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

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ClinicalTrials.gov Identifier: NCT00430768
Recruitment Status : Completed
First Posted : February 2, 2007
Results First Posted : December 15, 2016
Last Update Posted : December 15, 2016
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Applied Genetic Technologies Corp
Alpha-1 Foundation
University of Florida
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
Terence Flotte, University of Massachusetts, Worcester

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Alpha 1-Antitrypsin Deficiency
Intervention Biological: rAAV1-CB-hAAT
Enrollment 9
Recruitment Details 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.
Pre-assignment Details Subjects on alpha-1 antitrypsin (AAT) protein replacement product prior to study, discontinued treatment 4 weeks (Group 1) and 8 weeks (Groups 2 and 3) prior to study agent administration and were able to resume treatment 11 weeks after study agent had been administered. The group was determined by when the subject joined the study.
Arm/Group Title Group 1 Low Dose Group 2 Middle Dose Group 3 High Dose
Hide Arm/Group Description

6.9 x10e12 vector genomes (vg)

Group 1 receives rAAV1-CB-hAAT 6.9 x10e12 vg.

2.1 x 10e13 vector genomes; 2.2 x 10e13 vector genomes

Group 2, 1 subject received rAAV1-CB-hAAT 2.1 x10e13 vg; 202 and 203 received rAAV1-CB-hAAT 2.2 x10e13 vg

rAAV1-CB-hAAT 6.0 x10e13 vg

Group 3 receives rAAV1-CB-hAAT 6.0 x10e13 vg

Period Title: Overall Study
Started 3 3 3
Completed 3 3 3
Not Completed 0 0 0
Arm/Group Title Group 1 Low Dose Group 2 Middle Dose Group 3 High Dose Total
Hide Arm/Group Description

6.9 x10e12 vector genomes

Group 1 receives rAAV1-CB-hAAT 6.9 x1012 vg (vector genomes), e

2.1 x 10e13 vector genomes

Group 2 receives rAAV1-CB-hAAT 2.1 x1013 vg

rAAV1-CB-hAAT 6.0 x10e13 vg

Group 2 receives rAAV1-CB-hAAT 2.1 x1013 vg

Total of all reporting groups
Overall Number of Baseline Participants 3 3 3 9
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 3 participants 3 participants 3 participants 9 participants
69
(66 to 73)
54
(38 to 59)
47
(35 to 61)
54
(35 to 73)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 9 participants
Female
2
  66.7%
0
   0.0%
2
  66.7%
4
  44.4%
Male
1
  33.3%
3
 100.0%
1
  33.3%
5
  55.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 9 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
3
 100.0%
3
 100.0%
3
 100.0%
9
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 9 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
White
3
 100.0%
3
 100.0%
3
 100.0%
9
 100.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 3 participants 3 participants 3 participants 9 participants
3 3 3 9
FEV1 (% predicted)   [1] 
Median (Full Range)
Unit of measure:  Percent predicted
Number Analyzed 3 participants 3 participants 3 participants 9 participants
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)
[1]
Measure Description: forced expiratory volume in 1 second; percent predicted for race, height, and weight
Weight (kg)  
Median (Full Range)
Unit of measure:  Kilograms
Number Analyzed 3 participants 3 participants 3 participants 9 participants
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  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 9 participants
Yes 2 1 1 4
No 1 2 2 5
1.Primary Outcome
Title Adverse Events Possibly, Probably or Definitely Related to Study Drug
Hide Description

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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
subjects in the group reporting the event
Arm/Group Title Group 1 Low Dose Group 2 Middle Dose Group 3 High Dose
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 3 3 3
Measure Type: Number
Unit of Measure: participants
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
2.Secondary Outcome
Title hAAT Expression in Blood Measured Using M-specific Allele ELISA
Hide Description 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
AAT Levels of each subject at various time points Baseline and Days following administration. 202 Day 365 blood hemolyzed; not determinable, 201 and 303 went back on AAT protein augmentation therapy after day 90, unable to collect M-specific levels on day 180, 270 and 303.
Arm/Group Title 201 (Medium Dose) 202 (Medium Dose) 203 (Medium Dose) 301 (High Dose) 302 (High Dose) 303 (High Dose)
Hide Arm/Group Description:
Subject 201 M-specific AAT Level
Subject 202 M-specific AAT Level
Subject 203 M-specific AAT Level
Subject 301M-specific AAT Level
Subject 302 M-specific AAT Level
Subject 303 M-specific AAT Level
Overall Number of Participants Analyzed 1 1 1 1 1 1
Measure Type: Number
Unit of Measure: nM
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 [1]  9.8 10.8 41.7 26.4 NA [1] 
Day 270 Level NA [1]  8.0 7.0 47.9 33.5 NA [1] 
Day 365 Level NA [1]  NA [2]  24.2 50.9 33.4 NA [1] 
[1]
resumed AAT protein therapy
[2]
blood hemolyzed
Time Frame 1 year active study; 4 years long term follow up
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Group 1 Low Dose Group 2 Middle Dose Group 3 High Dose
Hide Arm/Group Description

6.9 x10e12 vector genomes

e. Group 1 receives rAAV1-CB-hAAT 6.9 x10e12 vg (vector genomes)

2.2 x 10e13 vector genomes

Group 2 receives rAAV1-CB-hAAT 2.1 x10e13 vg

rAAV1-CB-hAAT 6.0 x10e13 vg

Group 3 receives rAAV1-CB-hAAT 6.0 x10e13 vg

All-Cause Mortality
Group 1 Low Dose Group 2 Middle Dose Group 3 High Dose
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Group 1 Low Dose Group 2 Middle Dose Group 3 High Dose
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/3 (33.33%)      0/3 (0.00%)      0/3 (0.00%)    
Gastrointestinal disorders       
Pharyngoesophageal diverticulum repair with complications * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Reproductive system and breast disorders       
E. coli Epididymitis * 1 [2]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, vocabulary,MedDRA
[1]
Subject received study agent 14Mar2006.Surgical repair 20Jan2010 for pharyngoesophageal diverticulum.Hospitalized 27Jan2010 with GI anastomotic leak following surgery, treated with feeding tube, resolved, considered not related to study agent.
[2]
69 y/o man low dose of study drug 14MAR2006. 6 Apr 2006 diagnosed with E coli epididymitis confirmed by testicular ultrasound and urine culture. Event considered not related to study agent.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Group 1 Low Dose Group 2 Middle Dose Group 3 High Dose
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/3 (100.00%)      2/3 (66.67%)      3/3 (100.00%)    
Cardiac disorders       
Palpitations * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Eye disorders       
Lacrimation increased * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Gastrointestinal disorders       
Dry mouth * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Pharyngoesophageal diverticulum * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
General disorders       
Injection site erythema  1  2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0
Injection site hematoma  1  1/3 (33.33%)  1 2/3 (66.67%)  2 3/3 (100.00%)  3
Injection site induration  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Injection site pain  1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Injection site swelling  1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0
Injection site warmth  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0
Malaise * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Pyrexia * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Infections and infestations       
Escherichia urinary tract infection * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Herpes zoster * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Nasopharyngitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Oral candidiasis * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Pharyngitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Sinusitis * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Tooth infection * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Upper respiratory tract infection * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0
Bronchitis * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Tooth infection * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Injury, poisoning and procedural complications       
Fall * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Limb injury * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 2/3 (66.67%)  2
Skin injury * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Gastrointestinal anastomotic leak * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Road Traffic Accident * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Wrist Fracture * 1 [1]  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0
Investigations       
Alanine aminotransferase increased  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Alkaline phosphatase increased  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Aspartate aminotransferase increased  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Blood cholesterol increased * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Gamma-glutamyl transferase increased  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Metabolism and nutrition disorders       
Anorexia * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Muscular weakness * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Myalgia * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1
Nervous system disorders       
headache * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1
Psychiatric disorders       
depression * 1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Renal and urinary disorders       
Hematuria * 1 [1]  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0
Reproductive system and breast disorders       
Prostate Cancer * 1 [1]  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Dry throat * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Nasal congestion * 1  0/3 (0.00%)  0 2/3 (66.67%)  2 1/3 (33.33%) 
Nasal mucosal disorder * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Rhinorrhea * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Sinus Congestion * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Sinus headache * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Throat Irritation * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Wheezing * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0
Chest Pain * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Cough * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Dyspnea * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Skin and subcutaneous tissue disorders       
Subcutaneous abscess * 1 [1]  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, vocabulary,MedDRA
[1]
Long Term Follow up
Study results based on small number of subjects No statistical analysis.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Dr. Terry Flotte
Organization: UMASS Medical School
Phone: (508) 856-2107
Responsible Party: Terence Flotte, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier: NCT00430768     History of Changes
Other Study ID Numbers: 438
5R01HL069877 ( U.S. NIH Grant/Contract )
NIH-OBA 0404-638 ( Registry Identifier: Gene Therapy Protocol Number )
NCRR-supported GCRC# 611 ( Other Identifier: University of Florida )
UF IBC RD 2630 ( Other Identifier: University of Florida )
AGTC-AAV1-001 ( Other Identifier: Applied Genetics Technologies C )
WIRB # 20052374 ( Other Identifier: Western Institutional Review B )
BB-IND 12728 ( Other Identifier: FDA )
RR00032, RR00082 ( Other Grant/Funding Number: NCRR )
First Submitted: January 31, 2007
First Posted: February 2, 2007
Results First Submitted: September 21, 2016
Results First Posted: December 15, 2016
Last Update Posted: December 15, 2016