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Safety, Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT) (SEQUOIA)

Primary Purpose

Alpha 1-Antitrypsin Deficiency

Status

Active

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Fazisiran Injection

Placebo

About this trial

This is an interventional treatment trial for Alpha 1-Antitrypsin Deficiency

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of Alabama at Birmingham Medical Center
Mayo Clinic Arizona
University of California San Diego Altman Clinical and Translational Research Institute
UCLA David Geffen School of Medicine, Center for Health Sciences
University of California Davis Medical Center
UCSF Medical Center Benioff Children's Hospital
Stanford Health Care
University of Florida Hepatology Research at CTRB
Indiana University Health University Hospital
University of Iowa Hospitals and Clinics
SSM-Health Cardinal Glennon Children's Hospital
Columbia University Medical Center
Medical University of South Carolina (MUSC)
Vanderbilt University Medical Center
Baylor College of Medicine
University of Utah Hospital
Universitatsklinikum Aachen, Anstalt des offentlich
Fondazione IRCCS Policlinico S. Matteo
Leiden University Medical Center
Hospital Central Do Funchal (Hospital Nelio Mendoca)
Hospital Universitari Vall d'Hebron

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Experimental

Arm Label

Fazirsiran (also referred to as TAK-999 or ARO-AAT)

Placebo

Open-Label Fazisiran (also referred to as TAK-999 or ARO-AAT)

Arm Description

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.

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).

Outcomes

Primary Outcome Measures

Percentage Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT)

Secondary Outcome Measures

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) at Week 16 and over time through End of Study (EOS)

Absolute Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

Percent Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

Absolute Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

Percent Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

Absolute Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

Percent Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

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

Percent Change from Baseline in Liver Function Tests: ALT, AST, ALP, GGT at Week 16 and over time through EOS

Absolute Change from Baseline in Liver Function Tests: Total Bilirubin, Direct Bilirubin at Week 16 and over time through EOS

Percent Change from Baseline in Liver Function Tests: Total Bilirubin, Direct Bilirubin at Week 16 and over time through EOS

Absolute Change from Baseline in Liver Function Tests: International Normalized Ratio (INR) at Week 16 and over time through EOS

Percent Change from Baseline in Liver Function Tests: INR at Week 16 and over time through EOS

Absolute Change in Serum Z-AAT Over Time through EOS

Percent Change in Serum Z-AAT Over Time through EOS

Pharmacokinetics (PK) of Fazirsiran: Maximum Observed Plasma Concentration (Cmax)

PK of Fazirsiran: Time to Maximum Observed Plasma Concentration (Tmax)

PK of Fazirsiran: Terminal Elimination Half-Life (t1/2)

PK of Fazirsiran: Area Under the Plasma Concentration Versus Time Curve from Zero to the Last Time Point with a Quantifiable Concentration (AUC0-t)

PK of Fazirsiran: Area Under the Plasma Concentration Versus Time Curve from Zero to Infinity (AUCinf)

Incidence of Anti-Drug Antibodies to Fazirsiran

Change from Baseline in Metavir Fibrosis Stage at Post-Dose Biopsy for Participants with Fibrosis

Full Information

NCT ID

NCT03945292

First Posted

May 8, 2019

Last Updated

July 26, 2023

Sponsor

Arrowhead Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT03945292

Brief Title

Safety, Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT)

Acronym

SEQUOIA

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]

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

August 7, 2019 (Actual)

Primary Completion Date

November 8, 2021 (Actual)

Study Completion Date

September 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Arrowhead Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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).

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alpha 1-Antitrypsin Deficiency

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

40 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Fazirsiran (also referred to as TAK-999 or ARO-AAT)

Arm Type

Experimental

Arm Description

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.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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.

Arm Title

Open-Label Fazisiran (also referred to as TAK-999 or ARO-AAT)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Fazisiran Injection

Other Intervention Name(s)

ARO-AAT Injection, TAK-999 Injection

Intervention Description

solution for subcutaneous (sc) injection

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

sterile normal saline (0.9% NaCl), calculated to match active comparator, for sc injection

Primary Outcome Measure Information:

Title

Percentage Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT)

Time Frame

Baseline, Week 16 (+/- 2 weeks)

Secondary Outcome Measure Information:

Title

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)

Title

Absolute Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

Time Frame