Clinical trial NCT00331006: Rituximab to Treat Severe Hemophilia A
Official title: Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (A TMH CTN Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hemophilia A
Keywords: Blood Coagulation Factor Inhibitors
Lead sponsor: Carelon Research
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Genentech, Inc.
First posted: 2006-05-29
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Hemophilia A is a serious blood clotting disorder caused by a lack of factor VIII, a specialized protein needed for normal blood clotting to occur. Individuals with this disease may experience spontaneous bleeding, pain and swelling in their joints due to excess bleeding, and bruising. A common treatment for severe hemophilia A is to intravenously replace the deficient blood clotting factor; however, some individuals may develop antibodies to this replacement factor. This study will evaluate the effectiveness of rituximab at reducing the antibodies that develop in response to the replacement factor in individuals with severe hemophilia A.

Detailed description: Hemophilia A is a hereditary blood clotting disorder. It is caused by a deficiency or abnormality of the blood clotting protein factor VIII. Individuals with hemophilia A are unable to form blood clots to stop bleeding and are at risk for experiencing serious and life-threatening bleeding episodes. The most common treatment for this disease is intravenous replacement of factor VIII. However, between 30 to 40% of individuals eventually develop inhibitors, or antibodies, to the replacement factor. In these individuals, the immune system recognizes the replacement factor as foreign and attacks it, thereby countering any potential benefits of the treatment. Some individuals with severe hemophilia A may undergo immune tolerance therapy (ITT), in which they receive replacement factor on a regular basis as a way for the body to adjust to the factor and stop inhibitor production. This treatment, however, is not always effective for everyone. Preliminary research has shown that rituximab, a medication used to treat non-Hodgkin's lymphoma, may be successful in suppressing or eliminating the inhibitors that develop. The purpose of this study is to evaluate the effectiveness of rituximab at lowering the levels of factor VIII inhibitors in individuals with severe hemophilia A.

This study will enroll individuals with severe hemophilia A. At study entry, participants will receive one intravenous dose of factor VIII. Inhibitor levels will be measured with a blood test 5 to 7 days following this procedure. If peak inhibitor level is above 5 Bethesda units (BU)/mL, 5 to 9 days later participants will begin receiving rituximab intravenously once a week for 4 weeks. Blood will be collected at each visit for laboratory testing. Two weeks following the last rituximab treatment, participants will have blood drawn for inhibitor testing; this testing will occur every 4 weeks through Week 22. If the participant's inhibitor level falls below 5 BU/mL, participants will receive a repeat dose of factor VIII, and blood will be drawn 5 to 7 days later for inhibitor testing. Follow-up visits will occur at Weeks 36, 52, and 100, and will include a physical examination, blood collection, and monitoring of bleeding events and infections. Telephone interviews will be conduced at Weeks 64, 76, and 88 to monitor bleeding events and infections.

Eligibility criteria: Inclusion Criteria:

* Severe congenital hemophilia A
* Documented historical inhibitor titer to factor VIII of at least 5 BU/mL
* Inhibitor level greater than or equal to 5 BU/mL 5 to 14 days after initial factor VIII exposure during screening

Exclusion Criteria:

* Known hypersensitivities or allergies to murine and/or humanized antibodies
* Currently participating in investigational hemophilia studies
* HIV infected
* Any immunodeficiency disorder
* Liver disease and serum ALT or AST is greater than three times the upper limit of normal, albumin is less than 2.5g/dl, and/or INR is greater than 1.7
* Received interferon or other immunomodulatory drugs, such as steroids or cytotoxic therapy in the 30 days prior to study entry
* History of cardiac arrhythmias, any active febrile illness, kidney insufficiency, or pulmonary infiltrates
* Has previously received rituximab treatment
* Currently undergoing immune tolerance therapy
* Evidence of Hepatitis B (HBV) infection, defined as one of the following:

  * HBsAg positive
  * HBsAg negative, HBsAb negative, HBcAb positive, and HBV DNA positive
* Participants with a high responding inhibitor (at least 5 BU/mL) first detected fewer than 12 months prior to study entry, unless the participant has failed immune tolerance therapy, defined as one of the following:

  1. Failure to fulfill the criteria for full or partial success within 33 months, as defined by a factor VIII recovery greater than or equal to 66% of expected and half-life greater than or equal to 6 hours measured after a 72-hour treatment-free washout period
  2. Failure to achieve greater than 20% reduction in inhibitor titer during each interim non-overlapping 6-month period of ITT in the absence of documented infection, with 9 months as the minimum treatment period and 33 months as the maximum possible duration of unsuccessful ITT
  3. Withdrawal from ITT for any other reason
* Routinely receive factor VIII concentrate for the treatment of both major and minor bleeding events
* Has received factor VIII concentrate in the 7 days prior to study entry

Primary outcomes:
measure: Proportion of Subjects With Major Response, i.e. Inhibitor Level Falls to Less Than 5 BU/mL Between Weeks 6 to 22 and Remains Below 5 BU/mL at 5-7 Days Following Re-challenge With FVIII
timeFrame: Measured within approximately 22 weeks
Secondary outcomes:
measure: Proportion of Subjects With at Least Minor Response, i.e. Inhibitor Level Falls to <5 BU/mL Between Weeks 6-22 and Either Remains <5 BU/mL 5-7 Days Following FVIII Rechallenge or Titer Following FVIII Rechallenge is 5-10 BU/mL & <50% of Original Peak
timeFrame: Measured within approximately 22 weeks
measure: Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge
timeFrame: Measured within approximately 22 weeks
measure: Median Number of Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event
timeFrame: Measured through Week 100
measure: Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event
timeFrame: Measured through Week 100
measure: Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events
timeFrame: Measured through Week 100
measure: Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event
timeFrame: Measured through Week 100
measure: Proportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported
timeFrame: Measured at Week 1 through Week 4
Other outcomes:
Locations:
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Chapel Hill
country: United States
facility: UNC at Chapel Hill Hospital
state: North Carolina
city: Cleveland
country: United States
facility: University Hospital of Cleveland
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Hemophilia Center of Western Pennsylvania
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Milwaukee
country: United States
facility: Comprehensive Center for Bleeding Disorders
state: Wisconsin
Study officials:
affiliation: NERI
name: Susan F. Assmann, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tulane University Health Sciences Center
name: Cindy Leissinger, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Versiti
name: Joan Gill, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Cleveland
name: Keith McCrae, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: Ellis Neufeld, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Healthcare of Atlanta
name: Cassandra Josephson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of North Carolina
name: Nigel Key, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Oklahoma
name: Charles Sexauer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas Southwestern Medical Center
name: Janna Journeycake, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Philadelphia
name: Leslie Raffini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hemophilia Center of Western Pennsylvania
name: Margaret Ragni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rush University Medical Center
name: Leonard Valentino, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Orange County
name: Diane Nugent, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cook Children's Medical Center
name: Marcella Torres, MD
role: PRINCIPAL_INVESTIGATOR
References: