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
- Conditions
- Alpha1-Antitrypsin Deficiency
- Interventions
- Other: PlaceboDrug: Fazirsiran Injection
- Registration Number
- NCT05677971
- Lead Sponsor
- Takeda
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 160
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Participants will receive placebo on Day 1, at Week 4, and Q12 W thereafter up to Week 196. Fazirsiran Fazirsiran Injection 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.
- Primary Outcome Measures
Name Time Method 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 Baseline, Week 106 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 will be assessed.
- Secondary Outcome Measures
Name Time Method 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 Baseline, Week 106 Percent change from baseline in intrahepatic Z-AAT protein in AATD-LD with METAVIR stage F2 to F3 fibrosis will be assessed.
Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy Baseline, Week 106 and Week 202 Reduction from baseline of at least 1 stage of histologic fibrosis (METAVIR Staging) in the centrally read liver biopsy in participants with AATD-LD with METAVIR stage fibrosis will be assessed.
Number of Participants With Liver Related Clinical Events up to Week 202 Baseline up to Week 202 Number of participants with any qualifying liver-related clinical events up to Week 202 in AATD-LD with METAVIR stage F2 to F4 fibrosis will be assessed.
Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) Protein Baseline, Week 106, Week 202 Change from baseline in serum Z-AAT protein in participants with AATD-LD with METAVIR stage fibrosis will be assessed.
Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining Baseline, Week 106, Week 202 Change from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining liver biopsy in participants with AATD-LD with METAVIR stage fibrosis will be assessed.
Change From Baseline in Intrahepatic Portal Inflammation Baseline, Week 106, Week 202 Change from baseline in intrahepatic portal inflammation liver biopsy in participants with AATD-LD with METAVIR stage fibrosis will be assessed.
Change From Baseline in Vibration-Controlled Transient Elastography (VCTE)/Magnetic Resonance Elastography (MRE)-derived Liver Stiffness Baseline, Week 106, Week 196 and Week 202 Change from baseline in VCTE/MRE-derived liver stiffness in participants with AATD-LD with METAVIR stage fibrosis will be assessed.
Change From Baseline in Model of End-Stage Liver Disease (MELD) Score Baseline, Week 106, and Week 202 The MELD scoring system is used to assess the severity of chronic liver disease. The MELD score is derived from the participant's serum total bilirubin, serum creatinine, and prothrombin international normalized ratio (INR): 3.78\*log e serum bilirubin (milligram per deciliter \[mg/dL\]) + 11.20\* log e INR + 9.57\* log e serum creatinine (mg/dL) + 6.43 (constant for liver disease etiology). The MELD score ranges from 6 to 40 with higher scores indicating more severe liver disease and a worse outcome. Change from baseline in MELD score in participants with AATD-LD with METAVIR stage fibrosis will be assessed.
Change From Baseline in Liver Injury Baseline, Week 106 and Week 202 Change from baseline in liver injury in participants with AATD-LD with METAVIR stage fibrosis will be assessed.
Percent Change from Baseline in Intrahepatic Z-AAT Protein in AATD-LD With METAVIR Stage F2 to F4 Fibrosis Baseline, Week 106 and Week 202 Percent change from baseline in intrahepatic Z-AAT protein in AATD-LD with METAVIR stage F2 to F4 fibrosis will be assessed.
Observed Plasma Concentrations of Fazirsiran Pre-dose up to Week 220 Observed Plasma Concentrations of Fazirsiran will be assessed.
Number of Participants with Treatment-emergent adverse event (TEAE) and Serious TEAEs From start of study drug administration up to end of the study (EOS) (Week 230) An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this investigational product (IP) or medicinal product. An SAE is any untoward medical occurrence that at any dose met one, more of the following criteria: results in death, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent, significant disability/incapacity, a congenital abnormality/birth defect, an important medical event. A TEAE is any event emerging or manifesting at or after the initiation of treatment with an IP or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the IP or medicinal product. Number of participants with TEAEs and serious TEAEs will be assessed.
Number of Participants with Clinically Significant Declines in Lung Function Parameters From start of study drug administration up to EOS (Week 230) Standard pulmonary function parameters measured will be used to study lung function.
Change From Baseline in Whole Lung PD15 (15th percentile point) Measured by CT lung Densitometry Baseline up to Week 196 Change from baseline in whole lung PD15 (15th percentile point) as measured by CT lung densitometry will be assessed.
Number of Participants with Clinically Significant Change in Vital Signs From start of study drug administration up to EOS (Week 230) Vital signs will include body temperature, respiratory rate, blood pressure, pulse and amount of oxygen in the blood. Any change in vital signs which are deemed clinically significant by the investigator will be reported as AE.
Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters From start of study drug administration up to EOS (Week 230) 12-lead ECG will be evaluated. Any change in ECG assessments which are deemed clinically significant by the investigator will be reported as AE.
Number of Participants with Clinically Significant Changes in Clinical Laboratory Assessments From start of study drug administration up to EOS (Week 230) Clinical laboratory assessments include hematology, serum chemistry, coagulation, and urinalysis. Changes in laboratory values may be considered as AE if they were judged to be clinically significant.
Trial Locations
- Locations (69)
University of Maryland Medical Center
🇺🇸Baltimore, Maryland, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
St. Joseph's Hospital and Medical Center
🇺🇸Phoenix, Arizona, United States
Mayo Clinic
🇺🇸Phoenix, Arizona, United States
University of Arizona Thomas D. Boyer Liver Institute
🇺🇸Tucson, Arizona, United States
Gastroenterology & Liver Institute
🇺🇸Escondido, California, United States
University of California San Diego, Altman Clinical and Translational Institute
🇺🇸La Jolla, California, United States
UCLA Pulmonary and Critical Care
🇺🇸Los Angeles, California, United States
Stanford University
🇺🇸Palo Alto, California, United States
University of California Benioff Children's Hospital
🇺🇸San Francisco, California, United States
University of Florida
🇺🇸Gainesville, Florida, United States
Schiff Center for Liver Diseases/University of Miami
🇺🇸Miami, Florida, United States
Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States
Indiana University School of Medicine - Indianapolis
🇺🇸Indianapolis, Indiana, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Brigham and Womens Hospital
🇺🇸Boston, Massachusetts, United States
Boston Medical Center
🇺🇸Boston, Massachusetts, United States
University of Michigan Hospital
🇺🇸Ann Arbor, Michigan, United States
Henry Ford Medical Center - Columbus
🇺🇸Novi, Michigan, United States
Mayo Clinic - PPDS
🇺🇸Rochester, Minnesota, United States
Cardinal Glennon Children's Hospital
🇺🇸Saint Louis, Missouri, United States
Washington University School of Medicine in St. Louis
🇺🇸Saint Louis, Missouri, United States
NYU Langone Health
🇺🇸New York, New York, United States
Morgan Stanley Childrens Hospital of New York Presbyterian (CHONY) - PIN
🇺🇸New York, New York, United States
Columbia University Irving Medical Center
🇺🇸New York, New York, United States
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Penn State Health Milton S. Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
The Texas Liver Institute
🇺🇸San Antonio, Texas, United States
Bon Secours St. Mary's Hospital
🇺🇸Richmond, Virginia, United States
VCU Medical Center North Hospital
🇺🇸Richmond, Virginia, United States
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
St Vincents Hospital Melbourne - PPDS
🇦🇺Fitzroy, Victoria, Australia
LKH-Universitätsklinikum Graz
🇦🇹Graz, Austria
Klinikum Klagenfurt Am Wörthersee
🇦🇹Klagenfurt, Austria
Medizinische Universität Wien (Medical University of Vienna)
🇦🇹Vienna, Austria
UZ Antwerpen
🇧🇪Antwerpen, Belgium
UZ Leuven
🇧🇪Leuven, Belgium
Hospital Sirio-Libanes
🇧🇷Sao Paulo, Brazil
Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina Campus de Botucatu
🇧🇷São Paulo, Brazil
GI Research Institute
🇨🇦Vancouver, British Columbia, Canada
Inspiration Research Limited
🇨🇦Toronto, Ontario, Canada
Institut klinicke a experimentalni mediciny
🇨🇿Prague, Czechia
Hôpital Beaujon
🇫🇷Clichy, France
Hôpital de La Croix Rousse
🇫🇷Lyon, France
Hopital PONTCHAILLOU CHU de Rennes
🇫🇷Rennes, France
Hospital Purpan
🇫🇷Toulouse, France
Hôpital Paul Brousse
🇫🇷Val-de-Marne, France
Universitätsklinikum der RWTH Aachen
🇩🇪Aachen, Germany
Charité - Campus Virchow-Klinikum-Ostring 1
🇩🇪Berlin, Germany
Hannover Medical School
🇩🇪Hannover, Germany
Universitätsklinikum Tübingen
🇩🇪Tübingen, Germany
Fondazione IRCCS Policlinico San Matteo di Pavia
🇮🇹Pavia, Italy
Amsterdam UMC - VUmc - De Boelelaan
🇳🇱Amsterdam, Netherlands
Leiden University Medical Center
🇳🇱Leiden, Netherlands
ID Clinic Arkadiusz Pisula
🇵🇱Slaskie, Poland
CCA Hospital Braga
🇵🇹Braga, Portugal
Hospital Nélio Mendonça
🇵🇹Funchal, Portugal
Hospital Dr. Nélio Mendonça
🇵🇹Funchal, Portugal
Centro Hospitalar do Porto
🇵🇹Porto, Portugal
Hospital Universitario Vall d'Hebron - PPDS
🇪🇸Barcelona, Spain
Hospital Universitario Virgen del Rocio - PPDS
🇪🇸Sevilla, Spain
Karolinska Universitetssjukhuset Huddinge
🇸🇪Huddinge, Sweden
Inselspital Bern
🇨🇭Bern, Switzerland
Royal Infirmary of Edinburgh
🇬🇧Edinburgh, United Kingdom
King's College Hospital
🇬🇧London, United Kingdom
Queen's Medical Centre
🇬🇧Nottingham, United Kingdom
Derriford Hospital
🇬🇧Plymouth, United Kingdom