Safety, Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT) (SEQUOIA)
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| ClinicalTrials.gov Identifier: NCT03945292 |
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Recruitment Status :
Completed
First Posted : May 10, 2019
Last Update Posted : January 10, 2024
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Sponsor:
Arrowhead Pharmaceuticals
Information provided by (Responsible Party):
Arrowhead Pharmaceuticals
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Brief Summary:
The purpose of AROAAT2001 (SEQUOIA) is to evaluate the safety, efficacy and tolerability of multiple doses of the investigational product, Fazirsiran Injection, administered subcutaneously to participants with alpha-1 antitrypsin deficiency (AATD).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Alpha 1-Antitrypsin Deficiency | Drug: Fazisiran Injection Other: Placebo | Phase 2 |
Participants will be enrolled to receive multiple subcutaneous injections of Fazirsiran Injection (also referred to as TAK-999 Injection or ARO-AAT Injection) or placebo. Eligible participants will require a pre-dose biopsy completed as part of the study within the screening window. However, any participant with a biopsy result within 1 year of screening showing no fibrosis does not require a pre-dose biopsy. Only participants who have liver fibrosis will undergo a post-dose biopsy and may continue treatment in an open-label phase.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 40 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Placebo-Controlled, Multi-dose, Phase 2 Study to Determine the Safety, Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT) in Patients With Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA] |
| Actual Study Start Date : | August 7, 2019 |
| Actual Primary Completion Date : | November 8, 2021 |
| Actual Study Completion Date : | September 18, 2023 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Alpha-1 antitrypsin deficiency
MedlinePlus related topics:
Alpha-1 Antitrypsin Deficiency
| Arm | Intervention/treatment |
|---|---|
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Experimental: Fazirsiran (also referred to as TAK-999 or ARO-AAT)
Participants with no fibrosis: Administered on Day 1 and Week 4 Participants with fibrosis: Administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses. |
Drug: Fazisiran Injection
solution for subcutaneous (sc) injection
Other Names:
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Placebo Comparator: Placebo
Participants with no fibrosis: Administered on Day 1 and Week 4 Participants with fibrosis: Administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses. |
Other: Placebo
sterile normal saline (0.9% NaCl), calculated to match active comparator, for sc injection |
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Experimental: Open-Label Fazisiran (also referred to as TAK-999 or ARO-AAT)
After all enrolled participants completed the Week 16 visit, an interim analysis was performed to select a single dose level (25, 100 or 200 mg) for the open-label phase of the study. Fazirsiran 200 mg was the selected dose and all participants with fibrosis at Screening who completed the post-dose liver biopsy at Week 48 (or Week 72 or 96) receive this dose every 12 weeks for the duration of the study (open-label phase).
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Drug: Fazisiran Injection
solution for subcutaneous (sc) injection
Other Names:
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Primary Outcome Measures :
- Percentage Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) [ Time Frame: Baseline, Week 16 (+/- 2 weeks) ]
Secondary Outcome Measures :
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) at Week 16 and over time through End of Study (EOS) [ Time Frame: Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis) ]
- Absolute Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis [ Time Frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks) ]
- Percent Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis [ Time Frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks) ]
- Absolute Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis [ Time Frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks) ]
- Percent Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis [ Time Frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks) ]
- Absolute Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis [ Time Frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks) ]
- Percent Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis [ Time Frame: Baseline, Week 48 (+/- 2 weeks), or Week 72 (+/- 4 weeks), or Week 96 (+/- 4 weeks) ]
- Absolute Change from Baseline in Liver Function Tests: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), Gamma-Glutamyl Transferase (GGT) at Week 16 and over time through EOS [ Time Frame: Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis) ]
- Percent Change from Baseline in Liver Function Tests: ALT, AST, ALP, GGT at Week 16 and over time through EOS [ Time Frame: Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis) ]
- Absolute Change from Baseline in Liver Function Tests: Total Bilirubin, Direct Bilirubin at Week 16 and over time through EOS [ Time Frame: Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis) ]
- Percent Change from Baseline in Liver Function Tests: Total Bilirubin, Direct Bilirubin at Week 16 and over time through EOS [ Time Frame: Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis) ]
- Absolute Change from Baseline in Liver Function Tests: International Normalized Ratio (INR) at Week 16 and over time through EOS [ Time Frame: Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis) ]
- Percent Change from Baseline in Liver Function Tests: INR at Week 16 and over time through EOS [ Time Frame: Baseline, Week 16 (+/- 2 weeks) through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis) ]
- Absolute Change in Serum Z-AAT Over Time through EOS [ Time Frame: Baseline, through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis) ]
- Percent Change in Serum Z-AAT Over Time through EOS [ Time Frame: Baseline, through Week 64 (+/- 2 weeks; participants without fibrosis) or Week 16 (+/- 2 weeks) through Week 208 (participants with fibrosis) ]
- Pharmacokinetics (PK) of Fazirsiran: Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day) ]
- PK of Fazirsiran: Time to Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day) ]
- PK of Fazirsiran: Terminal Elimination Half-Life (t1/2) [ Time Frame: Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day) ]
- PK of Fazirsiran: Area Under the Plasma Concentration Versus Time Curve from Zero to the Last Time Point with a Quantifiable Concentration (AUC0-t) [ Time Frame: Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day) ]
- PK of Fazirsiran: Area Under the Plasma Concentration Versus Time Curve from Zero to Infinity (AUCinf) [ Time Frame: Participants without fibrosis: Pre-dose, 1 hour, 2 hour & 24 or 48 hours post-dose on Day 1 (+/- 1 day). Participants with fibrosis: Pre-dose, 1 hour, 2 hours & 24 or 48 hours post-dose on Days 1 and 113 (+/- 1 day) ]
- Incidence of Anti-Drug Antibodies to Fazirsiran [ Time Frame: Participants Without Fibrosis: Pre-dose on Days 1 & 29, and on Days 113, 197 and 281; Participants With Fibrosis: Pre-dose on all dosing visits (Days 1, 29, 113, and every 12 weeks up to Week 196) ]
- Change from Baseline in Metavir Fibrosis Stage at Post-Dose Biopsy for Participants with Fibrosis [ Time Frame: Post-dose at Weeks 48 (+/- 2 weeks) or Week 72 (+/- 4 weeks) or Week 96 (+/- 4 weeks) ]
Information from the National Library of Medicine
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| Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Diagnosis of AATD
- Liver biopsy at Screening indicating liver fibrosis (score less than F4); a patient with no fibrosis may participate based on a previous biopsy conducted within one year
- Women of childbearing potential must have a negative pregnancy test, cannot be breastfeeding, 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
- Previous lung or liver transplant due to AATD
- 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03945292
Locations
Show 21 study locations
Sponsors and Collaborators
Arrowhead Pharmaceuticals
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Arrowhead Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT03945292 |
| Other Study ID Numbers: |
AROAAT2001 2018-003385-14 ( EudraCT Number ) |
| First Posted: | May 10, 2019 Key Record Dates |
| Last Update Posted: | January 10, 2024 |
| Last Verified: | January 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | Yes |
Additional relevant MeSH terms:
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Alpha 1-Antitrypsin Deficiency Liver Diseases Digestive System Diseases Lung Diseases Respiratory Tract Diseases |
Genetic Diseases, Inborn Subcutaneous Emphysema Emphysema Pathologic Processes |