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

Alpha1-Antitrypsin Deficiency Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05677971
• Other study ID #: TAK-999-3001
• Secondary ID: 2022-501943-34
• Status: Recruiting
• Phase: Phase 3
• Start date: March 6, 2023
• Est. completion date: March 31, 2029

Study information

• Verified date: March 2024
• Source: Takeda
• Contact: Takeda Contact
• Phone: 1-877-825-3327
• Email: medinfoUS[@]takeda.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: March 31, 2029
• Est. primary completion date: March 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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. 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.

Related Conditions & MeSH terms

• Alpha 1-Antitrypsin Deficiency
• Alpha1-Antitrypsin Deficiency
• Liver Diseases

Intervention

Drug:
• 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:
• 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.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	St Vincents Hospital Melbourne - PPDS	Fitzroy	Victoria
Austria	LKH-Universitätsklinikum Graz	Graz
Austria	Medizinische Universität Wien (Medical University of Vienna)	Vienna
Belgium	UZ Antwerpen	Antwerpen
Belgium	UZ Leuven	Leuven
Canada	Inspiration Research Limited	Toronto	Ontario
France	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
Germany	Universitätsklinikum der RWTH Aachen	Aachen
Germany	Charité - Campus Virchow-Klinikum-Ostring 1	Berlin
Germany	Universitätsklinikum Tübingen	Tübingen
Italy	Fondazione IRCCS Policlinico San Matteo di Pavia	Pavia
Poland	ID Clinic Arkadiusz Pisula	Slaskie
Portugal	CCA Hospital Braga	Braga
Portugal	Hospital Nélio Mendonça	Funchal
Portugal	Centro Hospitalar do Porto	Porto
Spain	Hospital Universitario Vall d'Hebron - PPDS	Barcelona
Switzerland	Inselspital Bern	Bern
United Kingdom	Royal Infirmary of Edinburgh	Edinburgh
United Kingdom	Derriford Hospital	Plymouth
United States	University of Michigan Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham and Womens Hospital	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Gastroenterology & Liver Institute	Escondido	California
United States	University of Florida	Gainesville	Florida
United States	Penn State Health Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Indiana University School of Medicine - Indianapolis	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of California San Diego, Altman Clinical and Translational Institute	La Jolla	California
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	Schiff Center for Liver Diseases/University of Miami	Miami	Florida
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia University Irving Medical Center	New York	New York
United States	Morgan Stanley Childrens Hospital of New York Presbyterian (CHONY) - PIN	New York	New York
United States	NYU Langone Health	New York	New York
United States	Henry Ford Medical Center - Columbus	Novi	Michigan
United States	Stanford University	Palo Alto	California
United States	Mayo Clinic	Phoenix	Arizona
United States	St. Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Bon Secours St. Mary's Hospital	Richmond	Virginia
United States	VCU Medical Center North Hospital	Richmond	Virginia
United States	The Texas Liver Institute	San Antonio	Texas
United States	University of California Benioff Children's Hospital	San Francisco	California
United States	University of Arizona Thomas D. Boyer Liver Institute	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Takeda	Takeda Development Center Americas, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Italy,  Poland,  Portugal,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	Baseline, Week 106
Secondary	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	Percent change from baseline in intrahepatic Z-AAT protein in AATD-LD with METAVIR stage F2 to F3 fibrosis will be assessed.	Baseline, Week 106
Secondary	Reduction From Baseline of at Least 1 Stage of Histologic Fibrosis (METAVIR Staging) in the Centrally Read Liver Biopsy	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.	Baseline, Week 106 and Week 202
Secondary	Number of Participants With Liver Related Clinical Events 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.	Baseline up to Week 202
Secondary	Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) Protein	Change from baseline in serum Z-AAT protein in participants with AATD-LD with METAVIR stage fibrosis will be assessed.	Baseline, Week 106, Week 202
Secondary	Change From Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining	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.	Baseline, Week 106, Week 202
Secondary	Change From Baseline in Intrahepatic Portal Inflammation	Change from baseline in intrahepatic portal inflammation liver biopsy in participants with AATD-LD with METAVIR stage fibrosis will be assessed.	Baseline, Week 106, Week 202
Secondary	Change From Baseline in Vibration-Controlled Transient Elastography (VCTE)/Magnetic Resonance Elastography (MRE)-derived Liver Stiffness	Change from baseline in VCTE/MRE-derived liver stiffness in participants with AATD-LD with METAVIR stage fibrosis will be assessed.	Baseline, Week 106, Week 196 and Week 202
Secondary	Change From Baseline in Model of End-Stage Liver Disease (MELD) Score	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.	Baseline, Week 106, and Week 202
Secondary	Change From Baseline in Liver Injury	Change from baseline in liver injury in participants with AATD-LD with METAVIR stage fibrosis will be assessed.	Baseline, Week 106 and Week 202
Secondary	Percent Change from Baseline in Intrahepatic Z-AAT Protein in AATD-LD With METAVIR Stage F2 to F4 Fibrosis	Percent change from baseline in intrahepatic Z-AAT protein in AATD-LD with METAVIR stage F2 to F4 fibrosis will be assessed.	Baseline, Week 106 and Week 202
Secondary	Observed Plasma Concentrations of Fazirsiran	Observed Plasma Concentrations of Fazirsiran will be assessed.	Pre-dose up to Week 196
Secondary	Number of Participants with Treatment-emergent adverse event (TEAE) and Serious TEAEs	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.	From start of study drug administration up to end of the study (EOS) (Week 220)
Secondary	Number of Participants with Clinically Significant Declines in Lung Function Parameters	Standard pulmonary function parameters measured will be used to study lung function.	From start of study drug administration up to EOS (Week 220)
Secondary	Change From Baseline in Whole Lung PD15 (15th percentile point) Measured by CT lung Densitometry	Change from baseline in whole lung PD15 (15th percentile point) as measured by CT lung densitometry will be assessed.	Baseline up to EOS (Week 220)
Secondary	Number of Participants with Clinically Significant Change in Vital Signs	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.	From start of study drug administration up to EOS (Week 220)
Secondary	Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Parameters	12-lead ECG will be evaluated. Any change in ECG assessments which are deemed clinically significant by the investigator will be reported as AE.	From start of study drug administration up to EOS (Week 220)
Secondary	Number of Participants with Clinically Significant Changes in Clinical Laboratory Assessments	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.	From start of study drug administration up to EOS (Week 220)

External Links

•   To obtain more information on the study, click here/on this link