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A Study on Safety and Efficacy of Tocilizumab (RoActemra/Actemra) Alone or in Combination With Non-Biologic Antirheumatics in Participants With Rheumatoid Arthritis (OSCAR)

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ClinicalTrials.gov Identifier: NCT01987479
Recruitment Status : Completed
First Posted : November 19, 2013
Results First Posted : June 19, 2017
Last Update Posted : June 19, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
This multi-center, open-label single arm Phase IIIb study will evaluate the safety and efficacy of subcutaneous (SC) tocilizumab administered as monotherapy and/or in combination with methotrexate or other non-biologic disease modifying antirheumatic drugs (DMARDs) in participants with rheumatoid arthritis (RA) with an inadequate response to non-biologic DMARDs.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Drug: Non-Biologic DMARDs Drug: Tocilizumab Drug: Methotrexate Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 150 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multi-Center, Open Label, Single Arm Phase IIIB Study on Safety and Efficacy of Subcutaneous Tocilizumab in Monotherapy or in Combination With Methotrexate or Other Non-Biologic Disease Modifying Antirheumatic Drugs in Rheumatoid Arthritis Patients With an Inadequate Response to Non-Biologic DMARDs - OSCAR
Actual Study Start Date : January 30, 2014
Actual Primary Completion Date : May 26, 2016
Actual Study Completion Date : May 26, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tocilizumab Alone or in Combination with Methotrexate or DMARD
Participants will receive a weekly SC injection of tocilizumab 162 milligrams (mg) as monotherapy or in combination with methotrexate or other non-biologic DMARDs for 24 weeks.
Drug: Non-Biologic DMARDs
Treatment with non-biologic DMARDs, at a stable dose that was initiated at least 4 weeks prior to baseline, is permitted during the study and is at the investigator's discretion.

Drug: Tocilizumab
Tocilizumab 162 mg will be administered once a week by SC injection and as a single fixed dose, irrespective of body weight, for the treatment duration of 24 weeks.
Other Name: RoActemra, Actemra

Drug: Methotrexate
Methotrexate will be administered per investigator's discretion.




Primary Outcome Measures :
  1. Percentage of Participants With Adverse Events [ Time Frame: Baseline up to Week 32 ]
    An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Adverse events included serious as well as non-serious adverse events.


Secondary Outcome Measures :
  1. Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) Score at Weeks 2, 4, 8, 12, 16, 20, 24, and Early Withdrawal [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    DAS28 was calculated from swollen joint count (SJC) and tender joint count (TJC) using 28 joints count, erythrocyte sedimentation rate (ESR; millimeters per hour [mm/hour]), and patient's global assessment of disease activity (measured on a 0 to 100 mm Visual Analog Scale [VAS] where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR less than or equal to (≤) 3.2 implied low disease activity and greater than (>) 3.2 to 5.1 implied moderate to high disease activity, and DAS28-ESR less than (<) 2.6 implied clinical remission.

  2. Percentage of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    A participant had an ACR20 response if there was at least a 20 percent (%) improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either C-reactive protein [CRP] or ESR).

  3. Percentage of Participants Achieving an ACR50 Response [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    A participant had an ACR50 response if there was at least a 50% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR).

  4. Percentage of Participants Achieving an ACR70 Response [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    A participant had an ACR70 response if there was at least a 70% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR).

  5. Percentage of Participants Achieving an ACR90 Response [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    A participant had an ACR90 response if there was at least a 90% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR).

  6. Percentage of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (VAS: 0 mm=no disease activity to 100 mm=maximum disease activity). DAS28-ESR scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. The DAS28-ESR based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders had a change from baseline >1.2 with a DAS28 score ≤3.2; moderate responders had a change from baseline >1.2 with a DAS28 score >3.2 or a change from baseline >0.6 to ≤1.2 with a DAS28 score ≤5.1. Participants with change from baseline >0.6 to ≤1.2 with a DAS28 score >5.1, or any score with change from baseline ≤0.6, were assessed as non-responders.

  7. Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, and Early Withdrawal [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    The SDAI is the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, patient and physician global assessment of disease activity assessed on 0-10 centimeter (cm) VAS (0 cm= no disease activity and 10 cm= worst disease activity), and CRP in milligrams per liter (mg/L). SDAI total score = 0-86. SDAI <=3.3 indicates clinical remission, >3.4 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high (or severe) disease activity .

  8. Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 16, 20, 24, and Early Withdrawal [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    The CDAI is the numerical sum of four outcome parameters: TJC and SJC based on a 28-joint assessment, patient and physician's global assessment of disease activity assessed on 0-10 cm VAS (0 cm= no disease activity and 10 cm= worst disease activity). CDAI total score = 0-76. CDAI <= 2.8 indicates clinical remission, >2.8 to 10 = low disease activity, >10 to 22 = moderate disease activity, and >22 = high (or severe) disease activity.

  9. Change From Baseline in Total TJC at Weeks 2, 4, 8, 12, 16, 20, 24, and Early Withdrawal [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    Number of tender joints was determined by examining 28 joints for TJC28 and 68 joints for TJC68, and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28 for a TJC28 and 68 for a TJC68. A reduction in number of tender joints compared to baseline indicates improvement.

  10. Change From Baseline in Total SJC at Weeks 2, 4, 8, 12, 16, 20, 24, and Early Withdrawal [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and at Early Withdrawal (up to Week 24) ]
    Number of swollen joints was determined by examination of 28 joints for SJC28 and 66 joints for SJC66 and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28 for a SJC28 and 66 for a SJC66. A reduction in number of swollen joints compared to baseline indicates improvement.

  11. Percentage of Participants With Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Dose Reductions or Discontinuation Categorized by Reasons [ Time Frame: From Week 16 and before Week 20; From Week 20 and before Week 24 ]
    Results are reported for percentage of participants who had NSAIDs dose reductions or discontinuation by reasons for dose reductions or discontinuation (unknown reasons, safety reasons, other reasons, lack of efficacy, and discomfort).

  12. Percentage of Participants With Corticosteroid Dose Reductions or Discontinuation Categorized by Reasons [ Time Frame: From Week 16 and before Week 20; From Week 20 and before Week 24 ]
    Results are reported for percentage of participants who had corticosteroid dose reductions or discontinuation by reasons for dose reductions or discontinuation (unknown reasons, safety reasons, other reasons, lack of efficacy, and discomfort).

  13. Time to Discontinuation or First Dose Reduction of Corticosteroids or NSAIDs [ Time Frame: Baseline up to Week 32 ]
    Time to discontinuation or first dose reduction of corticosteroids or NSAIDs (weeks) = (Date of the first dose reduction or end date of corticosteroids or NSAIDs treatment - date of first drug intake of this study) + 1. Time to discontinuation or first dose reduction was based on the first occurring event (corticosteroid discontinuation or corticosteroid first dose reduction or NSAIDs discontinuation or NSAIDs first dose reduction, whichever occurred first).

  14. Percentage of Participants With Anti-Tocilizumab Antibodies [ Time Frame: Baseline, Weeks 12 and 24, early withdrawal (up to Week 24), follow-up visit (8 weeks after last dose of tocilizumab, up to 32 weeks) ]
  15. Serum Levels of Tocilizumab [ Time Frame: Baseline, Weeks 12 and 24, Early Withdrawal (up to Week 24), Follow-up Visit (8 weeks after last dose of tocilizumab, up to 32 weeks) ]
  16. Serum Levels of Soluble Interleukin-6 Receptors (sIL-6Rs) [ Time Frame: Baseline, Weeks 12 and 24, Early Withdrawal (up to Week 24), Follow-up Visit (8 weeks after last dose of tocilizumab, up to 32 weeks) ]
  17. Patient Global Assessment of Disease Activity VAS Scores [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and Early withdrawal (up to Week 24) ]
    Patient global assessment of disease activity was measured on a 0 to 100 mm horizontal VAS where 0 mm=no disease activity and 100 mm=maximum disease activity.

  18. Patient Pain VAS Scores [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and Early withdrawal (up to Week 24) ]
    This assessment represents the participant's assessment of his/her current level of pain on a 100 mm horizontal VAS where 0 mm= no pain to 100 mm= unbearable pain.

  19. Health Assessment Questionnaire-Disability Index (HAQ-DI) Score [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and early withdrawal (up to Week 24) ]
    The HAQ-DI questionnaire measures functional status (disability) and health-related quality of life. It measures the participant's ability to perform everyday tasks. The index consists of 20 questions regarding the function of the upper and lower extremities. These questions are summarized in 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common activities over past week. Each question is evaluated according to the degree of severity on a 4-point scale. Total score for HAQ-DI was the average of all questions and ranges from 0 = without any difficulty to 3 = unable to do.

  20. Percentage of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 24, and early withdrawal (up to Week 24) ]
    A diary card was provided to participants to record home injections. Participants were asked to return all empty drug supply boxes, unused pre-filled syringe, and diary cards to the clinic at each visit as a measure of drug accountability and participant compliance. A participant was considered compliant if the participant correctly administered all scheduled doses of SC tocilizumab during the assessment period.

  21. Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score [ Time Frame: Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, and early withdrawal (up to Week 24) ]
    The FACIT-F score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participants fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants with a diagnosis of active RA according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria.
  • Oral corticosteroids (≤10 mg/day prednisone or equivalent), nonsteroidal anti-inflammatory drugs (NSAIDs) and non-biologic DMARDs are permitted if on a stable dose regimen for greater than or equal to (≥]) 4 weeks prior to Baseline.
  • Use of effective contraception throughout the study as defined by protocol; female participants of childbearing potential cannot be pregnant.

Exclusion Criteria:

  • Presence of clinically significant medical conditions.
  • History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower gastrointestinal disease that might predispose to perforation.
  • Current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections.
  • Any infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening.
  • Clinically significant findings on laboratory tests.
  • Positive hepatitis B surface antigen or hepatitis C antibody.
  • Active tuberculosis requiring treatment within the previous 3 years.
  • Evidence of active malignant disease, malignancies diagnosed within the previous 10 years, or breast cancer diagnosed within the previous 20 years.
  • History of alcohol, drug, or chemical abuse within 1 year prior to Screening.
  • Neuropathies or other conditions that might interfere with pain evaluation.
  • Major surgery (including joint surgery) within 8 weeks prior to Screening or planned major surgery within 6 months following Baseline.
  • Rheumatic autoimmune disease other than RA, including systemic lupus erythematosis, mixed connective tissue disorder, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty's syndrome). Secondary Sjögren's syndrome with RA is permitted.
  • Functional Class IV as defined by the ACR Classification of Functional Status in RA.
  • Diagnosis of juvenile idiopathic arthritis or juvenile RA, and/or RA before the age of 16 years.
  • Prior history of or current inflammatory joint disease other than RA.
  • Exposure to tocilizumab (either intravenous or SC) at any time prior to Baseline.
  • Treatment with any investigational agent within 4 weeks (or five half-lives of the investigational drug, whichever is longer) of Screening.
  • Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
  • Treatment with IV gamma globulin, plasmapheresis within 6 months of Baseline.
  • Immunization with a live/attenuated vaccine within 4 weeks prior to Baseline.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01987479


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01987479    
Other Study ID Numbers: ML28702
2013-000342-19 ( EudraCT Number )
First Posted: November 19, 2013    Key Record Dates
Results First Posted: June 19, 2017
Last Update Posted: June 19, 2017
Last Verified: May 2017

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors