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A Study of Belcesiran in Patients With AATLD

NCT ID: NCT04764448

Last Updated: 2024-12-31

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE2

Total Enrollment

16 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-02-12

Study Completion Date

2024-05-29

Brief Summary

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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

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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.

Conditions

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Alpha 1-Antitrypsin Deficiency

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

OTHER

Blinding Strategy

TRIPLE

Participants Investigators Outcome Assessors
Double blind

Study Groups

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Belcesiran Cohort 1

Group Type EXPERIMENTAL

Belcesiran

Intervention Type DRUG

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

Placebo Cohort 1

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type OTHER

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.

Belcesiran Cohort 2

Group Type EXPERIMENTAL

Belcesiran

Intervention Type DRUG

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

Placebo Cohort 2

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type OTHER

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

Belcesiran Cohort 3

Group Type EXPERIMENTAL

Belcesiran

Intervention Type DRUG

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

Placebo Cohort 3

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type OTHER

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

Interventions

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Belcesiran

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

Intervention Type DRUG

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.

Intervention Type OTHER

Belcesiran

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

Intervention Type DRUG

Placebo

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

Intervention Type OTHER

Belcesiran

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

Intervention Type DRUG

Placebo

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

Intervention Type OTHER

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Thomas Bowman, MD

Role: STUDY_DIRECTOR

Dicerna Pharmaceuticals / Novo Nordisk

Locations

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University of California - San Diego

La Jolla, California, United States

Site Status

University of Florida

Gainesville, Florida, United States

Site Status

Medical University of South Carolina

Charleston, South Carolina, United States

Site Status

St Vincent's Hospital Melbourne

Melbourne, , Australia

Site Status

Medizinische Universitaet Innsbruck

Innsbruck, , Austria

Site Status

Universitaire Ziekenhuizen Leuven

Leuven, , Belgium

Site Status

Centre Hospitalier de l'Universite de Montreal (CHUM)

Montreal, Quebec, Canada

Site Status

CHU Bordeaux - Hopital Haut-Leveque - Centre François Magendie

Pessac, , France

Site Status

Universitaetsklinikum Aachen, AoeR

Aachen, , Germany

Site Status

Universitaetsklinikum Schleswig-Holstein Campus Kiel

Kiel, , Germany

Site Status

Beaumont Hospital

Dublin, , Ireland

Site Status

Leiden University Medical Center

Leiden, , Netherlands

Site Status

Auckland Clinical Studies

Grafton, Auckland, New Zealand

Site Status

Waikato Hospital

Hamilton, , New Zealand

Site Status

Hospital da Senhora da Oliveira - Guimaraes

Creixomil, , Portugal

Site Status

Centro Hospitalar Universitario de Sao Joao

Porto, , Portugal

Site Status

Centro Hospitalar de Trás-os-Montes e Alto Douro, EPE

Vila Real, , Portugal

Site Status

Hospital Universitario Marques de Valdecilla Santander

Santander, Cantabria, Spain

Site Status

Hospital Universitario La Paz

Madrid, , Spain

Site Status

CTC Clinical Trial Consultants AB Uppsala

Uppsala, , Sweden

Site Status

Addenbrooke's Hospital, Cambridge University

Cambridge, , United Kingdom

Site Status

Leeds Teaching Hospitals NHS Trust

Leeds, , United Kingdom

Site Status

Royal Free London NHS Foundation Trust, Royal Free Hospital

London, , United Kingdom

Site Status

Countries

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

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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DCR-A1AT-201

Identifier Type: -

Identifier Source: org_study_id