A Study of the Safety of Rituximab in Combination With Other Anti-Rheumatic Drugs in Subjects With Active Rheumatoid Arthritis

Study Overview
=================
Brief Summary
-----------------
This is a Phase III, open-label study of a total of approximately 560 subjects with active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). Enrollment in the study was conducted in two stages. In Stage I of the study, approximately 400 subjects receiving non-biological DMARDs (with the exception of methotrexate [MTX] monotherapy or MTX and leflunomide combination therapy) were enrolled. In Stage II of the study, approximately 160 subjects receiving a Federal Drug Administration-approved biological DMARD at the time of screening were enrolled.

Official Title
-----------------
An Open-Label, Prospective Study of the Safety of Rituximab in Combination With Other Disease-Modifying Anti-Rheumatic Drugs in Subjects With Active Rheumatoid Arthritis

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: Rituximab
* Drug: Anti-inflammatory drugs


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria (Stage I): Male or female subjects, between 18 and 80 years of age, who have a documented diagnosis of active rheumatoid arthritis (RA) for ≥ 6 months Receiving treatment for RA on an outpatient basis Have had an inadequate response to at least one non-biological disease-modifying anti-rheumatic drug (DMARD) and have been receiving this DMARD(s) for ≥ 12 weeks prior to baseline, with stable dose greater than or equal to 4 weeks prior to baseline Demonstrated tolerability to currently prescribed DMARDs If taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to the first day of treatment with rituximab (Day 1) Use of one nonsteroidal anti-inflammatory drug (NSAID) is permitted if the dose is stable for ≥ 2 weeks prior to Day 1 Exclusion Criteria (Stage I): Rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis, or Felty's syndrome) Functional Class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in Rheumatoid Arthritis History of or current inflammatory joint disease other than RA or other systemic autoimmune disorder Diagnosis of juvenile idiopathic arthritis, or juvenile RA, and/or RA before age 16 years Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 24 weeks of enrollment Lack of peripheral venous access Significant cardiac or pulmonary disease (including obstructive pulmonary disease) Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders that, in the investigator's opinion, would preclude subject participation Primary or secondary immunodeficiency (history of or currently active), including known history of human immunodeficiency virus (HIV) infection Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with intravenous (IV) antibiotics within 4 weeks of baseline or completion of oral antibiotics within 2 weeks prior to baseline History of medically significant opportunistic infection History of serious recurrent or chronic infection History of deep space/tissue infection within 52 weeks prior to baseline History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured) History of significant cytopenias or other bone marrow disorders History of alcohol, drug, or chemical abuse within 24 weeks prior to baseline Pregnancy or lactation Neuropathies and neurovasculopathies that might interfere with pain evaluation Methotrexate (MTX) monotherapy at the time of screening Concurrent treatment with MTX and leflunomide in combination Concurrent treatment with any biologic agent Prior to Day 1, subjects will be discontinued from all DMARDs/combinations that are prohibited in the protocol History of a severe allergic or anaphylactic reaction to a biologic agent, or known hypersensitivity to any component of rituximab or to murine proteins Previous treatment with an anti-α4 integrin agent Previous treatment with any cell-depleting therapies, including investigational agents Receipt of any vaccine within 28 days prior to baseline Intolerance or contraindications to IV corticosteroids Receipt of IV immunoglobulin (IVIG) or Prosorba<TM> column within 6 months prior to baseline Any previous treatment with rituximab Positive hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody Inclusion Criteria (Stage II): Male or female subjects, between 18 and 80 years of age, who have a documented diagnosis of active RA for ≥ 6 months, diagnosed according to the revised 1987 ACR criteria for the classification of RA Receiving treatment for RA on an outpatient basis Have had an inadequate response to at least one biologic DMARD and have been receiving this agent at screening and for ≥ 12 weeks prior to baseline, with stable dose greater than or equal to 4 weeks prior to baseline Have demonstrated tolerability to currently prescribed DMARDs/biologics If taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to baseline Use of one NSAID is permitted if the dose is stable for ≥ 2 weeks prior to baseline Exclusion Criteria (Stage II): Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis, or Felty's syndrome) Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis History of, or current, inflammatory joint disease other than RA or other systemic autoimmune disorder Diagnosis of juvenile idiopathic arthritis, or juvenile RA, and/or RA before age 16 years Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 24 weeks of randomization Lack of peripheral venous access Significant cardiac or pulmonary disease (including obstructive pulmonary disease) Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine or gastrointestinal disorders that, in the investigator's opinion, would preclude subject participation Primary or secondary immunodeficiency (history of or currently active), including known history of HIV infection Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of baseline or completion of oral antibiotics within 2 weeks prior to baseline History of medically significant opportunistic infection History of serious recurrent or chronic infection History of deep space/tissue infection within 52 weeks prior to baseline History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured) History of significant cytopenias or other bone marrow disorders History of alcohol, drug, or chemical abuse within 24 weeks prior to baseline Pregnancy or lactation Neuropathies and neurovasculopathies that might interfere with pain evaluation Infliximab monotherapy at the time of screening (infliximab should be in combination with MTX) Concurrent treatment with MTX and leflunomide in combination Concurrent treatment with more than one biologic agent Prior to Day 1, subjects will be discontinued from all DMARDs/combinations that are prohibited in the protocol History of a severe allergic or anaphylactic reaction to a biologic agent, or known hypersensitivity to any component of rituximab or to murine proteins Previous treatment with an anti-α4 integrin agent Previous treatment with any cell-depleting therapies Treatment with any investigational agent within 28 days of baseline or 5 half-lives of the investigational drug (whichever is the longer) Receipt of any vaccine within 28 days prior to baseline Intolerance or contraindications to IV corticosteroids Receipt of IVIG or Prosorba<TM> column within 6 months prior to baseline Any previous treatment with rituximab Positive hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody Positive purified protein derivative (PPD) skin test not adequately treated according to Center for Disease Control (CDC) guidelines

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab 1000 mg (Stage I patients)<br>Stage I patients received 2 doses of rituximab 1000 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 1000 mg given 14 days apart. Concomitant non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations. | Drug: Rituximab<br>* Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials.<br>Drug: Anti-inflammatory drugs<br>* Each rituximab infusion was preceded by methylprednisolone 100 mg IV. Use of stable doses of oral corticosteroids was permitted (≤ 10 mg of prednisone or equivalent per day) as were stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs).<br>|
| Experimental: Rituximab 500 mg (Stage II patients)<br>Stage II patients received 2 doses of rituximab 500 mg administered intravenously (IV) 14 days apart at the beginning of the study (Days 1 and 15). During Weeks 24 to 40, patients who met disease activity and safety criteria were eligible to receive 2 additional IV infusions of rituximab 500 mg given 14 days apart. Concomitant biological and non-biological disease-modifying anti-rheumatic drug (DMARD) therapy, at a stable dose and route, was continued during the study, except for protocol defined prohibited DMARDs/combinations. | Drug: Rituximab<br>* Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials.<br>Drug: Anti-inflammatory drugs<br>* Each rituximab infusion was preceded by methylprednisolone 100 mg IV. Use of stable doses of oral corticosteroids was permitted (≤ 10 mg of prednisone or equivalent per day) as were stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Developing a Serious Adverse Event (SAE) Within 24 Weeks After Receiving the First Course of Rituximab Treatment | An adverse event (AE) is any unfavorable and unintended sign, symptom, significantly abnormal laboratory finding, or disease temporally associated with the use of an investigational medical product or other protocol-imposed intervention. An AE was classified as an SAE if it: Resulted in death, persistent or significant disability/incapacity, or congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product; required or prolonged inpatient hospitalization; was life-threatening or considered a significant medical event by the investigator. | From first treatment with rituximab (Day 1) through Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Developed a Serious Adverse Event (SAE) During or Within 24 Hours of Rituximab Infusions | The percentage of patients developing a SAE during or within 24 hours of a rituximab infusion is reported separately for each of the 2 infusions in the first course of treatment (Days 1 and 15) and the second course of treatment (optional retreatment during Weeks 24 to 40). See the Primary Outcome Measure for a definition of a SAE. | From start of rituximab treatment through 24 hours | 
| Percentage of Patients Who Developed a Serious Adverse Event (SAE) Within 24 Weeks After Receiving the Second Course (Optional Retreatment) of Rituximab Treatment | An adverse event (AE) is any unfavorable and unintended sign, symptom, significantly abnormal laboratory finding, or disease temporally associated with the use of an investigational medical product or other protocol-imposed intervention. An AE was classified as an SAE if it: Resulted in death, persistent or significant disability/incapacity, or congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product; required or prolonged inpatient hospitalization; was life-threatening or considered a significant medical event by the investigator. | From start of the second course of rituximab treatment through Week 48 | 
| Percentage of Patients With an Improvement of 20%, 50%, and 70% in American College of Rheumatology (ACR) Scores (ACR20/50/70) From Baseline at Weeks 24 and 48 | Improvement must be seen in tender and swollen joint counts and in at least 3 of the following 5 parameters. Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate. | Baseline to Week 24 and Week 48 | 
| Percentage of Patients Achieving Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS 28-ESR) Remission and DAS 28-ESR Low Disease Activity Scores at Weeks 24 and 48 | DAS 28-ESR was calculated using counts of tender and swollen joints (28 joints, 28TJC and 28SJC), a patient assessment (PA) of disease activity (DA) in previous 24 hours on a visual analog scale (no DA to maximum DA), and ESR at the current visit, using the following formula: 0.56 × 28TJC + 0.28 × 28SJC + 0.70 × ln(ESR) + 0.014 × PADA. The DAS 28-ESR score ranges from 0 to 10, with higher scores indicating more rheumatoid arthritis. DAS28-ESR Remission was defined as a DAS 28-ESR score of < 2.6. DAS28-ESR Low Disease Activity was defined as a DAS28-ESR score of ≤ 3.2. | Week 24 and Week 48 | 
| Percentage of Patients With European League Against Rheumatism (EULAR) Good and Moderate Responses at Weeks 24 and 48 | Improvement in the post-baseline DAS 28-ESR score from baseline was used to determine the EULAR responses of moderate response and good response. The DAS 28-ESR score ranges from 0 to 10, with higher scores indicating more rheumatoid arthritis. For a post-baseline score ≤ 3.2, an improvement > 0.6 to ≤ 1.2 was a moderate response and ≥ 1.2 a good response. For a post-baseline score > 3.2 to ≤ 5.1, an improvement > 0.6 was a moderate response. For a post-baseline score > 5.1, an improvement ≥ 1.2 was a moderate response. A good response could not be achieved for post-baseline scores > 3.2. | Baseline to Week 24 and Week 48 | 
| Health Assessment Questionnaire-Disability Index (HAQ-DI) Change From Baseline at Weeks 24 and 48 | The HAQ-DI assesses how well the patient is able to perform 8 activities: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. The patient answers 20 questions with 1 of 4 responses with the past week as the time frame: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The highest score for any question in a category determines the category score. The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement. | Baseline to Week 24 and Week 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rituxan, RA, DMARD, Active Rheumatoid Arthritis