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 6-minute walk test (6MWT)
  • Tempo: at Week 24
  • Descrizione: The 6 MWT measures the distance walked over a total of six minutes on a hard, and flat surface.




OBIETTIVO SECONDARIO


  
  • Misura: Change from baseline in 6-minute walk test (6MWT)
  • Tempo: at Weeks 4 and 12
  • Descrizione: The 6 MWT measures the distance walked over a total of six minutes on a hard, and flat surface.
  • Misura: Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) domain
  • Tempo: at Weeks 12 and 24
  • Descrizione: 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.
  • Misura: Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) as measured by Total Symptom Score (TSS) domain
  • Tempo: at Weeks 12 and 24
  • Descrizione: 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.
  • Misura: Change from baseline in Patient Global Impression score of Severity(PGI-S) of heart failure symptoms and physical activity limitations
  • Tempo: at Weeks 12 and 24
  • Descrizione: Measured by the scale of: none, mild, moderate, severe or very severe (listed from better to worse)
  • Misura: Change from baseline in Patient Global Impression score of Change (PGI-C) in heart failure symptoms and physical activity limitations
  • Tempo: at Weeks 12 and 24
  • Descrizione: 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)
  • Tempo: at Weeks 4, 12 and 24
  • Descrizione: 
  • Misura: Evaluate the impact of ARRY-371797 (PF-07265803) on composite endpoint of all-cause mortality, or worsening heart failure (WHF).
  • Tempo: From randomization up to 80 months.
  • 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).
  • Misura: Evaluate the impact of ARRY-371797 (PF-07265803) on overall survival (OS).
  • Tempo: From randomization up to 80 months.
  • Descrizione: Defined as the time from randomization until death due to any cause.
  • Misura: Evaluate the safety of ARRY-371797 (PF-07265803).
  • Tempo: From randomization up to 80 months.
  • Descrizione: 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.




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
Presidio Ospedaliero Madonna del Soccorso
San Benedetto del Tronto, 63074
Ospedale Di Cattinara
Trieste, 34149