A Study of Belcesiran in Patients With AATLD

Alpha 1-Antitrypsin Deficiency Clinical Trial

— 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04764448
• Other study ID #: DCR-A1AT-201
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: February 12, 2021
• Est. completion date: December 1, 2026

Study information

• Verified date: March 2024
• Source: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 46
• Est. completion date: December 1, 2026
• Est. primary completion date: December 8, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alpha 1-Antitrypsin Deficiency

Intervention

Drug:
• Belcesiran
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.

Other:
• Placebo
Comparator: Placebo Cohort 1 Administered sterile normal saline (0.9% NaCl) matching volume of belcesiran by subcutaneous (sc) injection for 24 weeks. Extension offered to participants.

Drug:
• Belcesiran
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.

Other:
• Placebo
Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 48 weeks. Extension offered to participants.

Drug:
• Belcesiran
Administered multiple fixed doses of belcesiran by subcutaneous (sc) injection for 96 weeks.

Other:
• Placebo
Administered sterile normal saline (0.9% NaCl) matching volumes of belcesiran by subcutaneous (sc) injection for 96 weeks.

Locations

Country	Name	City	State
Australia	St Vincent's Hospital Melbourne	Melbourne
Austria	Medizinische Universitaet Innsbruck	Innsbruck
Belgium	Universitaire Ziekenhuizen Leuven	Leuven
Canada	Centre Hospitalier de l'Universite de Montreal (CHUM)	Montreal	Quebec
France	CHU Bordeaux - Hopital Haut-Leveque - Centre François Magendie	Pessac
Germany	Universitaetsklinikum Aachen, AoeR	Aachen
Germany	Universitaetsklinikum Schleswig-Holstein Campus Kiel	Kiel
Ireland	Beaumont Hospital	Dublin
Netherlands	Leiden University Medical Center	Leiden
New Zealand	Auckland Clinical Studies	Grafton	Auckland
New Zealand	Waikato Hospital	Hamilton
Portugal	Hospital da Senhora da Oliveira - Guimaraes	Creixomil
Portugal	Centro Hospitalar Universitario de Sao Joao	Porto
Portugal	Centro Hospitalar de Trás-os-Montes e Alto Douro, EPE	Vila Real
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Marques de Valdecilla Santander	Santander	Cantabria
Sweden	CTC Clinical Trial Consultants AB Uppsala	Uppsala
United Kingdom	Addenbrooke's Hospital, Cambridge University	Cambridge
United Kingdom	Leeds Teaching Hospitals NHS Trust	Leeds
United Kingdom	Royal Free London NHS Foundation Trust, Royal Free Hospital	London
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Florida	Gainesville	Florida
United States	University of California - San Diego	La Jolla	California

Sponsors (1)

Lead Sponsor	Collaborator
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Ireland,  Netherlands,  New Zealand,  Portugal,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The incidence and nature of treatment emergent adverse events (TEAE)		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in pulmonary function tests (PFTs): Forced Vital Capacity (FVC)		Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in pulmonary function tests (PFTs): Forced Expiratory Volume in One Second (FEV1)		Time Frame: up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in pulmonary function tests (PFTs): Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO)		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in 12-lead ECGs: Heart Rate		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in 12-lead ECGs: Ventricular Rate		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in 12-lead ECGs: RR interval		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in 12-lead ECGs: PR interval		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in 12-lead ECGs: QRS interval		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in 12-lead ECGs: QT interval		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in 12-lead ECGs: corrected QT interval		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	The incidence of clinically significant physical examination (PE) findings		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in vital sign measurements: temperature		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in vital sign measurements: pulse rate		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in vital sign measurements: respiratory rate		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in vital sign measurements: blood pressure		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in clinical laboratory tests: clinical chemistry		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in clinical laboratory tests: hematology		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in clinical laboratory tests: Coagulation		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in clinical laboratory tests: Serum AFP		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in clinical laboratory tests: Total complement hemolytic activity CH50		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in clinical laboratory tests: C-reactive protein (CRP)		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline in clinical laboratory tests: Antidrug antibodies		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from Baseline in serum AAT concentration		up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)
Primary	Change from baseline to Week 24 in serum Z-AAT protein levels		up to 24 weeks (Cohort 3)
Primary	Change from baseline to Week 24 in liver Z-AAT liver protein levels		up to 24 weeks (Cohort 3)