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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 : Active, not recruiting
First Posted : June 20, 2014
Last Update Posted : December 3, 2018
Sponsor:
Information provided by (Responsible Party):
Adverum Biotechnologies, Inc.

Tracking Information
First Submitted Date  ICMJE June 10, 2014
First Posted Date  ICMJE June 20, 2014
Last Update Posted Date December 3, 2018
Actual Study Start Date  ICMJE November 28, 2017
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 11, 2018)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 17, 2014)
Change in adverse events as a measure of safety and tolerability [ Time Frame: Screening, pre-therapy, 3, 6, and 12 months post-vector administration ]
The following study parameters will assess safety: clinical assessment, routine bloodwork, routine urinalysis, EKG, chest x-ray and lung function test
Change History Complete list of historical versions of study NCT02168686 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 29, 2017)
  • Changes in plasma concentrations of M-specific A1AT up to 52 weeks [ Time Frame: 1 year ]
    Efficacy will be assessed by measured bloodwork.
  • Changes in total plasma concentrations of A1AT up to 52 weeks [ Time Frame: 1 year ]
    Efficacy will be assessed by measured bloodwork.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 17, 2014)
Change in therapeutic serum and alveolar epithelial lining fluid levels of a1AT as a preliminary measure of efficacy [ Time Frame: Screening, pre-therapy, 3, 6, and 12 months post-vector administration ]
The following study parameter will measure preliminary efficacy: bloodwork and bronchoscopy
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety Dose Finding Study of ADVM-043 Gene Therapy to Treat Alpha-1 Antitrypsin (A1AT) Deficiency
Official Title  ICMJE 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
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.
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 (epithelial lining fluid is only to be collected in subjects who are dosed intrapleurally). 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. Safety and efficacy data from the IV cohorts will be considered when determining whether to proceed to intrapleural administration. After completion of this study, subjects will be asked to enroll in a Long Term Follow Up study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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
Condition  ICMJE Alpha 1-Antitrypsin Deficiency
Intervention  ICMJE Genetic: ADVM-043
Gene transfer vector administration
Other Names:
  • AAVrh.10halpha1AT
  • AAVrh.10hA1AT
Study Arms  ICMJE
  • Experimental: Part A: 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
    Intervention: Genetic: ADVM-043
  • Experimental: Part A: 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
    Intervention: Genetic: ADVM-043
  • Experimental: Part A: 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
    Intervention: Genetic: ADVM-043
  • Experimental: Part A: Dose 4
    ADVM-043 administered at a dose that will be determined
    Intervention: Genetic: ADVM-043
  • Experimental: Part B (optional): Intrapleural administration
    ADVM-043 administered intrapleurally at a dose that will be determined
    Intervention: Genetic: ADVM-043
Publications * Not Provided

*   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
Estimated Enrollment  ICMJE
 (submitted: June 17, 2014)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2019
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (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 United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02168686
Other Study ID Numbers  ICMJE ADVM-043-01
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Adverum Biotechnologies, Inc.
Study Sponsor  ICMJE Adverum Biotechnologies, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Adverum Biotechnologies, Inc.
Verification Date November 2018

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