RATE-RA: A Study on The Safety of Administering Rituximab at A More Rapid Rate in Patients With Rheumatoid Arthritis

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01382940
• Collaborator: (none)
• Enrollment: 351
• Locations: 86
• Arm: 1
• Actual Duration (Months): 17.4
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study was designed to evaluate the safety of administering rituximab at a more rapid infusion rate in patients with moderate to severe rheumatoid arthritis who have had an inadequate response to biopharmaceuticals that treat diseases by interfering with tumor necrosis factor (anti-TNF therapies), and were receiving methotrexate therapy for more than eight weeks.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: rituximab; Drug: methotrexate; Drug: methylprednisolone; Drug: acetaminophen; Drug: antihistamine	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 351 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open-label, Single-arm Study to Evaluate the Safety Administering Rituximab at a More Rapid Infusion Rate in Patients With Rheumatoid Arthritis
• Actual Study Start Date: Jul 26, 2011
• Actual Primary Completion Date: Jan 6, 2013
• Actual Study Completion Date: Jan 6, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Rituximab Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.

Drug: rituximab; 1000 mg in 250 mL intravenous infusion; Other Names: Rituxan® MabThera® ; Drug: methotrexate; 10 to 25 mg/week (oral or parenteral); Drug: methylprednisolone; 100 mg methylprednisolone administered by slow intravenous infusion at least 30 minutes prior to the start of each study drug infusion; Drug: acetaminophen; 1 gram acetaminophen administered orally 30 to 60 minutes prior to the start of each study drug infusion; Drug: antihistamine; 50 mg diphenhydramine hydrochloride or equivalent dose of alternate antihistamine administered orally 30 to 60 minutes prior to the start of each study drug infusion

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Experiencing Any Infusion-related Reaction (IRR) Associated With the Second Rituximab Infusion [Within 24 hours of beginning infusion on Day 15]

   The primary criterion for assessing safety of the faster infusion was the incidence of infusion related reaction (IRRs). IRRs were adverse events (AEs) that occurred within 24 hours of beginning infusion that were among a pre-specified list of preferred terms from the Medical Dictionary for Regulatory Activities (MedDRA). "Incidence" is defined as the percentage of participants experiencing an IRR.

Secondary Outcome Measures

1. Percentage of Participants Experiencing Any Serious IRR (SIRR) Associated With the Second Rituximab Infusion [Within 24 hours of beginning infusion on Day 15]

   A serious infusion-related reaction (SIRR) is an IRR that meets the definition of a serious adverse event. A serious adverse event (SAE) is any experience that suggests a significant hazard, contraindication, side effect or precaution.

2. Percentage of Participants Experiencing Any IRR or SIRR Associated With the Third Rituximab Infusion [Within 24 hours of beginning infusion on Day 168]

   IRRs are AEs that occurred within 24 hours of beginning infusion that were included on a pre-specified list of MedDRA preferred terms, and an SIRR is an IRR that suggests a significant hazard, contraindication, side effect or precaution.

3. Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Second Rituximab Infusion [Within 24 hours of beginning infusion on Day 15]

   The intensity of AEs were graded on a 5-point scale (Grade 1 to 5) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0), where Grade 1 indicates "Mild" severity and Grade 5 indicates "Death". The CTCAE defines Grades 3 and 4 as follows: - Grade 3 means "Severe", indicating considerable interference with the patient's daily activities; medical intervention/therapy required; and hospitalization possible. - Grade 4 means "Life-threatening, Disabling", based on extreme limitation in activity; significant medical intervention/therapy required, and hospitalization probable.

4. Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Second Rituximab Infusion [During the infusion (a 2-hour period) on Day 15]

   Participants who experienced a moderate or serious IRR had their infusion interrupted immediately and received aggressive symptomatic treatment. The CTCAE includes the following severity descriptions: - "Moderate" means mild to moderate interference with the patient's daily activities, no or minimal medical intervention/therapy required; - "Severe" means considerable interference with the patient's daily activities, medical intervention/therapy required, hospitalization possible. If the IRR was moderate, the infusion was not to be restarted before all the symptoms disappeared, and then at half the rate. If the participant tolerated the reduced rate for 30 minutes, the infusion rate was increased to the next rate on the protocol-specified infusion schedule. If the symptoms did not resolve with treatment, the participant was withdrawn from the treatment period of the study. Participants who experienced a severe IRR to rituximab treatment were discontinued from the study.

5. Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Third Rituximab Infusion [Within 24 hours of beginning infusion on Day 168]

   The intensity of AEs experienced within 24 hours of beginning infusion were graded on NCI's CTCAE (v. 4.0) intensity scale from Grade 1 ("Mild") to Grade 5 ("Death"). Grade 3 AEs are "Severe" and Grade 4 AEs are "Life-threatening, Disabling".

6. Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Third Rituximab Infusion [During the infusion (a 2-hour period) on Day 168]

   Participants who experienced a moderate or serious IRR had their infusion interrupted immediately and received aggressive symptomatic treatment. The CTCAE includes the following severity descriptions: - "Moderate" means mild to moderate interference with the patient's daily activities, no or minimal medical intervention/therapy required; - "Severe" means considerable interference with the patient's daily activities, medical intervention/therapy required, hospitalization possible. If the IRR was moderate, the infusion was not to be restarted before all the symptoms disappeared, and then at half the rate. If the participant tolerated the reduced rate for 30 minutes, the infusion rate was increased to the next rate on the protocol-specified infusion schedule. If the symptoms did not resolve with treatment, the participant was withdrawn from the treatment period of the study. Participants who experienced a severe IRR to rituximab treatment were discontinued from the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Adult patients, ≥ 18 years of age

• Rheumatoid arthritis of ≥ 6 months duration, diagnosed according to the revised 1987 American College of Rheumatology criteria

• Inadequate response to at least one approved anti-TNF agent (adalimumab, etanercept, infliximab, golimumab, or certolizumab)

• Patients who have received 1 to 2 prior courses of rituximab (RTX) may be enrolled, provided their most recent course of RTX occurred over 6 months but no more than 9 months prior to baseline. The RTX dosage must have been two 1000 mg infusions per course administered at the standard approved rate

• Methotrexate treatment between 10 and 25 mg/week (oral or parenteral) for at least 8 weeks immediately prior to baseline

Key Exclusion Criteria:

• Major surgery (including joint surgery) within 8 weeks prior to screening or planned surgery within 6 months following baseline

• Rheumatic autoimmune disease other than rheumatoid arthritis

• Functional class IV as defined by American College of Rheumatology (ACR) criteria

• Prior history of or current inflammatory joint disease other than rheumatoid arthritis

• History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies

• Previous serious infusion reaction to any prior biologic therapy

• Known active current or history of recurrent infection

• Evidence of chronic hepatitis B or C infection

• Pregnant or lactating women

• Body weight of > 150 kg

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Uni Of Alabama,Birmingham; Medicine - Rheumatology	Birmingham	Alabama	United States	35294
2	Clnical & Translational Reseach Center for Alabama, PC	Tuscaloosa	Alabama	United States	35406
3	ArthroCare, Arthritis Care; and Research P.C.	Gilbert	Arizona	United States	85234
4	Valley Arthritis Care	Phoenix	Arizona	United States	85027
5	Catalina Pointe Rheumatology	Tucson	Arizona	United States	85704
6	Medvin Clinical Research	Covina	California	United States	91723
7	Triwest Research Associates	La Mesa	California	United States	91942
8	Medvin Clinical Research	Los Angeles	California	United States	90048
9	Brigid Freyne-Private Practice; Internal Medicine, Rheum	Murrieta	California	United States	92563
10	Desert Medical Advances; Rheumatology	Palm Desert	California	United States	92260
11	San Diego Arthritis Med Clnc	San Diego	California	United States	92108
12	Pacific Arthritis Ctr Med Grp	Santa Maria	California	United States	93454
13	Inland Rheumatology; Clinical Trials, Inc.	Upland	California	United States	91786
14	Medvin Clinical Research	Whittier	California	United States	90606
15	Arthritis Assoc & Osteoporosis; Ctr of Colorado Springs	Colorado Springs	Colorado	United States	80920
16	Denver Arthritis Clinic	Denver	Colorado	United States	80230-7127
17	Rheum & Internal Med Assoc-Bri	Bridgeport	Connecticut	United States	06606
18	Arthritis & Osteoporosis Center Pc	Hamden	Connecticut	United States	06518
19	Rheumatolgy Consultants of Deleware	Lewes	Delaware	United States	19958
20	Javed Rheumatology Associates, Inc.	Newark	Delaware	United States	19713
21	Arthritis & Rheumatism; Disease Specialities	Aventura	Florida	United States	33180
22	Florida Arthritis Center, PI	Lake Mary	Florida	United States	32746
23	Omega ResearchConsultants LLC	Orlando	Florida	United States	32804
24	Millenium Research	Ormond Beach	Florida	United States	32174
25	Arthritis Center Palm Harbor	Palm Harbor	Florida	United States	34684
26	Arthritis Rsrch of Florida, Inc.	Palm Harbor	Florida	United States	34684
27	Center For Arthritis; Research Dept	South Miami	Florida	United States	33143
28	University of South Florida	Tampa	Florida	United States	33612
29	Florida Medical Clinic; Clinical Research	Zephyrhills	Florida	United States	33613
30	Parris & Associates	Lawrenceville	Georgia	United States	30046
31	St. Luke's Intermountain Research Center	Boise	Idaho	United States	83702
32	Institute of Arthritis Research	Idaho Falls	Idaho	United States	83404
33	Quad City Rheumatology, Sc	Moline	Illinois	United States	61265
34	Physician'S Clinic of Iowa	Cedar Rapids	Iowa	United States	52401
35	Bluegrass Comm Research, Inc.	Lexington	Kentucky	United States	40515
36	Klein & Associates, M.D. P.A.	Cumberland	Maryland	United States	21502
37	Klein & Associates, M.D., P.A.	Hagerstown	Maryland	United States	21740
38	St. Luke's Hospital Association of Duluth	Duluth	Minnesota	United States	55805
39	Arthritis and Osteoporosis; Treatment and Research Center	Flowood	Mississippi	United States	39232
40	Jackson Arthritis Clinic	Flowood	Mississippi	United States	39232
41	North Mississippi Med Clinics, Inc.	Tupelo	Mississippi	United States	38801
42	David S Rosenberg	Florissant	Missouri	United States	63031
43	Arthritis Center of Reno	Reno	Nevada	United States	89502
44	Rheumatology Research Group	Lebanon	New Hampshire	United States	03756
45	Rheumatology Associates Of New Jersey	Teaneck	New Jersey	United States	07666
46	The Center for Rheumatology	Albany	New York	United States	12203
47	Arthritis & Osteoporosis Center	Brooklyn	New York	United States	11201
48	NYU Center for Musculoskeletal Care	New York	New York	United States	10003
49	Buffalo Rheumatology Associates	Orchard Park	New York	United States	14127
50	Office of Premier Chatpar Md	Plainview	New York	United States	11803
51	Aair Research Center	Rochester	New York	United States	14618
52	Rheumatology Associates of Long Island	Smithtown	New York	United States	11787
53	Arthritis Health Associates; Clinical Research	Syracuse	New York	United States	13210
54	Arth&OsteoConsof theCarolinas-Charlotte	Charlotte	North Carolina	United States	28207
55	Box Arthritis & Rheumatology	Charlotte	North Carolina	United States	28210
56	Carolina Bone & Joint P.A.	Charlotte	North Carolina	United States	28210
57	Physicians East Pa	Greenville	North Carolina	United States	27834
58	Shanahan Rheumatology & Immunology, PLLC	Raleigh	North Carolina	United States	27617
59	Crystal Arthritis Center, Inc.	Akron	Ohio	United States	44333
60	CarePoint East	Columbus	Ohio	United States	43203
61	Stat Research, Inc	Dayton	Ohio	United States	45402
62	Paramount Medical Research	Middleburg Heights	Ohio	United States	44130
63	LION Research	Norman	Oklahoma	United States	73069
64	Arthritis and Rheumatology; Center of Oklahoma PLLC	Oklahoma City	Oklahoma	United States	73103
65	East Penn Rheumatology Associates, Pc	Bethlehem	Pennsylvania	United States	18015
66	Altoona Center For Clinical Research	Duncansville	Pennsylvania	United States	16635
67	Pivotal Clinical Research, Llc	Perkasie	Pennsylvania	United States	18944
68	Arthritis Group	Philadelphia	Pennsylvania	United States	19152
69	Rheumatic Disease Associates; Clinical Research Unit	Willow Grove	Pennsylvania	United States	19090
70	Clinical Research Center of Reading	Wyomissing	Pennsylvania	United States	19610
71	Pennsylvania Regional Center for Arthritis and Osteoporosis Research	Wyomissing	Pennsylvania	United States	19610
72	Low Country Rheumatology, PA	Charleston	South Carolina	United States	29406
73	Rheumatology Associates	Charleston	South Carolina	United States	29407
74	West Tennessee Research Institute	Jackson	Tennessee	United States	38305
75	Ramesh Gupta - PP	Memphis	Tennessee	United States	38119
76	Amarillo Center For Clinical Research	Amarillo	Texas	United States	79124
77	Lovelace Scientific Resources Inc.	Austin	Texas	United States	78758
78	Adriana Pop-Moody MD Clinic PA	Corpus Christi	Texas	United States	78404
79	Arthritis Centers of Texas	Dallas	Texas	United States	75246
80	Southwest Rheumatology	Mesquite	Texas	United States	75150
81	Arthritis Clinic of Northern Virginia	Arlington	Virginia	United States	22205
82	Apex Clinical Research	Kennewick	Washington	United States	99336
83	Seattle Arthritis Clinic	Seattle	Washington	United States	98133
84	Arthritis Northwest, Spokane	Spokane	Washington	United States	99204
85	Cedar Medical Center	Tacoma	Washington	United States	98405
86	Rheumatic Disease Center	Glendale	Wisconsin	United States	53217

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01382940
• Other Study ID Numbers: ML25641
• First Posted: Jun 27, 2011
• Last Update Posted: Aug 1, 2017
• Last Verified: Jul 1, 2017

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Acetaminophen; Methylprednisolone; Rituximab; Methotrexate; Histamine Antagonists; Histamine H1 Antagonists

Study Results

Participant Flow

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
Period Title: Overall Study
STARTED	351
Received Day 1 Infusion	351
Received Day 15 Infusions	341
Received Day 168 Infusion	290
Received Day 182 Infusion	278
COMPLETED	278
NOT COMPLETED	73

Baseline Characteristics

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
Overall Participants	351
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.5 (11.5)
Sex: Female, Male (Count of Participants)
Female	279 79.5%
Male	72 20.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Experiencing Any Infusion-related Reaction (IRR) Associated With the Second Rituximab Infusion
Description	The primary criterion for assessing safety of the faster infusion was the incidence of infusion related reaction (IRRs). IRRs were adverse events (AEs) that occurred within 24 hours of beginning infusion that were among a pre-specified list of preferred terms from the Medical Dictionary for Regulatory Activities (MedDRA). "Incidence" is defined as the percentage of participants experiencing an IRR.
Time Frame	Within 24 hours of beginning infusion on Day 15

Outcome Measure Data

Analysis Population Description

All randomized participants who received infusion at the faster rate on Day 15. Four participants who received the Day 15 rituximab infusion were excluded from the primary analysis population because their infusion rates could not be determined.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
Measure Participants	337
Number (95% Confidence Interval) [percentage of participants]	6.5 (6.5) 1.9%

2. Secondary Outcome

Title	Percentage of Participants Experiencing Any Serious IRR (SIRR) Associated With the Second Rituximab Infusion
Description	A serious infusion-related reaction (SIRR) is an IRR that meets the definition of a serious adverse event. A serious adverse event (SAE) is any experience that suggests a significant hazard, contraindication, side effect or precaution.
Time Frame	Within 24 hours of beginning infusion on Day 15

Outcome Measure Data

Analysis Population Description

All randomized participants who received infusion at the faster rate on Day 15. Four participants who received the Day 15 rituximab infusion were excluded from the primary analysis population because their infusion rates could not be determined.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
Measure Participants	337
Number (95% Confidence Interval) [percentage of participants]	0.0 0%

3. Secondary Outcome

Title	Percentage of Participants Experiencing Any IRR or SIRR Associated With the Third Rituximab Infusion
Description	IRRs are AEs that occurred within 24 hours of beginning infusion that were included on a pre-specified list of MedDRA preferred terms, and an SIRR is an IRR that suggests a significant hazard, contraindication, side effect or precaution.
Time Frame	Within 24 hours of beginning infusion on Day 168

Outcome Measure Data

Analysis Population Description

All randomized participants who received infusion at the faster rate on Day 168. One participant received the Day 168 rituximab infusion at the labeled rate rather than at the faster rate and was excluded from the analysis population.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
Measure Participants	289
Any IRR	5.9 1.7%
Any SIRR	0.0 0%

4. Secondary Outcome

Title	Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Second Rituximab Infusion
Description	The intensity of AEs were graded on a 5-point scale (Grade 1 to 5) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0), where Grade 1 indicates "Mild" severity and Grade 5 indicates "Death". The CTCAE defines Grades 3 and 4 as follows: - Grade 3 means "Severe", indicating considerable interference with the patient's daily activities; medical intervention/therapy required; and hospitalization possible. - Grade 4 means "Life-threatening, Disabling", based on extreme limitation in activity; significant medical intervention/therapy required, and hospitalization probable.
Time Frame	Within 24 hours of beginning infusion on Day 15

Outcome Measure Data

Analysis Population Description

All randomized participants who received infusion at the faster rate on Day 15. Four participants who received the Day 15 rituximab infusion were excluded from the primary analysis population because their infusion rates could not be determined.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
Measure Participants	337
Number (95% Confidence Interval) [percentage of participants]	0.6 0.2%

5. Secondary Outcome

Title	Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Second Rituximab Infusion
Description	Participants who experienced a moderate or serious IRR had their infusion interrupted immediately and received aggressive symptomatic treatment. The CTCAE includes the following severity descriptions: - "Moderate" means mild to moderate interference with the patient's daily activities, no or minimal medical intervention/therapy required; - "Severe" means considerable interference with the patient's daily activities, medical intervention/therapy required, hospitalization possible. If the IRR was moderate, the infusion was not to be restarted before all the symptoms disappeared, and then at half the rate. If the participant tolerated the reduced rate for 30 minutes, the infusion rate was increased to the next rate on the protocol-specified infusion schedule. If the symptoms did not resolve with treatment, the participant was withdrawn from the treatment period of the study. Participants who experienced a severe IRR to rituximab treatment were discontinued from the study.
Time Frame	During the infusion (a 2-hour period) on Day 15

Outcome Measure Data

Analysis Population Description

All randomized participants who received infusion at the faster rate on Day 15. Four participants who received the Day 15 rituximab infusion were excluded from the primary analysis population because their infusion rates could not be determined.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
Measure Participants	337
Number (95% Confidence Interval) [percentage of participants]	3.9 1.1%

6. Secondary Outcome

Title	Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Third Rituximab Infusion
Description	The intensity of AEs experienced within 24 hours of beginning infusion were graded on NCI's CTCAE (v. 4.0) intensity scale from Grade 1 ("Mild") to Grade 5 ("Death"). Grade 3 AEs are "Severe" and Grade 4 AEs are "Life-threatening, Disabling".
Time Frame	Within 24 hours of beginning infusion on Day 168

Outcome Measure Data

Analysis Population Description

All randomized participants who received infusion at the faster rate on Day 168. One participant received the Day 168 rituximab infusion at the labeled rate rather than at the faster rate and was excluded from the analysis population.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
Measure Participants	289
Number (95% Confidence Interval) [percentage of participants]	0.0 0%

7. Secondary Outcome

Title	Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Third Rituximab Infusion
Description	Participants who experienced a moderate or serious IRR had their infusion interrupted immediately and received aggressive symptomatic treatment. The CTCAE includes the following severity descriptions: - "Moderate" means mild to moderate interference with the patient's daily activities, no or minimal medical intervention/therapy required; - "Severe" means considerable interference with the patient's daily activities, medical intervention/therapy required, hospitalization possible. If the IRR was moderate, the infusion was not to be restarted before all the symptoms disappeared, and then at half the rate. If the participant tolerated the reduced rate for 30 minutes, the infusion rate was increased to the next rate on the protocol-specified infusion schedule. If the symptoms did not resolve with treatment, the participant was withdrawn from the treatment period of the study. Participants who experienced a severe IRR to rituximab treatment were discontinued from the study.
Time Frame	During the infusion (a 2-hour period) on Day 168

Outcome Measure Data

Analysis Population Description

All randomized participants who received infusion at the faster rate on Day 168. One participant received the Day 168 rituximab infusion at the labeled rate rather than at the faster rate and was excluded from the analysis population.

Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
Measure Participants	289
Number (95% Confidence Interval) [percentage of participants]	6.6 1.9%

Adverse Events

Time Frame	Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210).
Adverse Event Reporting Description	The safety evaluable population included all participants who received rituximab during the study and had at least one safety assessment during or after the rituximab infusion.
Arm/Group Title	Rituximab
Arm/Group Description	Rituximab intravenous (IV) infusions were administered over a 4.25-hour period on Day 1, and over a 2-hour period on Day 15 (first course) and on Days 168 and 182 (second course). All participants continued to receive methotrexate as prescribed by their treating physician. Premedication included methylprednisolone, an antihistamine and acetaminophen.
All Cause Mortality
	Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	30/351 (8.5%)
Blood and lymphatic system disorders
Febrile neutropenia	1/351 (0.3%)
Cardiac disorders
Atrial fibrillation	2/351 (0.6%)
Cardiac failure congestive	1/351 (0.3%)
Myocardial infarction	1/351 (0.3%)
Pericardial effusion	1/351 (0.3%)
Ear and labyrinth disorders
Deafness neurosensory	1/351 (0.3%)
Gastrointestinal disorders
Colitis ischaemic	1/351 (0.3%)
General disorders
Device breakage	1/351 (0.3%)
Chest discomfort	1/351 (0.3%)
Infections and infestations
Pneumonia	4/351 (1.1%)
Sepsis	1/351 (0.3%)
Septic shock	1/351 (0.3%)
Urosepsis	1/351 (0.3%)
Diverticulitis	1/351 (0.3%)
Injury, poisoning and procedural complications
Hip fracture	2/351 (0.6%)
Femur fracture	1/351 (0.3%)
Joint dislocation	1/351 (0.3%)
Fall	1/351 (0.3%)
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis	2/351 (0.6%)
Costochondritis	1/351 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/351 (0.3%)
Nervous system disorders
VIIth nerve paralysis	1/351 (0.3%)
Complex partial seizures	1/351 (0.3%)
Convulsion	1/351 (0.3%)
Renal and urinary disorders
Nephrolithiasis	1/351 (0.3%)
Reproductive system and breast disorders
Menorrhagia	1/351 (0.3%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/351 (0.3%)
Other (Not Including Serious) Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	37/351 (10.5%)
Infections and infestations
Upper Respiratory Tract Infection	19/351 (5.4%)
Nervous system disorders
Headache	20/351 (5.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.