The liver produces a protein called alpha-1 antitrypsin (AAT). AAT is normally released into the bloodstream. In some people, the liver makes an abnormal version of the AAT protein, called Z-AAT. Making an abnormal version of the AAT protein can result in liver disease as Z-AAT builds up in liver cells, which leads to liver problems such as liver scarring (fibrosis), continuing liver damage (cirrhosis), and eventually end stage liver disease. Fazirsiran is a medicine that reduces the creation of the Z-AAT protein and thus the build-up of this abnormal protein in the liver. People with this type of liver disease who already have mild liver scarring will take part in the study. They will be treated with fazirsiran or a placebo for about 2 years. This study will check the long-term safety of fazirsiran, whether participants tolerate the treatment and if there are any effects on liver scarring. A liver biopsy, a way of collecting a small tissue sample from the liver, will be taken twice during the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
50
Fazirsiran will be injected subcutaneously.
Fazirsiran matching placebo.
St Joseph's Hospital and Medical Center
Phoenix, Arizona, United States
RECRUITINGMayo Clinic - PPDS
Phoenix, Arizona, United States
RECRUITINGUniversity of Arizona Thomas D. Boyer Liver Institute
Tucson, Arizona, United States
RECRUITINGUniversity of California San Diego
La Jolla, California, United States
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of the study intervention, whether or not it is considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study intervention. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect, suspected transmission of any infectious agent, an important medical event. AEs and SAEs including any pulmonary AEs or SAEs indicative of worsening pulmonary condition (example, pulmonary exacerbation, respiratory infection, significant pulmonary function test decline) will be reported.
Time frame: From start of study drug administration up to End of study (EOS) (Week 124)
Number of Participants With Clinically Significant Change From Baseline in Pulmonary Function Parameters
Standard pulmonary function parameters will be used to study lung function. Clinical significance of pulmonary function parameters will be determined at the investigator's discretion.
Time frame: From start of study drug administration up to EOS (Week 124)
Change From Baseline in Whole Lung 15th Percentile Density as Measured by Computed Tomography (CT) Lung Densitometry
Change from baseline in whole lung 15th percentile density as measured by CT lung densitometry will be assessed.
Time frame: Baseline up to Week 100
Number of Participants With Clinically Significant Changes in Vital Signs
Vital signs include body temperature, respiratory rate, blood pressure (systolic and diastolic), pulse (beats per minute) and pulse oximetry. Clinical significance of vital signs will be determined at the investigator's discretion.
Time frame: From start of study drug administration up to EOS (Week 124)
Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters
12-lead ECG will be evaluated. Any clinically significant change in ECG assessments will be determined at the investigator's discretion.
Time frame: From start of study drug administration up to EOS (Week 124)
Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters
Laboratory parameters assessments include hematology, biochemistry including liver tests, coagulation, and urinalysis. Clinical significance of laboratory parameters will be determined at the investigator's discretion.
Time frame: From start of study drug administration up to EOS (Week 124)
Change From Baseline in Serum Z-AAT Protein Over Time to Week 106
Change From Baseline in Serum Z-AAT Protein will be assessed.
Time frame: Baseline up to Week 106
Percent Change From Baseline in Intrahepatic Liver Z-AAT Protein at Week 106
Percent change from baseline in intrahepatic liver Z-AAT protein will be assessed.
Time frame: Baseline up to Week 106
Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining in Liver Biopsy at Week 106
Change from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining in liver biopsy will be assessed.
Time frame: Baseline up to Week 106
Number of Participants with No Change or Decrease From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by PAS+D staining at Week 106
Number of participants with no change or decrease from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining will be reported.
Time frame: Baseline up to Week 106
Change From Baseline in Intrahepatic Portal Inflammation Score in Liver Biopsy at Week 106
Change in portal inflammation score in liver biopsy is based on pathology slide reads. Inflammation will be assessed on a scale of 0-3, with higher scores showing more severe inflammation.
Time frame: Baseline up to Week 106
Number of Participants with No Change or Decrease From Baseline in Intrahepatic Portal Inflammation Score at Week 106
No Change or decrease in portal inflammation score is based on pathology slide reads. Inflammation will be assessed on a scale of 0-3, with higher scores showing more severe inflammation. Number of Participants with no change or decrease from baseline in intrahepatic portal inflammation score will be reported.
Time frame: Baseline up to Week 106
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UCLA Pulmonary and Critical Care
Los Angeles, California, United States
RECRUITINGUniversity of California Benioff Children's Hospital
San Francisco, California, United States
RECRUITINGPeak Gastroenterology Associates
Colorado Springs, Colorado, United States
RECRUITINGSchiff Center for Liver Diseases/University of Miami
Miami, Florida, United States
RECRUITINGIndiana University School of Medicine-Indianapolis
Indianapolis, Indiana, United States
RECRUITINGUniversity Of Iowa Hospitals And Clinics
Iowa City, Iowa, United States
RECRUITING...and 31 more locations
Number of Participants With No Change or Decrease From Baseline in Histologic Fibrosis Score (Meta-analysis of Histological Data in Viral Hepatitis [METAVIR] Staging ) at Week 106
No change or decrease in histologic fibrosis (METAVIR staging) will be assessed using a fibrosis score of F0-F4, where higher scores mean a worse result. Number of participants with no change or decrease from baseline in histologic fibrosis score (by \[METAVIR\] staging) at Week 106 will be reported.
Time frame: Baseline up to Week 106
Change From Baseline in Vibration-Controlled Transient Elastography (VCTE)-Derived Liver Stiffness
Change from baseline in VCTE-derived liver stiffness will be assessed.
Time frame: Baseline up to Week 106
Change From Baseline in Markers of Liver Injury
Change from baseline in marker (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], glutamyl transferase \[GGT\]) of liver injury will be assessed.
Time frame: Baseline up to Week 106