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Trial of Rituximab Versus Oral Cyclophosphamide to Eradicate or Suppress Autoimmune Anti-Factor VIII Antibodies in Acquired Hemophilia A

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ClinicalTrials.gov Identifier: NCT00306670
Recruitment Status : Terminated (Sponsor no longer funding study.)
First Posted : March 24, 2006
Results First Posted : February 10, 2017
Last Update Posted : February 10, 2017
Genentech, Inc.
Information provided by (Responsible Party):
Craig Kessler, Georgetown University

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.

Condition or disease Intervention/treatment Phase
Hemophilia A Drug: Rituxan Drug: prednisone Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : April 2006
Actual Primary Completion Date : January 2011
Actual Study Completion Date : August 2011

Arm Intervention/treatment
Experimental: Rituximab
Patients will receive rituximab.
Drug: Rituxan
Acquired Hemophilia A Patients Who Have Developed Anti-Factor VIII Antibodies
Other Name: Rituximab

Drug: prednisone
<30 mg/day
Other Name: corticosteroids

Active Comparator: Oral cyclophosphamide
Patients will receive oral cyclophosphamide.
Drug: prednisone
<30 mg/day
Other Name: corticosteroids

Primary Outcome Measures :
  1. 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. [ Time Frame: When 25 patients have completed the study. ]
    the 2 recruited patients did not eradicate their inhibitors with 3 weeks of corticosteroids and did not progress in clinical trial since funding was eliminated and study terminated

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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.

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): NCT00306670

Sponsors and Collaborators
Georgetown University
Genentech, Inc.
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Principal Investigator: Craig Kessler, MD Georgetown University Hospital
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Responsible Party: Craig Kessler, Professor, Georgetown University
ClinicalTrials.gov Identifier: NCT00306670    
Other Study ID Numbers: U2688
First Posted: March 24, 2006    Key Record Dates
Results First Posted: February 10, 2017
Last Update Posted: February 10, 2017
Last Verified: December 2016
Keywords provided by Craig Kessler, Georgetown University:
Acquired Hemophilia A
Anti-Factor VIII antibodies
Anti-Factor VIII inhibitors
Hemophilia A
Factor VIII inhibitors
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
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal