Alpha 1-Antitrypsin DeficiencyPhase 1AATNCT00430768

Experimental Gene Transfer Procedure to Treat Alpha 1-Antitrypsin (AAT) Deficiency

A Phase 1 study testing rAAV1-CB-hAAT in people with Alpha 1-Antitrypsin Deficiency, run by University of Massachusetts, Worcester at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Alpha 1-Antitrypsin Deficiency
What is being tested?: rAAV1-CB-hAAT
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 9 participants
Where: 2 sitesUnited States
Study dates: Feb 2006to Jan 2015
Phase: Phase 1
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

Diagnosed with AAT deficiency
Forced expiratory volume in one second (FEV1) greater than 24% of predicted value (post bronchodilator)
Willing to discontinue AAT protein replacement 4 weeks (Group 1) and 8 weeks (Groups 2 and 3) prior to study entry, and to resume 11 weeks after rAAV1-CB-hAAT has been administered
Willing to discontinue aspirin, aspirin-containing products, and other drugs that may alter platelet function 7 days prior to study entry, and to resume 24 hours after rAAV1-CB-hAAT has been administered
Willing to use contraception throughout the study

Who cannot join

Required antibiotic therapy for a respiratory infection in the 28 days prior to rAAV1-CB-hAAT administration
Required oral or systemic corticosteroids in the 28 days prior to rAAV1-CB-hAAT administration
Liver disease
Currently receiving or has received an investigational study agent in the 30 days prior to study entry
Received gene transfer agents in the 6 months prior to study entry
Currently smokes cigarettes or uses illegal drugs

Show all 12Show fewer

History of immune response to human AAT replacement
History of platelet dysfunction
Abnormal ECG, heart disease, pulmonary edema, or embolism in the 6 months prior to study entry
Current or recent facial or chest trauma that makes it medically impossible to perform pulmonary function tests (PFTs)
Any other medical condition that the investigator deems unsuitable for study participation
Pregnant or breastfeeding

Trial locations and contacts

2 sites in 1 country.

United States2 sites

University of Florida, College of Medicine, Department of Pediatrics
Gainesville, Florida, 32610
University of Massachusetts School of Medicine
Worcester, Massachusetts, 01655

Other trials in United States

About this study

Official title: Preclinical & Phase I/II Trials of AAV-AAT Vectors: Phase I Trial of Intramuscular Injection of a Recombinant Adeno-Associated Virus Alpha 1-Antitrypsin (rAAV1-CB-hAAT) Gene Vector to AAT-Deficient Adults

Individuals with a deficiency of the alpha 1-antitrypsin (AAT) protein are at risk for developing emphysema and liver damage. Researchers have developed a way to introduce normal AAT genes into muscle cells with the expectation that the AAT protein may be produced at normal levels. This study will evaluate the safety of the experimental gene transfer procedure in individuals with AAT deficiency. The study will also determine what dose may be required to achieve normal levels of AAT.

Read the detailed description

AAT deficiency is a genetic disorder in which individuals have inadequate levels of the AAT protein. AAT protects the lungs from white blood cell enzymes that can damage air sacs within the lungs, potentially leading to emphysema. Experimental gene transfer procedures, in which normal copies of genes are inserted into cells, are being developed to treat many genetic diseases, including AAT deficiency. In this study, a modified virus, adeno-associated virus (AAV), has been genetically engineered to contain a normal copy of the AAT gene. When AAV is combined with the AAT gene, the resulting agent, Recombinant Adeno-Associated Virus Alpha 1-Antitrypsin (rAAV1-CB-hAAT) Gene Vector with a chicken beta actin promoter (CB), may be able to carry normal copies of the AAT gene into muscle cells with the expectation that additional AAT would be produced. The purpose of this study is to evaluate the safety of injecting rAAV1-CB-hAAT into individuals with AAT deficiency.

This 14-month study will enroll individuals with AAT deficiency. Participants currently using AAT protein replacement will discontinue its use for 19 weeks during the study. Participants will first attend a baseline study visit, which will include a medical history review; a physical examination; an electrocardiogram (ECG) to record heart activity; blood, urine, and semen collection; pulmonary function tests; and chest and arm scans. Participants will then attend a 5-day inpatient visit, during which they will receive a series of injections consisting of one of four different doses of rAAV1-CB-hAAT. Physical examinations will occur on all 5 inpatient days; pulmonary function testing, arm circumference measurements, and collection of blood, urine, and semen will occur on selected days of the inpatient stay. Follow-up study visits, with possible overnight stays, will occur on Days 14 and 90. On Days 30, 45, 60, 75, 180, 270, and 365, participants will have blood drawn at a local clinic. On these same days, study staff will contact participants by telephone to review their medical history and symptoms. Unused blood and semen samples will be frozen and stored for future research purposes. Participants will have yearly follow-up evaluations by either telephone or mail for a total of 5 years.

Conditions: Alpha 1-Antitrypsin Deficiency
Being tested: rAAV1-CB-hAAT
Keywords: Gene Transfer Techniques, Gene Therapy, AAV, AAT, Phase I, Intramuscular transfer
Medical subject headings: alpha 1-Antitrypsin Deficiency

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

rAAV1-CB-hAATBiological

Study groups in NCT00430768
Study group	Role	What they receive
Group 1 Low Dose	Experimental	rAAV1-CB-hAAT 6.9 x10e12 vector genomes (vg) administered in a 9.9 ml volume of study agent in nine separate 1.1 mL injections in the deltoid muscle of the "non-dominant" side under ultrasound guidance Receives: Biological: rAAV1-CB-hAAT
Group 2 Middle Dose	Experimental	rAAV1-CB-hAAT 2.2 x 10e13 vg administered in a 9.9 ml volume of study agent in nine separate 1.1 mL injections in the deltoid muscle of the "non-dominant" side under ultrasound guidance Receives: Biological: rAAV1-CB-hAAT
Group 3 High Dose	Experimental	rAAV1-CB-hAAT 6.0 x10e13 vg administered in a 9.9 ml volume of study agent in nine separate 1.1 mL injections in the deltoid muscle of the "non-dominant" side under ultrasound guidance Receives: Biological: rAAV1-CB-hAAT

What is being measured

The primary outcome is the main question the study is designed to answer.

Adverse Events Possibly, Probably or Definitely Related to Study Drug
Adverse events considered possibly, probably or definitely related to study drug/study drug procedure Criteria to evaluate severity according to Attachment 2 of the Protocol
1. Mild toxicity, usually transient, requiring no special treatment and generally not interfering with usual daily activities
2. Moderate toxicity which may be ameliorated by simple therapeutic maneuvers, and impairs usual activities
3. Severe toxicity which requires therapeutic intervention and interrupts usual activities. Hospitalization may or may not be required
4. Life-threatening toxicity which requires hospitalization
Measured: During 1 year after study agent administration

Secondary outcomes (1)

hAAT Expression in Blood Measured Using M-specific Allele ELISA
4 subjects received prior AAT augmentation therapy; 2 subjects from Group 1 having only washed out for only 28 days complicated the measurement of M-specific levels 2 subjects from group 1 and the other subject did not have an appreciable change in M-specific AAT levels. Thus reporting only Cohorts 2 and 3. After day 90 patients were able to resume AAT protein therapy and thus levels were not collected following commencement of therapy on 201 and 303. 202, Day 365 blood hemolyzed; level not determinable.
Measured: Baseline, Days 14, 30, 45, 60, 90, (180, 270, and 365 if not on protein replacement therapy)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Feb 2006Jan 2015

First posted2 Feb 2007 (estimated)
Study startFeb 2006
Primary completionJan 2015
Study completionJan 2015

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 (3)Papers the sponsor has linked to this study.
Other trials for Alpha 1-Antitrypsin DeficiencyStudies of the same condition, open and under way.
More trials run by University of Massachusetts, WorcesterThe sponsor's other registered studies.
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
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 9 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00430768
Sponsor's protocol ID: 438
Other IDs: 5R01HL069877, NIH-OBA 0404-638, NCRR-supported GCRC# 611, UF IBC RD 2630, AGTC-AAV1-001, WIRB # 20052374, BB-IND 12728, RR00032, RR00082
Acronym: AAT
Status last verified: Dec 2016
First submitted: 31 Jan 2007
Last updated: 15 Dec 2016
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
Individual data sharing: Yes: Laboratory information shared as received; copy of manuscript given to patients; at 5 year follow up Principal investigator explained results to patients

Publications

Song S, Morgan M, Ellis T, Poirier A, Chesnut K, Wang J, Brantly M, Muzyczka N, Byrne BJ, Atkinson M, Flotte TR. Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14384-8. doi: 10.1073/pnas.95.24.14384.
PubMed 9826709
Lu Y, Choi YK, Campbell-Thompson M, Li C, Tang Q, Crawford JM, Flotte TR, Song S. Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. J Gene Med. 2006 Jun;8(6):730-5. doi: 10.1002/jgm.896.
PubMed 16518879
Brantly ML, Spencer LT, Humphries M, Conlon TJ, Spencer CT, Poirier A, Garlington W, Baker D, Song S, Berns KI, Muzyczka N, Snyder RO, Byrne BJ, Flotte TR. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther. 2006 Dec;17(12):1177-86. doi: 10.1089/hum.2006.17.1177.
PubMed 17115945

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

RecruitingObservational study
Role of Genetic Factors in the Development of Lung Disease
Cystic Fibrosis, Pulmonary Fibrosis
RecruitingPhase 1/2
A Study of TSRA-196 in Adults With PiZZ Alpha-1 Antitrypsin Deficiency (AATD)
Alpha-1 Antitrypsin Deficiency (AATD)
RecruitingPhase 4
Genetic Variation in IgG in Alpha 1 Antitrypsin Deficiency
Alpha 1-Antitrypsin, COPD
Enrolling by invitationObservational study
AATD-Liver Scan Study
Alpha-1 Antitrypsin Deficiency, AATD
RecruitingPhase 3
A Non-inferiority Pharmacokinetic and Safety/Tolerability Study of Two Different Doses of Weekly SC Alpha1-PI 15% Compared With Corresponding Standard IV Alpha1-PI in Participants With Alpha1-Antitrypsin Deficiency (AATD)
Alpha 1 Antitrypsin Deficiency

All Alpha 1-Antitrypsin Deficiency trials

Study at a glance

From the registry record, last updated by the sponsor on 15 Dec 2016. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Preclinical & Phase I/II Trials of AAV-AAT Vectors: Phase I Trial of Intramuscular Injection of a Recombinant Adeno-Associated Virus Alpha 1-Antitrypsin (rAAV1-CB-hAAT) Gene Vector to AAT-Deficient Adults
ClinicalTrials.gov ID: NCT00430768
Acronym / sponsor ID: AAT / 438
Conditions: Alpha 1-Antitrypsin Deficiency
Keywords: Gene Transfer Techniques, Gene Therapy, AAV, AAT, Phase I, Intramuscular transfer
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 9 participants (actual)
Lead sponsor: University of Massachusetts, WorcesterUniversity, hospital or other
Collaborators: National Heart, Lung, and Blood Institute (NHLBI), Beacon Therapeutics, Alpha-1 Foundation, University of Florida, National Center for Research Resources (NCRR)
Study start: Feb 2006
Primary completion: Jan 2015 (actual)
Study completion: Jan 2015 (actual)
First posted: 2 Feb 2007 (estimated)
Results: Posted 15 Dec 2016

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 3

Arm	Type	Receives
Group 1 Low Dose	Experimental	Biological: rAAV1-CB-hAATrAAV1-CB-hAAT 6.9 x10e12 vector genomes (vg) administered in a 9.9 ml volume of study agent in nine separate 1.1 mL injections in the deltoid muscle of the "non-dominant" side under ultrasound guidance
Group 2 Middle Dose	Experimental	Biological: rAAV1-CB-hAATrAAV1-CB-hAAT 2.2 x 10e13 vg administered in a 9.9 ml volume of study agent in nine separate 1.1 mL injections in the deltoid muscle of the "non-dominant" side under ultrasound guidance
Group 3 High Dose	Experimental	Biological: rAAV1-CB-hAATrAAV1-CB-hAAT 6.0 x10e13 vg administered in a 9.9 ml volume of study agent in nine separate 1.1 mL injections in the deltoid muscle of the "non-dominant" side under ultrasound guidance

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

Diagnosed with AAT deficiency
Forced expiratory volume in one second (FEV1) greater than 24% of predicted value (post bronchodilator)
Willing to discontinue AAT protein replacement 4 weeks (Group 1) and 8 weeks (Groups 2 and 3) prior to study entry, and to resume 11 weeks after rAAV1-CB-hAAT has been administered
Willing to discontinue aspirin, aspirin-containing products, and other drugs that may alter platelet function 7 days prior to study entry, and to resume 24 hours after rAAV1-CB-hAAT has been administered
Willing to use contraception throughout the study

Key exclusion criteria (12 listed)

Required antibiotic therapy for a respiratory infection in the 28 days prior to rAAV1-CB-hAAT administration
Required oral or systemic corticosteroids in the 28 days prior to rAAV1-CB-hAAT administration
Liver disease
Currently receiving or has received an investigational study agent in the 30 days prior to study entry
Received gene transfer agents in the 6 months prior to study entry

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
rAAV1-CB-hAAT	Biological	Group 1 Low Dose, Group 2 Middle Dose, Group 3 High Dose

Primary outcome

Adverse Events Possibly, Probably or Definitely Related to Study Drug
Time frame: During 1 year after study agent administration
Adverse events considered possibly, probably or definitely related to study drug/study drug procedure Criteria to evaluate severity according to Attachment 2 of the Protocol 1. Mild toxicity, usually transient, requiring no special treatment and generally not interfering with usual daily activities 2. Moderate toxicity which may be ameliorated by simple therapeutic maneuvers, and impairs usual activities 3. Severe toxicity which requires therapeutic intervention and interrupts usual activities. Hospitalization may or may not be required 4. Life-threatening toxicity which requires hospitalization

1 secondary outcome

hAAT Expression in Blood Measured Using M-specific Allele ELISA
Time frame: Baseline, Days 14, 30, 45, 60, 90, (180, 270, and 365 if not on protein replacement therapy)

Results and safety

Results posted to the registry on 15 Dec 2016, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Group 1 Low Dose	3	3
Group 2 Middle Dose	3	3
Group 3 High Dose	3	3

Primary outcome: Adverse Events Possibly, Probably or Definitely Related to Study Drug

Time frame: During 1 year after study agent administration. Number. Unit: participants

Measure	Group 1 Low Dose n = 3	Group 2 Middle Dose n = 3	Group 3 High Dose n = 3
Number with one or more related AE	2	2	3
injection site erythema mild	2	0	0
Inject site hematoma mild	1	2	3
Inject site induration mild	1	0	0
Inject site pain mild	0	0	1
Inject site swelling mild	1	1	0
Injection site warmth	0	1	0

Population analysed: subjects in the group reporting the event

1 secondary outcome is reported in the full results.

Adverse events

Time frame: 1 year active study; 4 years long term follow up. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Group 1 Low Dose	1 of 3 (33.3%)	3 of 3 (100%)	Not reported
Group 2 Middle Dose	0 of 3 (0%)	2 of 3 (66.7%)	Not reported
Group 3 High Dose	0 of 3 (0%)	3 of 3 (100%)	Not reported

Limitations and caveats (from the sponsor): Study results based on small number of subjects No statistical analysis.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 15 Dec 2016.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 9826709Song S, Morgan M, Ellis T, Poirier A, Chesnut K, Wang J, Brantly M, Muzyczka N, Byrne BJ, Atkinson M, Flotte TR. Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14384-8. doi: 10.1073/pnas.95.24.14384.
Background: PubMed 16518879Lu Y, Choi YK, Campbell-Thompson M, Li C, Tang Q, Crawford JM, Flotte TR, Song S. Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. J Gene Med. 2006 Jun;8(6):730-5. doi: 10.1002/jgm.896.
Background: PubMed 17115945Brantly ML, Spencer LT, Humphries M, Conlon TJ, Spencer CT, Poirier A, Garlington W, Baker D, Song S, Berns KI, Muzyczka N, Snyder RO, Byrne BJ, Flotte TR. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther. 2006 Dec;17(12):1177-86. doi: 10.1089/hum.2006.17.1177.
Individual participant dataSharing planned: Yes. Laboratory information shared as received; copy of manuscript given to patients; at 5 year follow up Principal investigator explained results to patients

Related trials for Alpha 1-Antitrypsin Deficiency

RecruitingObservational study
Role of Genetic Factors in the Development of Lung Disease
Cystic Fibrosis, Pulmonary Fibrosis
RecruitingPhase 1/2
A Study of TSRA-196 in Adults With PiZZ Alpha-1 Antitrypsin Deficiency (AATD)
Alpha-1 Antitrypsin Deficiency (AATD)
RecruitingPhase 4
Genetic Variation in IgG in Alpha 1 Antitrypsin Deficiency
Alpha 1-Antitrypsin, COPD
Enrolling by invitationObservational study
AATD-Liver Scan Study
Alpha-1 Antitrypsin Deficiency, AATD
RecruitingPhase 3
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Alpha 1 Antitrypsin Deficiency

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.

Terence R. Flotte, MD principal investigator

UMass Medical School

Mark L Brantly, MD principal investigator

University of Florida

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing rAAV1-CB-hAAT in people with Alpha 1-Antitrypsin Deficiency, run by University of Massachusetts, Worcester 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 5 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 15 Dec 2016. 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 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.

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 15 Dec 2016). 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?

Adverse Events Possibly, Probably or Definitely Related to Study Drug (time frame: During 1 year after study agent administration). 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 NCT00430768, which also lists 3 linked publications.

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 15 Dec 2016.