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

This study has been completed.
Sponsor:
Collaborator:
Biogen Idec
Information provided by (Responsible Party):
Genentech
ClinicalTrials.gov Identifier:
NCT00443651
First received: March 2, 2007
Last updated: May 20, 2013
Last verified: May 2013
  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:


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
Study Completion Date: February 2013
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).

  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 by Genentech

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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: May 20, 2013
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 April 17, 2014