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A Study of Belcesiran in Patients With AATLD (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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04764448
Recruitment Status : Active, not recruiting
First Posted : February 21, 2021
Last Update Posted : March 28, 2024
Sponsor:
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Tracking Information
First Submitted Date  ICMJE January 27, 2021
First Posted Date  ICMJE February 21, 2021
Last Update Posted Date March 28, 2024
Actual Study Start Date  ICMJE February 12, 2021
Actual Primary Completion Date December 8, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 29, 2022)
  • The incidence and nature of treatment emergent adverse events (TEAE) [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in pulmonary function tests (PFTs): Forced Vital Capacity (FVC) [ Time Frame: Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in pulmonary function tests (PFTs): Forced Expiratory Volume in One Second (FEV1) [ Time Frame: Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in pulmonary function tests (PFTs): Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in 12-lead ECGs: Heart Rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in 12-lead ECGs: Ventricular Rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in 12-lead ECGs: RR interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in 12-lead ECGs: PR interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in 12-lead ECGs: QRS interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in 12-lead ECGs: QT interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in 12-lead ECGs: corrected QT interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • The incidence of clinically significant physical examination (PE) findings [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in vital sign measurements: temperature [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in vital sign measurements: pulse rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in vital sign measurements: respiratory rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in vital sign measurements: blood pressure [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in clinical laboratory tests: clinical chemistry [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in clinical laboratory tests: hematology [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in clinical laboratory tests: Coagulation [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in clinical laboratory tests: Serum AFP [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in clinical laboratory tests: Total complement hemolytic activity CH50 [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in clinical laboratory tests: C-reactive protein (CRP) [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline in clinical laboratory tests: Antidrug antibodies [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from Baseline in serum AAT concentration [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  • Change from baseline to Week 24 in serum Z-AAT protein levels [ Time Frame: up to 24 weeks (Cohort 3) ]
  • Change from baseline to Week 24 in liver Z-AAT liver protein levels [ Time Frame: up to 24 weeks (Cohort 3) ]
Original 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
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
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 AATLD
Official Title  ICMJE A Phase 2, Randomized, Double-blind, Placebo-Controlled Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Two Dose Levels of Belcesiran in Patients With Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
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 AATD-associated liver disease (AATLD).

The study will be conducted in 3 separate cohorts. A total of up to 16 participants may be enrolled in Cohort 1 and 2. A total number of 30 subjects will be enrolled in cohort 3. The 3 cohorts are differentiated by the duration of the treatment period, the number of doses administered, and the timing of the second liver biopsy.
Detailed Description

AATD-associated liver disease is a progressive condition resulting in liver fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. The lack of functional alpha-1 antitrypsin (AAT) 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 may be addressed by use of intravenous augmentation therapy, which aims to substitute the missing AAT by infusing alpha-1 proteinase inhibitor (A1PI), purified from pooled human plasma.

While augmentation therapy can address the loss of AAT 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
    Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.
  • Other: Placebo
    Comparator: Placebo Cohort 1 Administered sterile normal saline (0.9% NaCl) matching volume of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.
  • Drug: Belcesiran
    Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.
  • Other: Placebo
    Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.
  • Drug: Belcesiran
    Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 96 weeks.
  • Other: Placebo
    Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 96 weeks.
Study Arms  ICMJE
  • Experimental: Belcesiran Cohort 1
    Intervention: Drug: Belcesiran
  • Placebo Comparator: Placebo Cohort 1
    Intervention: Other: Placebo
  • Experimental: Belcesiran Cohort 2
    Intervention: Drug: Belcesiran
  • Placebo Comparator: Placebo Cohort 2
    Intervention: Other: Placebo
  • Experimental: Belcesiran Cohort 3
    Intervention: Drug: Belcesiran
  • Placebo Comparator: Placebo Cohort 3
    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 Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: November 29, 2022)		 46
Original Estimated Enrollment  ICMJE
 (submitted: February 17, 2021)		 54
Estimated Study Completion Date  ICMJE December 1, 2026
Actual Primary Completion Date December 8, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 18 to 75 years, inclusive, at the time of consent.
  • Documented diagnosis of PiZZ-type alpha-1 antitrypsin deficiency, confirmed by genotyping. Historical genotyping data may be used, if available.
  • AATD-associated liver disease documented by liver biopsy at Screening.
  • Consent to undergo paired liver biopsies.
  • 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:

  • History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other than PiZZ-type alpha-1 antitrypsin deficiency.
  • Child-Pugh Score B or C.
  • History of one single severe exacerbation of underlying lung disease in the year prior to randomization.
  • History of clinically significant respiratory infections (including pneumonia and lower respiratory tract infections), as determined by the Investigator, in the 3 months prior to screening
  • Use of an RNAi drug at any time.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   France,   Germany,   Ireland,   Netherlands,   New Zealand,   Portugal,   Spain,   Sweden,   United Kingdom,   United States
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: Yes
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
Current Responsible Party Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Thomas Bowman, MD Dicerna Pharmaceuticals / Novo Nordisk
PRS Account Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Verification Date March 2024

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