Alpha1-Antitrypsin Deficiency
Conditions
Brief summary
The main aim of this study is to learn if fazirsiran is safe during long-term use in people with liver disease caused by the abnormal Z-alpha-1 antitrypsin (Z-AAT) protein. People who have taken part in previous fazirsiran studies (AROAAT2001 \[NCT03945292\] or AROAAT2002 \[NCT03946449\]) can continue to receive fazirsiran every 3 months as long as they participate in this study, the study is ongoing or until health authorities in their country approve fazirsiran to be publicly available. The study may also provide information on whether fazirsiran has a long-term effect in reducing liver fibrosis or slowing down the progression of liver fibrosis in people with liver disease due to the abnormal Z-AAT protein.
Interventions
Fazirsiran will be injected subcutaneously.
Sponsors
Takeda
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must meet all of the following criteria to be eligible for inclusion in the study: * The participant is willing and able to understand and fully comply with study procedures and requirements, in the opinion of the investigator. * The participant is able to read, understand, and complete the study questionnaires electronically per investigator's judgment. * The participant has provided informed consent (ICF) (that is, in writing, documented via a signed and dated ICF) and any required privacy authorization before the initiation of any study procedures. Note: For participants who comprehend, can provide informed consent, and are unable to sign the ICF, an impartial witness may sign the ICF on behalf of the participant after the participant has orally consented to the participant's participation in the study. * The participant enrolling in this open-label extension (OLE) study will have participated in a previously qualifying study, and will be considered for eligibility based on the following study-specific criteria: * AROAAT2001: * Participants with fibrosis may roll over into this OLE study after they reach their next regularly scheduled, Q12W visit. * Participants with fibrosis who have completed the AROAAT2001 study may be enrolled into the OLE study. * AROAAT2002: * Participants in Cohorts 1 and 1b may roll over after completing the 24-week primary study period. * Participants in Cohort 2 may roll over after completing the 48-week primary study period. * Participants who have completed the study may be enrolled into the OLE study. * The participant is a nonsmoker (defined as: does not smoke cigarettes daily for at least 24 weeks) with current nonsmoking status confirmed by urine cotinine at Day 1. * E-cigarettes (vapor) are not permitted. * The participant may be on nicotine replacement (patch or gum). A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the investigator. * The participant must have suitable venous access for blood sampling. * It must be confirmed that the participant does not have hepatocellular carcinoma (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 computed tomography (CT) or magnetic resonance imaging (MRI) imaging to exclude HCC before enrollment. * AFP \>20 nanogram per milliliter (ng/mL). * AFP 15 to 19 ng/mL at enrollment if that is \>2 times prestudy levels (if available). * Any liver lesion \>10 millimeter (mm) (longest diameter) detected by ultrasound. * Poor visibility of liver on ultrasound. * A person of childbearing potential (POCBP) must have a negative urine pregnancy test performed within 3 days prior to Day 1 dosing in this study (sensitive to 25 International Unit \[IU\] human chorionic gonadotropin \[hCG\]). * The participant must use appropriate contraception methods (that is, highly effective methods for female and medically appropriate methods for male study participants) for the entire duration of the study. Participants who terminate early must use appropriate contraception methods for 6 months after the last dose of study intervention. Male participants who terminate early must not donate sperm for at least 6 months after the last dose of study intervention. * Sexual abstinence, for the purposes of this study, is only considered a highly effective method of contraception when considered to align with the preferred and usual lifestyle of the participant. It will be employed for the entire duration of the study and the 6 months after last dose of study intervention. * Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea methods are not considered true abstinence and are not acceptable methods of contraception.
Exclusion criteria
* The participant will be excluded from the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | From start of study drug administration (in current study) up to End of study (EOS) (current study [up to 10 years]) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of the study intervention, whether or not it is considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study intervention. An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect, suspected transmission of any infectious agent, an important medical event. AEs and SAEs including any pulmonary AEs or SAEs indicative of worsening pulmonary condition (example, pulmonary exacerbation, respiratory infection, significant pulmonary function test decline) will be reported. |
| Number of Participants With Clinically Significant Changes From Baseline in Pulmonary Function Parameters | Baseline (current study), up to EOS (current study up to 10 years]) | Standard pulmonary function parameters measured will be used to study lung function. Clinical significance of pulmonary function parameters will be determined at the investigator's discretion. |
| Number of Participants With Clinically Significant Changes in Vital Signs | From start of study drug administration (in current study) up to EOS (current study [up to 10 years]) | Vital signs include body temperature, respiratory rate, sitting blood pressure (systolic and diastolic, resting more than 5 minutes), pulse, oxygen saturation. Clinical significance of vital signs will be determined at the investigator's discretion. |
| Number of Participants With Clinically Significant Changes in Laboratory Parameters | From start of study drug administration (in current study) up to EOS (current study [up to 10 years]) | Laboratory parameters include hematology, biochemistry including liver tests, coagulation, and urinalysis. Clinical significance of laboratory parameters will be determined at the investigator's discretion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in Liver Stiffness Assessed by Magnetic Resonance Elastography (MRE) | Baseline (current study), up to EOS (current study up to 10 years]) | Change from baseline in MRE-derived liver stiffness will be assessed. |
| Number of Participants With no Progression from Baseline of At least 1 Stage of Histologic Fibrosis on Liver Biopsy at Week 102 | At Week 102 (current study) | Number of participants with no progression from baseline of at least 1 stage of histologic fibrosis (by Meta-Analysis of Histological Data in Viral Hepatitis \[METAVIR\] staging) on liver biopsy at Week 102 will be reported. |
| Change from Baseline in Liver Stiffness Assessed by Vibration-Controlled Transient Elastography (VCTE) | Baseline (current study), up to EOS (current study up to 10 years]) | Change from baseline in VCTE-derived liver stiffness will be assessed. |
| Number of Participants With Reduction from Baseline of At least 1 Stage of Histologic Fibrosis on Liver Biopsy at Week 102 | At Week 102 (current study) | Number of participants with baseline fibrosis of F1 or higher, a decrease from baseline of at least 1 stage of histologic fibrosis (by METAVIR staging) on liver biopsy at Week 102 will be reported. |
| Change from Baseline in Intrahepatic Z-AAT Protein Polymer Burden Assessed by Periodic Acid Schiff Plus Diastase (PAS+D) Staining in Liver Biopsy at Week 102 | Baseline (current study), Week 102 (current study) | Change from baseline in intrahepatic Z-AAT protein polymer burden assessed by PAS+D staining in liver biopsy will be assessed. |
| Change from Baseline in Intrahepatic Portal Inflammation Score at Week 102 in Liver Biopsy | Baseline (current study), Week 102 (current study) | Change in portal inflammation score in liver biopsy, based on pathology slide reads. Inflammation will be assessed on a scale of 0-3, with higher scores showing more severe inflammation. |
Countries
Austria, Germany, Portugal, United Kingdom, United States
Outcome results
None listed