Back to resultsA Study of Belcesiran in Patients With AATLD (ESTRELLA)
Primary Purpose
Alpha 1-Antitrypsin Deficiency
Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Belcesiran
Placebo
Belcesiran
Placebo
Belcesiran
Placebo
Sponsored by
About this trial
This is an interventional other trial for Alpha 1-Antitrypsin Deficiency
Eligibility 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
Sites / Locations
- University of California - San DiegoRecruiting
- University of FloridaRecruiting
- St Vincent's Hospital MelbourneRecruiting
- Medizinische Universitaet InnsbruckRecruiting
- Universitaire Ziekenhuizen LeuvenRecruiting
- Centre Hospitalier de l'Universite de Montreal (CHUM)Recruiting
- CHU Bordeaux - Hopital Haut-Leveque - Centre François MagendieRecruiting
- Universitaetsklinikum Aachen, AoeRRecruiting
- Universitaetsklinikum Schleswig-Holstein Campus KielRecruiting
- Beaumont HospitalRecruiting
- Leiden University Medical CenterRecruiting
- Auckland Clinical StudiesRecruiting
- Waikato HospitalRecruiting
- Hospital da Senhora da Oliveira - GuimaraesRecruiting
- Centro Hospitalar Universitario de Sao JoaoRecruiting
- Centro Hospitalar de Trás-os-Montes e Alto Douro, EPERecruiting
- Hospital Universitario Marques de Valdecilla SantanderRecruiting
- Hospital Universitario La PazRecruiting
- CTC Clinical Trial Consultants AB UppsalaRecruiting
- Addenbrooke's Hospital, Cambridge UniversityRecruiting
- Leeds Teaching Hospitals NHS TrustRecruiting
- Royal Free London NHS Foundation Trust, Royal Free HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Experimental
Placebo Comparator
Experimental
Placebo Comparator
Experimental
Placebo Comparator
Arm Label
Belcesiran Cohort 1
Placebo Cohort 1
Belcesiran Cohort 2
Placebo Cohort 2
Belcesiran Cohort 3
Placebo Cohort 3
Arm Description
Outcomes
Primary Outcome Measures
The incidence and nature of treatment emergent adverse events (TEAE)
Change from baseline in pulmonary function tests (PFTs): Forced Vital Capacity (FVC)
Change from baseline in pulmonary function tests (PFTs): Forced Expiratory Volume in One Second (FEV1)
Change from baseline in pulmonary function tests (PFTs): Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)
Change from baseline in 12-lead ECGs: Heart Rate
Change from baseline in 12-lead ECGs: Ventricular Rate
Change from baseline in 12-lead ECGs: RR interval
Change from baseline in 12-lead ECGs: PR interval
Change from baseline in 12-lead ECGs: QRS interval
Change from baseline in 12-lead ECGs: QT interval
Change from baseline in 12-lead ECGs: corrected QT interval
The incidence of clinically significant physical examination (PE) findings
Change from baseline in vital sign measurements: temperature
Change from baseline in vital sign measurements: pulse rate
Change from baseline in vital sign measurements: respiratory rate
Change from baseline in vital sign measurements: blood pressure
Change from baseline in clinical laboratory tests: clinical chemistry
Change from baseline in clinical laboratory tests: hematology
Change from baseline in clinical laboratory tests: Coagulation
Change from baseline in clinical laboratory tests: Serum AFP
Change from baseline in clinical laboratory tests: Total complement hemolytic activity CH50
Change from baseline in clinical laboratory tests: C-reactive protein (CRP)
Change from baseline in clinical laboratory tests: Antidrug antibodies
Change from Baseline in serum AAT concentration
Change from baseline to Week 24 in serum Z-AAT protein levels
Change from baseline to Week 24 in liver Z-AAT liver protein levels
Secondary Outcome Measures
Full Information
NCT ID
NCT04764448
First Posted
January 27, 2021
Last Updated
April 27, 2023
Sponsor
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
1. Study Identification
Unique Protocol Identification Number
NCT04764448
Brief Title
A Study of Belcesiran in Patients With AATLD
Acronym
ESTRELLA
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
Study Type
Interventional
2. Study Status
Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 12, 2021 (Actual)
Primary Completion Date
September 30, 2023 (Anticipated)
Study Completion Date
December 1, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
4. Oversight
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
Data Monitoring Committee
Yes
5. 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 AATD-associated liver disease (AATLD).
The study will be conducted in 3 separate cohorts. A total of up to 16 participants may be enrolled in Cohort 1 and 2. A total number of 30 subjects will be enrolled in cohort 3. The 3 cohorts are differentiated by the duration of the treatment period, the number of doses administered, and the timing of the second liver biopsy.
Detailed Description
AATD-associated liver disease is a progressive condition resulting in liver fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. The lack of functional alpha-1 antitrypsin (AAT) in individuals with the PiZZ genotype, in conjunction with other precipitating factors, can lead to unchecked activity of neutrophil elastases in the alveoli; causing emphysema and chronic obstructive pulmonary disease (COPD). This loss-of-function mechanism may be addressed by use of intravenous augmentation therapy, which aims to substitute the missing AAT by infusing alpha-1 proteinase inhibitor (A1PI), purified from pooled human plasma.
While augmentation therapy can address the loss of AAT in the lung, no treatment exists for the associated liver disease.
Given the severity of the disease, with approximately 10% of affected patients developing liver cirrhosis and a subgroup of those patients in need of liver transplantation, and the lack of an effective treatment that addresses the toxic hepatic "gain-of-function" mechanism, there is an urgent unmet medical need to develop a therapy that can help this particular patient population.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alpha 1-Antitrypsin Deficiency
7. Study Design
Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
Double blind
Allocation
Randomized
Enrollment
46 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Belcesiran Cohort 1
Arm Type
Experimental
Arm Title
Placebo Cohort 1
Arm Type
Placebo Comparator
Arm Title
Belcesiran Cohort 2
Arm Type
Experimental
Arm Title
Placebo Cohort 2
Arm Type
Placebo Comparator
Arm Title
Belcesiran Cohort 3
Arm Type
Experimental
Arm Title
Placebo Cohort 3
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Belcesiran
Intervention Description
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Belcesiran
Intervention Description
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.
Intervention Type
Drug
Intervention Name(s)
Belcesiran
Intervention Description
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 96 weeks.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 96 weeks.
Primary Outcome Measure Information:
Title
The incidence and nature of treatment emergent adverse events (TEAE)
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
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)
Title
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)
Title
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)
Title
Change from baseline in 12-lead ECGs: Heart Rate
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in 12-lead ECGs: Ventricular Rate
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in 12-lead ECGs: RR interval
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in 12-lead ECGs: PR interval
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in 12-lead ECGs: QRS interval
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in 12-lead ECGs: QT interval
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in 12-lead ECGs: corrected QT interval
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
The incidence of clinically significant physical examination (PE) findings
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in vital sign measurements: temperature
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in vital sign measurements: pulse rate
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in vital sign measurements: respiratory rate
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in vital sign measurements: blood pressure
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in clinical laboratory tests: clinical chemistry
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in clinical laboratory tests: hematology
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in clinical laboratory tests: Coagulation
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline in clinical laboratory tests: Serum AFP
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
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)
Title
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)
Title
Change from baseline in clinical laboratory tests: Antidrug antibodies
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from Baseline in serum AAT concentration
Time Frame
up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Title
Change from baseline to Week 24 in serum Z-AAT protein levels
Time Frame
up to 24 weeks (Cohort 3)
Title
Change from baseline to Week 24 in liver Z-AAT liver protein levels
Time Frame
up to 24 weeks (Cohort 3)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Medical Info
Phone
617-621-8097
Email
medicalinfo@dicerna.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas Bowman, MD
Organizational Affiliation
Dicerna Pharmaceuticals / Novo Nordisk
Official's Role
Study Director
Facility Information:
Facility Name
University of California - San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32611
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
St Vincent's Hospital Melbourne
City
Melbourne
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Medizinische Universitaet Innsbruck
City
Innsbruck
Country
Austria
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Universitaire Ziekenhuizen Leuven
City
Leuven
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Centre Hospitalier de l'Universite de Montreal (CHUM)
City
Montreal
State/Province
Quebec
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
CHU Bordeaux - Hopital Haut-Leveque - Centre François Magendie
City
Pessac
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Universitaetsklinikum Aachen, AoeR
City
Aachen
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Universitaetsklinikum Schleswig-Holstein Campus Kiel
City
Kiel
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Beaumont Hospital
City
Dublin
Country
Ireland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Leiden University Medical Center
City
Leiden
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Auckland Clinical Studies
City
Grafton
State/Province
Auckland
ZIP/Postal Code
1010
Country
New Zealand
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ed Gane, MD
Phone
+64 9 3733474
Facility Name
Waikato Hospital
City
Hamilton
Country
New Zealand
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Hospital da Senhora da Oliveira - Guimaraes
City
Creixomil
Country
Portugal
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Centro Hospitalar Universitario de Sao Joao
City
Porto
Country
Portugal
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Centro Hospitalar de Trás-os-Montes e Alto Douro, EPE
City
Vila Real
Country
Portugal
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Hospital Universitario Marques de Valdecilla Santander
City
Santander
State/Province
Cantabria
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Hospital Universitario La Paz
City
Madrid
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
CTC Clinical Trial Consultants AB Uppsala
City
Uppsala
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Addenbrooke's Hospital, Cambridge University
City
Cambridge
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Leeds Teaching Hospitals NHS Trust
City
Leeds
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
Facility Name
Royal Free London NHS Foundation Trust, Royal Free Hospital
City
London
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Principal Investigator
12. IPD Sharing Statement
Learn more about this trial
A Study of Belcesiran in Patients With AATLD
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