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CompletedNCT00331006RICHUpdated Jun 11, 2013Results posted

Rituximab to Treat Severe Hemophilia A

A Phase 2 interventional study of Rituximab in Hemophilia A, sponsored by Carelon Research. Completed at 13 sites in United States. Open to participants aged 18 Months and older. Per ClinicalTrials.gov, last updated 2013-06-11.

Sponsored by Carelon Research · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
23
Allocation
Not applicable
Ages
18 Months and older
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Hemophilia A

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Keywords

  • Blood Coagulation Factor Inhibitors
03

In context

Hemophilia A

866 studies on the registry are indexed under Hemophilia A; 137 are open to participants now.

This study's enrollment of 23 is below the median of 28 across 512 interventional studies indexed under Hemophilia A.

Browse Hemophilia A studies →

Lead sponsor

Carelon Research is the lead sponsor of 55 studies on the registry; 4 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Months and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
23 participants (actual)

Study arms

  • Experimental
    Rituximab

    Rituximab administered at a dose of 375 mg/m2 by slow intravenous infusion once per week for 4 weeks

    Drug: Rituximab

Interventions

  • DrugRituximab

    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

    Also known as: Rituxan

06

What researchers measure

Primary outcomes

  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

    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

    Time frame: Measured within approximately 22 weeks

Secondary outcomes

  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

    Presence or absence of at least a minor response in each participant

    Time frame: Measured within approximately 22 weeks

  2. Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge

    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.

    Time frame: Measured within approximately 22 weeks

  3. Median Number of Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event

    Median number of bleeding events per subject meeting the criteria of a serious adverse event

    Time frame: Measured through Week 100

  4. Median Number of Bleeding Events Per Subject Not 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

  5. Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events

    Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events

    Time frame: Measured through Week 100

  6. Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event

    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

  7. Proportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported

    Proportion of rituximab infusions in which a reaction to the infusion was reported

    Time frame: Measured at Week 1 through Week 4

07

Results

Posted Jun 11, 2013
Limitations and caveats
The study was terminated before reaching its target sample size of 50 subjects due to low enrollment rates. Therefore, confidence intervals for proportions are wide.

Participant flow

Subjects were recruited at clinical sites and Hemophilia Treatment Centers participating in the study. The recruitment period began in August 2006 and continued through November 2011.

Screening Phase
Participant flow — Screening Phase
MilestoneRituximab
Started23
Completed16
Not completed7
Withdrew: Withdrawal by subject1
Withdrew: Enrollment halted1
Withdrew: Lost to follow-up1
Withdrew: Ineligible for treatment phase4
Treatment Phase
Participant flow — Treatment Phase
MilestoneRituximab
Started16
Completed15
Not completed1
Withdrew: Withdrawal by subject1
Follow-Up Phase I
Participant flow — Follow-Up Phase I
MilestoneRituximab
Started15
Completed14
Not completed1
Withdrew: Lost to follow-up1
Follow-Up Phase II
Participant flow — Follow-Up Phase II
MilestoneRituximab
Started14
Completed11
Not completed3
Withdrew: Lost to follow-up3

Outcome measures

PrimaryProportion 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

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

Time frame:
Measured within approximately 22 weeks
Reported as:
Number · proportion of participants
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
proportion of participantsRituximab
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.1875 (0.053 to 1.0)
Statistical analysis
  • Rituximab · Exact Binomial · p = 0.043 (the a priori p-value was 0.05 for statistical significance) · Proportion: .1875
SecondaryProportion 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

Presence or absence of at least a minor response in each participant

Time frame:
Measured within approximately 22 weeks
Reported as:
Number · proportion of participants
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
proportion of participantsRituximab
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 Peak0.25 (0.073 to 0.524)
Statistical analysis
  • Rituximab · Exact Binomial · Proportion: .25 · 95% CI 0.073 to 0.524
SecondaryPercent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge

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.

Time frame:
Measured within approximately 22 weeks
Reported as:
Median · percentage change
Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge
percentage changeRituximab
Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge-64.31 (-77.11 to -44.49)
SecondaryMedian Number of Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event

Median number of bleeding events per subject meeting the criteria of a serious adverse event

Time frame:
Measured through Week 100
Reported as:
Median · participants
Median Number of Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event
participantsRituximab
Median Number of Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event0 (0 to 2)
SecondaryMedian Number of Bleeding Events Per Subject Not 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
Reported as:
Median · participants
Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event
participantsRituximab
Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event19.5 (11 to 41)
SecondaryMedian Number of Serious Adverse Events Per Subject Other Than Bleeding Events

Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events

Time frame:
Measured through Week 100
Reported as:
Median · participants
Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events
participantsRituximab
Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events1 (0 to 2.5)
SecondaryMedian Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event

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
Reported as:
Median · participants
Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event
participantsRituximab
Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event1.5 (0 to 4)
SecondaryProportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported

Proportion of rituximab infusions in which a reaction to the infusion was reported

Time frame:
Measured at Week 1 through Week 4
Reported as:
Number · proportion of rituximab infusions
Proportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported
proportion of rituximab infusionsRituximab
Proportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported0.11 (0.05 to 0.22)

Adverse events

Collected over Through week 100. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Rituximab—11/16 (68.8%)15/16 (93.8%)
Most frequent serious events
Showing 10 of 28
Most frequent serious events
EventRituximab
Joint bleeding - spontaneousMusculoskeletal and connective tissue disorders4/16
Joint bleeding due to injuryInjury, poisoning and procedural complications3/16
SynovectomySurgical and medical procedures2/16
DiarrheaGastrointestinal disorders1/16
Mallory-Weiss tearGastrointestinal disorders1/16
Allergic reaction/hypersensitivityGeneral disorders1/16
FeverGeneral disorders1/16
Central line infectionInfections and infestations1/16
Pulmonary/upper respiratory infectionInfections and infestations1/16
SepsisInfections and infestations1/16
Most frequent other events
Showing 10 of 71
Most frequent other events
EventRituximab
Joint bleeding, spontaneousMusculoskeletal and connective tissue disorders15/16
Joint bleeding due to injuryInjury, poisoning and procedural complications11/16
Bleed and/or hematoma - spontaneousMusculoskeletal and connective tissue disorders10/16
Hematoma - spontaneousSkin and subcutaneous tissue disorders9/16
Bleed and/or hematoma - spontaneousSkin and subcutaneous tissue disorders7/16
Hematoma due to injuryInjury, poisoning and procedural complications6/16
Bleeding - spontaneousGastrointestinal disorders4/16
Bleed and/or hematoma due to injuryInjury, poisoning and procedural complications4/16
Hematoma due to procedure complicationInjury, poisoning and procedural complications4/16
ChillsGeneral disorders3/16

Baseline characteristics

All subjects who began the screening phase

Age, Categorical
Age, Categorical(Participants)Rituximab
<=18 years19
Between 18 and 65 years4
>=65 years0
Age Continuous
Age Continuous(years)Rituximab
Mean15.85 ± 12.02
Sex: Female, Male
Sex: Female, Male(Participants)Rituximab
Female0
Male23
Region of Enrollment
Region of Enrollment(participants)Rituximab
United States23
08

Study locations

13 sites
  • Children's Hospital of Orange County
    Orange, California 92868, United States
  • Children's Healthcare of Atlanta
    Atlanta, Georgia 30322, United States
  • Rush University Medical Center
    Chicago, Illinois 60612, United States
  • Tulane University Health Sciences Center
    New Orleans, Louisiana 70112, United States
  • Children's Hospital Boston
    Boston, Massachusetts 02115, United States
  • UNC at Chapel Hill Hospital
    Chapel Hill, North Carolina 27514, United States
  • University Hospital of Cleveland
    Cleveland, Ohio 44106, United States
  • University of Oklahoma Health Sciences Center
    Oklahoma City, Oklahoma 73104, United States
  • Children's Hospital of Philadelphia
    Philadelphia, Pennsylvania 19104, United States
  • Hemophilia Center of Western Pennsylvania
    Pittsburgh, Pennsylvania 15213, United States
  • University of Texas Southwestern Medical Center
    Dallas, Texas 75390, United States
  • Cook Children's Medical Center
    Fort Worth, Texas 76104, United States
  • Comprehensive Center for Bleeding Disorders
    Milwaukee, Wisconsin 53201, United States
09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 11, 2013, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT00331006
Lead sponsor
Carelon Research
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), Genentech, Inc.
Responsible party
Sponsor
First posted
May 29, 2006
Start date
Jun 2006
Primary completion
Nov 2010
Completion
Jan 2012
Results posted
Jun 11, 2013
Last update
Jun 11, 2013

Study contacts

Susan F. Assmann, PhD
principal investigator · NERI
Cindy Leissinger, MD
principal investigator · Tulane University Health Sciences Center
Joan Gill, MD
principal investigator · Versiti
Keith McCrae, MD
principal investigator · University Hospital of Cleveland
Ellis Neufeld, MD
principal investigator · Boston Children's Hospital
Cassandra Josephson, MD
principal investigator · Children's Healthcare of Atlanta
Nigel Key, MD
principal investigator · University of North Carolina
Charles Sexauer, MD
principal investigator · University of Oklahoma
Janna Journeycake, MD
principal investigator · University of Texas Southwestern Medical Center
Leslie Raffini, MD
principal investigator · Children's Hospital of Philadelphia
Margaret Ragni, MD
principal investigator · Hemophilia Center of Western Pennsylvania
Leonard Valentino, MD
principal investigator · Rush University Medical Center
Diane Nugent, MD
principal investigator · Children's Hospital of Orange County
Marcella Torres, MD
principal investigator · Cook Children's Medical Center

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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