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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05677971




Registration number
NCT05677971
Ethics application status
Date submitted
28/12/2022
Date registered
10/01/2023

Titles & IDs
Public title
Study to Check the Safety of Fazirsiran and Learn if Fazirsiran Can Help People With Liver Disease and Scarring (Fibrosis) Due to an Abnormal Version of Alpha-1 Antitrypsin Protein
Scientific title
A Randomized, Double-blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Fazirsiran in the Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease With METAVIR Stage F2 to F4 Fibrosis
Secondary ID [1] 0 0
2022-501943-34
Secondary ID [2] 0 0
TAK-999-3001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alpha1-Antitrypsin Deficiency 0 0
Condition category
Condition code
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Cancer 0 0 0 0
Liver
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Respiratory 0 0 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Fazirsiran Injection
Other interventions - Placebo

Experimental: Fazirsiran - Participants will receive fazirsiran 200 milligram per milliliter (mg/ml) subcutaneous (SC) injection on Day 1, at Week 4, and then every 12 weeks (Q12 W) thereafter up to Week 196.

Placebo comparator: Placebo - Participants will receive placebo on Day 1, at Week 4, and Q12 W thereafter up to Week 196.


Treatment: Drugs: Fazirsiran Injection
Participants will receive fazirsiran 200 mg/ml SC injection on Day 1, at Week 4, and Q12 W thereafter up to Week 196.

Other interventions: Placebo
Participants will receive placebo (sterile normal saline \[0.9% NaCl\]) SC injection on Day 1, at Week 4, and Q12 W thereafter up to Week 196.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy at Week 106 in AATD-LD With METAVIR Stage F2 and F3 Fibrosis
Timepoint [1] 0 0
Baseline, Week 106
Secondary outcome [1] 0 0
Percent Change from Baseline in Intrahepatic Z-AAT Protein in Alpha-1 Antitrypsin Deficiency-Associated Liver Disease (AATD-LD) with METAVIR Stage F2 to F3 Fibrosis at Week 106
Timepoint [1] 0 0
Baseline, Week 106
Secondary outcome [2] 0 0
Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy
Timepoint [2] 0 0
Baseline, Week 106 and Week 202
Secondary outcome [3] 0 0
Number of Participants With Liver Related Clinical Events up to Week 202
Timepoint [3] 0 0
Baseline up to Week 202
Secondary outcome [4] 0 0
Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) Protein
Timepoint [4] 0 0
Baseline, Week 106, Week 202
Secondary outcome [5] 0 0
Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining
Timepoint [5] 0 0
Baseline, Week 106, Week 202
Secondary outcome [6] 0 0
Change From Baseline in Intrahepatic Portal Inflammation
Timepoint [6] 0 0
Baseline, Week 106, Week 202
Secondary outcome [7] 0 0
Change From Baseline in Vibration-Controlled Transient Elastography (VCTE)/Magnetic Resonance Elastography (MRE)-derived Liver Stiffness
Timepoint [7] 0 0
Baseline, Week 106, Week 196 and Week 202
Secondary outcome [8] 0 0
Change From Baseline in Model of End-Stage Liver Disease (MELD) Score
Timepoint [8] 0 0
Baseline, Week 106, and Week 202
Secondary outcome [9] 0 0
Change From Baseline in Liver Injury
Timepoint [9] 0 0
Baseline, Week 106 and Week 202
Secondary outcome [10] 0 0
Percent Change from Baseline in Intrahepatic Z-AAT Protein in AATD-LD With METAVIR Stage F2 to F4 Fibrosis
Timepoint [10] 0 0
Baseline, Week 106 and Week 202
Secondary outcome [11] 0 0
Observed Plasma Concentrations of Fazirsiran
Timepoint [11] 0 0
Pre-dose up to Week 196
Secondary outcome [12] 0 0
Number of Participants with Treatment-emergent adverse event (TEAE) and Serious TEAEs
Timepoint [12] 0 0
From start of study drug administration up to end of the study (EOS) (Week 220)
Secondary outcome [13] 0 0
Number of Participants with Clinically Significant Declines in Lung Function Parameters
Timepoint [13] 0 0
From start of study drug administration up to EOS (Week 220)
Secondary outcome [14] 0 0
Change From Baseline in Whole Lung PD15 (15th percentile point) Measured by CT lung Densitometry
Timepoint [14] 0 0
Baseline up to EOS (Week 220)
Secondary outcome [15] 0 0
Number of Participants with Clinically Significant Change in Vital Signs
Timepoint [15] 0 0
From start of study drug administration up to EOS (Week 220)
Secondary outcome [16] 0 0
Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters
Timepoint [16] 0 0
From start of study drug administration up to EOS (Week 220)
Secondary outcome [17] 0 0
Number of Participants with Clinically Significant Changes in Clinical Laboratory Assessments
Timepoint [17] 0 0
From start of study drug administration up to EOS (Week 220)

Eligibility
Key inclusion criteria
Inclusion criteria:

* The participant must have a diagnosis of the Z allele homozygotes (PiZZ) genotype AATD. PiZZ diagnosis from source verifiable medical records is permitted. Otherwise, participants must undergo PiZZ confirmatory testing (genotyping for PiS and PiZ alleles) at screening. PiMZ or PiSZ genotypes are not permitted.
* The participant, of any sex, is aged 18 to 75 years, inclusive.
* The participant's liver biopsy core sample collected should meet the requirements of the protocol.
* The participant has evidence of METAVIR stage F2, F3, or F4 liver fibrosis, evaluated by a centrally read baseline liver biopsy during the screening period; or confirmed as meeting all the entry criteria by central reading of a previous biopsy conducted within 6 months before the estimated enrollment date using an adequate liver biopsy and slides as defined in the study laboratory manual.
* The participant has a pulmonary status meeting the protocol's requirements.
* It must be confirmed that the participant does not have HCC. Participants will be screened for HCC with alpha-fetoprotein (AFP) and abdominal ultrasound. If the participant has any of the following, they will be required to have contrast-enhanced CT or MRI imaging to exclude HCC before randomization.
* An adult participant must have a body mass index (BMI) between 18.0 and 39.0 kilograms per meter square (kg^m2), inclusive.
* The participant is a nonsmoker for at least 12 months before screening.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

* The participant has a history of liver decompensating events (overt hepatic encephalopathy [West Haven Grade >=2] documented by a physician, clinically significant ascites, spontaneous bacterial peritonitis, GI bleeding from varices, hepatopulmonary syndrome, hepatorenal syndrome, portal pulmonary hypertension, or portal gastropathy).
* The participant has a history of the presence of medium or large varices or varices with red wale signs based on a previous esophagogastroduodenoscopy (EGD) within 6 months before the estimated enrollment date. For certain participants, an EGD will be required at screening if there is no EGD available within 6 months before the estimated enrollment date. Presence of small varices with no red wale signs on EGD and no history of bleeding will be acceptable for study eligibility.
* The participant has evidence of other forms of chronic liver diseases, including viral hepatitis B or C, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis.
* The participant has alanine transaminase (ALT) or aspartate transaminase (AST) levels >250 units per liter (U/L).
* The participant has a platelet count <60,000 per cubic millimeter (mm^3) (<60 × 10^9 per liter [10^9/L]).
* The participant has albumin <=2.8 gram per deciliter (g/dL) (28 grams per deciliter [g/L]).
* The participant has international normalized ratio (INR) >=1.7.
* The participant is expected to have severe and unavoidable high-level exposure to inhaled pulmonary toxins during the study such as may occur with occupational exposure to mineral dusts or metals.
* The participant has a history of drug abuse (such as cocaine, phencyclidine) within 1 year before the screening visit or has a positive urine drug screen at screening.
* The participant has previously been treated with fazirsiran or any other RNAi for AATD-LD.
* The participant has portal vein thrombosis.
* The participant has a prior transjugular portosystemic shunt procedure.
* The participant has a history of malignancy within the last 5 years, except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Participants with other curatively treated malignancies who have no evidence of metastatic disease and a greater than 1-year disease-free interval may be entered after approval by the medical monitor.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
6/03/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/03/2029
Actual
Sample size
Target
160
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 0 0
St Vincents Hospital Melbourne - PPDS - Fitzroy
Recruitment postcode(s) [1] 0 0
5000 - Adelaide
Recruitment postcode(s) [2] 0 0
3065 - Fitzroy
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Indiana
Country [7] 0 0
United States of America
State/province [7] 0 0
Iowa
Country [8] 0 0
United States of America
State/province [8] 0 0
Massachusetts
Country [9] 0 0
United States of America
State/province [9] 0 0
Michigan
Country [10] 0 0
United States of America
State/province [10] 0 0
Missouri
Country [11] 0 0
United States of America
State/province [11] 0 0
New York
Country [12] 0 0
United States of America
State/province [12] 0 0
Ohio
Country [13] 0 0
United States of America
State/province [13] 0 0
Pennsylvania
Country [14] 0 0
United States of America
State/province [14] 0 0
South Carolina
Country [15] 0 0
United States of America
State/province [15] 0 0
Tennessee
Country [16] 0 0
United States of America
State/province [16] 0 0
Texas
Country [17] 0 0
United States of America
State/province [17] 0 0
Virginia
Country [18] 0 0
Austria
State/province [18] 0 0
Graz
Country [19] 0 0
Austria
State/province [19] 0 0
Klagenfurt
Country [20] 0 0
Austria
State/province [20] 0 0
Vienna
Country [21] 0 0
Belgium
State/province [21] 0 0
Antwerpen
Country [22] 0 0
Belgium
State/province [22] 0 0
Leuven
Country [23] 0 0
Brazil
State/province [23] 0 0
São Paulo
Country [24] 0 0
Canada
State/province [24] 0 0
Ontario
Country [25] 0 0
France
State/province [25] 0 0
Clichy
Country [26] 0 0
France
State/province [26] 0 0
Lyon
Country [27] 0 0
France
State/province [27] 0 0
Rennes
Country [28] 0 0
France
State/province [28] 0 0
Toulouse
Country [29] 0 0
France
State/province [29] 0 0
Val-de-Marne
Country [30] 0 0
Germany
State/province [30] 0 0
Aachen
Country [31] 0 0
Germany
State/province [31] 0 0
Berlin
Country [32] 0 0
Germany
State/province [32] 0 0
Hannover
Country [33] 0 0
Germany
State/province [33] 0 0
Tübingen
Country [34] 0 0
Italy
State/province [34] 0 0
Pavia
Country [35] 0 0
Poland
State/province [35] 0 0
Slaskie
Country [36] 0 0
Portugal
State/province [36] 0 0
Braga
Country [37] 0 0
Portugal
State/province [37] 0 0
Funchal
Country [38] 0 0
Portugal
State/province [38] 0 0
Porto
Country [39] 0 0
Spain
State/province [39] 0 0
Barcelona
Country [40] 0 0
Switzerland
State/province [40] 0 0
Bern
Country [41] 0 0
United Kingdom
State/province [41] 0 0
Edinburgh
Country [42] 0 0
United Kingdom
State/province [42] 0 0
London
Country [43] 0 0
United Kingdom
State/province [43] 0 0
Nottingham
Country [44] 0 0
United Kingdom
State/province [44] 0 0
Plymouth

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Takeda
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Takeda Development Center Americas, Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Study Director
Address 0 0
Takeda
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Takeda Contact
Address 0 0
Country 0 0
Phone 0 0
1-877-825-3327
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Informed consent form (ICF), Clinical study report (CSR)
When will data be available (start and end dates)?
Available to whom?
IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://vivli.org/ourmember/takeda/


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT05677971