Rheumatoid Arthritis Clinical Trial
— SUNDIALOfficial 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
Verified date | May 2013 |
Source | Genentech, Inc. |
Contact | n/a |
Is FDA regulated | No |
Health authority | United States: Food and Drug Administration |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 578 |
Est. completion date | February 2013 |
Est. primary completion date | May 2011 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years to 80 Years |
Eligibility |
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-a4 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-a4 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 |
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
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n/a |
Lead Sponsor | Collaborator |
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Genentech, Inc. | Biogen |
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | Yes |
Secondary | 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 | Yes |
Secondary | 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 | Yes |
Secondary | 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 | No |
Secondary | 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 | No |
Secondary | 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 | No |
Secondary | 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 | No |
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