Trial Outcomes & Findings for A Study on The Safety of Administering Rituximab at A More Rapid Rate in Patients With Rheumatoid Arthritis (NCT NCT01382940)

Last Updated: 2017-08-01

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

351 participants

Primary outcome timeframe

Within 24 hours of beginning infusion on Day 15

Results posted on

2017-08-01

Participant Flow

Participant milestones

Participant milestones
Measure	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.
Overall Study STARTED	351
Overall Study Received Day 1 Infusion	351
Overall Study Received Day 15 Infusions	341
Overall Study Received Day 168 Infusion	290
Overall Study Received Day 182 Infusion	278
Overall Study COMPLETED	278
Overall Study NOT COMPLETED	73

Reasons for withdrawal

Reasons for withdrawal
Measure	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.
Overall Study Adverse Event	19
Overall Study Lost to Follow-up	4
Overall Study Physician Decision	7
Overall Study Withdrawal by Subject	23
Overall Study Protocol Violation	20

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab n=351 Participants 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.
Age, Continuous	55.5 years STANDARD_DEVIATION 11.5 • n=5 Participants
Sex: Female, Male Female	279 Participants n=5 Participants
Sex: Female, Male Male	72 Participants n=5 Participants

PRIMARY outcome

Timeframe: Within 24 hours of beginning infusion on Day 15

Population: 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.

Outcome measures

Outcome measures
Measure	Rituximab n=337 Participants 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.
Percentage of Participants Experiencing Any Infusion-related Reaction (IRR) Associated With the Second Rituximab Infusion	6.5 percentage of participants 95% Confidence Interval 6.5 • Interval 4.1 to 9.7

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rituximab n=337 Participants 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.
Percentage of Participants Experiencing Any Serious IRR (SIRR) Associated With the Second Rituximab Infusion	0.0 percentage of participants Interval 0.0 to 1.1

SECONDARY outcome

Timeframe: Within 24 hours of beginning infusion on Day 168

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Rituximab n=289 Participants 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.
Percentage of Participants Experiencing Any IRR or SIRR Associated With the Third Rituximab Infusion Any IRR	5.9 percentage of participants Interval 3.5 to 9.3
Percentage of Participants Experiencing Any IRR or SIRR Associated With the Third Rituximab Infusion Any SIRR	0.0 percentage of participants Interval 0.0 to 1.3

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rituximab n=337 Participants 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.
Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Second Rituximab Infusion	0.6 percentage of participants Interval 0.1 to 2.1

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rituximab n=337 Participants 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.
Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Second Rituximab Infusion	3.9 percentage of participants Interval 2.1 to 6.5

SECONDARY outcome

Timeframe: 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".

Outcome measures

Outcome measures
Measure	Rituximab n=289 Participants 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.
Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Third Rituximab Infusion	0.0 percentage of participants Interval 0.0 to 1.3

SECONDARY outcome

Timeframe: During the infusion (a 2-hour period) on Day 168

Outcome measures

Outcome measures
Measure	Rituximab n=289 Participants 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.
Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Third Rituximab Infusion	6.6 percentage of participants Interval 4.0 to 10.1

Adverse Events

Rituximab

Serious events: 30 serious events

Other events: 37 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Rituximab n=351 participants at risk 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.
Blood and lymphatic system disorders Febrile neutropenia	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Cardiac disorders Atrial fibrillation	0.57% 2/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Cardiac disorders Cardiac failure congestive	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Cardiac disorders Myocardial infarction	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Cardiac disorders Pericardial effusion	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Ear and labyrinth disorders Deafness neurosensory	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Gastrointestinal disorders Colitis ischaemic	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
General disorders Device breakage	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
General disorders Chest discomfort	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Infections and infestations Pneumonia	1.1% 4/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Infections and infestations Sepsis	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Infections and infestations Septic shock	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Infections and infestations Urosepsis	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Infections and infestations Diverticulitis	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Injury, poisoning and procedural complications Hip fracture	0.57% 2/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Injury, poisoning and procedural complications Femur fracture	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Injury, poisoning and procedural complications Joint dislocation	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Injury, poisoning and procedural complications Fall	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.57% 2/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Musculoskeletal and connective tissue disorders Costochondritis	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Nervous system disorders VIIth nerve paralysis	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Nervous system disorders Complex partial seizures	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Nervous system disorders Convulsion	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Renal and urinary disorders Nephrolithiasis	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Reproductive system and breast disorders Menorrhagia	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.28% 1/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.

Other adverse events

Other adverse events
Measure	Rituximab n=351 participants at risk 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.
Infections and infestations Upper Respiratory Tract Infection	5.4% 19/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.
Nervous system disorders Headache	5.7% 20/351 • Adverse events were collected at each visit and during a follow-up telephone visit four weeks after the last rituximab infusion (Day 210). 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.

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER