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History of Changes for Study: 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
Latest version (submitted February 22, 2024) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 December 28, 2022 None (earliest Version on record)
2 January 12, 2023 Study Status and References
3 February 2, 2023 Study Status and Study Identification
4 March 14, 2023 Recruitment Status, Study Status, Contacts/Locations and Study Identification
5 March 20, 2023 Contacts/Locations and Study Status
6 March 30, 2023 Contacts/Locations and Study Status
7 May 23, 2023 Study Status and Contacts/Locations
8 May 31, 2023 Outcome Measures and Study Status
9 June 5, 2023 Study Status and Contacts/Locations
10 June 15, 2023 Contacts/Locations and Study Status
11 July 12, 2023 Study Status and Contacts/Locations
12 July 19, 2023 Contacts/Locations and Study Status
13 July 20, 2023 Contacts/Locations and Study Status
14 July 28, 2023 Contacts/Locations and Study Status
15 August 11, 2023 Study Status, Contacts/Locations, Eligibility and Outcome Measures
16 August 17, 2023 Contacts/Locations and Study Status
17 August 31, 2023 Contacts/Locations, Eligibility and Study Status
18 September 14, 2023 Study Status and Contacts/Locations
19 September 29, 2023 Contacts/Locations and Study Status
20 October 23, 2023 Study Status and Contacts/Locations
21 November 8, 2023 Study Status and Contacts/Locations
22 November 23, 2023 Contacts/Locations and Study Status
23 December 1, 2023 Study Status and Contacts/Locations
24 December 15, 2023 Contacts/Locations and Study Status
25 January 15, 2024 Study Status and Contacts/Locations
26 January 30, 2024 Contacts/Locations and Study Status
27 February 12, 2024 Study Status and Contacts/Locations
28 February 22, 2024 Contacts/Locations and Study Status
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Changes (Merged) for Study: NCT05677971
July 20, 2023 (v13) -- July 28, 2023 (v14)

Changes in: Study Status and Contacts/Locations

Open or close this module Study Identification
Unique Protocol ID: TAK-999-3001
Brief Title: 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
Secondary IDs: 2022-501943-34 [EU CTIS]
Open or close this module Study Status
Record Verification: July 2023
Overall Status: Recruiting
Study Start: March 6, 2023
Primary Completion: March 31, 2027 [Anticipated]
Study Completion: March 31, 2029 [Anticipated]
First Submitted: December 28, 2022
First Submitted that
Met QC Criteria:
December 28, 2022
First Posted: January 10, 2023 [Actual]
Last Update Submitted that
Met QC Criteria:
July 20 28, 2023
Last Update Posted: July 21 August 1, 2023 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Takeda
Responsible Party: Sponsor
Collaborators: Takeda Development Center Americas, Inc.
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module 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.

Detailed Description:
Open or close this module Conditions
Conditions: Alpha1-Antitrypsin Deficiency
Keywords:
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation: Randomized
Enrollment: 160 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
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 Names:
  • 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.
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 Names:
  • Sodium chloride
Open or close this module 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.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age: 75 Years
Sex: All
Gender Based:
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.
Open or close this module Contacts/Locations
Central Contact Person: Takeda Contact
Telephone: 1-877-825-3327
Email: medinfoUS@takeda.com
Study Officials: Study Director
Study Director
Takeda
Locations: United States, Alabama
University of Alabama at Birmingham
[Recruiting]
Birmingham, Alabama, United States, 35233
Contact:Contact: Site Contact 205-934-9999 grayme@uab.edu
Contact:Principal Investigator: Meagan Gray
United States, California
Gastroenterology & Liver Institute
[Recruiting]
Escondido, California, United States, 92025
Contact:Contact: Site Contact 808-469-0575 giandliverinstitute@gmail.com
Contact:Principal Investigator: Naveen Gara
United States, Florida
University of Florida
[Recruiting]
Gainesville, Florida, United States, 32611
Contact:Contact: Site Contact 352-294-5152 briana.foerman@medicine.ufl.edu
Contact:Principal Investigator: Virginia Clark
United States, Iowa
University of Iowa Hospitals and Clinics
[Recruiting]
Iowa City, Iowa, United States, 52242
Contact:Contact: Site Contact 319-356-2577 tomohiro-tanaka@uiowa.edu
Contact:Principal Investigator: Tomohiro Tanaka
United States, Massachusetts
Brigham and Womens Hospital
[Recruiting]
Boston, Massachusetts, United States, 02115
Contact:Contact: Site Contact 617-525-1267 NHASHEMI@BWH.HARVARD.EDU
Contact:Principal Investigator: Nikroo Hashemi
United States, New York
NYU Langone Health
[Recruiting]
New York, New York, United States, 10016
Contact:Contact: Site Contact 212-263-3643 viviana.figueroadiaz@nyulangone.org
Contact:Principal Investigator: Viviana Figueroa Diaz
Morgan Stanley Childrens Hospital of New York Presbyterian (CHONY) - PIN
[Recruiting]
New York, New York, United States, 10032-1559
Contact:Contact: Site Contact 212-305-3000 dg2749@cumc.columbia.edu
Contact:Principal Investigator: Dana Goldner
United States, Pennsylvania
Penn State Health Milton S. Hershey Medical Center
[Not yet recruiting]
Hershey, Pennsylvania, United States, 17033
Contact:Contact: Site Contact 717-531-6525 tcraig@psu.edu
Contact:Principal Investigator: Timothy Craig
United States, South Carolina
Medical University of South Carolina
[Recruiting]
Charleston, South Carolina, United States, 29425
Contact:Contact: Site Contact 843-792-5300 strangec@musc.edu
Contact:Principal Investigator: Charlie Strange
United States, Tennessee
Vanderbilt University Medical Center
[Recruiting]
Nashville, Tennessee, United States, 37232-0028
Contact:Contact: Site Contact 615-322-8748 roman.perri@vumc.org
Contact:Principal Investigator: Roman Perri
United States, Texas
The Texas Liver Institute
[Recruiting]
San Antonio, Texas, United States, 78215
Contact:Contact: Site Contact 210-253-3426 lawitz@txliver.com
Contact:Principal Investigator: Eric Lawitz
United States, Virginia
Bon Secours St. Mary's Hospital
[Recruiting]
Richmond, Virginia, United States, 23226
Contact:Contact: Site Contact 804-977-8920 mitchell_shiffman@bshsi.org
Contact:Principal Investigator: Mitchell Shiffman
Belgium
UZ Antwerpen
[Recruiting]
Antwerpen, Belgium, 2650
Contact:Contact: Site Contact +3238213000 sven.francque@uza.be
Contact:Principal Investigator: Sven Francque
Portugal
CCA Hospital Braga
[Recruiting]
Braga, Portugal, 4710-243
Contact:Contact: Site Contact +351253027000 crolanda@med.uminho.pt
Contact:Principal Investigator: Carla Rolanda
Hospital Nélio Mendonça
[Recruiting]
Funchal, Portugal, 9000-168
Contact:Contact: Site Contact +351291705600 magnovitorp@gmail.com
Contact:Principal Investigator: Vitor Pereira
Spain
Hospital Universitario Vall d'Hebron - PPDS
[Recruiting]
Barcelona, Spain, 8025
Contact:Contact: Site Contact +34932742779 monica.pons@vhir.org
Contact:Principal Investigator: Monica Pons Delgado
Open or close this module IPDSharing
Plan to Share IPD: Yes
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 Information:
Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame:
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/
Open or close this module References
Citations:
Links: Description: To obtain more information on the study, click here/on this link
Available IPD/Information:

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