Clinical trial NCT01054339: Safety & Efficacy Study of rAAV1-CB-hAAT for Alpha-1 Antitrypsin Deficiency
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alpha-1 Antitrypsin Deficiency
Keywords: Alpha-1 antitrypsin deficiency
Adeno-associated virus vector
AAV
Gene therapy
Human gene transfer
Lead sponsor: Beacon Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2010-01-22
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

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.

The three groups were enrolled sequentially, with review of safety data by a Data and Safety Monitoring Board before enrollment of each higher dosage level group.

Safety was monitored by evaluation of adverse events, hematology and clinical chemistry parameters, histological examination of muscle biopsies, and measurement of serum antibodies to AAT. Efficacy was measured by evaluation of serum concentrations of M-specific AAT and total AAT, and serum AAT phenotype determined on isoelectric focusing gels. Additional information collected included 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 criteria: Inclusion Criteria:

1. 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
2. Be at least 18 and not more than 75 years of age
3. Have a forced expiratory volume at one second (FEV1) \>25% of predicted value (post bronchodilator)
4. Weigh ≤ 90 kg
5. 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
6. 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
7. 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)

     ≤ 36 seconds,
   * Normal urine dipstick (negative glucose, negative hemoglobin, and negative or trace protein),
8. 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
9. 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,
10. Provide signed informed consent before screening

Exclusion Criteria:

1. Prior receipt of any AAV gene therapy product
2. Use of anticoagulants or anti-platelet agents within 7 days prior to study agent administration
3. 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
4. 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)
5. Use of oral or systemic corticosteroids within 28 days prior to study agent administration
6. Use of any investigational agent, or any immunosuppressive drug(s), within 3 months prior to enrollment
7. 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.
8. Females who are breast feeding
9. Have a significant abnormal EKG finding at screening and/or cardiac disease (e.g. recent myocardial infarction or CHF) within past 6 months
10. Have had pulmonary edema or a pulmonary embolism within the past 6 months
11. 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

Primary outcomes:
measure: Frequency of Grade 3 or 4 Adverse Events
timeFrame: During 1 year after study agent administration
Secondary outcomes:
measure: Changes in Serum M-specific Alpha-1 Antitrypsin Concentration
timeFrame: During months 6-12 after study agent adminsitration
measure: Changes in Serum Total Alpha-1 Antitrypsin Concentrations
timeFrame: During months 6-12 after study agent adminstration
Other outcomes:
Locations:
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Worcester
country: United States
facility: University of Massachusetts Medical Center
state: Massachusetts
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Dublin
country: Ireland
facility: Beaumont Hospital
Study officials:
affiliation: University of Massachusetts Medical School, Worcester, MA
name: Terence R. Flotte, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH
name: Bruce C. Trapnell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Jewish Health, Denver, CO
name: Robert A. Sandhaus, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Beaumont Hospital, Dublin, Ireland
name: Noel G. McElvaney, MB, BCh, BAO
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.