Clinical trial NCT05677971: 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
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Alpha1-Antitrypsin Deficiency
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2023-01-10
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main aim of this study is to learn if fazirsiran reduces liver scarring (fibrosis) compared to placebo. Other aims are to learn if fazirsiran slows down the disease worsening in the liver, to get information on how fazirsiran affects the body (called pharmacodynamics), to learn if fazirsiran reduces other liver injury (inflammation) and the abnormal Z-AAT protein in the liver, to get information on how the body processes fazirsiran (called pharmacokinetics), to test how well fazirsiran works compared with a placebo in improving measures of liver scarring including imaging and liver biomarkers (substances in the blood that the body normally makes and help show if liver function is improving, staying the same, or getting worse) as well as to check for side effects in participants treated with fazirsiran compared with those who received placebo.

Participants will either receive fazirsiran or placebo. Liver biopsies, a way of collecting a small tissue sample from the liver, will be taken twice during this study.


Eligibility 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 6 months before screening.

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 bleeding portal hypertensive 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 cholangitis, 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.

Primary outcomes:
measure: 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
timeFrame: Baseline, Week 106
Secondary outcomes:
measure: 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
timeFrame: Baseline, Week 106
measure: Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy
timeFrame: Baseline, Week 106 and Week 202
measure: Number of Participants With Liver Related Clinical Events up to Week 202
timeFrame: Baseline up to Week 202
measure: Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) Protein
timeFrame: Baseline, Week 106, Week 202
measure: Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining
timeFrame: Baseline, Week 106, Week 202
measure: Change From Baseline in Intrahepatic Portal Inflammation
timeFrame: Baseline, Week 106, Week 202
measure: Change From Baseline in Vibration-Controlled Transient Elastography (VCTE)/Magnetic Resonance Elastography (MRE)-derived Liver Stiffness
timeFrame: Baseline, Week 106, Week 196 and Week 202
measure: Change From Baseline in Model of End-Stage Liver Disease (MELD) Score
timeFrame: Baseline, Week 106, and Week 202
measure: Change From Baseline in Liver Injury
timeFrame: Baseline, Week 106 and Week 202
measure: Percent Change from Baseline in Intrahepatic Z-AAT Protein in AATD-LD With METAVIR Stage F2 to F4 Fibrosis
timeFrame: Baseline, Week 106 and Week 202
measure: Observed Plasma Concentrations of Fazirsiran
timeFrame: Pre-dose up to Week 220
measure: Number of Participants with Treatment-emergent adverse event (TEAE) and Serious TEAEs
timeFrame: From start of study drug administration up to end of the study (EOS) (Week 230)
measure: Number of Participants with Clinically Significant Declines in Lung Function Parameters
timeFrame: From start of study drug administration up to EOS (Week 230)
measure: Change From Baseline in Whole Lung PD15 (15th percentile point) Measured by CT lung Densitometry
timeFrame: Baseline up to Week 196
measure: Number of Participants with Clinically Significant Change in Vital Signs
timeFrame: From start of study drug administration up to EOS (Week 230)
measure: Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters
timeFrame: From start of study drug administration up to EOS (Week 230)
measure: Number of Participants with Clinically Significant Changes in Clinical Laboratory Assessments
timeFrame: From start of study drug administration up to EOS (Week 230)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Thomas D. Boyer Liver Institute
state: Arizona
city: Escondido
country: United States
facility: Gastroenterology & Liver Institute
state: California
city: La Jolla
country: United States
facility: University of California San Diego, Altman Clinical and Translational Institute
state: California
city: Los Angeles
country: United States
facility: UCLA Pulmonary and Critical Care
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California Benioff Children's Hospital
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: Schiff Center for Liver Diseases/University of Miami
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University School of Medicine - Indianapolis
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Brigham and Womens Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospital
state: Michigan
city: Novi
country: United States
facility: Henry Ford Medical Center - Columbus
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - PPDS
state: Minnesota
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis
state: Missouri
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Morgan Stanley Childrens Hospital of New York Presbyterian (CHONY) - PIN
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine Medical Center
state: Texas
city: San Antonio
country: United States
facility: The Texas Liver Institute
state: Texas
city: Richmond
country: United States
facility: Bon Secours St. Mary's Hospital
state: Virginia
city: Richmond
country: United States
facility: VCU Medical Center North Hospital
state: Virginia
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Fitzroy
country: Australia
facility: St Vincents Hospital Melbourne - PPDS
state: Victoria
city: Graz
country: Austria
facility: LKH-Universitätsklinikum Graz
city: Klagenfurt
country: Austria
facility: Klinikum Klagenfurt Am Wörthersee
city: Vienna
country: Austria
facility: Medizinische Universität Wien (Medical University of Vienna)
city: Antwerpen
country: Belgium
facility: UZ Antwerpen
city: Leuven
country: Belgium
facility: UZ Leuven
city: Sao Paulo
country: Brazil
facility: Hospital Sirio-Libanes
city: São Paulo
country: Brazil
facility: Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina Campus de Botucatu
city: Vancouver
country: Canada
facility: GI Research Institute
state: British Columbia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Center
state: Nova Scotia
city: Toronto
country: Canada
facility: Inspiration Research Limited
state: Ontario
city: Prague
country: Czechia
facility: Institut klinicke a experimentalni mediciny
city: Clichy
country: France
facility: Hôpital Beaujon
city: Lyon
country: France
facility: Hôpital de La Croix Rousse
city: Pessac
country: France
facility: Centre Francois Magendie
city: Rennes
country: France
facility: Hopital PONTCHAILLOU CHU de Rennes
city: Toulouse
country: France
facility: Hospital Purpan
city: Val-de-Marne
country: France
facility: Hôpital Paul Brousse
city: Aachen
country: Germany
facility: Universitätsklinikum der RWTH Aachen
city: Berlin
country: Germany
facility: Charité - Campus Virchow-Klinikum-Ostring 1
city: Hannover
country: Germany
facility: Hannover Medical School
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo di Pavia
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC - VUmc - De Boelelaan
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Slaskie
country: Poland
facility: ID Clinic Arkadiusz Pisula
city: Braga
country: Portugal
facility: CCA Hospital Braga
city: Funchal
country: Portugal
facility: Hospital Nélio Mendonça
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio - PPDS
city: Huddinge
country: Sweden
facility: Karolinska Universitetssjukhuset Huddinge
city: Linköping
country: Sweden
facility: Universitetssjukhuset i Linköping
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: