Brief Title
Trial of Rituximab Versus Oral Cyclophosphamide to Eradicate or Suppress Autoimmune Anti-Factor VIII Antibodies in Acquired Hemophilia A
Official Title
A Prospective, Phase II/III Randomized, Mult-institutional Controlled, Open-label, Phase II Trial of Rituximab Versus Oral Cyclophosphamide to Eradicate or Suppress Autoimmune Anti-Factor VIII Antibodies in Patients With Acquired Hemophilia A
Brief Summary
The purpose of this study is to evaluate the rate of response when administering rituximab to
suppress or eliminate the anti-body in a patient's blood that inhibits the effectiveness of
their factor replacement product compared to treatment using cyclophosphamide. This is a
Phase 2/3 study to find out what effects (good and bad) and response rituximab has on a
patient and their anti-Factor VIII antibodies. Also, to compare the effect (good and bad) of
the rituximab with cyclophosphamide on a patient and their anti-Factor VIII antibodies to see
which is better. This research is being done because we do not know which treatment regimen
(rituximab or cyclophosphamide) is more effective in eliminating or suppressing the
anti-Factor VIII antibody in patients with acquired Hemophilia A.
Detailed Description
This is a prospective Phase II randomized multi-institutional controlled pilot trial
comparing the regimen of single agent rituximab with 6 weeks cytotoxic therapy with oral
cyclophosphamide to eradicate or suppress autoimmune anti-factor VIII antibodies in
individuals with acquired hemophilia A. Patients will be randomized to receive either of
these two regimens when their autoimmune anti-factor VIII antibodies prove to be refractory
to initial upfront immunosuppressive treatment with oral prednisone 1 mg/kg/day (or
equivalent corticosteroid doses) for 3 weeks. Patients will be randomized to the treatment
cohorts according to the biostatistical methods.
Study Phase
Phase 2/Phase 3
Study Type
Interventional
Primary Outcome
To Evaluate the Total Number of Circulating Lymphocytes and Lymphocyte Phenotypes and to Correlate With the Effectiveness of Rituximab and Oral Cyclophosphamide to Achieve and Preserve Complete Eradication of the Refractory Autoantibody.
Condition
Hemophilia A
Intervention
Rituxan
Study Arms / Comparison Groups
Rituximab
Description: Patients will receive rituximab.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
2
Start Date
April 2006
Completion Date
August 2011
Primary Completion Date
January 2011
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of acquired hemophilia A in a previously non-coagulopathic individual.
- Prior treatment with at least 3 weeks of immunosuppressive therapy
- Factor VIII: C levels <50% within 14 days prior to study entry, which do not correct
in coagulation assays in which normal plasma is mixed and incubated with patient
plasma.
- Measurable anti-factor VIII:C antibody inhibitor activity > 0.6 Bethesda Units/ml.
- Age ³18 years
- Written informed consent
- Use of an effective means to avoid pregnancy, including abstinence, for women of
childbearing potential,.
- Serum bilirubin less than or equal to the upper limit of normal (ULN); ALT and AST
£2.5´ ULN within 14 days prior to study entry
- Serum creatinine £1.5´ the ULN within 14 days prior to study entry
- Negative serum pregnancy test, for all women of childbearing potential, within 14 days
prior to study entry
Exclusion Criteria:
- Continued treatment requirement of prednisone ≥30mg/day or equivalent dosing of other
corticosteroid preparations to control serious symptoms of an underlying autoimmune
disease state.
- Treatment with cyclophosphamide, danazol, vinca alkaloids, azathioprine, IVIG, or
other immunosuppressive, immunomodulatory, or cytotoxic agents (other than decreasing
doses of corticosteroids) within 30 days prior to study entry.
- Anticipated need for repeated extracorporeal plasmapheresis in order to reverse
refractory bleeding associated with acquired hemophilia.
- Treatment with other experimental agents within 30 days prior to study entry
- Known sensitivity to murine or chimeric products
- Hepatitis BsAg positivity or high risk for reactivation of Hepatitis B.
- Active infection requiring antibiotic therapy within 7 days prior to study entry
- Current use of any required medications, which in the opinion of the treating
physician, could be inducing the formation of auto-FVIII:C inhibitory antibodies
- Prior treatment with rituximab or other monoclonal antibody therapy
- Known HIV antibody positivity
- NCI-CTC Grade ³1 cardiac arrhythmia ( refer to CTC v3)
- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications
- Currently pregnant women, lactating women, or women within 12 months of delivery,
spontaneous miscarriage, or therapeutic or elective termination of pregnancy.
- Known severe leucopenia (absolute neutrophil count <1000/µL) or thrombocytopenia
(<25,000/µL);
- Known pre-existing cystitis or severe urinary outflow obstruction.
- Known history of recurrent severe opportunistic infections, eg. generalized herpes
zoster;
- Inability or unwillingness to comply with study design and requirements and follow-up
procedures.
Gender
All
Ages
18 Years - 65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Contacts
Craig Kessler, MD, ,
Administrative Informations
NCT ID
NCT00306670
Organization ID
U2688
Responsible Party
Principal Investigator
Study Sponsor
Georgetown University
Collaborators
Genentech, Inc.
Study Sponsor
Craig Kessler, MD, Principal Investigator, Georgetown University Hospital
Verification Date
December 2016