Hemophilia A
Conditions
Keywords
Blood Coagulation Factor Inhibitors
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.
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
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Genentech, Inc.
Carelon Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Months to No maximum
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge | 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 | 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 | Measured through Week 100 | Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event |
| 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 | Measured within approximately 22 weeks | Presence or absence of at least a minor response in each participant |
| Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event | 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 | Measured at Week 1 through Week 4 | Proportion of rituximab infusions in which a reaction to the infusion was reported |
| Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events | Measured through Week 100 | Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events |
Countries
United States
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Rituximab administered at a dose of 375 mg/m\^2 by slow intravenous infusion once per week for 4 weeks | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow-Up Phase I | Lost to Follow-up | 1 |
| Follow-Up Phase II | Lost to Follow-up | 3 |
| Screening Phase | enrollment halted | 1 |
| Screening Phase | Ineligible for treatment phase | 4 |
| Screening Phase | Lost to Follow-up | 1 |
| Screening Phase | Withdrawal by Subject | 1 |
| Treatment Phase | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Rituximab |
|---|---|
| Age, Categorical <=18 years | 19 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age Continuous | 15.85 years STANDARD_DEVIATION 12.02 |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 16 |
| serious Total, serious adverse events | 11 / 16 |
Outcome results
Primary
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
Population: All participants who received at least one dose of rituximab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | 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 proportion of participants |
Comparison: The null hypothesis is that the 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 5-7 days following re-challenge with factor VIII is no more than 0.05p-value: 0.043Exact Binomial
Secondary
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
Population: Data on bleeding events were collected at every study visit for all study participants. Data for this outcome was collected through the particpants end of study or Week 100, whichever came first, and is restricted to the 16 subjects who received at least one dose of rituximab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab | Median Number of Adverse Events Per Subject That Were Not Bleeding Events and Did Not Meet the Criteria of a Serious Adverse Event | 1.5 participants |
Secondary
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
Population: Data on bleeding events were collected at every study visit for all study participants. Data for this outcome was collected through the particpants end of study or Week 100, whichever came first, and is restricted to the 16 subjects who received at least one dose of rituximab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab | Median Number of Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event | 0 participants |
Secondary
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
Population: Data on bleeding events were collected at every study visit for all study participants. Data for this outcome was collected through the particpants end of study or Week 100, whichever came first, and is restricted to the 16 subjects who received at least one dose of rituximab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab | Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event | 19.5 participants |
Secondary
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
Population: Data on bleeding events were collected at every study visit for all study participants. Data for this outcome was collected through the particpants end of study or Week 100, whichever came first, and is restricted to the 16 subjects who received at least one dose of rituximab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab | Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events | 1 participants |
Secondary
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
Population: All subjects who received a post-treatment rechallenge and had at least a minor response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab | Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge | -64.31 percentage change |
Secondary
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
Population: All rituximab infusions given to study participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Proportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported | 0.11 proportion of rituximab infusions |
Secondary
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
Population: All participants who received at least one dose of rituximab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | 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 | 0.25 proportion of participants |
Comparison: No hypothesis about the value of this proportion was specified in the study design95% CI: [0.073, 0.524]Exact Binomial