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

• ClinicalTrials.gov Identifier: NCT05677971
• Recruitment Status: Recruiting
• First Posted: January 10, 2023
• Last Update Posted: June 6, 2023
• Sponsor: Takeda
• Collaborator: Takeda Development Center Americas, Inc.
• Information provided by (Responsible Party): Takeda

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Alpha1-Antitrypsin Deficiency	Drug: Fazirsiran Injection; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: March 6, 2023
• Estimated Primary Completion Date: March 31, 2027
• Estimated Study Completion Date: March 31, 2029

Arms and Interventions

Arm	Intervention/treatment
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.	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 Name: TAK-999, ARO-AAT, ADS-001
Placebo Comparator: Placebo; Participants will receive placebo 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.; Other Name: Sodium chloride

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 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 :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 histopathology manual. The histopathology manual must be followed for all liver biopsies as study standard operating procedure.
• 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 (defined as does not smoke cigarettes daily for at least 12 months before screening) with current nonsmoking status confirmed by urine cotinine at 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 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. A urine drug screen positive for benzodiazepines, opioids, or tetrahydrocannabinol is acceptable for enrollment at the discretion of the investigator if the positive test is due to a substance used for medical reasons.
• 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.

Contacts and Locations

Contacts

Contact: Takeda Contact; 1-877-825-3327; medinfoUS@takeda.com

Locations

United States, California

Gastroenterology & Liver Institute; Recruiting

Escondido, California, United States, 92025

Principal Investigator: Naveen Gara

United States, Florida

University of Florida; Recruiting

Gainesville, Florida, United States, 32611

Principal Investigator: Virginia Clark

United States, Iowa

University of Iowa Hospitals and Clinics; Recruiting

Iowa City, Iowa, United States, 52242

Principal Investigator: Tomohiro Tanaka

United States, South Carolina

Medical University of South Carolina; Recruiting

Charleston, South Carolina, United States, 29425

Contact: Site Contact 843-792-5300 strangec@musc.edu

Principal Investigator: Charlie Strange

United States, Texas

The Texas Liver Institute; Recruiting

San Antonio, Texas, United States, 78215

Principal Investigator: Eric Lawitz

United States, Virginia

Bon Secours St. Mary's Hospital; Recruiting

Richmond, Virginia, United States, 23226

Principal Investigator: Mitchell Shiffman

Sponsors and Collaborators

Takeda

Takeda Development Center Americas, Inc.

Investigators

• Study Director: Study Director; Takeda

More Information

Additional Information:

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

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT05677971
• Other Study ID Numbers: TAK-999-3001; 2022-501943-34 ( Other Identifier: EU CTIS )
• First Posted: January 10, 2023
• Last Update Posted: June 6, 2023
• Last Verified: June 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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 Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Access Criteria: 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.
• URL: https://vivli.org/ourmember/takeda/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Liver Diseases; Alpha 1-Antitrypsin Deficiency; Pathologic Processes; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema