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A Study of Belcesiran in Patients With AATLD (ESTRELLA)

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ClinicalTrials.gov Identifier: NCT04764448
Recruitment Status : Recruiting
First Posted : February 21, 2021
Last Update Posted : January 31, 2023
Sponsor:
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc.

Study Description
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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.


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

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Double blind
Primary Purpose: Other
Official Title: 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
Actual Study Start Date : February 12, 2021
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : December 1, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Belcesiran Cohort 1 Drug: Belcesiran
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.
Placebo Comparator: Placebo Cohort 1 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.
Experimental: Belcesiran Cohort 2 Drug: Belcesiran
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.
Placebo Comparator: Placebo Cohort 2 Other: Placebo
Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.
Experimental: Belcesiran Cohort 3 Drug: Belcesiran
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 96 weeks.
Placebo Comparator: Placebo Cohort 3 Other: Placebo
Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 96 weeks.


Outcome Measures
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Primary Outcome Measures :
  1. The incidence and nature of treatment emergent adverse events (TEAE) [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  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) ]
  3. 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) ]
  4. 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) ]
  5. Change from baseline in 12-lead ECGs: Heart Rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  6. Change from baseline in 12-lead ECGs: Ventricular Rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  7. Change from baseline in 12-lead ECGs: RR interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  8. Change from baseline in 12-lead ECGs: PR interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  9. Change from baseline in 12-lead ECGs: QRS interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  10. Change from baseline in 12-lead ECGs: QT interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  11. Change from baseline in 12-lead ECGs: corrected QT interval [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  12. The incidence of clinically significant physical examination (PE) findings [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  13. Change from baseline in vital sign measurements: temperature [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  14. Change from baseline in vital sign measurements: pulse rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  15. Change from baseline in vital sign measurements: respiratory rate [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  16. Change from baseline in vital sign measurements: blood pressure [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  17. Change from baseline in clinical laboratory tests: clinical chemistry [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  18. Change from baseline in clinical laboratory tests: hematology [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  19. Change from baseline in clinical laboratory tests: Coagulation [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  20. Change from baseline in clinical laboratory tests: Serum AFP [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  21. 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) ]
  22. 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) ]
  23. Change from baseline in clinical laboratory tests: Antidrug antibodies [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  24. Change from Baseline in serum AAT concentration [ Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2) ]
  25. Change from baseline to Week 24 in serum Z-AAT protein levels [ Time Frame: up to 24 weeks (Cohort 3) ]
  26. Change from baseline to Week 24 in liver Z-AAT liver protein levels [ Time Frame: up to 24 weeks (Cohort 3) ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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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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Sponsors and Collaborators
Dicerna Pharmaceuticals, Inc.
Investigators
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Study Director: Thomas Bowman, MD Dicerna Pharmaceuticals / Novo Nordisk
More Information
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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: January 31, 2023
Last Verified: January 2023

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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