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

NCT01054339 | Completed Phase 2 Results DMC

• 4 other identifiers: AGTC-AAT-0022009-014286-20R01HL069877R01FD003896
• Study Type: interventional
• Target: 9
• Locations: 2 countries
• Sites: 4

Brief Summary

Assessment of the safety and efficacy of intramuscular (IM) administration of a recombinant adenoassociated virus (rAAV) alpha-1 antitrypsin (AAT) vector (rAAV1-CB-hAAT) in AAT-deficient adults at three dosage levels \[6.0 × 10e11, 1.9 × 10e12 and 6.0 × 10e12 vector genome particles (vg) per kg body weight\]. Funding Sources - The FDA Office of Orphan Products Development and NIH National Heart, Lung, and Blood Institute

Conditions

Alpha-1 Antitrypsin Deficiency

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Frequency of Grade 3 or 4 Adverse Events

  During 1 year after study agent administration

Secondary Outcomes (2)

• Changes in Serum M-specific Alpha-1 Antitrypsin Concentration

  During months 6-12 after study agent adminsitration

• Changes in Serum Total Alpha-1 Antitrypsin Concentrations

  During months 6-12 after study agent adminstration

Study Arms (3)

Low dose

EXPERIMENTAL

rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg

Drug: rAAV1-CB-hAAT

Middle dose

EXPERIMENTAL

rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg

Drug: rAAV1-CB-hAAT

High dose

EXPERIMENTAL

rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg

Drug: rAAV1-CB-hAAT

Interventions

rAAV1-CB-hAAT DRUG

Recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin

High dose; Low dose; Middle dose

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 forced expiratory volume at one second (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:
• Hemoglobin ≥ 11.2 g/dL for females, ≥ 12.8 g/dL for males,
• White blood cell count 3,300 - 12,000 cells/mm3,
• Platelet count 125,000 - 550,000/mm3,
• Serum creatine kinase (CK) ≤ 3 times upper normal range for study laboratory,
• Alanine aminotransferase (ALT) ≤ 2 times upper normal range for study laboratory,
• Serum bilirubin ≤ 1.5 times upper normal range for study laboratory,
• Serum creatinine within normal range for study laboratory,
• Prothrombin time (PT) ≤ 14.5 seconds and partial thromboplastin time (PTT)

You may not qualify if:

• 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) Note: At the Cincinnati Children's Hospital Medical Center site, women of childbearing potential were not permitted to enroll in the study.
• 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

Sponsors & Collaborators

• Beacon Therapeutics: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (4)

National Jewish Health

Denver, Colorado, 80206, United States

Location

University of Massachusetts Medical Center

Worcester, Massachusetts, 01655, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Beaumont Hospital

Dublin, 2, Ireland

Location

Related Publications (3)

• 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. doi: 10.1073/pnas.0904514106. Epub 2009 Aug 12.

  PMID: 19706466 BACKGROUND

• 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 viral vector expressing alpha1-antitrypsin: interim results. Hum Gene Ther. 2011 Oct;22(10):1239-47. doi: 10.1089/hum.2011.053. Epub 2011 Aug 24.

  PMID: 21609134 RESULT

• Mueller C, Chulay JD, Trapnell BC, Humphries M, Carey B, Sandhaus RA, McElvaney NG, Messina L, Tang Q, Rouhani FN, Campbell-Thompson M, Fu AD, Yachnis A, Knop DR, Ye GJ, Brantly M, Calcedo R, Somanathan S, Richman LP, Vonderheide RH, Hulme MA, Brusko TM, Wilson JM, Flotte TR. Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J Clin Invest. 2013 Dec;123(12):5310-8. doi: 10.1172/JCI70314. Epub 2013 Nov 15.

  PMID: 24231351 RESULT

Related Links

• Applied Genetic Technologies Corporation

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Study results based on small number of subjects.

Results Point of Contact

• Title: Ellery D. Mangas
• Organization: Applied Genetic Technologies Corp.

emangas@agtc.com

386-462-7106

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 21, 2010
• First Posted: January 22, 2010
• Study Start: June 1, 2010
• Primary Completion: October 1, 2011
• Study Completion: October 1, 2015
• Last Updated: March 28, 2019
• Results First Posted: September 14, 2012

Record last verified: 2016-07

Locations

US (3); IE (1)