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

• Sponsor: Georgetown University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00306670
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 2
• Arms: 2
• Duration (Months): 64

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Apr 1, 2006
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab Patients will receive rituximab.	Drug: Rituxan; Acquired Hemophilia A Patients Who Have Developed Anti-Factor VIII Antibodies; Other Names: Rituximab ; Drug: prednisone; <30 mg/day; Other Names: corticosteroids
Active Comparator: Oral cyclophosphamide Patients will receive oral cyclophosphamide.	Drug: prednisone; <30 mg/day; Other Names: corticosteroids

Outcome Measures

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. [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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• 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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Georgetown University
• Genentech, Inc.

Investigators

• Principal Investigator: Craig Kessler, MD, Georgetown University Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Craig Kessler, Professor, Georgetown University
• ClinicalTrials.gov Identifier: NCT00306670
• Other Study ID Numbers: U2688
• First Posted: Mar 24, 2006
• Last Update Posted: Feb 10, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by Craig Kessler, Professor, Georgetown University: Acquired Hemophilia A; Anti-Factor VIII antibodies; Anti-Factor VIII inhibitors; Hemophilia A; Factor VIII inhibitors
• Additional relevant MeSH terms: Hemophilia A; Prednisone; Rituximab

Study Results

Participant Flow

Arm/Group Title	Rituximab	Oral Cyclophosphamide
Arm/Group Description	Patients will receive rituximab. Rituxan: Acquired Hemophilia A Patients Who Have Developed Anti-Factor VIII Antibodies prednisone: <30 mg/day	Patients will receive oral cyclophosphamide. prednisone: <30 mg/day
Period Title: Overall Study
STARTED	0	2
COMPLETED	0	0
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Rituximab	Oral Cyclophosphamide	Total
Arm/Group Description	Patients will receive rituximab. Rituxan: Acquired Hemophilia A Patients Who Have Developed Anti-Factor VIII Antibodies prednisone: <30 mg/day	Patients will receive oral cyclophosphamide. prednisone: <30 mg/day	Total of all reporting groups
Overall Participants	0	2	2
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	60	60
Gender (Count of Participants)
Female	1 Infinity	1 50%
Male	1 Infinity	1 50%
Region of Enrollment (participants) [Number]
United States	2 Infinity	2 100%
factor VIII activity; factor VIII inhibitor titer (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	25	25

Outcome Measures

1. Primary Outcome

Title	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.
Description	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
Time Frame	When 25 patients have completed the study.

Outcome Measure Data

Analysis Population Description

2 patients with acquired hemophilia A: two patients were recruited, but the sponsor terminated the study before the patients started treatment

Arm/Group Title	Rituximab	Oral Cyclophosphamide
Arm/Group Description	Patients will receive rituximab. Rituxan: Acquired Hemophilia A Patients Who Have Developed Anti-Factor VIII Antibodies prednisone: <30 mg/day	Patients will receive oral cyclophosphamide. prednisone: <30 mg/day
Measure Participants	0	2
Count of Participants [Participants]	0 NaN

Adverse Events

Arm/Group Title	Rituximab		Oral Cyclophosphamide
Arm/Group Description	Patients will receive rituximab. Rituxan: Acquired Hemophilia A Patients Who Have Developed Anti-Factor VIII Antibodies prednisone: <30 mg/day		Patients will receive oral cyclophosphamide. prednisone: <30 mg/day
All Cause Mortality
	Rituximab		Oral Cyclophosphamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rituximab		Oral Cyclophosphamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Rituximab		Oral Cyclophosphamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

Sponsor terminated study prior to patient receiving first dose of study drug.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.