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

Conditions:Anemia, Hematology
Therapuetic Areas:Hematology
Age Range:18 - 75
Start Date:March 5, 2018
End Date:June 30, 2022
Contact:Rocio Iturbe, MSc

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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

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

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

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

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

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

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

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

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.
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