Alpha 1-Antitrypsin DeficiencyPhase 1/2ADVANCENCT02168686
Safety Dose Finding Study of ADVM-043 Gene Therapy to Treat Alpha-1 Antitrypsin (A1AT) Deficiency
A Phase 1/2 study testing ADVM-043 in people with Alpha 1-Antitrypsin Deficiency, run by Adverum Biotechnologies, Inc. at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Alpha 1-Antitrypsin Deficiency
- What is being tested?
- ADVM-043
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 2 sitesUnited States
- Study dates
- 28 Nov 2017to 29 Aug 2019
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Medical University of South Carolina
Charleston, South Carolina, 29425
University of Florida
Gainesville, Florida, 32610
About this study
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
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.
Read the 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.
- Conditions
- Alpha 1-Antitrypsin Deficiency
- Being tested
- ADVM-043
- 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
- Medical subject headings
- alpha 1-Antitrypsin Deficiency, Lung Diseases, Emphysema, Pulmonary Disease, Chronic Obstructive
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ADVM-043Genetic
Also called AAVrh.10halpha1AT, AAVrh.10hA1AT
Gene transfer vector administration
| Study group | Role | What they receive |
|---|---|---|
| Part A: Dose 1 | Experimental | 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 Receives: Genetic: ADVM-043 |
| Part A: Dose 2 | Experimental | 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 Receives: Genetic: ADVM-043 |
| Part A: Dose 3 | Experimental | 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 Receives: Genetic: ADVM-043 |
| Part A: Dose 4 | Experimental | ADVM-043 administered at a dose that will be determined Receives: Genetic: ADVM-043 |
| Part B (optional): Intrapleural administration | Experimental | ADVM-043 administered intrapleurally at a dose that will be determined Receives: Genetic: ADVM-043 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Treatment-emergent Adverse Events Related to ADVM-043
Number and proportion of subjects experiencing treatment-related adverse events related to ADVM-043
Measured: From ADVM-043 infusion through End-of-Study visit at 52 weeks
Abnormal Changes in Clinical Laboratory Parameters
Number of participants with ≥1 abnormal shift from Baseline in neutrophil count, hemoglobin, important serum chemistry parameters
Measured: From ADVM-043 infusion through End-of-Study visit at 52 weeks
Secondary outcomes (2)
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.
Measured: At Week 52
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
Measured: At Week 52
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jun 2014 (estimated)
- Study start28 Nov 2017
- Primary completion29 Aug 2019
- Study completion29 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Alpha 1-Antitrypsin DeficiencyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- 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)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Adverum Biotechnologies, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Charlton Strange, MD, Principal investigator, Medical University of South Carolina, Charleston, SC, USAFriedrich Kueppers, MD, Principal investigator, Temple University Hospital, Philadelphia, PA, USAMark Brantly, MD, Principal investigator, University of Florida, Gainesville, FL, USAKyle Hogarth, MD, Principal investigator, University of Chicago Medical Center, Chicago, IL, USAIgor Barjakatarevic, MD, Principal investigator, Ronald Reagan UCLA Medical Center, Santa Monica, CA, USA
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02168686
- Sponsor's protocol ID
- ADVM-043-01
- Acronym
- ADVANCE
- Status last verified
- Sep 2023
- First submitted
- 10 Jun 2014
- Last updated
- 5 Oct 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
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.
PubMed 34256305
Study at a glance
From the registry record, last updated by the sponsor on 5 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02168686
- Acronym / sponsor ID
- ADVANCE / ADVM-043-01
- Conditions
- Alpha 1-Antitrypsin Deficiency
- Keywords
- alpha-1 antitrypsin deficiency, alpha1-antitrypsin deficiency, alpha-1-antitrypsin deficiency, alpha1AT, A1AT, ADVM-043, AAVrh.10halpha1AT, AAVrh.10hA1AT
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Adverum Biotechnologies, Inc.Industry (pharma, biotech, devices)
- Study start
- 28 Nov 2017 (actual)
- Primary completion
- 29 Aug 2019 (actual)
- Study completion
- 29 Aug 2019 (actual)
- First posted
- 20 Jun 2014 (estimated)
- Results
- Posted 8 Aug 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 5
- 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.
| Arm | Type | Receives |
|---|---|---|
| Part A: Dose 1 | Experimental | Genetic: ADVM-043ADVM-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 |
| Part A: Dose 2 | Experimental | Genetic: ADVM-043ADVM-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 |
| Part A: Dose 3 | Experimental | Genetic: ADVM-043ADVM-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 |
| Part A: Dose 4 | Experimental | Genetic: ADVM-043ADVM-043 administered at a dose that will be determined |
| Part B (optional): Intrapleural administration | Experimental | Genetic: ADVM-043ADVM-043 administered intrapleurally at a dose that will be determined |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ADVM-043Also: AAVrh.10halpha1AT, AAVrh.10hA1ATGene transfer vector administration | Genetic | Part A: Dose 1, Part A: Dose 2, Part A: Dose 3, Part A: Dose 4, Part B (optional): Intrapleural administration |
Primary outcome
Treatment-emergent Adverse Events Related to ADVM-043
Time frame: From ADVM-043 infusion through End-of-Study visit at 52 weeks
Number and proportion of subjects experiencing treatment-related adverse events related to ADVM-043
Abnormal Changes in Clinical Laboratory Parameters
Time frame: From ADVM-043 infusion through End-of-Study visit at 52 weeks
Number of participants with ≥1 abnormal shift from Baseline in neutrophil count, hemoglobin, important serum chemistry parameters
2 secondary outcomes
Change in Plasma Concentrations of M-specific A1AT up to 52 Weeks
Time frame: At Week 52
Changes in Total Plasma Concentrations of A1AT up to 52 Weeks
Time frame: At Week 52
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34256305Remih 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Charlton Strange, MD principal investigator
Medical University of South Carolina, Charleston, SC, USA
Friedrich Kueppers, MD principal investigator
Temple University Hospital, Philadelphia, PA, USA
Mark Brantly, MD principal investigator
University of Florida, Gainesville, FL, USA
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing ADVM-043 in people with Alpha 1-Antitrypsin Deficiency, run by Adverum Biotechnologies, Inc. at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Aug 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Treatment-emergent Adverse Events Related to ADVM-043 (time frame: From ADVM-043 infusion through End-of-Study visit at 52 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02168686, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2023; AzTrials last refreshed its copy on 6 Nov 2026.