Rituximab to Treat Severe Hemophilia A (RICH)

• 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: HealthCore-NERI
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Genentech, Inc.
• Information provided by (Responsible Party): HealthCore-NERI

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hemophilia A	Drug: Rituximab	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (A TMH CTN Study)
• Study Start Date: June 2006
• Actual Primary Completion Date: November 2010
• Actual Study Completion Date: January 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: Rituximab; Rituximab administered at a dose of 375 mg/m2 by slow intravenous infusion once per week for 4 weeks	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

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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
2. 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.
3. 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
4. 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
5. 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
6. 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
7. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Months and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

Children's Hospital of Orange County

Orange, California, United States, 92868

United States, Georgia

Children's Healthcare of Atlanta

Atlanta, Georgia, United States, 30322

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Louisiana

Tulane University Health Sciences Center

New Orleans, Louisiana, United States, 70112

United States, Massachusetts

Children's Hospital Boston

Boston, Massachusetts, United States, 02115

United States, North Carolina

UNC at Chapel Hill Hospital

Chapel Hill, North Carolina, United States, 27514

United States, Ohio

University Hospital of Cleveland

Cleveland, Ohio, United States, 44106

United States, Oklahoma

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States, 73104

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Hemophilia Center of Western Pennsylvania

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

Cook Children's Medical Center

Fort Worth, Texas, United States, 76104

United States, Wisconsin

Comprehensive Center for Bleeding Disorders

Milwaukee, Wisconsin, United States, 53201

Sponsors and Collaborators

HealthCore-NERI

National Heart, Lung, and Blood Institute (NHLBI)

Genentech, Inc.

Investigators

• Principal Investigator: Susan F. Assmann, PhD; NERI
• Principal Investigator: Cindy Leissinger, MD; Tulane University Health Sciences Center
• Principal Investigator: Joan Gill, MD; Versiti
• 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

More Information

• Responsible Party: HealthCore-NERI
• ClinicalTrials.gov Identifier: NCT00331006
• Other Study ID Numbers: 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 )
• First Posted: May 29, 2006
• Results First Posted: June 11, 2013
• Last Update Posted: June 11, 2013
• Last Verified: June 2013

Keywords provided by HealthCore-NERI:

Blood Coagulation Factor Inhibitors

Additional relevant MeSH terms:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Rituximab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents