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

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ClinicalTrials.gov Identifier: NCT03370172
Recruitment Status : Recruiting
First Posted : December 12, 2017
Last Update Posted : August 15, 2018
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

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

Condition or disease Intervention/treatment Phase
Hemophilia A Drug: BAX 888 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A 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
Actual Study Start Date : March 5, 2018
Estimated Primary Completion Date : June 30, 2022
Estimated Study Completion Date : June 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: Cohort 1
Low dose
Drug: BAX 888
An Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor VIII (BDD-FVIII)
Other Name: BAX888

Experimental: Cohort 2
High dose
Drug: BAX 888
An Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor VIII (BDD-FVIII)
Other Name: BAX888




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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)

  5. 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).

  6. 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).

  7. 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.

  8. 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



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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, or to any of the excipients.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03370172


Contacts
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Contact: Rocio Iturbe, MSc +1-617-588-8275 rocio.iturbe@shire.com
Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com

Locations
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United States, Arizona
Phoenix Childrens Hospital Recruiting
Phoenix, Arizona, United States, 85016
United States, California
Orthopaedic Hemophilia Treatment Center Recruiting
Los Angeles, California, United States, 90007
United States, Colorado
University of Colorado Hemophilia & Thrombosis Center Recruiting
Aurora, Colorado, United States, 80045
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
United States, South Carolina
Medical University of South Carolina (MUSC) Recruiting
Charleston, South Carolina, United States, 29425
United States, Texas
Gulf States Hemophilia and Thrombophilia Center City Recruiting
Houston, Texas, United States, 77030-4009
Spain
Hospital Universitario La Paz Recruiting
Madrid, Spain, 28046
Hospital Regional Universitario de Malaga Recruiting
Malaga, Spain, 29010
Hospital Universitario de Salamanca Recruiting
Salamanca, Spain, 37007
Sponsors and Collaborators
Baxalta now part of Shire
Baxalta Innovations GmbH, now part of Shire
Investigators
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Study Director: Study Director Shire

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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT03370172     History of Changes
Other Study ID Numbers: 201501
2015-005576-22 ( EudraCT Number )
First Posted: December 12, 2017    Key Record Dates
Last Update Posted: August 15, 2018
Last Verified: August 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants