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

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ClinicalTrials.gov Identifier: NCT03945292
Recruitment Status : Recruiting
First Posted : May 10, 2019
Last Update Posted : June 16, 2021
Sponsor:
Information provided by (Responsible Party):
Arrowhead Pharmaceuticals

Study Description
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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, ARO-AAT, administered subcutaneously to participants with alpha-1 antitrypsin deficiency (AATD).

Condition or disease Intervention/treatment Phase
Alpha 1-Antitrypsin Deficiency Drug: ARO-AAT Injection Other: Placebo Phase 2

Detailed Description:
Participants will be enrolled to receive multiple subcutaneous injections of ARO-AAT 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 extension.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 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 ARO-AAT in Patients With Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA]
Actual Study Start Date : August 7, 2019
Estimated Primary Completion Date : August 1, 2022
Estimated Study Completion Date : August 1, 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: 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 15 total doses.

 Drug: ARO-AAT Injection
solution for subcutaneous (sc) injection
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 15 total doses.

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


Outcome Measures
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Primary Outcome Measures :
  1. Percentage Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) [ Time Frame: Baseline, Week 16 (+/- 2 weeks) ]

Secondary Outcome Measures :
  1. 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) ]
  2. 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) ]
  3. 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) ]
  4. 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) ]
  5. 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) ]
  6. 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) ]
  7. Number of Participants With Adverse Events (AEs) 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 172 (participants with fibrosis) ]
  8. 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), Participants Without Fibrosis: through Week 64 (+/- 2 Weeks), Participants With Fibrosis: through Week 172 ]
  9. 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), Participants Without Fibrosis: through Week 64 (+/- 2 Weeks), Participants With Fibrosis: through Week 172 ]
  10. 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), Participants Without Fibrosis: through Week 64 (+/- 2 Weeks), Participants With Fibrosis: through Week 172 ]
  11. 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), Participants Without Fibrosis: through Week 64 (+/- 2 Weeks), Participants With Fibrosis: through Week 172 ]
  12. 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), Participants Without Fibrosis: through Week 64 (+/- 2 Weeks), Participants With Fibrosis: through Week 172 ]
  13. Percent Change from Baseline in Liver Function Tests: INR at Week 16 and over time through EOS [ Time Frame: Baseline, Week 16 (+/- 2 Weeks), Participants Without Fibrosis: through Week 64 (+/- 2 Weeks), Participants With Fibrosis: through Week 172 ]
  14. Absolute Change in Serum Z-AAT Over Time through EOS [ Time Frame: Baseline, Participants Without Fibrosis: through Week 64 (+/- 2 Weeks), Participants With Fibrosis: through Week 172 ]
  15. Percent Change in Serum Z-AAT Over Time through EOS [ Time Frame: Baseline, Participants Without Fibrosis: through Week 64 (+/- 2 Weeks), Participants With Fibrosis: through Week 172 ]
  16. Pharmacokinetics (PK) of ARO-AAT: 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) ]
  17. PK of ARO-AAT: 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) ]
  18. PK of ARO-AAT: Terminal Elimination Half-Life (t1/2) [ Time Frame: Participants Without Fibrosis: Pre-dose, 1 hour, 2 hours & 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) ]
  19. PK of ARO-AAT: 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) ]
  20. PK of ARO-AAT: 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) ]

Eligibility Criteria
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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

Contacts and Locations
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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


Contacts
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Contact: Medical Monitor 626-304-3400 medicalmonitor@arrowheadpharma.com

Locations
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Sponsors and Collaborators
Arrowhead Pharmaceuticals
More Information
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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: June 16, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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