RICH: Rituximab to Treat Severe Hemophilia A

• Sponsor: HealthCore-NERI (Other)
• Overall Status: Completed
• CT.gov ID: NCT00331006
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Genentech, Inc. (Industry)
• Enrollment: 23
• Locations: 13
• Arm: 1
• Duration (Months): 67
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

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
• 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: Jun 1, 2006
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Jan 1, 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 Names: 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 [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 [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 [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 [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 [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 [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 [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 [Measured at Week 1 through Week 4]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Months and Older
• Sexes Eligible for Study: 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:

• 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

	Site	City	State	Country	Postal Code
1	Children's Hospital of Orange County	Orange	California	United States	92868
2	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
3	Rush University Medical Center	Chicago	Illinois	United States	60612
4	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
5	Children's Hospital Boston	Boston	Massachusetts	United States	02115
6	UNC at Chapel Hill Hospital	Chapel Hill	North Carolina	United States	27514
7	University Hospital of Cleveland	Cleveland	Ohio	United States	44106
8	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
9	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
10	Hemophilia Center of Western Pennsylvania	Pittsburgh	Pennsylvania	United States	15213
11	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
12	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
13	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: HealthCore-NERI
• ClinicalTrials.gov Identifier: NCT00331006
• Other Study ID Numbers: 374; U01HL072268; U01HL072274; U01HL072290; U01HL072033; U01HL072291; U01HL072248; U01HL072355; U01HL072283; U01HL072346; U01HL072331
• First Posted: May 29, 2006
• Last Update Posted: Jun 11, 2013
• Last Verified: Jun 1, 2013

• Keywords provided by HealthCore-NERI: Blood Coagulation Factor Inhibitors
• Additional relevant MeSH terms: Hemophilia A; Rituximab

Study Results

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.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Period Title: Screening Phase
STARTED	23
COMPLETED	16
NOT COMPLETED	7
Period Title: Screening Phase
STARTED	16
COMPLETED	15
NOT COMPLETED	1
Period Title: Screening Phase
STARTED	15
COMPLETED	14
NOT COMPLETED	1
Period Title: Screening Phase
STARTED	14
COMPLETED	11
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Participants	23
Age (Count of Participants)
<=18 years	19 82.6%
Between 18 and 65 years	4 17.4%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.85 (12.02)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	23 100%
Region of Enrollment (participants) [Number]
United States	23 100%

Outcome Measures

1. Primary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of rituximab

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Measure Participants	16
Number (95% Confidence Interval) [proportion of participants]	.1875 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab
	Comments	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 0.05
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.043
	Comments	the a priori p-value was 0.05 for statistical significance
	Method	Exact Binomial
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	.1875
	Confidence Interval	(1-Sided) 95%; .053 to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	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
Description	Presence or absence of at least a minor response in each participant
Time Frame	Measured within approximately 22 weeks

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of rituximab

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Measure Participants	16
Number (95% Confidence Interval) [proportion of participants]	0.25 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab
	Comments	No hypothesis about the value of this proportion was specified in the study design
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	.25
	Confidence Interval	(2-Sided) 95%; 0.073 to 0.524
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All subjects who received a post-treatment rechallenge and had at least a minor response.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Measure Participants	4
Median (Inter-Quartile Range) [percentage change]	-64.31

4. Secondary Outcome

Title	Median Number of Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event
Description	Median number of bleeding events per subject meeting the criteria of a serious adverse event
Time Frame	Measured through Week 100

Outcome Measure Data

Analysis Population Description

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/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Measure Participants	16
Median (Inter-Quartile Range) [participants]	0 0%

5. Secondary Outcome

Title	Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event
Description	Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event
Time Frame	Measured through Week 100

Outcome Measure Data

Analysis Population Description

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/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Measure Participants	16
Median (Inter-Quartile Range) [participants]	19.5 84.8%

6. Secondary Outcome

Title	Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events
Description	Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events
Time Frame	Measured through Week 100

Outcome Measure Data

Analysis Population Description

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/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Measure Participants	16
Median (Inter-Quartile Range) [participants]	1 4.3%

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Measure Participants	16
Median (Inter-Quartile Range) [participants]	1.5 6.5%

8. Secondary Outcome

Title	Proportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported
Description	Proportion of rituximab infusions in which a reaction to the infusion was reported
Time Frame	Measured at Week 1 through Week 4

Outcome Measure Data

Analysis Population Description

All rituximab infusions given to study participants

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Measure Participants	16
Measure rituximab infusions	61
Number (95% Confidence Interval) [proportion of rituximab infusions]	0.11

Adverse Events

Time Frame	Through week 100
Adverse Event Reporting Description	Restricted to the 16 subjects who received at least one dose of rituximab.
Arm/Group Title	Rituximab
Arm/Group Description	Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
All Cause Mortality
	Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	11/16 (68.8%)
Gastrointestinal disorders
Diarrhea	1/16 (6.3%)	1
Mallory-Weiss tear	1/16 (6.3%)	1
General disorders
Allergic reaction/hypersensitivity	1/16 (6.3%)	1
Fever	1/16 (6.3%)	1
Infections and infestations
Central line infection	1/16 (6.3%)	1
Pulmonary/upper respiratory infection	1/16 (6.3%)	1
Sepsis	1/16 (6.3%)	1
Viral meningitis	1/16 (6.3%)	1
Zoster infection	1/16 (6.3%)	1
Injury, poisoning and procedural complications
Bleeding and/or hematoma due to injury	1/16 (6.3%)	1
Bleeding and/or hematoma due to procedure complication	1/16 (6.3%)	1
Hematoma due to injury	1/16 (6.3%)	2
Hematoma due to procedure complication	1/16 (6.3%)	1
Joint and other bleeding due to injury	1/16 (6.3%)	2
Joint bleeding due to injury	3/16 (18.8%)	6
Joint bleeding due to procedure complication	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Bleeding and/or hematoma - spontaneous	1/16 (6.3%)	1
Bone fracture	1/16 (6.3%)	1
Joint and other bleeding - spontaneous	1/16 (6.3%)	1
Joint bleeding - spontaneous	4/16 (25%)	11
Nervous system disorders
Headache	1/16 (6.3%)	1
Subdural hemorrhage	1/16 (6.3%)	2
Respiratory, thoracic and mediastinal disorders
Shortness of breath	1/16 (6.3%)	1
Surgical and medical procedures
Port placement	1/16 (6.3%)	1
Port removal and replacement	1/16 (6.3%)	1
Synovectomy	2/16 (12.5%)	2
Vascular disorders
Hypotension	1/16 (6.3%)	1
Splenic hematoma	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	15/16 (93.8%)
Blood and lymphatic system disorders
Anemia	1/16 (6.3%)	3
Enlarged lymph nodes	1/16 (6.3%)	1
Increased blood lymphocytes	1/16 (6.3%)	1
Increased blood monocytes	1/16 (6.3%)	2
Neutropenia	1/16 (6.3%)	1
White blood cell decrease	1/16 (6.3%)	3
Endocrine disorders
Sweating	1/16 (6.3%)	1
Eye disorders
Pink eye	1/16 (6.3%)	1
Gastrointestinal disorders
Abdominal pain	2/16 (12.5%)	3
Bleeding - spontaneous	4/16 (25%)	12
Diarrhea	1/16 (6.3%)	1
Heartburn	1/16 (6.3%)	1
Nausea	1/16 (6.3%)	3
Toothache	1/16 (6.3%)	1
Vomiting	1/16 (6.3%)	4
General disorders
Bleed and/or hematoma	1/16 (6.3%)	1
Chills	3/16 (18.8%)	3
fatigue	1/16 (6.3%)	2
Fever	2/16 (12.5%)	4
Lethargy	1/16 (6.3%)	1
Hepatobiliary disorders
Decreased ALT	1/16 (6.3%)	3
Elevated ALT	1/16 (6.3%)	7
Immune system disorders
Allergy	1/16 (6.3%)	1
Infections and infestations
Cold sore	1/16 (6.3%)	1
Group A strep	1/16 (6.3%)	2
Influenza	2/16 (12.5%)	2
Septic polyarthritis	1/16 (6.3%)	1
Sinusitis	1/16 (6.3%)	1
Injury, poisoning and procedural complications
Bleed and/or hematoma due to injury	4/16 (25%)	12
Bleeding due to injury	3/16 (18.8%)	9
Bleeding due to procedure complication	2/16 (12.5%)	2
Head injury	2/16 (12.5%)	2
Joint bleeding due to injury	11/16 (68.8%)	31
Joint pain due to injury	1/16 (6.3%)	1
vaccination site reaction	1/16 (6.3%)	1
Hematoma due to injury	6/16 (37.5%)	14
Hematoma due to procedure complication	4/16 (25%)	5
Pain	1/16 (6.3%)	1
Metabolism and nutrition disorders
Anorexia	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Joint bleeding, spontaneous	15/16 (93.8%)	262
Joint pain	1/16 (6.3%)	1
Joint pain, spontaneous	1/16 (6.3%)	2
Joint range of motion decreased	2/16 (12.5%)	2
Muscle pain, spontaneous	1/16 (6.3%)	2
Pain	2/16 (12.5%)	2
Bleed and/or hematoma - spontaneous	10/16 (62.5%)	26
Bleeding - spontaneous	1/16 (6.3%)	1
Hematoma - spontaneous	3/16 (18.8%)	3
Nervous system disorders
Bells palsy	1/16 (6.3%)	1
Bleeding - spontaneous	1/16 (6.3%)	1
Headache	2/16 (12.5%)	2
Intolerance to light	1/16 (6.3%)	1
Renal and urinary disorders
Bleeding - spontaneous	1/16 (6.3%)	2
Hematuria	1/16 (6.3%)	1
Reproductive system and breast disorders
Cold	2/16 (12.5%)	2
Respiratory, thoracic and mediastinal disorders
Asthma	1/16 (6.3%)	3
Bleeding - spontaneous	1/16 (6.3%)	1
Cough	1/16 (6.3%)	3
Elevated carbon dioxide in the blood	1/16 (6.3%)	1
Nasal congestion	1/16 (6.3%)	1
Runny nose	2/16 (12.5%)	3
Sore throat	1/16 (6.3%)	1
Wheezing	1/16 (6.3%)	2
Skin and subcutaneous tissue disorders
Bleed and/or hematoma - spontaneous	7/16 (43.8%)	20
Hematoma - spontaneous	9/16 (56.3%)	24
Rash	2/16 (12.5%)	3
Sunburn	1/16 (6.3%)	1
Bleeding - spontaneous	1/16 (6.3%)	1
Vascular disorders
High blood pressure	1/16 (6.3%)	1
Low blood pressure	1/16 (6.3%)	4
Pulmonary hypertension	1/16 (6.3%)	1

Limitations/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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Baxter donated Factor VIII and Genentech donated rituximab for the study. Both Baxter and Genentech can review results communications prior to public release for a period of time less than or equal to 60 days from the time submitted to them for review. These companies cannot require changes to the communication.