Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03945292
Recruitment Status : Active, not recruiting
First Posted : May 10, 2019
Last Update Posted : September 10, 2021
Sponsor:
Information provided by (Responsible Party):
Arrowhead Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE May 8, 2019
First Posted Date  ICMJE May 10, 2019
Last Update Posted Date September 10, 2021
Actual Study Start Date  ICMJE August 7, 2019
Estimated Primary Completion Date July 13, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 4, 2021)
Percentage Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) [ Time Frame: Baseline, Week 16 (+/- 2 weeks) ]
Original Primary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
  • Part A: Percentage Change From Baseline in Soluble Liver Z-Alpha-1 Antitrypsin (Z-AAT), insoluble liver Z-AAT Levels at Day 113 [ Time Frame: Baseline, Day 113 ]
  • Part A: Percentage Change From Baseline in Serum AAT Levels at Day 113 [ Time Frame: Baseline, Day 113 ]
  • Part A:Number of Participants with Adverse Events (AEs) Possibly or Probably Related to Treatment [ Time Frame: Up to Day 113 ]
  • Part B:Number of Participants Achieving a 2-Point Improvement in a Histologic Grading Scale of AATD Associated Liver Disease AND No Worsening of Liver Fibrosis Based on Ishak Score [ Time Frame: End of Study Biopsy (84 days +/- 14 days after last Part B dose) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 4, 2021)
  • 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) ]
  • 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) ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
  • Part B: Change from Baseline Over Time in a Histologic Grading Scale of AATD Associated Liver Disease [ Time Frame: Baseline, End of Study Biopsy (84 days +/- 14 days after last Part B dose) ]
  • Part B: Number of Participants with Ishak Fibrosis Stage 1 or Greater Achieving at Least a 1-Stage Improvement [ Time Frame: End of Study Biopsy (84 days +/- 14 days after last Part B dose) ]
  • Part B: Change from Baseline Over Time in Ishak Fibrosis Score [ Time Frame: Baseline, End of Study Biopsy (84 days +/- 14 days after last Part B dose) ]
  • Part B: Number of Participants with AEs Possibly or Probably Related to Treatment [ Time Frame: Up Through End of Study Biopsy (84 days +/- 14 days after last Part B dose) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability and Pharmacodynamic Effect of ARO-AAT
Official Title  ICMJE 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]
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).
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Alpha 1-Antitrypsin Deficiency
Intervention  ICMJE
  • Drug: ARO-AAT Injection
    solution for subcutaneous (sc) injection
  • Other: Placebo
    sterile normal saline (0.9% NaCl), calculated to match active comparator, for sc injection
Study Arms  ICMJE
  • 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.

    Intervention: Drug: ARO-AAT 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.

    Intervention: Other: Placebo
Publications * Remih K, Amzou S, Strnad P. Alpha1-antitrypsin deficiency: New therapies on the horizon. Curr Opin Pharmacol. 2021 Aug;59:149-156. doi: 10.1016/j.coph.2021.06.001. Epub 2021 Jul 10. Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 16, 2021)
40
Original Estimated Enrollment  ICMJE
 (submitted: May 8, 2019)
120
Estimated Study Completion Date  ICMJE July 13, 2022
Estimated Primary Completion Date July 13, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   Italy,   Netherlands,   Portugal,   Spain,   Sweden,   United States
Removed Location Countries Canada,   Ireland
 
Administrative Information
NCT Number  ICMJE NCT03945292
Other Study ID Numbers  ICMJE AROAAT2001
2018-003385-14 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Arrowhead Pharmaceuticals
Study Sponsor  ICMJE Arrowhead Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Arrowhead Pharmaceuticals
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP