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Safety Dose Finding Study of ADVM-043 Gene Therapy to Treat Alpha-1 Antitrypsin (A1AT) Deficiency (ADVANCE)

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ClinicalTrials.gov Identifier: NCT02168686
Recruitment Status : Recruiting
First Posted : June 20, 2014
Last Update Posted : September 13, 2018
Sponsor:
Information provided by (Responsible Party):
Adverum Biotechnologies, Inc.

Brief Summary:
The ADVANCE study is being conducted by Adverum Biotechnologies, Inc. as an open-label, multicenter, dose-escalation study in order to assess the safety and protein expression of ADVM-043 following a single intravenous or intrapleural administration.

Condition or disease Intervention/treatment Phase
Alpha 1-Antitrypsin Deficiency Genetic: ADVM-043 Phase 1 Phase 2

Detailed Description:

Alpha-1 Antitrypsin (A1AT) is a major inhibitor of serine proteases and plays an important role in the lung as an inhibitor of neutrophil elastase. A1AT deficiency is associated with decreases in plasma A1AT levels and is associated with an increased risk for developing asthma, emphysema/COPD, and bronchiectasis. Much of the lung damage is thought to be caused by proteolytic damage from neutrophil elastase and other proteases.

ADVM-043 is an investigational gene therapy product (serotype AAVrh.10 vector) expressing human A1AT that is intended to deliver a functional gene to the liver of patients with A1AT deficiency. Study ADVM-043-01 will study up to 4 dose levels in up to 20 patients and assess the hypothesis that a single administration of an AAV vector expressing the human M-type A1AT (i.e., ADVM-043) to patients with A1AT deficiency is safe and results in persistent therapeutic levels of A1AT in blood and alveolar epithelial lining fluid. The primary endpoint is safety, and changes in plasma A1AT levels at multiple time points up to 52 weeks after dosing. A prophylactic tapering corticosteroid regimen will be used to protect against potential vector induced transaminitis. Subjects will be followed for up to 52 weeks after dosing. After completion of this study, subjects will be asked to enroll in a Long Term Follow Up study.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Open-label, multicenter, dose-escalation clinical study to assess the safety and treatment effect of ADVM-043 in subjects with Alpha-1 Antitrypsin Deficiency.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study of Intravenous or Intrapleural Administration of a Serotype rh.10 Replication Deficient Adeno-associated Virus Gene Transfer Vector Expressing the Human Alpha-1 Antitrypsin cDNA to Individuals With Alpha-1 Antitrypsin Deficiency
Actual Study Start Date : November 28, 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : August 2019


Arm Intervention/treatment
Experimental: Dose 1
ADVM-043, at the lowest dose of three planned dose levels, of 8E13 total vg (equivalent to 1E12 vg/kg based on an 80-kg patient) administered IV
Genetic: ADVM-043
Gene transfer vector administration
Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT

Experimental: Dose 2
ADVM-043 at the intermediate dose of three planned dose levels, of 4E14 total vg (equivalent to 5E12 vg/kg based on an 80-kg patient) administered IV
Genetic: ADVM-043
Gene transfer vector administration
Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT

Experimental: Dose 3
ADVM-043 at the highest dose of three planned dose levels, of 1.2E15 total vg (equivalent to 1.5E13 vg/kg based on an 80-kg patient) administered IV
Genetic: ADVM-043
Gene transfer vector administration
Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT

Experimental: Dose 4
ADVM-043 administered at a dose that will be determined
Genetic: ADVM-043
Gene transfer vector administration
Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT




Primary Outcome Measures :
  1. Number and proportion of subjects experiencing adverse events [ Time Frame: 1 year ]
    Safety will be assessed by vital signs, ECG, blood work, immunological responses, pulmonary functions tests.

  2. Number and proportion of subjects experiencing abnormal changes in clinical laboratory parameters [ Time Frame: 1 year ]
    Safety will be assessed by blood work and immunological responses.


Secondary Outcome Measures :
  1. Changes in plasma concentrations of M-specific A1AT up to 52 weeks [ Time Frame: 1 year ]
    Efficacy will be assessed by measured bloodwork.

  2. Changes in total plasma concentrations of A1AT up to 52 weeks [ Time Frame: 1 year ]
    Efficacy will be assessed by measured bloodwork.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Capable of providing informed consent
  • Alpha1AT genotype of ZZ or Z Null
  • Males and females 18 years and older
  • Ongoing treatment with A1AT augmentation is not required, however any subject receiving A1AT augmentation therapy must be willing to washout. Washout is defined as at least 8 weeks between last augmentation therapy and pre-treatment plasma A1AT level
  • Willing to remain off PAT for at least 3 months following treatment
  • Body mass index 18 to 35 kg/m2
  • Fertile men and women of childbearing potential must agree to use barrier contraception for 3 months after treatment

Key Exclusion Criteria:

  • FEV1 <35 percent of predicted value at the Screening visit
  • Receiving systemic corticosteroids or other immunosuppressive medications
  • Immunodeficiency disease or evidence of active infection of any type, including human immunodeficiency virus
  • Abnormal liver function tests
  • Organ transplant recipient or awaiting transplantation
  • Participation in another current or previous gene transfer study
  • AAVrh.10 neutralizing antibody titer ≥ 1:5
  • Female who is pregnant or lactating
  • History of alcohol or drug abuse within the past 5 years
  • Any history of allergies that may prohibit study-specific investigations
  • Receiving an investigational medicinal product or participating in another investigational study within 3 months prior to consent
  • Cigarette smoking, or any other tobacco use, e-cigarettes or other recreational inhalant within 1 year of the Screening Visit

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): NCT02168686


Contacts
Contact: Heather Jividen +1 (650) 665-7246 hjividen@adverum.com

Locations
United States, California
Ronald Reagan UCLA Medical Center Recruiting
Santa Monica, California, United States, 90095
Contact: Roslynn Marzan-McGill    310-825-2616    RMcGill@mednet.ucla.edu   
Principal Investigator: Igor Barjakatarevic, MD         
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Jesse West    866-229-6312    jesse.west@medicine.ufl.edu   
Principal Investigator: Mark Brantly, MD         
United States, Illinois
University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Cynthia Warnes, RN    773-834-8874    cwarnes@medicine.bsd.uchicago.edu   
Principal Investigator: Kyle Hogarth, MD         
United States, Pennsylvania
Temple University Hospital Not yet recruiting
Philadelphia, Pennsylvania, United States, 19140
Principal Investigator: Friedrich Kueppers, MD         
United States, South Carolina
Medical University of South Carolina Recruiting
Charleston, South Carolina, United States, 29425
Contact: Gwen Blanton    843-792-8438    blantonm@musc.edu   
Principal Investigator: Charlton Strange, MD         
Sponsors and Collaborators
Adverum Biotechnologies, Inc.
Investigators
Principal Investigator: Charlton Strange, MD Medical University of South Carolina, Charleston, SC, USA
Principal Investigator: Friedrich Kueppers, MD Temple University Hospital, Philadelphia, PA, USA
Principal Investigator: Mark Brantly, MD University of Florida, Gainesville, FL, USA
Principal Investigator: Kyle Hogarth, MD University of Chicago Medical Center, Chicago, IL, USA
Principal Investigator: Igor Barjakatarevic, MD Ronald Reagan UCLA Medical Center, Santa Monica, CA, USA

Responsible Party: Adverum Biotechnologies, Inc.
ClinicalTrials.gov Identifier: NCT02168686     History of Changes
Other Study ID Numbers: ADVM-043-01
First Posted: June 20, 2014    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Adverum Biotechnologies, Inc.:
alpha-1 antitrypsin deficiency
alpha1-antitrypsin deficiency
alpha-1-antitrypsin deficiency
alpha1AT
A1AT
ADVM-043
AAVrh.10halpha1AT
AAVrh.10hA1AT
Gene transfer vector
Gene therapy
Lung disease
Emphysema
COPD
ADVANCE study

Additional relevant MeSH terms:
Alpha 1-Antitrypsin Deficiency
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema
Pathologic Processes
Alpha 1-Antitrypsin
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action