Alpha 1-Antitrypsin Deficiency
Conditions
Keywords
Gene Transfer Techniques, Gene Therapy, AAV, AAT, Phase I, Intramuscular transfer
Brief 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.
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.
Interventions
BIOLOGICALrAAV1-CB-hAAT
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Beacon Therapeutics
Alpha-1 Foundation
University of Florida
National Center for Research Resources (NCRR)
University of Massachusetts, Worcester
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events Possibly, Probably or Definitely Related to Study Drug | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| hAAT Expression in Blood Measured Using M-specific Allele ELISA | Baseline, Days 14, 30, 45, 60, 90, (180, 270, and 365 if not on protein replacement therapy) | 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. |
Countries
United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Low Dose 6.9 x10e12 vector genomes
Group 1 receives rAAV1-CB-hAAT 6.9 x1012 vg (vector genomes), e | 3 |
| Group 2 Middle Dose 2.1 x 10e13 vector genomes
Group 2 receives rAAV1-CB-hAAT 2.1 x1013 vg | 3 |
| Group 3 High Dose rAAV1-CB-hAAT 6.0 x10e13 vg
Group 2 receives rAAV1-CB-hAAT 2.1 x1013 vg | 3 |
| Total | 9 |
Baseline characteristics
| Characteristic | Total | Group 1 Low Dose | Group 2 Middle Dose | Group 3 High Dose |
|---|---|---|---|---|
| Age, Customized | 54 years | 69 years | 54 years | 47 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 3 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| FEV1 (% predicted) | 58.0 percent predicted | 86.7 percent predicted | 50.8 percent predicted | 58.0 percent predicted |
| Gender Female | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
| Gender Male | 5 Participants | 1 Participants | 3 Participants | 1 Participants |
| Prior AAT Protein Augmentation Therapy No | 5 participants | 1 participants | 2 participants | 2 participants |
| Prior AAT Protein Augmentation Therapy Yes | 4 participants | 2 participants | 1 participants | 1 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 3 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 9 participants | 3 participants | 3 participants | 3 participants |
| Weight (kg) | 72.6 kilograms | 66.5 kilograms | 83.0 kilograms | 72.6 kilograms |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 2 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
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
Population: subjects in the group reporting the event
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 Low Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | injection site erythema mild | 2 participants |
| Group 1 Low Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site pain mild | 0 participants |
| Group 1 Low Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site induration mild | 1 participants |
| Group 1 Low Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Number with one or more related AE | 2 participants |
| Group 1 Low Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Injection site warmth | 0 participants |
| Group 1 Low Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site swelling mild | 1 participants |
| Group 1 Low Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site hematoma mild | 1 participants |
| Group 2 Middle Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site induration mild | 0 participants |
| Group 2 Middle Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Number with one or more related AE | 2 participants |
| Group 2 Middle Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | injection site erythema mild | 0 participants |
| Group 2 Middle Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site hematoma mild | 2 participants |
| Group 2 Middle Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site pain mild | 0 participants |
| Group 2 Middle Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site swelling mild | 1 participants |
| Group 2 Middle Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Injection site warmth | 1 participants |
| Group 3 High Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site pain mild | 1 participants |
| Group 3 High Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | injection site erythema mild | 0 participants |
| Group 3 High Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Injection site warmth | 0 participants |
| Group 3 High Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site swelling mild | 0 participants |
| Group 3 High Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site induration mild | 0 participants |
| Group 3 High Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Inject site hematoma mild | 3 participants |
| Group 3 High Dose | Adverse Events Possibly, Probably or Definitely Related to Study Drug | Number with one or more related AE | 3 participants |
Secondary
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)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 365 Level | NA nM |
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Baseline Level | 33 nM |
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 30 Level | 7.5 nM |
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 14 Level | 7.5 nM |
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 45 Level | 6.2 nM |
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 75 Level | 14.6 nM |
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 90 Level | 26.8 nM |
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 180 Level | NA nM |
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 60 Level | 15.1 nM |
| Group 1 Low Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 270 Level | NA nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Baseline Level | 10.8 nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 75 Level | 14.7 nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 90 Level | 12.6 nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 14 Level | 12.7 nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 30 Level | 17.8 nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 270 Level | 8.0 nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 45 Level | 16.7 nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 60 Level | 16.8 nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 365 Level | NA nM |
| Group 2 Middle Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 180 Level | 9.8 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 45 Level | 14.5 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 365 Level | 24.2 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Baseline Level | 11.2 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 180 Level | 10.8 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 14 Level | 12.0 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 90 Level | 14.6 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 270 Level | 7.0 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 75 Level | 12.9 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 30 Level | 14.7 nM |
| Group 3 High Dose | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 60 Level | 20.7 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 270 Level | 47.9 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Baseline Level | 9.6 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 14 Level | 13.2 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 30 Level | 24.7 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 45 Level | 22.6 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 60 Level | 20.8 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 75 Level | 21.8 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 90 Level | 42.6 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 180 Level | 41.7 nM |
| 301 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 365 Level | 50.9 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 90 Level | 6.7 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 30 Level | 16.6 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 365 Level | 33.4 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 270 Level | 33.5 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 180 Level | 26.4 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 14 Level | 10.3 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 60 Level | 10.5 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 45 Level | 18.5 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 75 Level | 14.3 nM |
| 302 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Baseline Level | 7.1 nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 60 Level | 37.7 nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 90 Level | 48.5 nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 365 Level | NA nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 45 Level | 41.5 nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 180 Level | NA nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 30 Level | 10.5 nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 14 Level | 7.8 nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 270 Level | NA nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Baseline Level | 18.3 nM |
| 303 (High Dose) | hAAT Expression in Blood Measured Using M-specific Allele ELISA | Day 75 Level | 45.9 nM |