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A Study of Tocilizumab in Combination With DMARDs in Patients With Moderate to Severe Rheumatoid Arthritis (ROSE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00531817
First received: September 18, 2007
Last updated: August 13, 2012
Last verified: August 2012
History of Changes
  Purpose

This 2-arm study assessed the safety and efficacy of tocilizumab versus placebo, both in combination with disease modifying antirheumatic drugs (DMARDs), in regard to reduction in signs and symptoms, in patients with moderate to severe active rheumatoid arthritis with an inadequate response to DMARDs. Patients were randomized in a ratio of 2:1 to receive either tocilizumab 8 mg/kg intravenously (IV) or placebo IV every 4 weeks. All patients also received stable antirheumatic therapy, including permitted DMARDs. The anticipated time on study treatment was 3-12 months and the target sample size was 500+ individuals.


Condition Intervention Phase
Rheumatoid Arthritis
 Drug: Tocilizumab
Drug: Placebo
Drug: Permitted DMARDs
 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Parallel-group Study to Evaluate the Safety and Efficacy of Tocilizumab (TCZ) Versus Placebo in Combination With Disease Modifying Antirheumatic Drugs (DMARDs) in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA)

Resource links provided by NLM:

Drug Information available for: Tocilizumab
U.S. FDA Resources

Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Patients With an Improvement of at Least 50% in American College of Rheumatology (ACR) Score (ACR50) From Baseline at Week 24 [ Time Frame: Baseline to Week 24 ] [ 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.


Secondary Outcome Measures:
  • Percentage of Patients With an Improvement of at Least 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20, ACR50, ACR70) From Baseline at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Baseline to Weeks 4, 8, 12, 16, 20, 24 ] [ 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.

  • Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Baseline to Weeks 4, 8, 12, 16, 20, 24 ] [ Designated as safety issue: No ]
    DAS28 was calculated using the following formula: 0.56 × sqrt(TJC) + 0.28 × sqrt(SJC) + 0.70 × ln(ESR) + 0.014 × GH, where TJC = tender joint count on 28 joints, SJC = swollen joint count on 28 joints, ESR = erythrocyte sedimentation rate at the current visit (mm/hr), and GH = general health, ie, the patient's global assessment of disease activity (DA) in the previous 24 hours on a 100 mm visual analog scale (no DA to maximum DA). The DAS28 score ranges from 0 to 10, with higher scores indicating more rheumatoid arthritis. A negative change score indicates improvement.

  • Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Baseline to Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    Change of the DAS28 score from baseline was used to determine the EULAR responses of good, moderate, or no response. For a post-baseline score ≤ 3.2, a change from baseline of < -1.2 was a good response, < -0.6 to ≥ -1.2 was a moderate response, and ≥ -0.6 was no response. For a post-baseline score > 3.2 to ≤ 5.1, a change from baseline of < -0.6 was a moderate response and ≥ -0.6 was no response. For a post-baseline score > 5.1, a change from baseline < -1.2 was a moderate response and ≥ -1.2 was no response. A good response could not be achieved for post-baseline scores > 3.2.

  • Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Baseline to Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    Derived from the Multidimensional Health Assessment Questionnaire (MDHAQ), the RAPID includes 3 domains that assess disease activity in rheumatoid arthritis: A physical function score (MDHAQ items 1a-j), a pain visual analog scale score (VAS, item 2 in the MDHAQ), and a global assessment of disease activity VAS score (item 6 in the MDHAQ). Each domain is scored on a scale of 0-10. The RAPID score is the sum of the 3 domain scores divided by 3 resulting in a total score on a scale of 0-10. Higher scores indicate more disease activity and a negative change from baseline indicates improvement.

  • Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Baseline to Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The SF-12 is a self-report measure of general health status with 1 or 2 items for each of 8 domains: Physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health. Two component summaries, physical (PCS-12) and mental (MCS-12) were calculated using norm-based scoring, resulting in means of 50 and standard deviations of 10 in the 1998 general United States population. Higher scores represent better health and a positive change from baseline represents improvement.

  • Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Baseline to Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The FACIT-F is a 13-item patient self-report questionnaire that assesses fatigue over the previous 7 days by scoring each item on a 5-point scale (0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Very much). An overall FACIT-F score was obtained by summing the scores of all 13 items. The overall score ranged from 0 to 52. A lower score indicates less fatigue. A negative change score indicates improvement.

  • Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24 [ Time Frame: Baseline to Weeks 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
    The MOS Sleep Scale is a 12-item patient self-report instrument that assesses the quality and quantity of sleep over the previous 4 weeks. A sleep problems index (SLP9) was generated using 9 of the 12 items (1, 3, 4, 5, 6, 7, 8, 9, 12). Each item was normalized so that the lowest and highest possible scores were set to 0 and 100, respectively. The SLP9 score is the average of the recoded 9 items. The SLP9 score ranged from 0 to 100. Higher scores represent greater sleep problems. A negative change score indicates improvement.

  • Mean Change From Baseline in Individual Components of the Routine Assessment Patient Index Data (RAPID) at Each Day During the First 7 Days of Treatment [ Time Frame: Baseline through Day 7 ] [ Designated as safety issue: No ]
    Derived from the Multidimensional Health Assessment Questionnaire (MDHAQ), the RAPID includes 3 domains that assess disease activity in rheumatoid arthritis: A physical function score (0-10), a pain visual analog scale score (VAS, 0-100), and a global assessment of disease activity VAS score (0-100). Each domain was assessed with the Patient Take Home Form (PTHF). Higher scores indicate more disease activity. A negative change score indicates improvement.

  • Percentage of Patients With an Improvement of at Least 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20, ACR50, ACR70) From Baseline at Day 7 [ Time Frame: Baseline to Day 7 ] [ 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.

  • Mean Change From Baseline in C-reactive Protein (CRP) at Days 3 and 7 [ Time Frame: Baseline to Days 3 and 7 ] [ Designated as safety issue: No ]
    Serum concentration of CRP (high-sensitivity CRP [hsCRP] test) was analyzed by a central laboratory.


Enrollment: 619
Study Start Date: October 2007
Study Completion Date: March 2011
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tocilizumab 8 mg/kg + DMARDs Drug: Tocilizumab
Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Other Names:
  • Actemra
  • RoActemra
Drug: Permitted DMARDs
As prescribed. The following DMARDs were permitted in this study: methotrexate (MTX), chloroquine, hydroxychloroquine, parenteral gold, sulfasalazine, azathioprine, and leflunomide. These DMARDs could be used alone or in combination, except for the combination of MTX and leflunomide, which was not allowed.
Placebo Comparator: Placebo + DMARDs Drug: Placebo
Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Drug: Permitted DMARDs
As prescribed. The following DMARDs were permitted in this study: methotrexate (MTX), chloroquine, hydroxychloroquine, parenteral gold, sulfasalazine, azathioprine, and leflunomide. These DMARDs could be used alone or in combination, except for the combination of MTX and leflunomide, which was not allowed.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients, ≥18 years of age
  • Active rheumatoid arthritis of >6 months duration
  • Received permitted DMARDs each at a stable dose for at least 7 weeks prior to baseline

Exclusion Criteria:

  • Rheumatic autoimmune disease or inflammatory joint disease other than rheumatoid arthritis
  • Major surgery within 8 weeks prior to screening or planned within 6 months following randomization
  • Unsuccessful treatment with a biologic agent, including an anti-TNF agent
  • Previous treatment with tocilizumab
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00531817

  Show 157 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Additional Information:
Clinical Study Report Synopsis  This link exits the ClinicalTrials.gov site

No publications provided by Hoffmann-La Roche

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00531817     History of Changes
Other Study ID Numbers: ML21136
Study First Received: September 18, 2007
Results First Received: July 6, 2010
Last Updated: August 13, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
 Autoimmune Diseases
Immune System Diseases
Antirheumatic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 23, 2013