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

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ClinicalTrials.gov Identifier: NCT04764448
Recruitment Status : Recruiting
First Posted : February 21, 2021
Last Update Posted : February 23, 2021
Sponsor:
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc.

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.


Condition or disease Intervention/treatment Phase
Alpha 1-Antitrypsin Deficiency Drug: belcesiran Other: Placebo Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Double blind
Primary Purpose: Other
Official Title: A Phase 2a, Randomized, Double-blind, Placebo Controlled, Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of Belcesiran in Patients With PiZZ Alpha-1 Antitrypsin Deficiency
Actual Study Start Date : February 12, 2021
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : December 1, 2023


Arm Intervention/treatment
Experimental: Experimental: belcesiran
Patients diagnosed with A1ATD-Associated Liver Disease will be administered belcesiran.
Drug: belcesiran
belcesiran will be administered subcutaneously (SC). Dose level to be determined upon review of data from DCR-A1AT-101.

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).
Other: Placebo
Placebo will be administered subcutaneously (SC). Sterile normal saline (0.9% NaCL) matching volume of belcesiran doses will be administered subcutaneously (SC).




Primary Outcome Measures :
  1. 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) ]
  2. The incidence of clinically significant physical examination (PE) findings. [ Time Frame: up to 24 weeks (Cohort 1) ]
  3. 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

  4. 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

  5. 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

  6. 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

  7. 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)

  8. 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)

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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)

  18. 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)

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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)

  28. 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)

  29. 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

  30. 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

  31. 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)

  32. 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)

  33. 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),

  34. 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),

  35. 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)

  36. 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)

  37. 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)

  38. 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)

  39. 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)

  40. 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

  41. 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)

  42. 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

  43. 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)

  44. 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

  45. 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)

  46. 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

  47. 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)

  48. 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

  49. 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

  50. 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)

  51. 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)

  52. 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)

  53. 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

  54. 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

  55. 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] ]
  56. 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] ]
  57. 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) ]
  58. The incidence of clinically significant physical examination (PE) findings. [ Time Frame: approximately up to 48 weeks (Cohort 2) ]
  59. 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 %)

  60. 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 %)

  61. 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 %)

  62. 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 %)

  63. 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 %)

  64. 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)

  65. 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)

  66. 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)

  67. 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

  68. 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

  69. 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

  70. 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

  71. 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

  72. 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

  73. 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

  74. 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

  75. 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

  76. 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

  77. 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)

  78. 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)

  79. 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)

  80. 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 %)

  81. 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 %)

  82. 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 %)

  83. 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 %)

  84. 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 %)

  85. 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)

  86. 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

  87. 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

  88. 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

  89. 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

  90. 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

  91. 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

  92. 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

  93. 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

  94. 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

  95. 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

  96. 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)

  97. 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

  98. 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

  99. 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

  100. 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

  101. 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

  102. 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

  103. 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

  104. 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

  105. 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

  106. 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


Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. Predose plasma concentration of Belcesiran [ Time Frame: [Cohort 2 only on Day 197, Day 225, Day 253, Day 281, Day 309, and Day 337] ]
  4. Predose plasma concentration of Belcesiran [ Time Frame: [Cohort 1 and Cohort 2 on Day 57, Day 85, Day 113, Day 141, Day 169 ] ]
  5. 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)

  6. 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)

  7. 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)

  8. 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)

  9. 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)

  10. 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)

  11. 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)

  12. 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)

  13. 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)

  14. 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)

  15. 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)

  16. 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)

  17. 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)

  18. 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)

  19. 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)

  20. 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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04764448


Contacts
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Contact: Medical Info 617-621-8097 medicalinfo@dicerna.com

Locations
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New Zealand
Auckland Clinical Studies Recruiting
Grafton, Auckland, New Zealand, 1010
Contact: Ed Gane, MD    +64 9 3733474      
Sponsors and Collaborators
Dicerna Pharmaceuticals, Inc.
Investigators
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Study Director: Hardean Achneck, MD Dicerna Pharmaceuticals
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Responsible Party: Dicerna Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04764448    
Other Study ID Numbers: DCR-A1AT-201
First Posted: February 21, 2021    Key Record Dates
Last Update Posted: February 23, 2021
Last Verified: February 2021

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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
Additional relevant MeSH terms:
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Alpha 1-Antitrypsin Deficiency
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Pathologic Processes