Safety and Dose Escalation Study of an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia A Subjects

ID: NCT03370172
Status: Recruiting
Phase: Phase 1/Phase 2
Start Date: March 01, 2018
First Submitted: November 22, 2017
Last Updated: February 21, 2018
Results: N/A
Organization: Shire
Sponsors & Collaborators: Baxalta now part of Shire
Location: United States
Conditions: Hemophilia A
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Study Description

Brief Summary

The purpose of this study is to evaluate the safety and determine the dose of BAX 888

Detailed Description

Condition or disease Intervention/treatment Phase

Hemophilia A

Drug: BAX 888
Other Names
BAX888
Phase 1/Phase 2

Tracking Information

First Submitted DateNovember 22, 2017
Last Update Posted DateFebruary 21, 2018
Anticipated Start DateMarch 01, 2018
Anticipated Completion DateJune 30, 2022
Anticipated Primary Completion DateJune 30, 2022
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Incidence of BAX 888-related adverse events (AEs) [Time Frame: Throughout the study period of approximately 3 years per participant.]

    Includes serious or non-serious adverse events

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Median plasma Factor VIII (FVIII) activity level [Time Frame: From screening visit to last study visit, at approximately 40 visits (screening & study visits), up to approximately 3 years per participant]

    Circulating plasma FVIII activity level, based on one-stage clotting assay

  • Median plasma Factor VIII (FVIII) antigen level [Time Frame: From screening visit to last study visit, at approximately 40 visits (screening & study visits), up to approximately 3 years per participant]

    Circulating plasma FVIII antigen (protein) level in the plasma

  • Annualized bleed rate (ABR) [Time Frame: Throughout the study period of approximately 3 years per participant.]

    Annualized bleed rate (ABR) in comparison to before gene transfer

  • Consumption of exogenous Factor VIII (FVIII) [Time Frame: Historical data from 12 months prior to study enrollment; and 12 months post-infusion and 3 years post-infusion.]

    The percentage of participants with a reduction in exogenous FVIII consumption 12 months post-infusion and 3 years post-infusion compared to the historical consumption (consumption of exogenous FVIII during the 12 month period prior to BAX 888 infusion)

  • Number of participants with inhibitory antibodies to FVIII [Time Frame: Throughout the study period of approximately 3 years per participant.]

    Development of inhibitory antibodies to FVIII (Nijmegen assay).

  • Number of participants with total binding antibodies to FVIII [Time Frame: Throughout the study period of approximately 3 years per participant.]

    Development of total binding antibodies to FVIII (IgG and IgM).

  • Number of participants with humoral and cell-mediated immune response to AAV8 and FVIII proteins. [Time Frame: Throughout the study period of approximately 3 years per participant.]

    Humoral (antibody-mediated) and cell-mediated immune response to adeno-associated virus (AAV8) (the vector) and Factor VIII (FVIII) proteins.

  • Surveillance of AAV8 genome shedding [Time Frame: Throughout the study period of approximately 3 years per participant.]

    Surveillance of adeno-associated virus (AAV8) genome shedding in blood, saliva, semen, urine and stool

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleSafety and Dose Escalation Study of an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia A Subjects
Official TitleA Global, Open-Label, Multicenter, Phase 1/2 Study of the Safety and Dose Escalation of BAX 888, an Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor VIII (BDD-FVIII) in Severe Hemophilia A Subjects Administered a Single Intravenous Infusion
Brief Summary

The purpose of this study is to evaluate the safety and determine the dose of BAX 888

Detailed Description

Study TypeInterventional
Study PhasePhase 1/Phase 2
Estimated Enrollment
10
Allocation
Non-Randomized
Interventional Model
Sequential Assignment
Masking
None (Open Label)
Primary Purpose
Prevention
Conditions
Hemophilia A
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: BAX 888

An Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor VIII (BDD-FVIII)

Other Names
BAX888
Study Groups/Cohorts
Cohort 1
Low dose

Cohort 2
High dose

Study Arms
Experimental Cohort 1
Low dose
Drug : BAX 888
An Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor VIII (BDD-FVIII)

Experimental Cohort 2
High dose
Drug : BAX 888
An Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor VIII (BDD-FVIII)

Arm Intervention/Treatment
Experimental Cohort 1
Low dose
Drug : BAX 888
Experimental Cohort 2
High dose
Drug : BAX 888

Recruitment Information

Recruitment Status:Recruiting
Enrollment10
Completion DateJune 30, 2022
Eligibility Criteria: Inclusion Criteria:
1. Male, aged 18 to 75 years at the time of screening.
2. Established severe hemophilia A (factor VIII procoagulant activity (FVIII:C) <1%, measured following ≥5 days without factor VIII (FVIII) treatment), and/or documented intron 1 inversion or intron 22 inversion mutation in the F8 gene, consistent with severe hemophilia A, AND documented evidence of ≥3 hemorrhages over the previous 12 months requiring treatment with exogenous FVIII or use of FVIII prophylaxis because of history of frequent bleeding episodes.
3. History of >150 exposure days to exogenously administered FVIII concentrates or cryoprecipitate.
4. Normal prothrombin time (PT).
5. Sexually active men must agree to use barrier contraception (combination of a condom and spermicide) or limit sexual intercourse to post-menopausal, surgically sterilized, or contraception-practicing partners for a minimum of 6 months after administration of BAX 888, or until BAX 888 genomes are no longer detected in the semen, whichever is sooner.
6. Participant is willing and able to comply with the requirements of the protocol, including provision of semen samples, maintenance of a diary of bleeding episodes and FVIII protein use.
7. Signed informed consent.

Exclusion Criteria:
1. Bleeding disorder(s) other than hemophilia A.
2. Personal laboratory evidence of having developed inhibitors to FVIII protein at any time (≥0.6 Bethesda units (BU) on any single test).
3. Documented prior allergic reaction to any FVIII product.
4. Adeno-associated virus, serotype 8 (AAV8) neutralizing antibody titer greater than or equal to 1:5.
5. Positive AAV8-specific T-cell ELISPOTs for any AAV8 peptide pools.
6. Known hypersensitivity to prednisolone or prednisone.
7. Having a disease in which treatment with prednisolone or prednisone is not tolerated (including but not limited to osteoporosis with vertebral fractures, severe labile hypertension, and brittle diabetes).
8. Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease:
1. Anti-smooth muscle antibody assay results ≥40 (Inova QUANTA LiteTM Actin IgG enzyme-linked immunosorbent assay [ELISA]); values of 31 to 39 will be flagged as possibly abnormal and the Investigator and Medical Monitor will evaluate the participant for eligibility.
2. Elevated anti-liver-kidney microsomal antibody type 1 (LKM1) titers.
3. Total immunoglobulin G (IgG) >1.5x upper limit of normal (ULN).
4. Antinuclear antibody (ANA) titer > 1:320; OR ANA titer > 1:80 if demonstrated concurrently with alanine aminotransferase (ALT) that is > ULN.
9. Active Hepatitis C: As indicated by detectable hepatitis C virus (HCV) ribonucleic acid (RNA) by polymerase chain reaction (PCR).
10. Hepatitis B: If surface antigen is positive.
11. Seropositive for Human Immunodeficiency Virus (HIV).
12. Receiving systemic antiviral and/or interferon therapy within 4 weeks prior to enrollment.
13. Clinically significant infections (e.g., systemic fungal infections) requiring systemic treatment.
14. Known immune disorder (including myeloma and lymphoma).
15. Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or other disorders.
16. An absolute neutrophil count <1000 cells/mm^3.
17. Markers of hepatic inflammation or cirrhosis as evidenced by 1 or more of the following:
1. Platelet count of <150,000/μL.
2. Albumin ≤3.5 g/dL.
3. Total bilirubin >1.5x ULN and direct bilirubin ≥0.5 mg/dL.
4. ALT or aspartate aminotransferase (AST) >1.0x ULN.
5. Alkaline phosphatase (AP) >2.0x ULN.
6. History of liver biopsy indicating moderate or severe fibrosis (Metavir staging of F2 or greater).
7. History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy.
8. FibroSURE Score of ≥0.4.
18. Serum creatinine >1.5 mg/dL.
19. Urine protein >30 mg/dL OR <0.5 g/day.
20. Body mass index >38.
21. Major surgery or an orthopedic surgical procedure planned within 6 months after enrollment.
22. Acute or chronic disease that, in the opinion of the investigator, would adversely affect subject safety or compliance or interpretation of study results.
23. Received an AAV vector previously or any other gene transfer agent in the previous 12 months prior to Study Day 0.
24. Received an investigational intervention or participated in another clinical trial within 4 weeks prior to enrollment or within 5 half-lives of the investigational drug administration, whichever is longer.
25. Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease).
26. Recent history of psychiatric illness or cognitive dysfunction (including drug or alcohol abuse) that in the opinion of the investigator, is likely to impair subject's ability to comply with protocol mandated procedures.
27. Sensitivity to penicillin.
28. Participant is a family member or employee of the investigator.
GenderMale
Age18 Years to 75 Years
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
United States

Administrative Information

NCT Number:NCT03370172
Other Study ID Numbers
201501
2015-005576-22
Has Data Monitoring CommitteeYes
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Baxalta now part of Shire
Collaborators
Not Available
Investigators
Study Director
John Chapin, MD
Baxalta now part of Shire