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

Purpose

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.

Condition	Intervention	Phase
Rheumatoid Arthritis	Drug: Rituximab Drug: Anti-inflammatory drugs	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
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

Resource links provided by NLM:

MedlinePlus related topics: Rheumatoid Arthritis

Drug Information available for: Rituximab

U.S. FDA Resources

Further study details as provided by Genentech:

Primary Outcome Measures:

Percentage of Patients Developing a Serious Adverse Event (SAE) Within 24 Weeks After Receiving the First Course of Rituximab Treatment [ Time Frame: From first treatment with rituximab (Day 1) through Week 24 ] [ Designated as safety issue: Yes ]
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.

Secondary Outcome Measures:

Percentage of Patients Who Developed a Serious Adverse Event (SAE) During or Within 24 Hours of Rituximab Infusions [ Time Frame: From start of rituximab treatment through 24 hours ] [ Designated as safety issue: Yes ]
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.
Percentage of Patients Who Developed a Serious Adverse Event (SAE) Within 24 Weeks After Receiving the Second Course (Optional Retreatment) of Rituximab Treatment [ Time Frame: From start of the second course of rituximab treatment through Week 48 ] [ Designated as safety issue: Yes ]
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.
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 [ Time Frame: Baseline to Week 24 and Week 48 ] [ Designated as safety issue: No ]
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.
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 [ Time Frame: Week 24 and Week 48 ] [ Designated as safety issue: No ]
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.
Percentage of Patients With European League Against Rheumatism (EULAR) Good and Moderate Responses at Weeks 24 and 48 [ Time Frame: Baseline to Week 24 and Week 48 ] [ Designated as safety issue: No ]
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.
Health Assessment Questionnaire-Disability Index (HAQ-DI) Change From Baseline at Weeks 24 and 48 [ Time Frame: Baseline to Week 24 and Week 48 ] [ Designated as safety issue: No ]
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.

Enrollment:	578
Study Start Date:	January 2007
Estimated Study Completion Date:	December 2012
Primary Completion Date:	May 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Rituximab 1000 mg (Stage I patients) 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 Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials. Drug: Anti-inflammatory drugs 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).
Experimental: Rituximab 500 mg (Stage II patients) 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 Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials. Drug: Anti-inflammatory drugs 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).

Arms

Assigned Interventions

Experimental: Rituximab 1000 mg (Stage I patients)

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

Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials.

Drug: Anti-inflammatory drugs

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).

Experimental: Rituximab 500 mg (Stage II patients)

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

Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials.

Drug: Anti-inflammatory drugs

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).

Eligibility

Ages Eligible for Study:	18 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00443651

Sponsors and Collaborators

Genentech

Biogen Idec

Investigators

Study Director:

Micki Klearman, M.D.

Genentech

More Information

No publications provided

Responsible Party:	Genentech
ClinicalTrials.gov Identifier:	NCT00443651 History of Changes
Other Study ID Numbers:	U3924g
Study First Received:	March 2, 2007
Results First Received:	April 18, 2012
Last Updated:	July 31, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Genentech:

Rituxan
RA
DMARD
Active Rheumatoid Arthritis

Additional relevant MeSH terms:

Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases

Rituximab
Antirheumatic Agents
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents

ClinicalTrials.gov processed this record on May 19, 2013

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