Alpha-1 Antitrypsin DeficiencyPhase 2NCT01054339
Safety & Efficacy Study of rAAV1-CB-hAAT for Alpha-1 Antitrypsin Deficiency
A Phase 2 study testing rAAV1-CB-hAAT in people with Alpha-1 Antitrypsin Deficiency, run by Beacon Therapeutics at 4 sites in 2 countries.
Trial 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]. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Alpha-1 Antitrypsin Deficiency
- What is being tested?
- rAAV1-CB-hAAT
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 4 sitesin 2 countries
- Study dates
- Jun 2010to Oct 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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),
- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
4 sites in 2 countries.
4 sites in 2 countries
United States3 sites
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
National Jewish Health
Denver, Colorado, 80206
University of Massachusetts Medical Center
Worcester, Massachusetts, 01655
About this study
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
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
Read the 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.
- Conditions
- Alpha-1 Antitrypsin Deficiency
- Being tested
- rAAV1-CB-hAAT
- Keywords
- Alpha-1 antitrypsin deficiency, Adeno-associated virus vector, AAV, Gene therapy, Human gene transfer
- Medical subject headings
- alpha 1-Antitrypsin Deficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
rAAV1-CB-hAATDrug
Recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin
| Study group | Role | What they receive |
|---|---|---|
| Low dose | Experimental | rAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg Receives: Drug: rAAV1-CB-hAAT |
| Middle dose | Experimental | rAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg Receives: Drug: rAAV1-CB-hAAT |
| High dose | Experimental | rAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg Receives: Drug: rAAV1-CB-hAAT |
What is being measured
The primary outcome is the main question the study is designed to answer.
Frequency of Grade 3 or 4 Adverse Events
Measured: During 1 year after study agent administration
Secondary outcomes (2)
Changes in Serum M-specific Alpha-1 Antitrypsin Concentration
Results are the mean ± SD for pre-treatment (Screening and Baseline) and Months 6-12 values and mean ± SE for the difference between the pre-treatment and months 6-12 means for 2 subjects in the low dose group and 3 subjects in each of the other two groups. The monoclonal antibody used to determine serum M-specific AAT concentrations has very little cross-reactivity with Z type AAT but cross-reacts strongly with S type AAT, causing results for this assay to be spuriously high for subject 303 in the low dose group.
Measured: During months 6-12 after study agent adminsitration
Changes in Serum Total Alpha-1 Antitrypsin Concentrations
Results are the mean ± SD for pre-treatment (Screening and Baseline) and Months 6-12 data and mean ± SE for the difference between the pre-treatment and months 6-12 means for 3 subjects per group.
Measured: During months 6-12 after study agent adminstration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jan 2010 (estimated)
- Study startJun 2010
- Primary completionOct 2011
- Study completionOct 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Alpha-1 Antitrypsin DeficiencyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Beacon Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor
- Investigators
- Terence R. Flotte, MD, Principal investigator, University of Massachusetts Medical School, Worcester, MABruce C. Trapnell, MD, Principal investigator, Cincinnati Children's Hospital Medical Center, Cincinnati, OHRobert A. Sandhaus, MD, PhD, Principal investigator, National Jewish Health, Denver, CONoel G. McElvaney, MB, BCh, BAO, Principal investigator, Beaumont Hospital, Dublin, Ireland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01054339
- Sponsor's protocol ID
- AGTC-AAT-002
- Other IDs
- 2009-014286-20, R01HL069877, R01FD003896, 2009
- Status last verified
- Jul 2016
- First submitted
- 21 Jan 2010
- Last updated
- 28 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 19706466Flotte 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.
PubMed 21609134Mueller 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.
PubMed 24231351
Study at a glance
From the registry record, last updated by the sponsor on 28 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01054339
- Acronym / sponsor ID
- AGTC-AAT-002
- Conditions
- Alpha-1 Antitrypsin Deficiency
- Keywords
- Alpha-1 antitrypsin deficiency, Adeno-associated virus vector, AAV, Gene therapy, Human gene transfer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Beacon TherapeuticsIndustry (pharma, biotech, devices)
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Jun 2010
- Primary completion
- Oct 2011 (actual)
- Study completion
- Oct 2015 (actual)
- First posted
- 22 Jan 2010 (estimated)
- Results
- Posted 14 Sep 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Low dose | Experimental | Drug: rAAV1-CB-hAATrAAV1-CB-hAAT at dosage level of 6 x 10e11 vg/kg |
| Middle dose | Experimental | Drug: rAAV1-CB-hAATrAAV1-CB-hAAT at dosage level of 1.9 x 10e12 vg/kg |
| High dose | Experimental | Drug: rAAV1-CB-hAATrAAV1-CB-hAAT at dosage level of 6 x 10e12 vg/kg |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- 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
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| rAAV1-CB-hAATRecombinant adeno-associated virus vector expressing human alpha-1 antitrypsin | Drug | High dose, Low dose, Middle dose |
Primary outcome
Frequency of Grade 3 or 4 Adverse Events
Time frame: During 1 year after study agent administration
2 secondary outcomes
Changes in Serum M-specific Alpha-1 Antitrypsin Concentration
Time frame: During months 6-12 after study agent adminsitration
Changes in Serum Total Alpha-1 Antitrypsin Concentrations
Time frame: During months 6-12 after study agent adminstration
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19706466Brantly 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.
- Results publication: PubMed 21609134Flotte 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.
- Results publication: PubMed 24231351Mueller 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.
- Applied Genetic Technologies CorporationLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Terence R. Flotte, MD principal investigator
University of Massachusetts Medical School, Worcester, MA
Bruce C. Trapnell, MD principal investigator
Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Robert A. Sandhaus, MD, PhD principal investigator
National Jewish Health, Denver, CO
4 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing rAAV1-CB-hAAT in people with Alpha-1 Antitrypsin Deficiency, run by Beacon Therapeutics at 4 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States, Ireland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Sep 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Frequency of Grade 3 or 4 Adverse Events (time frame: During 1 year after study agent administration). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01054339, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Mar 2019.