CompletedNCT00430768AATUpdated Dec 15, 2016Results posted

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

A Phase 1 interventional study of rAAV1-CB-hAAT in Alpha 1-Antitrypsin Deficiency, sponsored by University of Massachusetts, Worcester. Completed at 2 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2016-12-15.

Sponsored by University of Massachusetts, Worcester · Phase 1, Interventional, and Treatment

Phase: Phase 1
Study type: Interventional
Enrollment: 9
Allocation: Non-randomized
Ages: 18 Years and older
Sex: All

Study summary

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 studied

Alpha 1-Antitrypsin Deficiency

Browse trials for

Alpha 1-Antitrypsin Deficiency 94

Keywords

Gene Transfer Techniques
Gene Therapy
AAV
AAT
Phase I
Intramuscular transfer

In context

Alpha 1-Antitrypsin Deficiency

94 studies on the registry are indexed under Alpha 1-Antitrypsin Deficiency; 5 are open to participants now.

This study's enrollment of 9 is below the median of 27 across 58 interventional studies indexed under Alpha 1-Antitrypsin Deficiency.

Browse Alpha 1-Antitrypsin Deficiency studies →

Lead sponsor

University of Massachusetts, Worcester is the lead sponsor of 288 studies on the registry; 54 are open to participants now.

Of its 25 completed or terminated interventional studies of FDA-regulated products, 18 (72%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

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

Exclusion criteria

Exclusion Criteria:

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
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

Study design

Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 9 participants (actual)

Study arms

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

Interventions

BiologicalrAAV1-CB-hAAT

What researchers measure

Primary outcomes

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
Time frame: During 1 year after study agent administration

Secondary outcomes

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.
Time frame: Baseline, Days 14, 30, 45, 60, 90, (180, 270, and 365 if not on protein replacement therapy)

Results

Posted Dec 15, 2016

Limitations and caveats

Study results based on small number of subjects No statistical analysis.

Participant flow

Subjects were recruited to the University of Florida, Clinical Research Center for the active study; long term follow up was completed at the University of Massachusetts, Medical School.

Participant flow — Overall Study
Milestone	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose
Started	3	3	3
Completed	3	3	3
Not completed	0	0	0

Outcome measures

PrimaryAdverse 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

Time frame:: During 1 year after study agent administration
Reported as:: Number · participants

Adverse Events Possibly, Probably or Definitely Related to Study Drug
participants	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose
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

SecondaryhAAT 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.

Time frame:: Baseline, Days 14, 30, 45, 60, 90, (180, 270, and 365 if not on protein replacement therapy)
Reported as:: Number · nM

hAAT Expression in Blood Measured Using M-specific Allele ELISA
nM	201 (Medium Dose)	202 (Medium Dose)	203 (Medium Dose)	301 (High Dose)	302 (High Dose)	303 (High Dose)
Baseline Level	33	10.8	11.2	9.6	7.1	18.3
Day 14 Level	7.5	12.7	12.0	13.2	10.3	7.8
Day 30 Level	7.5	17.8	14.7	24.7	16.6	10.5
Day 45 Level	6.2	16.7	14.5	22.6	18.5	41.5
Day 60 Level	15.1	16.8	20.7	20.8	10.5	37.7
Day 75 Level	14.6	14.7	12.9	21.8	14.3	45.9
Day 90 Level	26.8	12.6	14.6	42.6	6.7	48.5
Day 180 Level	NA	9.8	10.8	41.7	26.4	NA
Day 270 Level	NA	8.0	7.0	47.9	33.5	NA
Day 365 Level	NA	NA	24.2	50.9	33.4	NA

Adverse events

Collected over 1 year active study; 4 years long term follow up. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Group 1 Low Dose	—	1/3 (33.3%)	3/3 (100%)
Group 2 Middle Dose	—	0/3 (0%)	2/3 (66.7%)
Group 3 High Dose	—	0/3 (0%)	3/3 (100%)

Most frequent serious events

Most frequent serious events
Event	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose
E. coli EpididymitisReproductive system and breast disorders	1/3	0/3	0/3
Pharyngoesophageal diverticulum repair with complicationsGastrointestinal disorders	1/3	0/3	0/3

Most frequent other events

Showing 10 of 53

Most frequent other events
Event	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose
Injection site hematomaGeneral disorders	1/3	2/3	3/3
Injection site erythemaGeneral disorders	2/3	0/3	0/3
Limb injuryInjury, poisoning and procedural complications	0/3	0/3	2/3
Nasal congestionRespiratory, thoracic and mediastinal disorders	0/3	2/3	1/3
Lacrimation increasedEye disorders	0/3	0/3	1/3
Dry mouthGastrointestinal disorders	0/3	0/3	1/3
Injection site indurationGeneral disorders	1/3	0/3	0/3
Injection site painGeneral disorders	0/3	0/3	1/3
Injection site swellingGeneral disorders	1/3	1/3	0/3
Injection site warmthGeneral disorders	0/3	1/3	0/3

Baseline characteristics

Age, Customized
Age, Customized(years)	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose	Total
Median	69 (66 to 73)	54 (38 to 59)	47 (35 to 61)	54 (35 to 73)

Gender
Gender(Participants)	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose	Total
Female	2	0	2	4
Male	1	3	1	5

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose	Total
Hispanic or Latino	0	0	0	0
Not Hispanic or Latino	3	3	3	9
Unknown or Not Reported	0	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose	Total
American Indian or Alaska Native	0	0	0	0
Asian	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	0	0	0
White	3	3	3	9
More than one race	0	0	0	0
Unknown or Not Reported	0	0	0	0

Region of Enrollment
Region of Enrollment(participants)	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose	Total
United States	3	3	3	9

FEV1 (% predicted)
FEV1 (% predicted)(percent predicted)	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose	Total
Median	86.7 (53.6 to 92.1)	50.8 (40.5 to 93.0)	58.0 (54.9 to 97.6)	58.0 (40.5 to 97.6)

Weight (kg)
Weight (kg)(kilograms)	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose	Total
Median	66.5 (54.6 to 73.7)	83.0 (72.7 to 89.0)	72.6 (69.3 to 134.6)	72.6 (54.6 to 134.6)

Prior AAT Protein Augmentation Therapy
Prior AAT Protein Augmentation Therapy(participants)	Group 1 Low Dose	Group 2 Middle Dose	Group 3 High Dose	Total
Yes	2	1	1	4
No	1	2	2	5

Study locations

2 sites

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

References and documents

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 ↗

Individual participant data

Plan to share: Yes — Laboratory information shared as received; copy of manuscript given to patients; at 5 year follow up Principal investigator explained results to patients

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Dec 15, 2016, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT00430768
Lead sponsor: University of Massachusetts, Worcester
Collaborators: National Heart, Lung, and Blood Institute (NHLBI), Beacon Therapeutics, Alpha-1 Foundation, University of Florida, National Center for Research Resources (NCRR)
Responsible party: Terence Flotte (Study Principle Investigator, University of Massachusetts, Worcester) — Principal investigator
First posted: Feb 2, 2007
Start date: Feb 2006
Primary completion: Jan 2015
Completion: Jan 2015
Results posted: Dec 15, 2016
Last update: Dec 15, 2016

Study contacts

Terence R. Flotte, MD

principal investigator · UMass Medical School

Mark L Brantly, MD

principal investigator · University of Florida

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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