Clinical Trial Results:
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)
Summary
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EudraCT number |
2019-000068-86 |
Trial protocol |
GB DE AT |
Global end of trial date |
14 Dec 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Dec 2024
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First version publication date |
29 Dec 2024
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AROAAT2002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03946449 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Arrowhead Pharmaceuticals, Inc.
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Sponsor organisation address |
177 East Colorado Boulevard, Suite 700, Pasadena, CA, United States, 91105
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Public contact |
Mei Ling Chang-Lok, Arrowhead Pharmaceuticals, Inc., 001 6263043400, mchanglok@arrowheadpharma.com
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Scientific contact |
Chief Operating Officer, Arrowhead Pharmaceuticals, Inc., 001 6263043400, info@arrowheadpharma.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Dec 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Dec 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate change from baseline over time in total, soluble, and insoluble Z-AAT concentrations in the liver of patients with AAT-associated liver disease.
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Protection of trial subjects |
All eligible participants had the study explained by the PI or designee. They received a full explanation, in lay terms, of the aims of the study, the discomforts, risks and benefits in taking part as well as of insurance and other procedures for compensation in case of injury. It was explained that the study is for research purposes only and was not expected to provide any therapeutic benefit to the individual. It was pointed out that they could withdraw from the study at any time without prejudice.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Oct 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
Austria: 1
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Country: Number of subjects enrolled |
Germany: 13
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Worldwide total number of subjects |
16
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EEA total number of subjects |
14
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
14
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
All eligible subjects required a pre-dose biopsy completed as part of the study within the screening window. Participants consisted of male and female adult homozygous Z allele individuals (PiZZ; based on genotype completed at Screening or from a source verifiable document) alpha-1 antitrypsin patients. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Primary Study Period
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ARO-AAT 100 mg Cohort 1b | ||||||||||||||||||||||||
Arm description |
Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ARO-AAT Injection
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Investigational medicinal product code |
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Other name |
fazirsiran, TAK-999
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Each dose of fazirsiran will be administered by subcutaneous injection.
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Arm title
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ARO-AAT 200 mg Cohort 1 | ||||||||||||||||||||||||
Arm description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ARO-AAT Injection
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Investigational medicinal product code |
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Other name |
fazirsiran, TAK-999
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Each dose of fazirsiran will be administered by subcutaneous injection.
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Arm title
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ARO-AAT 200 mg Cohort 2 | ||||||||||||||||||||||||
Arm description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ARO-AAT Injection
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Investigational medicinal product code |
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Other name |
fazirsiran, TAK-999
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Each dose of fazirsiran will be administered by subcutaneous injection.
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Period 2
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Period 2 title |
Treatment Extension I
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ARO-AAT 100 mg Cohort 1b | ||||||||||||||||||||||||
Arm description |
Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ARO-AAT Injection
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Investigational medicinal product code |
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Other name |
fazirsiran, TAK-999
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Each dose of fazirsiran will be administered by subcutaneous injection.
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Arm title
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ARO-AAT 200 mg Cohort 1 | ||||||||||||||||||||||||
Arm description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ARO-AAT Injection
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Investigational medicinal product code |
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Other name |
fazirsiran, TAK-999
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Each dose of fazirsiran will be administered by subcutaneous injection.
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Arm title
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ARO-AAT 200 mg Cohort 2 | ||||||||||||||||||||||||
Arm description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ARO-AAT Injection
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Investigational medicinal product code |
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Other name |
fazirsiran, TAK-999
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Each dose of fazirsiran will be administered by subcutaneous injection.
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Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: One subject who completed the Primary Study Period did not continue to the Treatment Extension I. |
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Period 3
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Period 3 title |
Treatment Extension II
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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ARO-AAT 100 mg Cohort 1b | ||||||||||||||||||||||||
Arm description |
Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. As of global protocol version 7.0 (21-Jul-2022) / German protocol version 2.6 (29-Jul-2022) and after applicable regulatory, Ethics Committee and local approval, participants in cohort 1b switched from 100 mg to 200 mg while maintaining their dosing schedule. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ARO-AAT Injection
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Investigational medicinal product code |
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Other name |
fazirsiran, TAK-999
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Each dose of fazirsiran will be administered by subcutaneous injection.
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Arm title
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ARO-AAT 200 mg Cohort 1 | ||||||||||||||||||||||||
Arm description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ARO-AAT Injection
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Investigational medicinal product code |
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Other name |
fazirsiran, TAK-999
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Each dose of fazirsiran will be administered by subcutaneous injection.
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Arm title
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ARO-AAT 200 mg Cohort 2 | ||||||||||||||||||||||||
Arm description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
ARO-AAT Injection
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Investigational medicinal product code |
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Other name |
fazirsiran, TAK-999
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Each dose of fazirsiran will be administered by subcutaneous injection.
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Baseline characteristics reporting groups
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Reporting group title |
ARO-AAT 100 mg Cohort 1b
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Reporting group description |
Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ARO-AAT 200 mg Cohort 1
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ARO-AAT 200 mg Cohort 2
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
ARO-AAT 100 mg Cohort 1b
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Reporting group description |
Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||
Reporting group title |
ARO-AAT 200 mg Cohort 1
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||
Reporting group title |
ARO-AAT 200 mg Cohort 2
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses. | ||
Reporting group title |
ARO-AAT 100 mg Cohort 1b
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Reporting group description |
Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||
Reporting group title |
ARO-AAT 200 mg Cohort 1
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||
Reporting group title |
ARO-AAT 200 mg Cohort 2
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses. | ||
Reporting group title |
ARO-AAT 100 mg Cohort 1b
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Reporting group description |
Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. As of global protocol version 7.0 (21-Jul-2022) / German protocol version 2.6 (29-Jul-2022) and after applicable regulatory, Ethics Committee and local approval, participants in cohort 1b switched from 100 mg to 200 mg while maintaining their dosing schedule. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||
Reporting group title |
ARO-AAT 200 mg Cohort 1
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||
Reporting group title |
ARO-AAT 200 mg Cohort 2
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses. |
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End point title |
Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Partial (Soluble) Liver Z-AAT: Cohorts 1/1b [1] [2] | |||||||||||||||||||||
End point description |
Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
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End point type |
Primary
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End point timeframe |
Baseline, Week 24
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistics planned per protocol for this endpoint are presented in the data table. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
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No statistical analyses for this end point |
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End point title |
Percent Change From Baseline in Total Liver Z-AAT, Insoluble Liver-ZAAT, and Partial (Soluble) Liver Z-AAT: Cohort 2 [3] [4] | ||||||||||||||
End point description |
Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
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End point type |
Primary
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End point timeframe |
Baseline, Week 48
|
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistics planned per protocol for this endpoint are presented in the data table. [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||
End point title |
Percent Change From Baseline in Serum Z-AAT: Cohorts 1/1b [5] | |||||||||||||||||||||||||||
End point description |
Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 2, 4, 6, 16, 24
|
|||||||||||||||||||||||||||
Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||
End point title |
Percent Change From Baseline in Serum Z-AAT: Cohort 2 [6] | ||||||||||||||||||||||||||
End point description |
Full Analysis Set: all participants who received at least one dose of study drug and had baseline and post-dose liver biopsy histology results available.
|
||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 2, 4, 6, 16, 22, 28, 34, 40, 48
|
||||||||||||||||||||||||||
Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Alanine Aminotransferase (ALT) Values Over Time: Cohorts 1/1b [7] | |||||||||||||||||||||||||||||||||||||||
End point description |
Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point 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
|
|||||||||||||||||||||||||||||||||||||||
Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||
End point title |
ALT Values Over Time: Cohort 2 [8] | ||||||||||||||||||||||||||||||||||
End point description |
Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
|
||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||
End point 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
|
||||||||||||||||||||||||||||||||||
Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Gamma Glutamyl Transferase (GGT) Values Over Time: Cohorts 1/1b [9] | |||||||||||||||||||||||||||||||||||||||
End point description |
Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point 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
|
|||||||||||||||||||||||||||||||||||||||
Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||
End point title |
GGT Values Over Time: Cohort 2 [10] | ||||||||||||||||||||||||||||||||||
End point description |
Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
|
||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||
End point 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
|
||||||||||||||||||||||||||||||||||
Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Fibrosis-4 index (FIB4) Score Values Over Time: Cohorts 1/1b [11] | |||||||||||||||||||||||||||||||||||||||
End point description |
The FIB 4 score evaluates the degree of fibrosis in patients suspected of or already diagnosed with hepatic fibrosis. FIB-4 is calculated as (Age (years) * aspartate aminotransferease) / (platelets * √(ALT)).
The result provided from the above equation is interpreted according to two cut off values:
■ FIB 4 <1.45 indicates absence of cirrhosis (with a negative predictive value of 90% for advanced fibrosis);
■ FIB 4 between 1.45 - 3.25 are deemed inconclusive;
■ FIB 4 >3.25 indicates cirrhosis (with a positive predictive value of 65% for advanced fibrosis).
Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point 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
|
|||||||||||||||||||||||||||||||||||||||
Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||
End point title |
FIB4 Values Over Time: Cohort 2 [12] | ||||||||||||||||||||||||||||||||||
End point description |
The FIB 4 score evaluates the degree of fibrosis in patients suspected of or already diagnosed with hepatic fibrosis. FIB-4 is calculated as (Age (years) * aspartate aminotransferease) / (platelets * √(ALT)).
The result provided from the above equation is interpreted according to two cut off values:
■ FIB 4 <1.45 indicates absence of cirrhosis (with a negative predictive value of 90% for advanced fibrosis);
■ FIB 4 between 1.45 - 3.25 are deemed inconclusive;
■ FIB 4 >3.25 indicates cirrhosis (with a positive predictive value of 65% for advanced fibrosis).
Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
|
||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||
End point 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
|
||||||||||||||||||||||||||||||||||
Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||
End point title |
Aspartate aminotransferase-to-platelet ratio index (APRI) Values Over Time: Cohorts 1/1b [13] | |||||||||||||||||||||||||||||||||||||||
End point description |
APRI is calculated as 100*(aspartate aminotransferase/40) / platelets
The aspartate aminotransferase to platelet ratio index suggests the level of hepatic fibrosis and possible liver disease. Scores indicate the following:
< 0.5: fibrosis is ruled out
0.5 – 0.7: Associated with some kind of liver damage
0.7 - 1: Significant fibrosis
> 1: Associated with cirrhosis
Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
|
|||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||
End point 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
|
|||||||||||||||||||||||||||||||||||||||
Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||
End point title |
APRI Values Over Time: Cohort 2 [14] | ||||||||||||||||||||||||||||||||||
End point description |
APRI is calculated as 100*(aspartate aminotransferase/40) / platelets
The aspartate aminotransferase to platelet ratio index suggests the level of hepatic fibrosis and possible liver disease. Scores indicate the following:
< 0.5: fibrosis is ruled out
0.5 – 0.7: Associated with some kind of liver damage
0.7 - 1: Significant fibrosis
> 1: Associated with cirrhosis
Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
|
||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||
End point 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
|
||||||||||||||||||||||||||||||||||
Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
N-Terminal Type III Collagen Propeptide (PRO-C3) Values Over Time: Cohorts 1/1b [15] | ||||||||||||||||||||||||
End point description |
PRO-C3 may be a biomarker for the formation of fibrotic tissue in the liver. For serum, the normal range is 6.1 – 13.8 ng/mL (based on a study of human serum samples from healthy men and women). Due to ethnic, dietary and age variations, the reference limits given may not apply to all populations. A reduction in Pro-C3 over time may indicate a reduction in hepatic fibrogenesis.
Safety Analysis Set: all participants who received at least one dose of study drug.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 4, 16, 24
|
||||||||||||||||||||||||
Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
PRO-C3 Values Over Time: Cohort 2 [16] | ||||||||||||||||||||
End point description |
PRO-C3 may be a biomarker for the formation of fibrotic tissue in the liver. For serum, the normal range is 6.1 – 13.8 ng/mL (based on a study of human serum samples from healthy men and women). Due to ethnic, dietary and age variations, the reference limits given may not apply to all populations. A reduction in Pro-C3 over time may indicate a reduction in hepatic fibrogenesis.
Safety Analysis Set: all participants who received at least one dose of study drug.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline, Weeks 4, 16, 28, 40, 48
|
||||||||||||||||||||
Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
FibroScan® Values Over Time: Cohorts 1/1b [17] | ||||||||||||||||||
End point description |
FibroScan is a type of liver elastography. Normal results are usually between 2 and 7 kilopascals (kPa), with results higher than the normal range if liver disease is present. The highest possible result is 75 kPa.
Safety Analysis Set: all participants who received at least one dose of study drug.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||||||||
Notes [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
FibroScan® Values Over Time: Cohort 2 [18] | ||||||||||||
End point description |
FibroScan is a type of liver elastography. Normal results are usually between 2 and 7 kilopascals (kPa), with results higher than the normal range if liver disease is present. The highest possible result is 75 kPa.
Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 48
|
||||||||||||
Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Portal Inflammation Over Time: Cohorts 1/1b [19] | |||||||||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of portal inflammation, which was scored on a scale from 0 (none) to 3 (severe).
Safety Analysis Set: all participants who received at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
|||||||||||||||||||||
Notes [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
End point title |
Portal Inflammation Over Time: Cohort 2 [20] | ||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of portal inflammation, which was scored on a scale from 0 (none) to 3 (severe).
Safety Analysis Set: all participants who received at least one dose of study drug.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline, Week 48
|
||||||||||||||
Notes [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Interface Hepatitis Over Time: Cohorts 1/1b [21] | |||||||||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of interface hepatitis, which was scored on a scale from 0 (none) to 3 (severe).
Safety Analysis Set: all participants who received at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
|||||||||||||||||||||
Notes [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
End point title |
Interface Hepatitis Over Time: Cohort 2 [22] | ||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of interface hepatitis, which was scored on a scale from 0 (none) to 3 (severe).
Safety Analysis Set: all participants who received at least one dose of study drug.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline, Week 48
|
||||||||||||||
Notes [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Lobular Inflammation Over Time: Cohorts 1/1b [23] | |||||||||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of lobular inflammation, which was scored on a scale from 0 (none) to 3 (severe).
Safety Analysis Set: all participants who received at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
|||||||||||||||||||||
Notes [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
End point title |
Lobular Inflammation Over Time: Cohort 2 [24] | ||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of lobular inflammation, which was scored on a scale from 0 (none) to 3 (severe).
Safety Analysis Set: all participants who received at least one dose of study drug.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline, Week 48
|
||||||||||||||
Notes [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Hepatocyte Cell Death Over Time: Cohorts 1/1b [25] | |||||||||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of hepatocyte cell death. Hepatocyte Cell Death Score: 0 = No acidophil bodies; 1 = Few acidophil bodies; 2 = Many acidophil.
Safety Analysis Set: all participants who received at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
|||||||||||||||||||||
Notes [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
End point title |
Hepatocyte cell death Over Time: Cohort 2 [26] | ||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the liver biopsy parameter of hepatocyte cell death. Hepatocyte Cell Death Score: 0 = No acidophil bodies; 1 = Few acidophil bodies; 2 = Many acidophil.
Safety Analysis Set: all participants who received at least one dose of study drug.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline, Week 48
|
||||||||||||||
Notes [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
|||||||||||||||
|
|||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
METAVIR Fibrosis Stage Score Over Time: Cohorts 1/1b [27] | |||||||||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the METAVIR fibrosis stage score. The METAVIR scoring system is a system used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C. The stage represents the amount of fibrosis or scarring.
F0: no fibrosis
F1: portal fibrosis without septa
F2: portal fibrosis with few septa
F3: numerous septa without cirrhosis
F4: cirrhosis
Safety Analysis Set: all participants who received at least one dose of study drug.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 24
|
|||||||||||||||||||||
Notes [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
||||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||
End point title |
METAVIR Fibrosis Stage Score Over Time: Cohort 2 [28] | ||||||||||||||
End point description |
Percent of participants having ≥ 1-point improvement from baseline, no change from baseline, and ≥ 1-point worsening from the baseline category in the METAVIR fibrosis stage score. The METAVIR scoring system is a system used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy of patients with hepatitis C. The stage represents the amount of fibrosis or scarring.
F0: no fibrosis
F1: portal fibrosis without septa
F2: portal fibrosis with few septa
F3: numerous septa without cirrhosis
F4: cirrhosis
Safety Analysis Set: all participants who received at least one dose of study drug.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 48
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Notes [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Endpoints are presented by individual cohort per protocol. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
An Adverse Event (AE) is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. Serious Adverse Event (SAE) is an AE that results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, Is a medically important event or reaction. TEAEs are AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. Not related events include those reported as 'Not Related' to study drug. Related events include those reported as 'Possibly Related' or 'Probably Related' to study drug.
Safety Analysis Set: all participants who received at least one dose of study drug.
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End point type |
Secondary
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End point timeframe |
For a maximum duration of study follow-up of 202 weeks.
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
For a maximum duration of study follow-up of 202 weeks.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.1
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Reporting groups
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Reporting group title |
ARO-AAT 100 mg Cohort 1b
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Reporting group description |
Primary Study Period (6-12 months): 100 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 100 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 100 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ARO-AAT 200 mg Cohort 1
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 3 doses, with 2 optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 15 doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ARO-AAT 200 mg Cohort 2
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Reporting group description |
Primary Study Period (6-12 months): 200 mg dose of subcutaneous ARO-AAT for a minimum of 5 doses, with optional treatment extension periods. Treatment Extension I (12 months): 200 mg dose of subcutaneous ARO-AAT every 12 weeks (Q12W). Treatment Extension II (up to 24 Months): 200 mg dose of subcutaneous ARO-AAT Q12W. The maximum number of doses for participants completing the treatment extension periods was 17 doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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30 Apr 2019 |
OVERVIEW/RATIONALE:
1. The protocol was amended in response to recommendations based on review by the Medicines and Healthcare Products Regualtory Agency (MHRA).
2. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity. |
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10 Mar 2020 |
OVERVIEW/RATIONALE:
1. The protocol was amended to include cohort 1b at 100mg (N=4) as well as to add the inclusion of patients with Metavir F1 fibrosis or equivalent.
• A 100mg cohort was added to compare with the 200mg cohort to see if study endpoints may have a dose response relationship.
• An F1 fibrosis score (or equivalent) will be allowed as the study endpoints are now considered to be independent of the need to have Metavir fibrosis F2 and F3, or equivalent.
2. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity. |
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14 Oct 2020 |
OVERVIEW/RATIONALE:
1. The primary endpoint has been revised to evaluation of change (from baseline over time) in total, soluble and insoluble Z-AAT concentrations in the liver of study patients. The primary rationale for protocol version 4.0 is to better align primary and secondary endpoints with the stated purpose of the study. This is an open label pilot study, intended to evaluate various pharmacodynamic markers as well as to explore treatment effect variability with different treatment durations (e.g. biopsy at approximately 6, 12, 18- and 24-months post-dose). This will help to inform on the length of treatment required in later stage studies.
A histologic AATD liver disease activity scale was originally proposed as a primary endpoint. This was a placeholder endpoint as sponsor was investigating the development of a histologic grading scale of liver disease severity in AATD patients. While histologic endpoints are still included, in protocol version 4.0 the primary endpoint has been changed to liver Z-AAT protein. Liver Z-AAT has been thoroughly described as the causative factor of AATD liver disease and liver Z-AAT protein correlates with severity of liver fibrosis and with clinical outcomes. Intra-hepatic Z-AAT protein is also readily quantifiable using a validated assay and does not suffer from intra-reader or inter-reader variability as is the case for pathologist histologic evaluation. Thus, it is more likely to reliably identify differences in pharmacodynamic effect with different treatment durations. Additionally, histologic characteristics found in AATD liver disease (e.g. peri-portal inflammation, steatosis) overlap with those found in other common liver diseases such as NAFLD and NASH which may not respond to ARO-AAT and may confound evaluation of treatment effect. In contrast, intra-hepatic Z-AAT protein is only present in the livers of patients with AATD. For these reasons, liver Z-AAT is now the primary endpoint of the study. |
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14 Oct 2020 |
(continued)
2. Rationale for additional endpoint changes:
• Serum Z-AAT levels have been shifted to the 1st secondary endpoint as serum levels correlate well with intra-hepatic total Z-AAT, consistent with the liver as the main source of serum AAT.
• Changes in ALT and GGT were prioritized as secondary endpoints as these are clinically relevant biomarkers of liver disease and have been shown to associate with severity of liver disease in an AATD population (Clark et al., 2018).
• Other non-invasive measures of liver fibrosis including FibroScan and Pro-C3 have also been shifted to secondary endpoints. Histologic parameters are still included as secondary endpoints and will be evaluated.
• MRE has become more broadly available and is included as an additional exploratory assessment of liver fibrosis.
• Consequently, the study title was also revised.
3. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity. |
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10 Feb 2021 |
GENERAL OVERVIEW:
1. The Global Protocol has been amended to extend the Extension phase of the study by one year. For design clarity, the initial dosing period of the study is referred to as the Primary Study Period and the treatment extension period is referred to as Treatment Extension I and Treatment Extension II (12 month duration for each).
2. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity.
Major changes:
1. Protocol Synopsis: The study has been extended for an additional year to include a new Treatment Extension II after Week 44.
Rationale: The extension period allows subjects to remain on continuous ARO-AAT treatment for long-term safety evaluation. During this period, subjects will have the option to continue to receive the same dose level of ARO-AAT Q12W for up to an additional 12 months or until they roll over into another long-term Extension study, whichever comes first.
2. Protocol Synopsis: Secondary Endpoint : Secondary Endpoint was revised to replace Ishak with Metavir.
Rationale: Although both methods are recognized methods for evaluating fibrosis, Metavir has a smaller scale and is more widely used in clinical practice. |
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16 Nov 2021 |
(continued)
GENERAL OVERVIEW:
1. The Global Protocol has been amended to extend the Extension II part of the study by one year.
2. Assessment of immunogenicity (Incidence of anti-drug antibodies (ADAs) to ARO-AAT) was added as a safety endpoint.
3. Collection of ADAs was added.
4. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity.
Major Changes:
1. Protocol Synopsis: Study Design/Methods: Extension II part of the study has been extended for an additional year.
Rationale: The extension period allows subjects to remain on continuous ARO-AAT treatment for long-term safety evaluation. During this period, subjects will have the option to continue to receive the same dose level of ARO-AAT Q12W for up to an additional 12 months or until they roll over into another long-term Extension study, whichever comes first.
2. Protocol Synopsis: Secondary Endpoints: Assessment of immunogenicity (Incidence of anti-drug antibodies to ARO-AAT) was added as a safety endpoint.
Rationale: Although results from a Phase I study (AROAAT1001) showed no evidence of drug-induced de novo formation of anti-ARO-AAT antibody formation after single or repeat doses of ARO-AAT in the healthy adult volunteers enrolled in study, anti-drug antibody (ADA) assessment has been added as a safety endpoint in study AROAAT2002. ADA was included to further evaluate the potential for immunogenicity following ARO-AAT treatment in patients with AATD. |
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21 Jul 2022 |
GENERAL OVERVIEW:
1. This global protocol has been amended to inform of fazirsiran dose selection by the Sponsor based on review of cumulative safety, efficacy, and pharmacodynamics data from the fazirsiran clinical program . The amendment specifies that all subjects continuing in Extension Treatment Period II will receive the selected fazirsiran dose (200 mg) following the respective country regulatory and ethics committees’ approvals (including local approvals as necessary) of AROAAT2002 protocol amendment v7.0. As such, all ongoing subjects in Extension Treatment Period II will be consented and subjects in Cohort 1b (100 mg) will begin receiving the selected dose at the next scheduled dosing timepoint.
2. Pulmonary function test (PFT) text was updated to clarify instructions for performing spirometry and diffusing capacity for carbon monoxide (DLCO), to acknowledge acceptability of following bronchodilator administration as per site practice, and to describe specific PFT data to include on the electronic case report form (eCRF).
3. The repeat liver biopsy in the treatment extension period will be optional.
4. Vital signs measurement and electrocardiogram (ECG) assessment text was updated to clarify patient positioning during the assessments.
5. Methods sections were updated to change the current pre-dose window for assessments from 60 minutes to 3 hours.
6. Investigational product (IP) nomenclature was updated to include fazirsiran and TAK-999 (also referred to as ARO-AAT). Drug product nomenclature was updated to include Fazirsiran Injection.
7. Fazirsiran supply, preparation, storage, and labelling information was updated, and includes guidance on allowing the fazirsiran vial to come to room temperature before administration.
8. A new section was added to provide more detail on pregnancy reporting.
9. Text was revised to make administrative updates, correct grammatical and formatting errors and inconsistencies, update abbreviations, update references. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |