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Safety & Efficacy Study of rAAV1-CB-hAAT for Alpha-1 Antitrypsin Deficiency

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ClinicalTrials.gov Identifier: NCT01054339
Recruitment Status : Completed
First Posted : January 22, 2010
Results First Posted : September 14, 2012
Last Update Posted : August 12, 2016
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Applied Genetic Technologies Corp

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 Drug: rAAV1-CB-hAAT
Enrollment 9

Recruitment Details Subjects were recruited from two clinical trial sites (University of Massachusetts Medical Center and Cincinatti Children's Hospital Medical Center).
Pre-assignment Details  
Arm/Group Title Low Dose Middle Dose High Dose
Hide Arm/Group Description rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg administered as 10 IM injections in one arm rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg administered as 10 IM injections in one arm and 11 IM injections in each leg (total of 32 injections) rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg administered as 10 IM injections in each arm and 10 IM injections in each of four sites in each leg (total of 100 injections)
Period Title: Overall Study
Started 3 3 3
Completed 3 3 3
Not Completed 0 0 0
Arm/Group Title Low Dose Middle Dose High Dose Total
Hide Arm/Group Description rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg administered as 10 IM injections in one arm rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg administered as 10 IM injections in one arm and 11 IM injections in each leg (total of 32 injections) rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg administered as 10 IM injections in each arm and 10 IM injections in each of four sites in each leg (total of 100 injections) Total of all reporting groups
Overall Number of Baseline Participants 3 3 3 9
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 9 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
2
  66.7%
3
 100.0%
3
 100.0%
8
  88.9%
>=65 years
1
  33.3%
0
   0.0%
0
   0.0%
1
  11.1%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3 participants 3 participants 3 participants 9 participants
50.3  (26.4) 48.7  (9.3) 54.3  (3.5) 51.1  (14.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 9 participants
Female
3
 100.0%
2
  66.7%
2
  66.7%
7
  77.8%
Male
0
   0.0%
1
  33.3%
1
  33.3%
2
  22.2%
Alpha-1 antitrypsin phenotype   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 9 participants
ZZ 2 3 3 8
SZ 1 0 0 1
[1]
Measure Description: Alpha-1 antitrypsin phenotype determined by isoelectric focusing gel electrophoresis
Serum total alpha-1 antitrypsin concentration   [1] 
Mean (Standard Deviation)
Unit of measure:  microMolar
Number Analyzed 3 participants 3 participants 3 participants 9 participants
6.56  (2.00) 3.54  (0.12) 3.45  (0.19) 4.31  (1.88)
[1]
Measure Description: Average of values at screening and baseline visits. Includes 1 phenotype SZ subject in low dose group.
1.Primary Outcome
Title Frequency of Grade 3 or 4 Adverse Events
Hide Description [Not Specified]
Time Frame During 1 year after study agent administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis based on all subjects enrolled in study.
Arm/Group Title Low Dose Middle Dose High Dose
Hide Arm/Group Description:
rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg administered as 10 IM injections in one arm
rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg administered as 10 IM injections in one arm and 11 IM injections in each leg (total of 32 injections)
rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg administered as 10 IM injections in each arm and 10 IM injections in each of four sites in each leg (total of 100 injections)
Overall Number of Participants Analyzed 3 3 3
Measure Type: Number
Unit of Measure: participants
0 0 1
2.Secondary Outcome
Title Changes in Serum M-specific Alpha-1 Antitrypsin Concentration
Hide Description The change in serum M-specific alpha-1 antitrypsin concentration was calculated as the difference between the mean values at the screening and baseline visits and the mean values at the 6, 9 and 12 month visits. The standard error of the difference was calculated as sqrt(s1^2/n1 + s2^2/n2, where s1 is the standard deviation of the baseline mean, s2 is the standard deviation of the month 6-12 mean, n1 is the number of baseline values and n2 is the number of month 6-12 values.
Time Frame During months 6-12 after study agent adminsitration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
One subject in low dose group had AAT phenotype SZ, which made measurement of M-specific serum alpha-1 antitrypsin concentration invalid.
Arm/Group Title Low Dose Middle Dose High Dose
Hide Arm/Group Description:
rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg administered as 10 IM injections in one arm
rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg administered as 10 IM injections in one arm and 11 IM injections in each leg (total of 32 injections)
rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg administered as 10 IM injections in each arm and 10 IM injections in each of four sites in each leg (total of 100 injections)
Overall Number of Participants Analyzed 2 3 3
Mean (Standard Error)
Unit of Measure: nanomolar
31.5  (7.56) 71.8  (27.82) 239.2  (33.55)
3.Secondary Outcome
Title Changes in Serum Total Alpha-1 Antitrypsin Concentrations
Hide Description The change in serum total alpha-1 antitrypsin concentration was calculated as the difference between the mean values at the screening and baseline visits and the mean values at the 6, 9 and 12 month visits. The standard error of the difference was calculated as sqrt(s1^2/n1 + s2^2/n2, where s1 is the standard deviation of the baseline mean, s2 is the standard deviation of the month 6-12 mean, n1 is the number of baseline values and n2 is the number of month 6-12 values.
Time Frame During months 6-12 after study agent adminstration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis bsed on all subjects enrolled in study.
Arm/Group Title Low Dose Middle Dose High Dose
Hide Arm/Group Description:
rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg administered as 10 IM injections in one arm
rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg administered as 10 IM injections in one arm and 11 IM injections in each leg (total of 32 injections)
rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg administered as 10 IM injections in each arm and 10 IM injections in each of four sites in each leg (total of 100 injections)
Overall Number of Participants Analyzed 3 3 3
Mean (Standard Error)
Unit of Measure: micromolar
0.33  (1.14) 0.16  (0.10) 0.19  (0.16)
Time Frame 1 year
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Low Dose Middle Dose High Dose
Hide Arm/Group Description rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg administered as 10 IM injections in one arm rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg administered as 10 IM injections in one arm and 11 IM injections in each leg (total of 32 injections) rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg administered as 10 IM injections in each arm and 10 IM injections in each of four sites in each leg (total of 100 injections)
All-Cause Mortality
Low Dose Middle Dose High Dose
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Low Dose Middle Dose High Dose
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/3 (0.00%)      0/3 (0.00%)      1/3 (33.33%)    
Gastrointestinal disorders       
diverticulitis * 1 [1]  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (11.1)
[1]
A 51 y/o man received high dose of study drug on 5 Oct 2010, diverticulitis diagnosed on 14 Mar 2011, admitted to hospital, treated with antibiotics and symptoms resolved. The adverse event was 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%
Low Dose Middle Dose High Dose
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/3 (100.00%)      3/3 (100.00%)      3/3 (100.00%)    
General disorders       
Injection site discomfort * 1 [1]  2/3 (66.67%)  2 2/3 (66.67%)  2 2/3 (66.67%)  2
Influenza-like illness * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Injection site atrophy * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0
Injection site erythema * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0
Injection site pain * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Malaise * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Post-procedural discomfort * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1
Infections and infestations       
Ear infection * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0
Upper respiratory infection * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 2/3 (66.67%)  2
Investigations       
Blood creatine phosphokinase increased  1 [2]  0/3 (0.00%)  0 1/3 (33.33%)  1 3/3 (100.00%)  3
Musculoskeletal and connective tissue disorders       
Muscle spasms * 1  0/3 (0.00%)  0 2/3 (66.67%)  2 0/3 (0.00%)  0
Muscle strain * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0
Muscle twitching * 1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1
Nervous system disorders       
Headache * 1  0/3 (0.00%)  0 2/3 (66.67%)  2 0/3 (0.00%)  0
Vascular disorders       
Ecchymosis * 1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0
Phlebitis superficial * 1  0/3 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (11.1)
[1]
Because of small sample size, adverse events are listed only for (1) those considered possibly, probably or definitely related to study agent or study agent administration procedures, or (2) that occurred in more than 1 subject in the study.
[2]
One other subject in the low dose group and one other subject in the mid dose group had blood CPK increase that was not considered an adverse event.
Study results based on small number of subjects.
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: Jeffrey D. Chulay, MD
Organization: Applied Genetic Technologies Corp.
Phone: 386-462-2204 ext 205
Responsible Party: Applied Genetic Technologies Corp
ClinicalTrials.gov Identifier: NCT01054339     History of Changes
Other Study ID Numbers: AGTC-AAT-002
2009‐014286‐20 ( Registry Identifier: EudraCT )
R01HL069877 ( U.S. NIH Grant/Contract )
R01FD003896 ( U.S. FDA Grant/Contract )
First Submitted: January 21, 2010
First Posted: January 22, 2010
Results First Submitted: August 14, 2012
Results First Posted: September 14, 2012
Last Update Posted: August 12, 2016