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Rituximab to Treat Severe Hemophilia A (RICH)

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ClinicalTrials.gov Identifier: NCT00331006
Recruitment Status : Completed
First Posted : May 29, 2006
Results First Posted : June 11, 2013
Last Update Posted : June 11, 2013
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Genentech, Inc.
Information provided by (Responsible Party):
New England Research Institutes

May 26, 2006
May 29, 2006
January 7, 2013
June 11, 2013
June 11, 2013
June 2006
November 2010   (Final data collection date for primary outcome 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 [ Time Frame: Measured within approximately 22 weeks ]
Presence or absence of a major response in each participant. Major response is defined as occurring when 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
  • Proportion of participants in which the inhibitor level falls to less than 5 BU/mL between Weeks 6 to 22 and remains below 5 BU/mL at 5 to 7 days following re-challenge with factor VIII
  • (measured at Week 22)
Complete list of historical versions of study NCT00331006 on ClinicalTrials.gov Archive Site
  • 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 [ Time Frame: Measured within approximately 22 weeks ]
    Presence or absence of at least a minor response in each participant
  • Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge [ Time Frame: Measured within approximately 22 weeks ]
    percent change=100%*(A-B)/B where A=inhibitor titer measured within 5-7 days following FVIII rechallenge and B=inhibitor titer measured within 5-14 days following baseline FVIII challenge. A FVIII rechallenge was performed within 10-18 days of the first monthly study visit in which an inhibitor titer result <5 BU/mL was obtained beginning 2 weeks and continuing through 18 weeks following the last rituximab infusion.
  • Median Number of Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event [ Time Frame: Measured through Week 100 ]
    Median number of bleeding events per subject meeting the criteria of a serious adverse event
  • Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event [ Time Frame: Measured through Week 100 ]
    Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event
  • Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events [ Time Frame: Measured through Week 100 ]
    Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events
  • Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event [ Time Frame: Measured through Week 100 ]
    Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event
  • Proportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported [ Time Frame: Measured at Week 1 through Week 4 ]
    Proportion of rituximab infusions in which a reaction to the infusion was reported
  • Proportion of participants in which inhibitor level falls to less than 5 BU/mL between Weeks 6 to 22 and anamnestic peak following factor VIII re-challenge is 5 to 10 BU/mL and less than 50% of original peak
  • Percentage change in inhibitor titer on challenge with factor VIII from baseline challenge to post-treatment challenge (both measured at Week 22)
  • Safety of rituximab in participants with severe hemophilia A and high responding inhibitors (measured at Week 100)
Not Provided
Not Provided
 
Rituximab to Treat Severe Hemophilia A
Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (A TMH CTN Study)
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.

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.

Interventional
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Hemophilia A
Drug: Rituximab
Rituximab by slow intravenous infusion; for participants greater than or equal to 10 kg, 375 mg per m^2 BSA weekly for 4 weeks; for participants less than 10 kg, 12.5 mg/kg weekly for 4 weeks
Other Name: Rituxan
Experimental: Rituximab
Rituximab administered at a dose of 375 mg/m2 by slow intravenous infusion once per week for 4 weeks
Intervention: Drug: Rituximab
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
23
50
January 2012
November 2010   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Months and older   (Child, Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00331006
374
U01HL072268 ( U.S. NIH Grant/Contract )
U01HL072274 ( U.S. NIH Grant/Contract )
U01HL072290 ( U.S. NIH Grant/Contract )
U01HL072033 ( U.S. NIH Grant/Contract )
U01HL072291 ( U.S. NIH Grant/Contract )
U01HL072248 ( U.S. NIH Grant/Contract )
U01HL072355 ( U.S. NIH Grant/Contract )
U01HL072283 ( U.S. NIH Grant/Contract )
U01HL072346 ( U.S. NIH Grant/Contract )
U01HL072331 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
New England Research Institutes
New England Research Institutes
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Genentech, Inc.
Principal Investigator: Susan F. Assmann, PhD NERI
Principal Investigator: Cindy Leissinger, MD Tulane University Health Sciences Center
Principal Investigator: Joan Gill, MD Blood Center of Wisconsin
Principal Investigator: Keith McCrae, MD University Hospital of Cleveland
Principal Investigator: Ellis Neufeld, MD Boston Children’s Hospital
Principal Investigator: Cassandra Josephson, MD Children's Healthcare of Atlanta
Principal Investigator: Nigel Key, MD University of North Carolina
Principal Investigator: Charles Sexauer, MD University of Oklahoma
Principal Investigator: Janna Journeycake, MD University of Texas Southwestern Medical Center
Principal Investigator: Leslie Raffini, MD Children's Hospital of Philadelphia
Principal Investigator: Margaret Ragni, MD Hemophilia Center of Western Pennsylvania
Principal Investigator: Leonard Valentino, MD Rush University Medical Center
Principal Investigator: Diane Nugent, MD Children’s Hospital of Orange County
Principal Investigator: Marcella Torres, MD Cook Children's Medical Center
New England Research Institutes
June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP