Hemophilia B is a X-linked recessive bleeding disorder caused by mutations in the gene encoding clotting factor IX (FIX) that result in disruption of the normal clotting pathway. Hemophilia B affects 1 in 25,000 male births. Disease severity correlates directly with the concentration of functional FIX protein in the plasma. Severe disease is characterized as having <1% of normal plasma levels of FIX (100% = 1 IU activity/mL or approximately 5000 ng protein/mL). MedDRA version: 20.0 Level: LLT C
Conditions
Sponsors
Baxalta Innovations GmbH
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: The subject will not be considered eligible for the study without meeting all of the criteria below. 1. Male, aged 18 to 75 years at the time of screening. 2. Established severe or moderately severe hemophilia B (plasma FIX activity = 2% measured following = 5 half-lives of most recent exposure to exogenous FIX) and either = 3 hemorrhages per year requiring treatment with exogenous FIX or use of prophylactic therapy. 3. History of > 50 exposure days to exogenously administered FIX concentrates or cryoprecipitates. 4. 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 SHP648, or until SHP648 genomes are no longer detected in the semen (whichever is sooner). 5. Signed informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 19 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 2
Exclusion criteria
Exclusion criteria: The subject will be excluded from the study if any of the following exclusion criteria are met. 1. Bleeding disorder(s) other than hemophilia B. 2. Documented laboratory evidence of having developed inhibitors (= 0.6 BU on any single test) to FIX proteins at any time. 3. Documented prior allergic reaction to any FIX product. 4. Anti-AAV8 neutralizing antibody titer = 1:5. 5. Known hypersensitivity to prednisolone or prednisone, or to any of the excipients. 6. 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). 7. Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease: a. Anti-smooth muscle antibody (ASMA) titer = 1:40. Values of 1:31 to 1:39 will be flagged as possibly abnormal and the Investigator and Medical Monitor will evaluate the subject for eligibility. b. Elevated anti-liver-kidney microsomal antibody type 1 (LKM1) titers. c. Total IgG > 1.5x ULN. d. Antinuclear antibody (ANA) titer > 1:320 OR ANA titer > 1:80 if demonstrated concurrently with ALT that is > ULN. 8. Active Hepatitis C: As indicated by detectable HCV RNA by PCR. 9. Hepatitis B: If surface HBV antigen is positive. 10. Receiving chronic systemic antiviral and/or interferon therapy within 4 weeks prior to enrollment. 11. Clinically significant infections (e.g., systemic fungal infections) requiring systemic treatment. 12. Known immune disorder (including myeloma and lymphoma). 13. Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or other disorders. 14. An absolute neutrophil count 1.5x ULN and direct bilirubin = 0.5 mg/dL. d. ALT or AST > 1.0x ULN. e. Alkaline phosphatase > 2.0x ULN. f. History of liver biopsy or imaging indicating moderate or severe fibrosis (Metavir staging of F2 or greater). g. History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy. h. FibroSURE Score = 0.4. i. Prothrombin time INR = 1.4. 16. Serum creatinine > 1.5 mg/dL. 17. HIV if CD4+ cell count =200 mm3 and/or viral load >20 copies/mL. 18. Urine protein > 30 mg/dL. 19. Body mass index > 38. 20. Orthopedic or other major surgery planned within 6 months after enrollment. 21. Acute or chronic disease that, in the opinion of the Investigator, would adversely affect subject safety or compliance or interpretation of study results. 22. Received an AAV vector previously or any other gene transfer agent in the previous 12 months prior to Study Day 0. 23. 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). 24. History of arterial or venous thrombosis / thromboembolism, or a known pro-thrombotic condition. 25. 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. 26. Participation in another study involved with an investigational a
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to assess the safety of single, escalating, IV doses of SHP648.;Secondary Objective: The secondary objectives of the study are as follows: • Evaluate plasma FIX levels before and after SHP648 infusion and study the relationship between change in FIX activity and SHP648 dose. • Evaluate bleeding episodes post SHP648 administration. • Assess humoral and cellular immune responses to FIX and the viral capsid. • Determine the duration of SHP648 genomes present in bodily fluids. • Compare the consumption of exogenous FIX before and after gene transfer;Primary end point(s): Incidence of AEs (serious or non-serious) related to IP that include development of FIX inhibitory antibodies, ECG findings, and clinically significant changes in standard laboratory parameters and in vital signs;Timepoint(s) of evaluation of this end point: Subjects will be monitored for 1 year after dosing. Every effort will be made to enroll subjects to an extension study and follow them for approximately 4 additional years until a 5 year total post-gene transfer period is attained. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •Circulating plasma FIX activity and antigen levels •ABR in comparison to before gene transfer •Neutralizing and Binding antibody titers to AAV8 • T-cell response to AAV8 and FIX transgene products •Presence of SHP648 genome by type of bodily fluid •Percentage of change in consumption of exogenous FIX before and after gene transfer;Timepoint(s) of evaluation of this end point: Subjects will be monitored for 1 year after dosing. Every effort will be made to enroll subjects to an extension study and follow them for approximately 4 additional years until a 5 year total post-gene transfer period is attained. | — |
Countries
Austria, France, Germany, Hungary, Italy, Spain, Turkey
Contacts
Public ContactJudit Koranyi
Baxalta Innovations GmbH
Outcome results
None listed