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

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Study Record Versions

Version	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
29	March 4, 2024	Study Status and Contacts/Locations
30	March 14, 2024	Contacts/Locations and Study Status
31	March 28, 2024	Contacts/Locations and Study Status

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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]

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]

Sponsor/Collaborators


Sponsor:	Takeda
Responsible Party:	Sponsor
Collaborators:	Takeda Development Center Americas, Inc.

Oversight


U.S. FDA-regulated Drug:	Yes
U.S. FDA-regulated Device:	No
Data Monitoring:	Yes

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:

Conditions


Conditions:	Alpha1-Antitrypsin Deficiency
Keywords:

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]

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

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): 3.78log 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


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.

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

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/

References


Citations:
Links:	URL: https://clinicaltrials.takeda.com/study-detail/e37eea10ca934732?idFilter=%5B%22TAK-999-3001%22%5D Description: To obtain more information on the study, click here/on this link
Available IPD/Information: