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

• Sponsor: Dicerna Pharmaceuticals, Inc. (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04764448
• Collaborator: (none)
• Enrollment: 54
• Locations: 16
• Arms: 2
• Anticipated Duration (Months): 33.6
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• Anticipated 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: Feb 12, 2021
• Anticipated Primary Completion Date: Dec 1, 2022
• Anticipated Study Completion Date: Dec 1, 2023

Arms and Interventions

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).

Outcome Measures

Primary Outcome Measures

1. The incidence of adverse events (AE), serious adverse events (SAE), and AE leading to study drug discontinuation. [up to 24 weeks (Cohort 1)]

2. The incidence of clinically significant physical examination (PE) findings. [up to 24 weeks (Cohort 1)]

3. Change from baseline in coagulation parameters [[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 [[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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [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 [[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 [[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 [[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 [[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 [[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 [[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 [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 [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) [[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) [[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) [[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) [[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) [[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) [[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 [[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 [[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 [[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 [[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. [approximately up to 48 weeks (Cohort 2)]

58. The incidence of clinically significant physical examination (PE) findings. [approximately up to 48 weeks (Cohort 2)]

59. Change from baseline in hematologic parameters [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[Cohort 2 only on Day 197, Day 225, Day 253, Day 281, Day 309, and Day 337]]

4. Predose plasma concentration of Belcesiran [[Cohort 1 and Cohort 2 on Day 57, Day 85, Day 113, Day 141, Day 169 ]]

5. Changes from Baseline in liver disease scores [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[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 [[Cohort 2 only: from baseline to Day 337]]

    • Steatosis Score Brunt Macrovesicular Steatosis Score: from 0 - 3 Sirius Red Stain (% of area stained)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St Vincent's Hospital Melbourne	Melbourne		Australia
2	Universitaire Ziekenhuizen Leuven	Leuven		Belgium
3	Centre Hospitalier de l'Universite de Montreal (CHUM)	Montreal	Quebec	Canada
4	CHU Bordeaux - Hopital Haut-Leveque - Centre François Magendie	Pessac		France
5	Universitaetsklinikum Aachen, AoeR	Aachen		Germany
6	Universitaetsklinikum Schleswig-Holstein Campus Kiel	Kiel		Germany
7	Leiden University Medical Center	Leiden		Netherlands
8	Auckland Clinical Studies	Grafton	Auckland	New Zealand	1010
9	Waikato Hospital	Hamilton		New Zealand
10	Hospital da Senhora da Oliveira - Guimaraes	Creixomil		Portugal
11	Centro Hospitalar Universitario de Sao Joao	Porto		Portugal
12	Centro Hospitalar de Trás-os-Montes e Alto Douro, EPE	Vila Real		Portugal
13	Hospital Universitario Marques de Valdecilla Santander	Santander	Cantabria	Spain
14	Hospital Universitario La Paz	Madrid		Spain
15	CTC Clinical Trial Consultants AB Uppsala	Uppsala		Sweden
16	Addenbrooke's Hospital, Cambridge University	Cambridge		United Kingdom

Sponsors and Collaborators

• Dicerna Pharmaceuticals, Inc.

Investigators

• Study Director: Hardean Achneck, MD, Dicerna Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dicerna Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04764448
• Other Study ID Numbers: DCR-A1AT-201
• First Posted: Feb 21, 2021
• Last Update Posted: Aug 11, 2022
• Last Verified: Aug 1, 2022

• 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: Alpha 1-Antitrypsin Deficiency

Study Results

No Results Posted as of Aug 11, 2022