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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

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hemophilia A
Intervention Drug: Rituximab
Enrollment 23
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.
Pre-assignment Details  
Arm/Group Title Rituximab
Hide 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 [1]
Not Completed 7
Reason Not Completed
Withdrawal by Subject             1
enrollment halted             1
Lost to Follow-up             1
Ineligible for treatment phase             4
[1]
subjects eligible for the treatment phase if inhibitor titer following Factor VIII was at least 5 BU
Period Title: Treatment Phase
Started 16
Completed 15
Not Completed 1
Reason Not Completed
Withdrawal by Subject             1
Period Title: Follow-Up Phase I
Started 15
Completed 14
Not Completed 1
Reason Not Completed
Lost to Follow-up             1
Period Title: Follow-Up Phase II
Started 14
Completed 11
Not Completed 3
Reason Not Completed
Lost to Follow-up             3
Arm/Group Title Rituximab
Hide Arm/Group Description Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Number of Baseline Participants 23
Hide Baseline Analysis Population Description
All subjects who began the screening phase
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants
<=18 years
19
  82.6%
Between 18 and 65 years
4
  17.4%
>=65 years
0
   0.0%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 23 participants
15.85  (12.02)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants
Female
0
   0.0%
Male
23
 100.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 23 participants
23
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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of rituximab
Arm/Group Title Rituximab
Hide Arm/Group Description:
Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Number of Participants Analyzed 16
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
.1875
(0.053 to 1.0)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.043
Comments the a priori p-value was 0.05 for statistical significance
Method Exact Binomial
Comments [Not Specified]
Method of Estimation Estimation Parameter Proportion
Estimated Value .1875
Confidence Interval (1-Sided) 95%
.053
Estimation Comments [Not Specified]
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
Hide Description Presence or absence of at least a minor response in each participant
Time Frame Measured within approximately 22 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who received at least one dose of rituximab
Arm/Group Title Rituximab
Hide Arm/Group Description:
Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Number of Participants Analyzed 16
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of participants
0.25
(0.073 to 0.524)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Exact Binomial
Comments [Not Specified]
Method of Estimation Estimation Parameter Proportion
Estimated Value .25
Confidence Interval (2-Sided) 95%
0.073 to 0.524
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percent Change in Inhibitor Titer on Challenge With Factor VIII From Baseline Challenge to Post-treatment Challenge
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All subjects who received a post-treatment rechallenge and had at least a minor response.
Arm/Group Title Rituximab
Hide Arm/Group Description:
Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Number of Participants Analyzed 4
Median (Inter-Quartile Range)
Unit of Measure: percentage change
-64.31
(-77.11 to -44.49)
4.Secondary Outcome
Title Median Number of Bleeding Events Per Subject Meeting the Criteria of a Serious Adverse Event
Hide Description Median number of bleeding events per subject meeting the criteria of a serious adverse event
Time Frame Measured through Week 100
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide Arm/Group Description:
Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Number of Participants Analyzed 16
Median (Inter-Quartile Range)
Unit of Measure: participants
0
(0 to 2)
5.Secondary Outcome
Title Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event
Hide Description Median Number of Bleeding Events Per Subject Not Meeting the Criteria of a Serious Adverse Event
Time Frame Measured through Week 100
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide Arm/Group Description:
Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Number of Participants Analyzed 16
Median (Inter-Quartile Range)
Unit of Measure: participants
19.5
(11 to 41)
6.Secondary Outcome
Title Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events
Hide Description Median Number of Serious Adverse Events Per Subject Other Than Bleeding Events
Time Frame Measured through Week 100
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide Arm/Group Description:
Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Number of Participants Analyzed 16
Median (Inter-Quartile Range)
Unit of Measure: participants
1
(0 to 2.5)
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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide Arm/Group Description:
Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Number of Participants Analyzed 16
Median (Inter-Quartile Range)
Unit of Measure: participants
1.5
(0 to 4)
8.Secondary Outcome
Title Proportion of Rituximab Infusions in Which a Reaction to the Infusion Was Reported
Hide Description Proportion of rituximab infusions in which a reaction to the infusion was reported
Time Frame Measured at Week 1 through Week 4
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All rituximab infusions given to study participants
Arm/Group Title Rituximab
Hide Arm/Group Description:
Rituximab administered at a dose of 375 mg/m^2 by slow intravenous infusion once per week for 4 weeks
Overall Number of Participants Analyzed 16
Overall Number of Units Analyzed
Type of Units Analyzed: Rituximab infusions
61
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: proportion of rituximab infusions
0.11
(0.05 to 0.22)
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
Hide 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 (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Rituximab
Affected / at Risk (%) # Events
Total   11/16 (68.75%)    
Gastrointestinal disorders   
Diarrhea  1 [1]  1/16 (6.25%)  1
Mallory-Weiss tear  1  1/16 (6.25%)  1
General disorders   
Allergic reaction/hypersensitivity  1  1/16 (6.25%)  1
Fever  1 [1]  1/16 (6.25%)  1
Infections and infestations   
Central line infection  1  1/16 (6.25%)  1
Pulmonary/upper respiratory infection  1  1/16 (6.25%)  1
Sepsis  1  1/16 (6.25%)  1
Viral meningitis  1  1/16 (6.25%)  1
Zoster infection  1  1/16 (6.25%)  1
Injury, poisoning and procedural complications   
Bleeding and/or hematoma due to injury  1 [1]  1/16 (6.25%)  1
Bleeding and/or hematoma due to procedure complication  1 [1]  1/16 (6.25%)  1
Hematoma due to injury  1 [1]  1/16 (6.25%)  2
Hematoma due to procedure complication  1 [1]  1/16 (6.25%)  1
Joint and other bleeding due to injury  1 [1]  1/16 (6.25%)  2
Joint bleeding due to injury  1 [1]  3/16 (18.75%)  6
Joint bleeding due to procedure complication  1  1/16 (6.25%)  1
Musculoskeletal and connective tissue disorders   
Bleeding and/or hematoma - spontaneous  1 [1]  1/16 (6.25%)  1
Bone fracture  1  1/16 (6.25%)  1
Joint and other bleeding - spontaneous  1 [1]  1/16 (6.25%)  1
Joint bleeding - spontaneous  1 [1]  4/16 (25.00%)  11
Nervous system disorders   
Headache  1 [1]  1/16 (6.25%)  1
Subdural hemorrhage  1  1/16 (6.25%)  2
Respiratory, thoracic and mediastinal disorders   
Shortness of breath  1 [1]  1/16 (6.25%)  1
Surgical and medical procedures   
Port placement  1  1/16 (6.25%)  1
Port removal and replacement  1  1/16 (6.25%)  1
Synovectomy  1  2/16 (12.50%)  2
Vascular disorders   
Hypotension  1 [1]  1/16 (6.25%)  1
Splenic hematoma  1  1/16 (6.25%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, Modified CTCAE 3.0
[1]
Meeting Serious Adverse Event Criteria
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Rituximab
Affected / at Risk (%) # Events
Total   15/16 (93.75%)    
Blood and lymphatic system disorders   
Anemia  1  1/16 (6.25%)  3
Enlarged lymph nodes  1  1/16 (6.25%)  1
Increased blood lymphocytes  1  1/16 (6.25%)  1
Increased blood monocytes  1  1/16 (6.25%)  2
Neutropenia  1  1/16 (6.25%)  1
White blood cell decrease  1  1/16 (6.25%)  3
Endocrine disorders   
Sweating  1  1/16 (6.25%)  1
Eye disorders   
Pink eye  1  1/16 (6.25%)  1
Gastrointestinal disorders   
Abdominal pain  1  2/16 (12.50%)  3
Bleeding - spontaneous  1  4/16 (25.00%)  12
Diarrhea  1  1/16 (6.25%)  1
Heartburn  1  1/16 (6.25%)  1
Nausea  1  1/16 (6.25%)  3
Toothache  1  1/16 (6.25%)  1
Vomiting  1  1/16 (6.25%)  4
General disorders   
Bleed and/or hematoma  1  1/16 (6.25%)  1
Chills  1  3/16 (18.75%)  3
fatigue  1  1/16 (6.25%)  2
Fever  1  2/16 (12.50%)  4
Lethargy  1  1/16 (6.25%)  1
Hepatobiliary disorders   
Decreased ALT  1  1/16 (6.25%)  3
Elevated ALT  1  1/16 (6.25%)  7
Immune system disorders   
Allergy  1  1/16 (6.25%)  1
Infections and infestations   
Cold sore  1  1/16 (6.25%)  1
Group A strep  1  1/16 (6.25%)  2
Influenza  1  2/16 (12.50%)  2
Septic polyarthritis  1  1/16 (6.25%)  1
Sinusitis  1  1/16 (6.25%)  1
Injury, poisoning and procedural complications   
Bleed and/or hematoma due to injury  1  4/16 (25.00%)  12
Bleeding due to injury  1  3/16 (18.75%)  9
Bleeding due to procedure complication  1  2/16 (12.50%)  2
Head injury  1  2/16 (12.50%)  2
Joint bleeding due to injury  1  11/16 (68.75%)  31
Joint pain due to injury  1  1/16 (6.25%)  1
vaccination site reaction  1  1/16 (6.25%)  1
Hematoma due to injury  1  6/16 (37.50%)  14
Hematoma due to procedure complication  1  4/16 (25.00%)  5
Pain  1  1/16 (6.25%)  1
Metabolism and nutrition disorders   
Anorexia  1  1/16 (6.25%)  1
Musculoskeletal and connective tissue disorders   
Joint bleeding, spontaneous  1  15/16 (93.75%)  262
Joint pain  1  1/16 (6.25%)  1
Joint pain, spontaneous  1  1/16 (6.25%)  2
Joint range of motion decreased  1  2/16 (12.50%)  2
Muscle pain, spontaneous  1  1/16 (6.25%)  2
Pain  1  2/16 (12.50%)  2
Bleed and/or hematoma - spontaneous  1  10/16 (62.50%)  26
Bleeding - spontaneous  1  1/16 (6.25%)  1
Hematoma - spontaneous  1  3/16 (18.75%)  3
Nervous system disorders   
Bells palsy  1  1/16 (6.25%)  1
Bleeding - spontaneous  1  1/16 (6.25%)  1
Headache  1  2/16 (12.50%)  2
Intolerance to light  1  1/16 (6.25%)  1
Renal and urinary disorders   
Bleeding - spontaneous  1  1/16 (6.25%)  2
Hematuria  1  1/16 (6.25%)  1
Reproductive system and breast disorders   
Cold  1  2/16 (12.50%)  2
Respiratory, thoracic and mediastinal disorders   
Asthma  1  1/16 (6.25%)  3
Bleeding - spontaneous  1  1/16 (6.25%)  1
Cough  1  1/16 (6.25%)  3
Elevated carbon dioxide in the blood  1  1/16 (6.25%)  1
Nasal congestion  1  1/16 (6.25%)  1
Runny nose  1  2/16 (12.50%)  3
Sore throat  1  1/16 (6.25%)  1
Wheezing  1  1/16 (6.25%)  2
Skin and subcutaneous tissue disorders   
Bleed and/or hematoma - spontaneous  1  7/16 (43.75%)  20
Hematoma - spontaneous  1  9/16 (56.25%)  24
Rash  1  2/16 (12.50%)  3
Sunburn  1  1/16 (6.25%)  1
Bleeding - spontaneous  1  1/16 (6.25%)  1
Vascular disorders   
High blood pressure  1  1/16 (6.25%)  1
Low blood pressure  1  1/16 (6.25%)  4
Pulmonary hypertension  1  1/16 (6.25%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, Modified CTCAE 3.0
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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Susan F. Assmann, PhD
Organization: New England Research Institutes, Inc.
Phone: 617-972-3048
Responsible Party: New England Research Institutes
ClinicalTrials.gov Identifier: NCT00331006     History of Changes
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 Submitted: May 26, 2006
First Posted: May 29, 2006
Results First Submitted: January 7, 2013
Results First Posted: June 11, 2013
Last Update Posted: June 11, 2013