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

Primary Purpose

Alpha 1-Antitrypsin Deficiency

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

ADVM-043

About this trial

This is an interventional treatment trial for Alpha 1-Antitrypsin Deficiency focused on measuring 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, ADVM-043-01

Eligibility Criteria

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

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

Sites / Locations

University of Florida
Medical University of South Carolina

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Part A: Dose 1

Part A: Dose 2

Part A: Dose 3

Part A: Dose 4

Part B (optional): Intrapleural administration

Arm Description

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

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

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

ADVM-043 administered at a dose that will be determined

ADVM-043 administered intrapleurally at a dose that will be determined

Outcomes

Primary Outcome Measures

Treatment-emergent Adverse Events Related to ADVM-043

Number and proportion of subjects experiencing treatment-related adverse events related to ADVM-043

Abnormal Changes in Clinical Laboratory Parameters

Number of participants with ≥1 abnormal shift from Baseline in neutrophil count, hemoglobin, important serum chemistry parameters

Secondary Outcome Measures

Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks

Change from baseline at Week 52 of plasma concentration of M-specific A1AT for subjects who did not receive PAT post-dose Note: Two subjects in Dose 1 Arm/Group, had results available at Week 52; the remaining 4 subjects in Dose 2 Arm/Group and Dose 3 Arm/Group had resumed PAT therapy after Week 24, and their results were censored from the Week 52 timepoint. While data on the Total Plasma Concentrations of A1AT up to 52 Weeks were collected for 1 study participant in Part A: Dose 3, no data were collected on the Change in Plasma Concentrations of M-specific A1AT due to the initiation of PAT after 24 weeks in Part A: Dose 3 subjects.

Changes in Total Plasma Concentrations of A1AT up to 52 Weeks

Change from baseline at Week 24 and Week 52 of total A1At plasma concentration for subjects who did not receive PAT post -dose

Full Information

NCT ID

NCT02168686

First Posted

June 10, 2014

Last Updated

September 18, 2023

Sponsor

Adverum Biotechnologies, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02168686

Brief Title

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

Acronym

ADVANCE

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

November 28, 2017 (Actual)

Primary Completion Date

August 29, 2019 (Actual)

Study Completion Date

August 29, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Adverum Biotechnologies, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

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

Alpha 1-Antitrypsin Deficiency

Keywords

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, ADVM-043-01

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

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)

Allocation

Non-Randomized

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part A: Dose 1

Arm Type

Experimental

Arm Description

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

Arm Title

Part A: Dose 2

Arm Type

Experimental

Arm Description

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

Arm Title

Part A: Dose 3

Arm Type

Experimental

Arm Description

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

Arm Title

Part A: Dose 4

Arm Type

Experimental

Arm Description

ADVM-043 administered at a dose that will be determined

Arm Title

Part B (optional): Intrapleural administration

Arm Type

Experimental

Arm Description

ADVM-043 administered intrapleurally at a dose that will be determined

Intervention Type

Genetic

Intervention Name(s)

ADVM-043

Other Intervention Name(s)

AAVrh.10halpha1AT, AAVrh.10hA1AT

Intervention Description

Gene transfer vector administration

Primary Outcome Measure Information:

Title

Treatment-emergent Adverse Events Related to ADVM-043

Description

Number and proportion of subjects experiencing treatment-related adverse events related to ADVM-043

Time Frame

From ADVM-043 infusion through End-of-Study visit at 52 weeks

Title

Abnormal Changes in Clinical Laboratory Parameters

Description

Number of participants with ≥1 abnormal shift from Baseline in neutrophil count, hemoglobin, important serum chemistry parameters

Time Frame

From ADVM-043 infusion through End-of-Study visit at 52 weeks

Secondary Outcome Measure Information:

Title

Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks

Description

Time Frame

At Week 52

Title

Changes in Total Plasma Concentrations of A1AT up to 52 Weeks

Description

Change from baseline at Week 24 and Week 52 of total A1At plasma concentration for subjects who did not receive PAT post -dose

Time Frame

At Week 52

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials: