Clinical trial

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

ID

Name

DCR-A1AT-201

Description

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.

Trial arms

Trial start

2021-02-12

Estimated PCD

2023-12-08

Trial end

2026-12-01

Status

Active (not recruiting)

Phase

Early phase I

Treatment

Belcesiran

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

Arms:

Belcesiran Cohort 1

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.

Arms:

Placebo Cohort 1

Belcesiran

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

Arms:

Belcesiran Cohort 2

Placebo

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

Arms:

Placebo Cohort 2

Belcesiran

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

Arms:

Belcesiran Cohort 3

Placebo

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

Arms:

Placebo Cohort 3

Size

46

Primary endpoint

The incidence and nature of treatment emergent adverse events (TEAE)

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

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)

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)

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)

Change from baseline in 12-lead ECGs: Heart Rate

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in 12-lead ECGs: Ventricular Rate

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in 12-lead ECGs: RR interval

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in 12-lead ECGs: PR interval

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in 12-lead ECGs: QRS interval

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in 12-lead ECGs: QT interval

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in 12-lead ECGs: corrected QT interval

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

The incidence of clinically significant physical examination (PE) findings

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in vital sign measurements: temperature

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in vital sign measurements: pulse rate

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in vital sign measurements: respiratory rate

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in vital sign measurements: blood pressure

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in clinical laboratory tests: clinical chemistry

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in clinical laboratory tests: hematology

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in clinical laboratory tests: Coagulation

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in clinical laboratory tests: Serum AFP

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in clinical laboratory tests: Total complement hemolytic activity CH50

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in clinical laboratory tests: C-reactive protein (CRP)

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline in clinical laboratory tests: Antidrug antibodies

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from Baseline in serum AAT concentration

up to 24 weeks (Cohort 1), up to 48 weeks (Cohort 2)

Change from baseline to Week 24 in serum Z-AAT protein levels

up to 24 weeks (Cohort 3)

Change from baseline to Week 24 in liver Z-AAT liver protein levels

up to 24 weeks (Cohort 3)

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.

Protocol

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'primaryPurpose': 'OTHER', 'maskingInfo': {'masking': 'TRIPLE', 'maskingDescription': 'Double blind', 'whoMasked': ['PARTICIPANT', 'INVESTIGATOR', 'OUTCOMES_ASSESSOR']}}, 'enrollmentInfo': {'count': 46, 'type': 'ESTIMATED'}}

Updated at

2024-03-28

1 organization

1 product

1 indication

Organization

Dicerna Pharmaceuticals

Product

Indication

Alpha-1 Antitrypsin Deficiency