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A Study of Belcesiran in Patients With A1ATD-Associated Liver Disease (ESTRELLA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04764448
Recruitment Status : Recruiting
First Posted : February 21, 2021
Last Update Posted : December 2, 2021
Sponsor:
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE January 27, 2021
First Posted Date  ICMJE February 21, 2021
Last Update Posted Date December 2, 2021
Actual Study Start Date  ICMJE February 12, 2021
Estimated Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 17, 2021)
  • The incidence of adverse events (AE), serious adverse events (SAE), and AE leading to study drug discontinuation. [ Time Frame: up to 24 weeks (Cohort 1) ]
  • The incidence of clinically significant physical examination (PE) findings. [ Time Frame: up to 24 weeks (Cohort 1) ]
  • Change from baseline in coagulation parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    aPTT, PT, INR
  • Change from baseline in coagulation parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    aPTT, PT, INR
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    glucose
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    glucose
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    urea (BUN)
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    urea (BUN)
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    creatinine
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    creatinine
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    potassium
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    potassium
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    chloride
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    chloride
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    sodium
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    sodium
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    creatine kinase (CK)
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    creatine kinase (CK)
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    albumin
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    albumin
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    total protein
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    total protein
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    triglycerides
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    triglycerides
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    total cholesterol
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    total cholesterol
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    total and direct, lactate dehydrogenase (LDH)
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    total and direct, lactate dehydrogenase (LDH)
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    bilirubin
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    bilirubin
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    alkaline phosphatase (ALP)
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    gamma glutamyl transferase (GGT)
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    glutamate dehydrogenase (GLDH),
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    glutamate dehydrogenase (GLDH),
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    aspartate aminotransferase (AST)
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    aspartate aminotransferase (AST)
  • Changes from baseline in serum chemistries [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    Alanine aminotransferase (ALT)
  • Changes from baseline in serum chemistries [ Time Frame: Cohort 1 and Cohort 2: from baseline to Day 1, Day 2, Day 3, Day 15, Day 29, Day 30, Day 57, Day 85, Day 113, Day 141, Day 169] ]
    Alanine aminotransferase (ALT)
  • Changes from baseline (defined as predose Day 1) in vital sign measurements [ Time Frame: [Cohort 1 + Cohort 2: from baseline to end of injection, from baseline to 30 minutes postdose, from baseline to 60 minutes postdose, from baseline to 2 hours postdose, from baseline to 4 hours postdose, from baseline to 6 hours postdose, fr ]
    RR, PR, QRS, QT, and corrected QT interval (QTcF, Fridericia correction)
  • Changes from baseline (defined as predose Day 1) in vital sign measurements [ Time Frame: [Cohort 1 + Cohort 2: from baseline to end of injection, from baseline to 30 minutes postdose, from baseline to 60 minutes postdose, from baseline to 2 hours postdose, from baseline to 4 hours postdose, from baseline to 6 hours postdose, fr ]
    Heart rate, ventricular rate
  • Changes from baseline (defined as predose Day 29) in vital sign measurements [ Time Frame: [Cohort 1 + Cohort 2: from baseline to end of injection, from baseline to 30 minutes postdose, from baseline to 60 minutes postdose, from baseline to 2 hours postdose, from baseline to 4 hours postdose, from baseline to 6 hours postdose, from baseline t ]
    RR, PR, QRS, QT, and corrected QT interval (QTcF, Fridericia correction)
  • Changes from baseline (defined as predose Day 29) in vital sign measurements [ Time Frame: [Cohort 1 + Cohort 2: from baseline to end of injection, from baseline to 30 minutes postdose, from baseline to 60 minutes postdose, from baseline to 2 hours postdose, from baseline to 4 hours postdose, from baseline to 6 hours postdose, from baseline t ]
    Heart rate, ventricular rate
  • Changes from baseline (defined as predose Day 1) in vital sign measurements [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    RR, PR, QRS, QT, and corrected QT interval (QTcF, Fridericia correction)
  • Changes from baseline (defined as predose Day 1) in vital sign measurements [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    Heart rate, ventricular rate
  • Changes from baseline (defined as predose Day 29) in vital sign measurements [ Time Frame: measurements [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 3379] ]
    RR, PR, QRS, QT, and corrected QT interval (QTcF, Fridericia correction)
  • Changes from baseline (defined as predose Day 29) in vital sign measurements [ Time Frame: measurements [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 3379] ]
    Heart rate, ventricular rate
  • Changes from baseline (defined as predose Day 1) in 12-lead electrocardiograms (ECG) [ Time Frame: [Cohort 1 + Cohort 2: from baseline to 30 minutes postdose, from baseline to 6 hours postdose, from baseline to Day 2, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from base ]
    RR, PR, QRS, QT, and corrected QT interval (QTcF, Fridericia correction)
  • Changes from baseline (defined as predose Day 1) in 12-lead electrocardiograms (ECG) [ Time Frame: [Cohort 1 + Cohort 2: from baseline to 30 minutes postdose, from baseline to 6 hours postdose, from baseline to Day 2, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from base ]
    Heart rate, ventricular rate
  • Changes from baseline (defined as predose Day 29) in 12-lead electrocardiograms (ECG) [ Time Frame: [Cohort 1 + Cohort 2: from baseline to 30 minutes postdose, from baseline to 6 hours postdose, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    Heart rate, ventricular rate
  • Changes from baseline (defined as predose Day 29) in 12-lead electrocardiograms (ECG) [ Time Frame: [Cohort 1 + Cohort 2: from baseline to 30 minutes postdose, from baseline to 6 hours postdose, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    RR, PR, QRS, QT, and corrected QT interval (QTcF, Fridericia correction)
  • Changes from baseline (defined as predose Day 1) in 12-lead electrocardiograms (ECG) [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    Heart rate, ventricular rate, RR, PR, QRS, QT, and corrected QT interval (QTcF, Fridericia correction)
  • Changes from baseline (defined as predose Day 29) in 12-lead electrocardiograms (ECG) [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    Heart rate, ventricular rate, RR, PR, QRS, QT, and corrected QT interval (QTcF, Fridericia correction)
  • Changes from baseline in pulmonary function tests [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    FEV1, FVC, FEV1/FVC, and DLCO
  • Changes from baseline in pulmonary function tests [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    FEV1, FVC, FEV1/FVC, and DLCO
  • Changes from baseline in Serum A1AT protein concentrations [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
  • Changes from baseline in Serum A1AT protein concentrations [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
  • The incidence of adverse events (AE), serious adverse events (SAE), and AE leading to study drug discontinuation. [ Time Frame: approximately up to 48 weeks (Cohort 2) ]
  • The incidence of clinically significant physical examination (PE) findings. [ Time Frame: approximately up to 48 weeks (Cohort 2) ]
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    neutrophils (abs and %)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    basophils (abs and %)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    eosinophils (abs and %)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    monocytes (abs and %)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    lymphocytes (abs and %)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    mean corpuscular hemoglobin concentration (MCHC)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    mean corpuscular hemoglobin (MCH)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    mean corpuscular volume (MCV)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    reticulocytes
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    platelet count
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    hematocrit
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    hemoglobin
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 1 + Cohort 2: from baseline to Day 1, from baseline to Day 2, from baseline to Day 3, from baseline to Day 15, from baseline to Day 29, from baseline to Day 30, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from bas ]
    CBC
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    CBC
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    hemoglobin
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    hematocrit
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    platelet count
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    reticulocytes
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    mean corpuscular volume (MCV)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    mean corpuscular hemoglobin (MCH)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    mean corpuscular hemoglobin concentration (MCHC)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    lymphocytes (abs and %)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    monocytes (abs and %)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    eosinophils (abs and %)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    basophils (abs and %)
  • Change from baseline in hematologic parameters [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    neutrophils (abs and %)
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    microscopic examination (if blood or protein is abnormal)
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    leukocyte esterase by dipstick
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    nitrite
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    urobilinogen
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    bilirubin
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    ketones
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    blood
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    protein
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    glucose
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    pH
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 1 and Cohort 2: from baseline to Day 1, from baseline to Day 15, from baseline to Day 29, from baseline to Day 57, from baseline to Day 85, from baseline to Day 113, from baseline to Day 141, from baseline to Day 169] ]
    Specific gravity
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    microscopic examination (if blood or protein is abnormal)
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    leukocyte esterase by dipstick
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    nitrite
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    urobilinogen
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    bilirubin
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    ketones
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    blood
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    protein
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    glucose
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    pH
  • Changes from baseline in urinalysis [ Time Frame: [Cohort 2 only: from baseline to Day 197, from baseline to Day 225, from baseline to Day 253, from baseline to Day 281, from baseline to Day 309, from baseline to Day 337] ]
    Specific gravity
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 19, 2021)
  • Plasma concentration of Belcesiran on Day 1 [ Time Frame: [Cohort 1 + Cohort 2: at predose, at 5 minutes postdose, at 15 minutes postdose, at 30 minutes postdose, at 60 minutes postdose, at 2 hours postdose, at 4 hours postdose, at 6 hours postdose, at 8 hours postdose, at 12 hours postdose, at 24 hours postdo ]
  • Plasma concentration of Belcesiran on Day 29 [ Time Frame: [Cohort 1 + Cohort 2: at predose, at 5 minutes postdose, at 15 minutes postdose, at 30 minutes postdose, at 60 minutes postdose, at 2 hours postdose, at 4 hours postdose, at 6 hours postdose, at 8 hours postdose, at 12 hours postdose, at 24 hours postdo ]
  • Predose plasma concentration of Belcesiran [ Time Frame: [Cohort 2 only on Day 197, Day 225, Day 253, Day 281, Day 309, and Day 337] ]
  • Predose plasma concentration of Belcesiran [ Time Frame: [Cohort 1 and Cohort 2 on Day 57, Day 85, Day 113, Day 141, Day 169 ] ]
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    METAVIR Score Fibrosis sub-score: from F0 - F4 (F0 = no fibrosis, F4 = cirrhosis)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    METAVIR Score Activity sub-score: from A0 - A3 (A0 = no activity, A3 = severe activity)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    • Steatosis Score Brunt Macrovesicular Steatosis Score: from 0 - 3 Sirius Red Stain (% of area stained)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    • Ishak Score Focal lytic necrosis, apoptosis, and focal inflammation sub-score: from 0 - 4 (0 = absent, 4 = more than ten foci per 10x objective)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    • Ishak Score Portal inflammation sub-score: from 0 - 4 (0 = none, 4 = marked, all portal areas)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    • Ishak Score Confluent necrosis sub-score: from 0 - 6 (0 = absent, 6 = panacinar or multiacinar necrosis)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    • Ishak Score Fibrosis sub-score: from 0 - 6 (0 = no fibrosis, 6 = probable or definite cirrhosis)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    • Ishak Score Periportal or periseptal interface hepatitis sub-score: from 0 - 4 (0 = absent, 4 = severe, continuous around >50% of tracts or septa)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    METAVIR Score Fibrosis sub-score: from F0 - F4 (F0 = no fibrosis, F4 = cirrhosis)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    METAVIR Score Activity sub-score: from A0 - A3 (A0 = no activity, A3 = severe activity)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    • Ishak Score Fibrosis sub-score: from 0 - 6 (0 = no fibrosis, 6 = probable or definite cirrhosis)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    • Ishak Score Periportal or periseptal interface hepatitis sub-score: from 0 - 4 (0 = absent, 4 = severe, continuous around >50% of tracts or septa)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    • Ishak Score Confluent necrosis sub-score: from 0 - 6 (0 = absent, 6 = panacinar or multiacinar necrosis)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    • Ishak Score Focal lytic necrosis, apoptosis, and focal inflammation sub-score: from 0 - 4 (0 = absent, 4 = more than ten foci per 10x objective)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    • Ishak Score Portal inflammation sub-score: from 0 - 4 (0 = none, 4 = marked, all portal areas)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    • Steatosis Score Brunt Macrovesicular Steatosis Score: from 0 - 3 Sirius Red Stain (% of area stained)
Original Secondary Outcome Measures  ICMJE
 (submitted: February 17, 2021)
  • Plasma concentration of Belcesiran on Day 1 [ Time Frame: [Cohort 1 + Cohort 2: at predose, at 5 minutes postdose, at 15 minutes postdose, at 30 minutes postdose, at 60 minutes postdose, at 2 hours postdose, at 4 hours postdose, at 6 hours postdose, at 8 hours postdose, at 12 hours postdose, at 24 hours postdo ]
  • Plasma concentration of Belcesiran on Day 29 [ Time Frame: [Cohort 1 + Cohort 2: at predose, at 5 minutes postdose, at 15 minutes postdose, at 30 minutes postdose, at 60 minutes postdose, at 2 hours postdose, at 4 hours postdose, at 6 hours postdose, at 8 hours postdose, at 12 hours postdose, at 24 hours postdo ]
  • Predose plasma concentration of Belcesiran [ Time Frame: [Cohort 2 only on Day 197, Day 225, Day 253, Day 281, Day 309, and Day 337] ]
  • Predose plasma concentration of Belcesiran [ Time Frame: [Cohort 1 and Cohort 2 on Day 57, Day 85, Day 113, Day 141, Day 169 ] ]
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    METAVIR Score Fibrosis sub-score: from F0 - F4 (F0 = no fibrosis, F4 = cirrhosis) Activity sub-score: from A0 - A3 (A0 = no activity, A3 = severe activity)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    • Steatosis Score Brunt Macrovesicular Steatosis Score: from 0 - 3 Sirius Red Stain (% of area stained)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 1 only: from baseline to Day 169] ]
    • Ishak Score Fibrosis sub-score: from 0 - 6 (0 = no fibrosis, 6 = probable or definite cirrhosis) Periportal or periseptal interface hepatitis sub-score: from 0 - 4 (0 = absent, 4 = severe, continuous around >50% of tracts or septa) Confluent necrosis sub-score: from 0 - 6 (0 = absent, 6 = panacinar or multiacinar necrosis) Focal lytic necrosis, apoptosis, and focal inflammation sub-score: from 0 - 4 (0 = absent, 4 = more than ten foci per 10x objective) Portal inflammation sub-score: from 0 - 4 (0 = none, 4 = marked, all portal areas)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    METAVIR Score Fibrosis sub-score: from F0 - F4 (F0 = no fibrosis, F4 = cirrhosis) Activity sub-score: from A0 - A3 (A0 = no activity, A3 = severe activity)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    • Ishak Score Fibrosis sub-score: from 0 - 6 (0 = no fibrosis, 6 = probable or definite cirrhosis) Periportal or periseptal interface hepatitis sub-score: from 0 - 4 (0 = absent, 4 = severe, continuous around >50% of tracts or septa) Confluent necrosis sub-score: from 0 - 6 (0 = absent, 6 = panacinar or multiacinar necrosis) Focal lytic necrosis, apoptosis, and focal inflammation sub-score: from 0 - 4 (0 = absent, 4 = more than ten foci per 10x objective) Portal inflammation sub-score: from 0 - 4 (0 = none, 4 = marked, all portal areas)
  • Changes from Baseline in liver disease scores [ Time Frame: [Cohort 2 only: from baseline to Day 337] ]
    • Steatosis Score Brunt Macrovesicular Steatosis Score: from 0 - 3 Sirius Red Stain (% of area stained)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Belcesiran in Patients With A1ATD-Associated Liver Disease
Official Title  ICMJE A Phase 2a, Randomized, Double-blind, Placebo Controlled, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of Belcesiran in Patients With PiZZ Alpha-1 Antitrypsin Deficiency
Brief Summary

This is a multiple dose, randomized, placebo-controlled, double-blind study of belcesiran to evaluate the safety, tolerability, PK, and PD in adult patients with PiZZ A1ATD-associated liver disease.

The study will be conducted in 2 parallel cohorts. A total of up to 27 participants may be enrolled in a single cohort. The 2 cohorts are differentiated only by the duration of the treatment period, the number of doses administered, and the timing of the end-of-treatment (EOT) liver biopsy. Participants in Cohort 1 will undergo EOT biopsy at 24 weeks, and participants in Cohort 2 will undergo EOT biopsy at 48 weeks.

Detailed Description

A1ATD-associated liver disease is a progressive Alpha-1 Antitrypsin-Deficiency Associated Liver Disease condition resulting in liver fibrosis, cirrhosis, and hepatocellular carcinoma. The lack of functional A1AT in individuals with the PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity of neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism can be addressed with intravenous augmentation therapy, which aims to substitute the missing A1AT by infusing alpha-1 proteinase inhibitor (A1PI), purified from pooled human plasma.

While augmentation therapy can address the loss of A1AT in the lung, no treatment exists for the associated liver disease.

Given the severity of the disease, with approximately 10% of affected patients developing liver cirrhosis and a subgroup of those patients in need of liver transplantation, and the lack of an effective treatment that addresses the toxic hepatic "gain-of-function" mechanism, there is an urgent unmet medical need to develop a therapy that can help this particular patient population.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
Double blind
Primary Purpose: Other
Condition  ICMJE Alpha 1-Antitrypsin Deficiency
Intervention  ICMJE
  • Drug: belcesiran
    belcesiran will be administered subcutaneously (SC). Dose level to be determined upon review of data from DCR-A1AT-101.
  • Other: Placebo
    Placebo will be administered subcutaneously (SC). Sterile normal saline (0.9% NaCL) matching volume of belcesiran doses will be administered subcutaneously (SC).
Study Arms  ICMJE
  • Experimental: Experimental: belcesiran
    Patients diagnosed with A1ATD-Associated Liver Disease will be administered belcesiran.
    Intervention: Drug: belcesiran
  • Placebo Comparator: Placebo
    Patients diagnosed with A1ATD-Associated Liver Disease will be administered Sterile normal saline (0.9% NaCL) matching volume of belcesiran doses will be administered subcutaneously (SC).
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 17, 2021)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2023
Estimated Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 18 to 70 years, inclusive. Female participants must be either surgically sterile or postmenopausal. No women of childbearing potential are eligible for enrollment.
  • Documented diagnosis of PiZZ-type A1ATD, confirmed by genotyping. Historical genotyping data may be used, if available.
  • A1ATD-associated liver disease documented by liver biopsy.
  • Consent to undergo paired liver biopsies, one at Screening and one at either 24 weeks or 48 weeks of the first dose of the study intervention
  • Lung, renal and liver function within acceptable limits
  • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

  • Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially affect patient safety including, but not restricted to:
  • Severe intercurrent illness.
  • History of chronic liver disease from any cause other than PiZZ-type A1ATD,
  • A1AT augmentation therapy in the 6 months prior to Screening
  • Routine use of acetaminophen/paracetamol
  • Use of systemically acting steroids in the month prior to Screening and throughout the study period.
  • Participation in any clinical study in which they received an IMP within 4 months before Screening
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Medical Info 617-621-8097 medicalinfo@dicerna.com
Listed Location Countries  ICMJE Australia,   New Zealand,   Spain,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04764448
Other Study ID Numbers  ICMJE DCR-A1AT-201
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dicerna Pharmaceuticals, Inc.
Study Sponsor  ICMJE Dicerna Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Hardean Achneck, MD Dicerna Pharmaceuticals
PRS Account Dicerna Pharmaceuticals, Inc.
Verification Date December 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP