Clinical trial • Phase III • Rare Disease | Gastroenterology
FAZIRSIRAN for Alpha-1 antitrypsin deficiency-associated liver disease | Liver fibrosis (METAVIR F1)
Phase III trial of FAZIRSIRAN for Alpha-1 antitrypsin deficiency-associated liver disease | Liver fibrosis (METAVIR F1).
Overview
- Trial Therapeutic Area
- Rare Disease | Gastroenterology
- Trial Disease
- Alpha-1 antitrypsin deficiency-associated liver disease | Liver fibrosis (METAVIR F1)
- Trial Stage
- Phase III
- Drug Modality
- Oligonucleotide | Other
- Orphan Drug
- Yes
Key dates
- Initial CTIS Submission Date
- 27-11-2023
- First CTIS Authorization Date
- 27-03-2024
Trial design
Randomised, fazirsiran 200 mg (formulated as 200 mg/ml, 1.0 ml withdrawable volume) administered subcutaneously on day 1, week 4, then every 12 weeks vs placebo (0.9% sodium chloride injection) administered on the same schedule.-controlled Phase III trial across 20 sites in France, Austria, Ireland and others.
- Randomised
- Yes
- Comparator
- Fazirsiran 200 mg (formulated as 200 mg/mL, 1.0 mL withdrawable volume) administered subcutaneously on Day 1, Week 4, then every 12 weeks vs Placebo (0.9% sodium chloride injection) administered on the same schedule.
- Target Sample Size
- 25
- Trial Duration For Participant
- 924
Eligibility
Recruits 25 Vulnerable population selected (isVulnerablePopulationSelected = true). Participants are adults aged 18 to 75 years and provide informed consent. Subject information and informed consent form documents are provided (Main-ICF) and there are specific Pregnant-Partner ICF and optional genetic/DNA sample ICF documents included in the dossier. No assent/parental consent for minors is applicable as minimum age is 18..
- Vulnerable Population
- Vulnerable population selected (isVulnerablePopulationSelected = true). Participants are adults aged 18 to 75 years and provide informed consent. Subject information and informed consent form documents are provided (Main-ICF) and there are specific Pregnant-Partner ICF and optional genetic/DNA sample ICF documents included in the dossier. No assent/parental consent for minors is applicable as minimum age is 18.
Inclusion criteria
- {"criterion_text":"- 1. The participant must have a diagnosis of the PiZZ genotype AATD. A diagnosis of PiZZ 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.\n- 2. The participant, of any sex, is aged 18 to 75 years, inclusive.\n- 3. The participant has evidence of METAVIR stage 1 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 from a previous biopsy conducted within 1 year before the estimated enrollment date using an adequate liver biopsy and slides as defined in the study laboratory manual.\n- 4. The participant has a pulmonary status meeting the protocol requirements"}
Exclusion criteria
- {"criterion_text":"- 1. Evidence of ≥ F2 fibrosis based on liver biopsy during the screening period.\n- 2. The participant has a history of liver decompensating events (overt hepatic encephalopathy documented by a physician or trained professional, clinically significant ascites, spontaneous bacterial peritonitis, gastrointestinal (GI) bleeding from varices, hepatopulmonary syndrome, hepatorenal syndrome, portal pulmonary hypertension, or bleeding portal hypertensive gastropathy).\n- 3. The participant has evidence of other forms of chronic liver diseases, including viral hepatitis B or C, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis. Additional diagnosis will be allowed as per the protocol.\n- 4. 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 curatively treated malignancies who have no evidence of metastatic disease and a greater than 1 year disease-free interval may be enrolled after approval by the medical monitor.\n- 5. 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.\n- 6. The participant has a recent lower respiratory tract infection, such as pneumonia, within the last 6 months before screening. The participant may be screened earlier based on principal investigator (PI) assessment of clinical recovery and return to baseline pulmonary function in discussion with the medical monitor.\n- 7. The participant has a history of frequent pulmonary exacerbations (≥2 moderate or severe exacerbations within 52 weeks before screening).\n- 8. The participant is experiencing a pulmonary exacerbation at the time of screening (participant may be rescreened after the clinical resolution of an exacerbation).\n- 9. The participant is receiving long-term, around-the-clock oxygen supplementation, or supplemental oxygen with continuous positive airway pressure (CPAP) or bilevel positive airway pressure for acute respiratory failure. The following conditions are allowable for the participant to enter screening: short-term use of oxygen supplementation (eg, for the management of acute chronic obstructive pulmonary disease [COPD] exacerbation) or CPAP for obstructive sleep apnea."}
Endpoints
Primary endpoints
- {"endpoint_text":"- AEs and SAE including any pulmonary AEs or SAEs indicative of worsening pulmonary condition/function (eg, pulmonary exacerbation, respiratory infection, significant PFT decline).\n- Change from baseline over time to EOS in pulmonary function parameters at scheduled visits\n- Change from baseline in whole lung 15th percentile density as measured by computed tomography (CT) lung densitometry over time to Week 100.\n- Vital signs.\n- ECG measurements.\n- Clinical laboratory values (hematology, biochemistry including liver tests, coagulation, and urinalysis results).","definition_or_measurement_approach":"- AEs/SAEs: collection and reporting of adverse events and serious adverse events including pulmonary-specific events indicative of worsening pulmonary condition/function.\n- Pulmonary function: change from baseline over time to End Of Study (EOS) assessed at scheduled visits using pulmonary function tests (PFTs).\n- CT lung densitometry: change from baseline in whole lung 15th percentile density measured by CT lung densitometry to Week 100.\n- Vital signs: standard vital sign measurements at scheduled visits.\n- ECG measurements: standard ECG assessments at scheduled visits.\n- Clinical laboratory values: hematology, biochemistry (including liver tests), coagulation and urinalysis measured per protocol at scheduled timepoints."}
Secondary endpoints
- {"endpoint_text":"- Change from baseline in serum Z-AAT protein over time to Week 106.\n- Percent change from baseline in intrahepatic liver Z-AAT protein at Week 106.\n- Change from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining at Week 106.\n- No change or decrease from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining at Week 106.\n- Change from baseline in intrahepatic portal inflammation at Week 106.\n- No change or decrease from baseline in intrahepatic portal inflammation at Week 106.\n- No change or decrease from baseline in histologic fibrosis score (METAVIR staging) at Week 106.\n- Change from baseline in VCTE-derived liver stiffness over time to Week 106.\n- Change from baseline in markers of liver injury (alanine aminotransferase [ALT], aspartate aminotransferase [AST], γ-glutamyl transferase [GGT]) over time to Week 106.","definition_or_measurement_approach":"- Serum Z-AAT protein: serial serum measurements over time to Week 106.\n- Intrahepatic Z-AAT protein: measured in liver tissue at Week 106 (biopsy) with percent change from baseline.\n- Z-AAT polymer burden: assessed histologically by PAS+D staining on liver biopsy at Week 106.\n- Portal inflammation: histologic assessment on liver biopsy at Week 106.\n- Histologic fibrosis score (METAVIR): central reading of liver biopsy at Week 106.\n- VCTE-derived liver stiffness: measured by vibration-controlled transient elastography (FibroScan) over time to Week 106.\n- Liver injury markers (ALT, AST, GGT): clinical laboratory measurements over time to Week 106."}
Recruitment
- Digital Remote Recruitment
- Yes
- Planned Sample Size
- 25
- Recruitment Window Months
- 53
- Consent Approach
- Informed consent obtained from each participant (adults aged 18–75). Main informed consent forms (Main-ICF) are provided and available in multiple country-specific/local languages (documents in English, French, Italian, Polish, Portuguese, Swedish, German, Dutch, Spanish are present). Optional and supplementary consent documents are provided (e.g. Optional Genetic/DNA sample ICFs, Pregnant-Partner ICF). Country-specific recruitment and informed consent procedures documents (K1) are included.
Methods
- Site-based recruitment through listed hospital/clinic trial sites (country-specific site lists provided).
- GP letters (country-specific GP letter documents present, e.g. Ireland, Italy).
- Participant travel reimbursement and logistics notices (GreenPhire travel notice documents) to support participation.
- Digital patient engagement and remote support via Medidata Patient Cloud App and concierge email templates (documents present).
Geography
- Total Number Of Sites
- 20
- Total Number Of Participants
- 25
France
- Earliest CTIS Part Ii Submission Date
- 23-02-2024
- Latest Decision Or Authorization Date
- 21-11-2025
- Processing Time Days
- 637
- Number Of Sites
- 4
- Number Of Participants
- 4
Sites
- Site Name
- Centre Hospitalier Universitaire De Rennes
- Department Name
- Liver disease department
- Contact Person Name
- Edouard BARDOU-JACQUET
- Contact Person Email
- edouard.bardou.jacquet@chu-rennes.fr
- Site Name
- Hopital De La Croix Rousse
- Department Name
- Hepatogastro enterology
- Contact Person Name
- Teresa ANTONINI
- Contact Person Email
- teresa.antonini@chu-lyon.fr
- Site Name
- Centre Hospitalier Universitaire De Lille
- Department Name
- Service des Maladies de l'Appareil Digestif et de la nutrition
- Contact Person Name
- Alexandre LOUVET
- Contact Person Email
- alexandre.louvet@chu-lille.fr
- Site Name
- Hopital Paul Brousse
- Department Name
- Centre Hépato-Biliaire
- Contact Person Name
- Audrey COILLY
- Contact Person Email
- audrey.coilly@aphp.fr
Austria
- Earliest CTIS Part Ii Submission Date
- 07-05-2024
- Latest Decision Or Authorization Date
- 01-12-2025
- Processing Time Days
- 574
- Number Of Sites
- 2
- Number Of Participants
- 3
Sites
- Site Name
- Medical University Of Graz
- Department Name
- Department of Internal Medicine - Division of Gastroenterology and Hepatology
- Contact Person Name
- Martin Wagner
- Contact Person Email
- martin.wagner@medunigraz.at
- Site Name
- Landeskrankenanstalten-Betriebsgesellschaft Kabeg
- Department Name
- Department of Internal Medicine, Gastroenterology, Hepatology, Endocrinology, Rheumatology
- Contact Person Name
- Markus Peck-Radosavljevic
- Contact Person Email
- markus.peckradosavljevic@kabeg.at
Ireland
- Earliest CTIS Part Ii Submission Date
- 19-02-2024
- Latest Decision Or Authorization Date
- 24-11-2025
- Processing Time Days
- 644
- Number Of Sites
- 1
- Number Of Participants
- 1
Sites
- Site Name
- Beaumont Hospital
- Department Name
- Department of Medicine
- Contact Person Name
- Noel G McElvaney
- Contact Person Email
- gmcelvaney@rcsi.ie
Belgium
- Earliest CTIS Part Ii Submission Date
- 04-03-2024
- Latest Decision Or Authorization Date
- 25-11-2025
- Processing Time Days
- 631
- Number Of Sites
- 2
- Number Of Participants
- 2
Sites
- Site Name
- Antwerp University Hospital
- Department Name
- Gastroenterology and hepatology
- Contact Person Name
- Sven Francque
- Contact Person Email
- sven.francque@uza.be
- Site Name
- UZ Leuven
- Department Name
- xx
- Contact Person Name
- Jef Verbeek
- Contact Person Email
- jef.verbeek@uzleuven.be
Poland
- Earliest CTIS Part Ii Submission Date
- 05-03-2024
- Latest Decision Or Authorization Date
- 25-11-2025
- Processing Time Days
- 630
- Number Of Sites
- 1
- Number Of Participants
- 3
Sites
- Site Name
- ID Clinic Arkadiusz Pisula
- Contact Person Name
- Ewa Janczewska
- Contact Person Email
- idclinic@idclinic.eu
Spain
- Earliest CTIS Part Ii Submission Date
- 20-02-2024
- Latest Decision Or Authorization Date
- 24-11-2025
- Processing Time Days
- 633
- Number Of Sites
- 1
- Number Of Participants
- 2
Sites
- Site Name
- University Hospital Virgen Del Rocio S.L.
- Department Name
- Gastroenterology and Hepatology
- Contact Person Name
- Manuel Romero Gómez
- Contact Person Email
- manuel.romero.sspa@juntadeandalucia.es
Italy
- Earliest CTIS Part Ii Submission Date
- 08-02-2024
- Latest Decision Or Authorization Date
- 21-11-2025
- Processing Time Days
- 652
- Number Of Sites
- 1
- Number Of Participants
- 1
Sites
- Site Name
- Fondazione IRCCS Policlinico San Matteo
- Department Name
- S.C Pneumologia
- Contact Person Name
- Angelo Guido Corsico
- Contact Person Email
- corsico@unipv.it
Germany
- Earliest CTIS Part Ii Submission Date
- 26-01-2024
- Latest Decision Or Authorization Date
- 22-12-2025
- Processing Time Days
- 696
- Number Of Sites
- 4
- Number Of Participants
- 5
Sites
- Site Name
- Universitaetsklinikum Tuebingen AöR
- Department Name
- Innere Medizin Department I
- Contact Person Name
- Christoph Berg
- Contact Person Email
- christoph.berg@med.uni-tuebingen.de
- Site Name
- Universitaetsklinikum Aachen AöR
- Department Name
- Medizinische Klinik III
- Contact Person Name
- Pavel Strnad
- Contact Person Email
- pstrnad@ukaachen.de
- Site Name
- Charite Universitaetsmedizin Berlin KöR
- Department Name
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie
- Contact Person Name
- Frank Tacke
- Contact Person Email
- frank.tacke@charite.de
- Site Name
- Medizinische Hochschule Hannover
- Department Name
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie
- Contact Person Name
- Heiner (Hans Heinrich) Wedemeyer
- Contact Person Email
- wedemeyer.heiner@mh-hannover.de
Portugal
- Earliest CTIS Part Ii Submission Date
- 06-03-2024
- Latest Decision Or Authorization Date
- 21-11-2025
- Processing Time Days
- 625
- Number Of Sites
- 3
- Number Of Participants
- 3
Sites
- Site Name
- CCAB Centro Clinico Academico Braga Associacao
- Department Name
- Gastroenterology
- Contact Person Name
- Carla Rolanda
- Contact Person Email
- crolanda@med-uminho.pt
- Site Name
- Servico de Saude da Regiao Autonoma Da Madeira EPERAM
- Department Name
- Gastroenterology
- Contact Person Name
- Vítor Pereira
- Contact Person Email
- vitor.pereira@sesaram.pt
- Site Name
- Centro Hospitalar Universitario De Santo Antonio E.P.E.
- Department Name
- Gastroenterology
- Contact Person Name
- Luis Maia
- Contact Person Email
- luismaia.gastro@chporto.min-saude.pt
Sweden
- Earliest CTIS Part Ii Submission Date
- 01-03-2024
- Latest Decision Or Authorization Date
- 24-11-2025
- Processing Time Days
- 633
- Number Of Sites
- 1
- Number Of Participants
- 1
Sites
- Site Name
- Karolinska University Hospital
- Department Name
- Sektionen för lever och pankreassjukdomar
- Contact Person Name
- Staffan Wahlin
- Contact Person Email
- staffan.wahlin@ki.se
Sponsor
Primary sponsor
- Full Name
- Takeda Development Center Americas Inc.
- Organisation Type
- Pharmaceutical company
- Country Of Registered Address
- United States
Contract research organisations
- Name
- WCG Clinical Inc.
- Responsibilities
- Study site support services for patient reimbursement
- Name
- Certara USA Inc.
- Name
- Pharmaceutical Product Development LLC
- Name
- Perceptive Informatics Inc.
- Responsibilities
- Clinical Imaging
- Name
- Bioclinica Inc.
- Responsibilities
- Clinical Imaging
- Name
- Q2 Solutions LLC
- Name
- Suvoda LLC
- Name
- Cytel Inc.
Third parties
- {"country":"United States","full_name":"WCG Clinical Inc.","duties_or_roles":"Study site support services for patient reimbursement","organisation_type":"Pharmaceutical company"}
- {"country":"France","full_name":"Echosens","duties_or_roles":"VCTE Fibroscan Image analysis","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
- {"country":"United States","full_name":"Certara USA Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
- {"country":"Canada","full_name":"Charles River Laboratories Montreal ULC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Clinical Imaging","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
- {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"Clinical Imaging","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Cytel Inc.","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
- {"country":"United States","full_name":"Q2 Solutions LLC","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
- {"country":"Denmark","full_name":"Nordic Bioscience A/S","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
- {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Spirometry PFT DLCO analysis","organisation_type":"Pharmaceutical company"}
- {"country":"United Kingdom","full_name":"Perspectum Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
Investigational products
- Investigational Product Name
- Fazirsiran
- Active Substance
- FAZIRSIRAN
- Modality
- Oligonucleotide
- Routes Of Administration
- Subcutaneous injection
- Route
- Subcutaneous injection
- Authorisation Status
- Authorised
- Orphan Designation
- Yes
- Starting Dose
- 200 mg
- Dose Levels
- 200 mg
- Frequency
- Day 1, Week 4, then every 12 weeks
- Maximum Dose
- 200 mg
- Investigational Product Name
- SALINE
- Active Substance
- SALINE
- Modality
- Other
- Routes Of Administration
- Solution for injection
- Route
- Solution for injection
- Frequency
- Matched to active arm (Day 1, Week 4, then every 12 weeks)
Related trials
Other published trials that may interest you.
- TAK-360 for Narcolepsy without Cataplexy (NT2)
- N-{(6R)-7,7-DIFLUORO-2-[5-FLUORO-4-(2,4,6-TRIFLUOROPHENYL)-1,2-BENZOXAZOL-3-YL]-3-OXO-2,5,6,7-TETRAHYDRO-3H-PYRROLO[1,2-C]IMIDAZOL-6-YL}METHANESULFONAMIDE for Idiopathic hypersomnia
- ZASOCITINIB for Moderately to severely active ulcerative colitis | Ulcerative colitis
- ELRITERCEPT for Myelodysplastic syndrome
- MEZAGITAMAB for Chronic Primary Immune Thrombocytopenia