, United States
Rutgers New Jersey Medical School - Doctors Office Center
🇺🇸Newark, New Jersey, United States
AO Ospedale Policlinico Consorziale di Bari
🇮🇹Bari, Italy
Columbus Cardiology Associates Research - Centricity Research - HyperCore - PPDS
🇺🇸Columbus, Georgia, United States
Hospital Provincial Del Centenario
🇦🇷Rosario, Santa FE, Argentina
Sykehuset Innlandet HF Hamar
🇳🇴Hamar, Norway
Medical University of South Carolina - PPDS
🇺🇸Charleston, South Carolina, United States
Hospital Provincial Dr Jose Maria Cullen
🇦🇷Santa Fe, Argentina
NSHA QEII Health Sciences Halifax Infirmary
🇨🇦Halifax, Nova Scotia, Canada
Azienda Ospedaliera Sant'Andrea
🇮🇹Roma, Lazio, Italy
A.O.U. di Perugia Ospedale Santa Maria della Misericordia
🇮🇹Perugia, Italy
Amsterdam UMC, Location Academic Medical Center
🇳🇱Amsterdam, Noord-holland, Netherlands
Centre Intégré Universitaire de santé et de services sociaux de l'Estrie Centre hospitalier
🇨🇦Sherbrooke, Quebec, Canada
Cardiolink Clin Trials S.C.
🇲🇽Monterrey, Nuevo LEÓN, Mexico
Christus Muguerza Hospital Alta Especialidad
🇲🇽Monterrey, Nuevo LEÓN, Mexico
Lacopo Olivotto, Azienda Ospedaliera Universitaria Careggi
🇮🇹Florence, Tuscany, Italy
St Bartholomew's Hospital
🇬🇧London, United Kingdom
Hospital Universitario Vall d'Hebrón - PPDS
🇪🇸Barcelona, Spain
Hospital Británico de Buenos Aires
🇦🇷Buenos Aires, Argentina
Azienda Ospedaliera Spedali Civili di Brescia
🇮🇹Brescia, Italy
IRCCS Pavia - Istituti Clinici Scientifici Maugeri Spa ? Società Benefit
🇮🇹Pavia, Italy
A.O.U. di Perugia Ospedale Santa Maria Della Misericordia
🇮🇹Perugia, Italy
University of Alabama at Birmingham Hospital
🇺🇸Birmingham, Alabama, United States
University of Alabama at Birmingham the Kirklin Clinic
🇺🇸Birmingham, Alabama, United States
University of Ottawa Heart Institute
🇨🇦Ottawa, Ontario, Canada
Clinical Laboratories of Montreal Heart Institute
🇨🇦Montreal, Quebec, Canada
University of Colorado Clinical and Translational Research Center
🇺🇸Aurora, Colorado, United States
University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
University of South Florida
🇺🇸Tampa, Florida, United States
USF Health
🇺🇸Tampa, Florida, United States
Florida Cardiovascular Institute PA
🇺🇸Tampa, Florida, United States
The Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Cardiovascular Clinical Trials Unit
🇺🇸Birmingham, Alabama, United States
Valley Heart Rhythm Specialists, PLLC
🇺🇸Chandler, Arizona, United States
Cardiovascular and Stem Cell Consultants
🇺🇸Gilbert, Arizona, United States
IDS Pharmacy at UAB Hospital
🇺🇸Birmingham, Alabama, United States
Chandler Regional Medical Center
🇺🇸Chandler, Arizona, United States
CB Flock Research Corporation
🇺🇸Mobile, Alabama, United States
Cardiovascular Research Clinic
🇺🇸Gilbert, Arizona, United States
Dignity Health, Mercy Gilbert Medical Center
🇺🇸Gilbert, Arizona, United States
Children's Clinic
🇺🇸Tucson, Arizona, United States
Banner - Banner University Medical Center South
🇺🇸Tucson, Arizona, United States
Mercy Gilbert Medical Center
🇺🇸Gilbert, Arizona, United States
Banner - University Medical Center Tucson
🇺🇸Tucson, Arizona, United States
Ahmanson Cardiomyopathy Center Cardiovascular Genetics
🇺🇸Los Angeles, California, United States
Banner University Medical Center Tuscon
🇺🇸Tucson, Arizona, United States
Stanford Hospital and Clinics
🇺🇸Stanford, California, United States
University of Colorado Academic Offices Building
🇺🇸Aurora, Colorado, United States
Medstar Washington Hospital Center
🇺🇸Washington, District of Columbia, United States
Innovative Research of West Florida
🇺🇸Clearwater, Florida, United States
Columbus Regional Research Institute at Talbotton - Centricity Research - HyperCore - PPDS
🇺🇸Columbus, Georgia, United States
Columbus Cardiology Associates Research - IACT - HyperCore - PPDS
🇺🇸Columbus, Georgia, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Washington University Center For Advanced Medicine
🇺🇸Saint Louis, Missouri, United States
University of Pennsylvania Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Columbia University Irving Medical Center
🇺🇸New York, New York, United States
Stern Cardiovascular Foundation Inc
🇺🇸Germantown, Tennessee, United States
Baylor Scott and White Heart and Vascular Hospital
🇺🇸Dallas, Texas, United States
Meriter Hospital
🇺🇸Madison, Wisconsin, United States
Instituto CAICI
🇦🇷Rosario, Santa FE, Argentina
UZ Leuven
🇧🇪Leuven, Belgium
Kawartha Cardiology Clinical Trials
🇨🇦Peterborough, Ontario, Canada
Fondazione IRCCS Policlinico San Matteo di Pavia
🇮🇹Pavia, PV, Italy
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Italy
Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
🇮🇹Bari, Italy
Hospital Universitario Puerta de Hierro de Majadahonda
🇪🇸Majadahonda, Madrid, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario Puerta de Hierro - Majadahonda
🇪🇸Majadahonda, Spain
Hospital Universitario Son Llatzer
🇪🇸Palma de Mallorca, Spain
Washington University Center for Outpatient Health
🇺🇸Saint Louis, Missouri, United States
Banner University Medicine North
🇺🇸Tucson, Arizona, United States
Complejo Hospitalario Universitario de Vigo - H. Alvaro Cunqueiro
🇪🇸Vigo, Pontevedra, Spain
Royal Brompton Hospital
🇬🇧London, United Kingdom