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

Study Overview
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Brief Summary
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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.

Official Title
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A Multicenter, Open-label, Single-arm Study to Evaluate the Safety Administering Rituximab at a More Rapid Infusion Rate in Patients With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: rituximab
* Drug: methotrexate
* Drug: methylprednisolone
* Drug: acetaminophen
* Drug: antihistamine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>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<br>* 1000 mg in 250 mL intravenous infusion<br>* Other names: MabThera®;Drug: methotrexate<br>* 10 to 25 mg/week (oral or parenteral)<br>Drug: methylprednisolone<br>* 100 mg methylprednisolone administered by slow intravenous infusion at least 30 minutes prior to the start of each study drug infusion<br>Drug: acetaminophen<br>* 1 gram acetaminophen administered orally 30 to 60 minutes prior to the start of each study drug infusion<br>Drug: antihistamine<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Any Infusion-related Reaction (IRR) Associated With the Second Rituximab Infusion | 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. | Within 24 hours of beginning infusion on Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Any Serious IRR (SIRR) Associated With the Second Rituximab Infusion | 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. | Within 24 hours of beginning infusion on Day 15 | 
| Percentage of Participants Experiencing Any IRR or SIRR Associated With the Third Rituximab Infusion | 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. | Within 24 hours of beginning infusion on Day 168 | 
| Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Second Rituximab Infusion | 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. | Within 24 hours of beginning infusion on Day 15 | 
| Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Second Rituximab Infusion | 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. | During the infusion (a 2-hour period) on Day 15 | 
| Percentage of Participants Experiencing Any Common Toxicity Criteria (CTC) Grade 3 or 4 Adverse Events (AEs) Associated With the Third Rituximab Infusion | 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. | Within 24 hours of beginning infusion on Day 168 | 
| Percentage of Participants Experiencing the Stopping, Slowing or Interrupting of the Third Rituximab Infusion | 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. | During the infusion (a 2-hour period) on Day 168 |