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



Sponsor:   Pfizer


Sommario: 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.




TIPOLOGIA STUDIO

 
Interventistico



FASE

 
Fase 3




TRATTAMENTO

  
    
  
  • ARRY-371797 (PF-07265803)
  • Placebo
    • 






OBIETTIVO PRIMARIO


  
  • Misura: Change From Baseline in Six-Minute Walk Test (6 MWT) at Week 24
  • Tempo: Baseline, Week 24
  • Descrizione: 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.




OBIETTIVO SECONDARIO


  
  • Misura: Change From Baseline in 6 MWT at Weeks 4 and 12
  • Tempo: Baseline, Week 4, Week 12
  • Descrizione: 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.
  • Misura: Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) and Total Symptom Score (TSS) Domain Scores at Weeks 12 and 24
  • Tempo: Baseline, Week 12, Week 24
  • Descrizione: 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.
  • Misura: Number of Participants With Improvement From Baseline in Patient Global Impression of Severity (PGI-S) Score at Weeks 12 and 24
  • Tempo: Week 12, Week 24
  • Descrizione: 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).
  • Misura: Number of Participants With Improvement From Baseline in Patient Global Impression of Change (PGI-C) Score at Weeks 12 and 24
  • Tempo: Week 12, Week 24
  • Descrizione: 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).
  • Misura: Change From Baseline in N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) at Weeks 4, 12, and 24
  • Tempo: Baseline, Week 4, Week 12, Week 24
  • Descrizione: 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.
  • Misura: Composite Time to First Occurrence of All-Cause Mortality or Worsening Heart Failure (WHF)
  • Tempo: Maximum up to 212.28 weeks (maximum exposure was 208 weeks)
  • Descrizione: 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.
  • Misura: Overall Survival (OS)
  • Tempo: From randomization up to death due to any cause or censored date, maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
  • Descrizione: 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.
  • Misura: Number of Participants With Treatment Emergent Adverse Events (AEs) and by Severity
  • Tempo: Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
  • Descrizione: 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.
  • Misura: Number of Participants With Laboratory Test Abnormalities
  • Tempo: Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
  • Descrizione: 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).
  • Misura: Number of Participants According to Categorization of Abnormal Vital Signs
  • Tempo: Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
  • Descrizione: 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%).
  • Misura: Number of Participants According to Categorization of Electrocardiogram (ECG) Data
  • Tempo: Maximum up to 212.28 weeks (maximum exposure was of 208 weeks)
  • Descrizione: 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.
  • Misura: Number of Participants With a New Clinically Significant Ventricular or Atrial Arrhythmias
  • Tempo: Baseline, Week 12, Week 24
  • Descrizione: 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.




CRITERI DI ELIGIBILITA'


    
             
  • 
        Criteri di inclusione e esclusione
        
    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.
    
        
    • 
    




SESSO

  
Tutti




  


ETA' MINIMA



Età Minima: 18 Years

Età Massima: N/A






LUOGO


  
Ospedale Di Cattinara
Trieste, 34149
Azienda Ospedaliera Sant'Andrea
Roma, 00189
Ospedale Santa Maria Della Misericordia Perugia
Perugia - Località S. Andrea Delle Fratte, 6132
Fondazione IRCCS Policlinico San Matteo di Pavia
Pavia, 27100
Azienda Ospedaliera Universitaria Careggi
Firenze, 50134
Lacopo Olivotto, Azienda Ospedaliera Universitaria Careggi
Florence, 50134
A.O.U. di Perugia Ospedale Santa Maria della Misericordia
Perugia, 06156
AO Ospedale Policlinico Consorziale di Bari
Bari, 70124
Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
Bari, 70124
Azienda Ospedaliera Spedali Civili di Brescia
Brescia, 25123
Azienda Ospedaliera Universitaria Careggi
Firenze, 50134
IRCCS Pavia - Istituti Clinici Scientifici Maugeri Spa ? Società Benefit
Pavia, 27100
A.O.U. di Perugia Ospedale Santa Maria Della Misericordia
Perugia, 06132
A.O.U. di Perugia Ospedale Santa Maria della Misericordia
Perugia, 06156
Presidio Ospedaliero Madonna del Soccorso
San Benedetto del Tronto, 63074
Ospedale Di Cattinara
Trieste, 34149