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

Purpose

This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector expressing alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency. Three groups of three subjects each will receive the study drug by intramuscular injection, with progressively larger doses in the second and third groups.

Funding Sources - FDA OOPD and NIH NHLBI

Condition	Intervention	Phase
Alpha-1 Antitrypsin Deficiency	Drug: rAAV1-CB-hAAT	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Multiple-Site, Phase 2, Safety and Efficacy Trial of a Recombinant Adeno-associated Virus Vector Expressing Alpha-1 Antitrypsin (rAAV1-CB-hAAT) in Patients With Alpha-1 Antitrypsin Deficiency

Resource links provided by NLM:

Genetics Home Reference related topics: alpha-1 antitrypsin deficiency

MedlinePlus related topics: Alpha-1 Antitrypsin Deficiency

Drug Information available for: alpha 1-Antitrypsin

U.S. FDA Resources

Further study details as provided by Applied Genetic Technologies Corp:

Primary Outcome Measures:

Frequency of Grade 3 or 4 Adverse Events [ Time Frame: During 1 year after study agent administration ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Changes in Serum M-specific Alpha-1 Antitrypsin Concentration [ Time Frame: During months 6-12 after study agent adminsitration ] [ Designated as safety issue: No ]
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.
Changes in Serum Total Alpha-1 Antitrypsin Concentrations [ Time Frame: During months 6-12 after study agent adminstration ] [ Designated as safety issue: No ]
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.

Enrollment:	9
Study Start Date:	March 2010
Estimated Study Completion Date:	December 2015
Primary Completion Date:	November 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Low dose rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg	Drug: rAAV1-CB-hAAT Recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin
Experimental: Middle dose rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg	Drug: rAAV1-CB-hAAT Recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin
Experimental: High dose rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg	Drug: rAAV1-CB-hAAT Recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin

Detailed Description:

The study is a non-randomized, open-label, multi-center, sequential, three-arm, Phase 2 clinical trial evaluating the safety and efficacy of administration of a rAAV1-CB-hAAT vector administered by IM injection. Each participant will receive rAAV1-CB-hAAT on a single occasion. Three groups of three subjects each will receive rAAV1-CB-hAAT at dosage levels of 6 x 10e11 vg/kg, 1.9 x 10e12 vg/kg or 6 x 10e12 vg/kg by IM injection. Subjects in group 1 will receive a total of 10 IM injections distributed across a single muscle site, subjects in group 2 will receive a total of 32 IM injections distributed across three muscle sites, and subjects in group 3 will receive 100 IM injections distributed across 10 muscle sites. Each injection will be given in a volume of 1.35 mL, at the appropriate vector concentration to achieve the desired total vector dose, and the injection density at each administration site (nine IM injections per 4 cm2 skin surface area) will be the same as the injection density that was well tolerated in a previous Phase 1 clinical trial with rAAV1-CB-hAAT. Safety will be monitored by evaluation of adverse events, hematology and clinical chemistry parameters, histological examination of muscle biopsies, and measurement of serum antibodies to AAT. Efficacy will be measured by evaluation of serum concentrations of M-specific AAT and total AAT and serum AAT phenotype determined on isoelectric focusing gels. Additional information to be collected will include presence of the vector in blood or semen, changes in serum anti-AAV antibody titers, and changes in T cell responses to AAV and AAT.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Have a diagnosis of AAT-deficiency, as defined by a serum AAT level of less than 11 µM and a phenotype or genotype either homozygous for PI*Z or compound heterozygous consisting of PI*Z and another allele known to be associated with disease
Be at least 18 and not more than 75 years of age
Have a FEV1 >25% of predicted value (post bronchodilator)
Weigh ≤ 90 kg
Not receiving AAT augmentation therapy currently or with the past 3 months, and not planning to begin such therapy for at least 12 months after administration of rAAV1-CB-hAAT
Be willing to discontinue aspirin, aspirin-containing products, and other drugs that may alter platelet function, 7 days prior to dosing, resuming no earlier than 24 hours after the dose has been administered
Have acceptable laboratory parameters
For females of childbearing potential:
- A negative pregnancy test (urine or serum) at screening and at baseline (within 2 days before administration of study agent)
- Agreement to consistently use barrier contraception (condoms, diaphragm or cervical cap with spermicide) or another form of contraception (e.g. intrauterine device or hormonal contraception) from the screening visit until 12 months after administration of rAAV1-CB-hAAT, for sexual activity that could lead to pregnancy
For males of reproductive potential, agreement to consistently use barrier contraception (condoms with spermicide) for 12 months after administration of rAAV1-CB-hAAT, for sexual activity that could lead to pregnancy,
Provide signed informed consent before screening

Exclusion Criteria:

Prior receipt of any AAV gene therapy product
Use of anticoagulants or anti-platelet agents within 7 days prior to study agent administration
History of immune response to human AAT augmentation therapy as indicated by clinical history of an adverse immune response to infusion and/or decreased therapeutic effect in combination with documentation of serum anti-AAT antibodies
Use of acute oral or intravenous antibiotic therapy for a respiratory infection within 28 days prior to study agent administration (long-term maintenance or chronic suppressive oral antibiotics, and antibiotics for a non-respiratory indication, are allowed)
Use of oral or systemic corticosteroids within 28 days prior to study agent administration
Use of any investigational agent, or any immunosuppressive drug(s), within 3 months prior to enrollment
For females of childbearing potential, a positive pregnancy test at screening or baseline (within 2 days before rAAV1-CB-hAAT administration)
Females who are breast feeding
Have a significant abnormal EKG finding at screening and/or cardiac disease (e.g. recent myocardial infarction or CHF) within past 6 months
Have had pulmonary edema or a pulmonary embolism within the past 6 months
Have a history of immunodeficiency or other medical condition which leads the investigator to believe that the participant cannot comply with the protocol requirements or that may place the participant at an unacceptable risk for participation

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01054339

Locations

United States, Colorado
National Jewish Health
Denver, Colorado, United States, 80206
United States, Massachusetts
University of Massachusetts Medical Center
Worcester, Massachusetts, United States, 01655
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
Ireland
Beaumont Hospital
Dublin, Ireland, 2

Sponsors and Collaborators

Applied Genetic Technologies Corp

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator:	Terence R. Flotte, MD	University of Massachusetts Medical School, Worcester, MA
Principal Investigator:	Bruce C. Trapnell, MD	Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Principal Investigator:	Robert A. Sandhaus, MD, PhD	National Jewish Health, Denver, CO
Principal Investigator:	Noel G. McElvaney, MB, BCh, BAO	Beaumont Hospital, Dublin, Ireland

More Information

Additional Information:

Applied Genetic Technologies Corporation This link exits the ClinicalTrials.gov site

Publications:

Flotte TR, Trapnell BC, Humphries M, Carey B, Calcedo R, Rouhani F, Campbell-Thompson M, Yachnis AT, Sandhaus RA, McElvaney NG, Mueller C, Messina LM, Wilson JM, Brantly M, Knop DR, Ye GJ, Chulay JD. Phase 2 Clinical Trial of a Recombinant Adeno-associated Virus Vector Expressing Alpha 1 Antitrypsin: Interim Results. Hum Gene Ther. 2011 May 24; [Epub ahead of print]

Brantly ML, Chulay JD, Wang L, Mueller C, Humphries M, Spencer LT, Rouhani F, Conlon TJ, Calcedo R, Betts MR, Spencer C, Byrne BJ, Wilson JM, Flotte TR. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16363-8. Epub 2009 Aug 12. Erratum in: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17606.

Responsible Party:	Applied Genetic Technologies Corp
ClinicalTrials.gov Identifier:	NCT01054339 History of Changes
Other Study ID Numbers:	AGTC-AAT-002, 2009‐014286‐20, R01HL069877, R01 FD003896
Study First Received:	January 21, 2010
Results First Received:	August 14, 2012
Last Updated:	March 6, 2013
Health Authority:	United States: Food and Drug Administration Ireland: Irish Medicines Board

Keywords provided by Applied Genetic Technologies Corp:

Alpha-1 antitrypsin deficiency
Adeno-associated virus vector
AAV
Gene therapy
Human gene transfer

Additional relevant MeSH terms:

Alpha 1-Antitrypsin Deficiency
Alpha 1-Antitrypsin
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema

Pathologic Processes
Protein C Inhibitor
Trypsin Inhibitors
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on June 17, 2013