Prevention of inhibitor formation, and immune tolerance induction in patients with severe and moderately severe hemophilia A by early and low-dose prophylactic ADVATE therapy
Conditions
Interventions
Trade Name: ADVATE (rAHF-PFM)
Product Name: ADVATE (rAHF-PFM)
Product Code: not applicable
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: OCTOCOG ALFA
CAS Numb
Sponsors
Baxter Innovations GmbH
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: •Subjects who meet all of the following criteria are eligible for this study: •Subjects with severe and moderately severe hemophilia A (FVIII =2%) Certain FVIII mutation types (eg, large multi-domain deletions; nonsense mutations; insertions/deletions/inversions that result in a premature stop codon; intron 22 inversions) can be used to corroborate a severe hemophilia A phenotype when laboratory assays show FVIII levels =1% because of rounding errors or carryover effect from a previous FVIII administration; a central laboratory FVIII assay is required to confirm subject eligibility. •Subjects =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: •Life-threatening conditions (intracranial hemorrhage, severe trauma), or requirement for surgery at the time of enrollment •Evidence of inhibitor =0.6 BU in Njimegen-modified Bethesda Assay at study start (samples may be retested using lupus-insensitive inhibitor tests to reduce the number of false positive inhibitortesting for lupus anticoagulant will be done to eliminate false positives) •Inherited or acquired hemostatic defect other than hemophilia A •Any clinically significant, chronic disease other than hemophilia A •Known hypersensitivity to ADVATE or any of its constituents •Any planned elective surgery that cannot be postponed until after the first 20 EDs •Participation in the Hemophilia Inhibitor PUP Study (HIPS) •Application of red blood cell, platelet, or leukocyte concentrates, or plasma •Administration of any medication affecting coagulation or platelet function •Systemic administration of any immunomodulatory drug (eg, chemotherapy, intravenous glucocorticoids) •Participation in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or during the course of this studySubjects who meet any of the following criteria are not eligible for this study: •Life-threatening conditions (intracranial hemorrhage, severe trauma), or requirement for surgery at the time of enrollment •Evidence of inhibitor =0.6 BU in Njimegen-modified Bethesda Assay at study start (samples may be retested using lupus-insensitive inhibitor tests to reduce the number of false positive inhibitor) •Inherited or acquired hemostatic defect other than hemophilia A •Any clinically significant, chronic disease other than hemophilia A •Known hypersensitivity to ADVATE or any of its constituents •Any planned elective surgery that cannot be postponed until after the first 20 EDs •Participation in the Hemophilia Inhibitor PUP Study (HIPS) •Application of red blood cell, platelet, or leukocyte concentrates, or plasma •Administration of any medication affecting coagulation or platelet function •Systemic administration of any immunomodulatory drug (eg, chemotherapy, intravenous glucocorticoids) •Participation in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or during the course of this study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Determine the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A during the first 50 exposure days (EDs) to starting with a once weekly prophylactic regimen together with the minimization of immunological danger signals;Secondary Objective: •Determine the general safety and efficacy during the first 50 EDs to ADVATE of an once weekly early prophylactic regimen starting once weekly in PUPs with severe and moderately severe hemophilia A •Gather information about the temporal associations and molecular and cellular mechanisms involved in the development of an immune response to factor VIII (FVIII) during the first 50 EDs to ADVATE;Primary end point(s): •Incidence of inhibitor formation in severe and moderately severe hemophilia A (FVIII =2%) within the first 50 EDs to ADVATE (prior exposure to FVIII up to a maximum of 3 EDs but maximum 2 exposures per event - to any FVIII concentrate are allowed, and infusions for bleed management will be included in the 50-ED calculation);Timepoint(s) of evaluation of this end point: end of study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •Incidence of inhibitor formation in severe hemophilia A (FVIII =1% within the first 50 EDs of ADVATE •Time to inhibitor formation •Incidence rate for low-titer, high-titer, transient, and all inhibitors •Incidence of SAEs and non-serious AEs at least possibly related to ADVATE •Number, type, and severity of all bleeds experienced (eg, intracranial hemorrhage, joint, soft tissue) •Number, type, and severity of all bleeds experienced when different prophylactic dosing frequencies are used (once per week versus 2-3 times per week) •Number and type of surgeries (which cannot be postponed until after 20 EDs) •Association of known risk factors to inhibitor formation: FVIII gene mutation type, FVIII haplotype, HLA haplotypes, family history of inhibitors, infections, immunomodulatory gene polymorphisms (tumor necrosis factor-alpha [TNF-a], interleukin-10 [IL-10], cytotoxic T-lymphocyte antigen 4 [CTLA4]) •Total FVIII consumption (in international units [IU]) for each subject •FVIII-specific antibody isotype for all subjects at study entry and every 10 ED;Timepoint(s) of evaluation of this end point: end of study | — |
Countries
Austria, Belgium, Bulgaria, Canada, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Netherlands, Norway, Poland, Portugal, Romania, Russian Federation, Slovakia, Spain, Sweden, Switzerland, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactJudit Koranyi, MD - ClinOps
Baxter Innovations GmbH
Outcome results
None listed