Clinical trial NCT03946449: Study of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)
Official title: A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety and Efficacy of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alpha 1-Antitrypsin Deficiency
Lead sponsor: Arrowhead Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2019-05-10
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the the safety and efficacy of the investigational product, fazirsiran (TAK-999, ARO-AAT), administered subcutaneously to patients with alpha-1 antitrypsin deficiency associated liver disease (AATD).

Detailed description: Participants will be enrolled to receive multiple subcutaneous injections of fazirsiran (TAK-999, ARO-AAT). All eligible participants will require a pre-dose biopsy completed as part of the study within the screening window. All participants will undergo an end of study (EOS) biopsy. Treated participants will be offered the opportunity to continue treatment in an open label extension during which they will undergo a final biopsy.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of AATD
* Liver biopsy indicating Metavir F1-F3 liver fibrosis based on local pathology read.
* Women of childbearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use contraception
* Willing to provide written informed consent and to comply with study requirements
* Non-smoker for at least 1 year
* No abnormal finding of clinical relevance at screening

Exclusion Criteria:

* Clinically significant health concerns other than AATD
* Previous diagnosis or diagnosis at Screening of definitive liver cirrhosis
* Regular use of alcohol within one month prior to Screening
* Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving therapeutic intervention
* Use of illicit drugs within 1 year prior to Screening

Note: additional inclusion/exclusion criteria may apply, per protocol

Primary outcomes:
measure: Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 24: Cohorts 1/1b
timeFrame: Baseline, Week 24
measure: Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Soluble Liver Z-AAT at Week 48: Cohort 2
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: Percent Change From Baseline in Serum Z-AAT Over Time: Cohorts 1/1b
timeFrame: Baseline, Weeks 2, 4, 6, 16, 24
measure: Percent Change From Baseline in Serum Z-AAT Over Time: Cohort 2
timeFrame: Baseline, Weeks 2, 4, 6, 16, 22, 28, 34, 40, 48
measure: Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b
timeFrame: Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24
measure: ALT Values Over Time: Cohort 2
timeFrame: Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48
measure: Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b
timeFrame: Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 24
measure: GGT Values Over Time: Cohort 2
timeFrame: Baseline (Day 1), Day 2, Week 2, Week 4, Week 4 (24-48h post dose), Week 6, Week 16, Week 16 (24/48h post dose), Week 22, Week 28, Week 34, Week 40, Week 48
measure: Fibrosis-4 Index (FIB4) Score Values Over Time: Cohorts 1/1b
timeFrame: Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 24
measure: FIB4 Score Values Over Time: Cohort 2
timeFrame: Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 22, Week 28, Week 28 + 1 day, Week 34, Week 40, Week 48
measure: Aspartate Aminotransferase-to-platelet Ratio Index (APRI) Values Over Time: Cohorts 1/1b
timeFrame: Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 24
measure: APRI Values Over Time: Cohort 2
timeFrame: Baseline (Day 1), Day 2 (24-48 hr post-dose), Week 2, Week 4, Week 4 (24-48 hr post-dose), Week 6, Week 16, Week 16 (24-48 hr post-dose), Week 22, Week 28, Week 34, Week 40, Week 48
measure: N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b
timeFrame: Baseline, Weeks 4, 16, 24
measure: PRO-C3 Values Over Time: Cohort 2
timeFrame: Baseline, Weeks 4, 16, 28, 40, 48
measure: FibroScan® Values Over Time: Cohorts 1/1b
timeFrame: Baseline, Week 24
measure: FibroScan® Values Over Time: Cohort 2
timeFrame: Baseline, Week 24
measure: Portal Inflammation Over Time: Cohorts 1/1b
timeFrame: Baseline, Week 24
measure: Portal Inflammation Over Time: Cohort 2
timeFrame: Baseline, Week 48
measure: Interface Hepatitis Over Time: Cohorts 1/1b
timeFrame: Baseline, Week 24
measure: Interface Hepatitis Over Time: Cohort 2
timeFrame: Baseline, Week 48
measure: Lobular Inflammation Over Time: Cohorts 1/1b
timeFrame: Baseline, Week 24
measure: Lobular Inflammation Over Time: Cohort 2
timeFrame: Baseline, Week 48
measure: Hepatocyte Cell Death Over Time: Cohorts 1/1b
timeFrame: Baseline, Week 24
measure: Hepatocyte Cell Death Over Time: Cohort 2
timeFrame: Baseline, Week 48
measure: Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohorts 1/1b
timeFrame: Baseline, Week 24
measure: Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) Fibrosis Stage Score Over Time: Cohort 2
timeFrame: Baseline, Week 48
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From first dose of study drug up to a maximum duration of study follow-up of 202 weeks.
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna Division of Gastroenterology and Hepatology
city: Aachen
country: Germany
facility: Universitatsklinikum Aachen, Anstalt des offentlich
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh, NHS Lothian
Study officials:
References:
citation: Strnad P, Mandorfer M, Choudhury G, Griffiths W, Trautwein C, Loomba R, Schluep T, Chang T, Yi M, Given BD, Hamilton JC, San Martin J, Teckman JH. Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency. N Engl J Med. 2022 Aug 11;387(6):514-524. doi: 10.1056/NEJMoa2205416. Epub 2022 Jun 25.