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A Study to Compare Subcutaneous Versus Intravenous Administration of RoActemra/Actemra (Tocilizumab) in Participants With Moderate to Severe Active Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01194414
First received: September 1, 2010
Last updated: May 11, 2016
Last verified: September 2013
  Purpose
This randomized, double-blind, parallel group study compares the efficacy and safety of subcutaneous (sc) versus intravenous (iv) administration of tocilizumab in participants with moderate to severe active rheumatoid arthritis. Participants were randomized to receive either tocilizumab 162 mg sc weekly plus iv placebo every 4 weeks, or tocilizumab 8 mg/kg iv every 4 weeks plus sc placebo weekly during the double-blind period from baseline to Week 24. The double-blind period was followed by a 72-week open-label treatment with some switching of sc and iv administration. No placebo was administered in the open-label phase. Participants continued on their stable dose of disease-modifying antirheumatic drugs (DMARDs) throughout the study. Anticipated time on study treatment was 2 years.

Condition Intervention Phase
Rheumatoid Arthritis
Drug: tocilizumab SC
Drug: tocilizumab IV
Drug: placebo to tocilizumab SC
Drug: placebo to tocilizumab IV
Drug: Disease-modifying antirheumatic drugs (DMARDs)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Parallel Group Study of the Safety and Effect on Clinical Outcome of Tocilizumab SC Versus Tocilizumab IV, in Combination With Traditional Disease Modifying Anti-rheumatic Drugs (DMARDs), in Patients With Moderate to Severe Active Rheumatoid Arthritis

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR20) Response at Week 24 [ Time Frame: Baseline, 24 weeks ] [ Designated as safety issue: No ]
    ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the five additional ACR core set variables: Patient's Assessment of Pain over the previous 24 hours using a Visual Analog Scale (VAS) where left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions in 8 areas (dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities) answered on a scale of 0=without difficulty to 3=unable to do; and acute-phase reactant (either C-reactive protein [CRP] or Erythrocyte Sedimentation Rate [ESR]).

  • Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments [ Time Frame: Baseline to up to 3 months after last dose of study drug (approximately up to 2 years) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR50) Response at Week 24 [ Time Frame: Baseline, 24 weeks ] [ Designated as safety issue: No ]
    ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the five additional ACR core set variables: Patient's Assessment of Pain over the previous 24 hours using a Visual Analog Scale (VAS) where left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions in 8 areas (dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities) answered on a scale of 0=without difficulty to 3=unable to do; and acute-phase reactant (either C-reactive protein or Erythrocyte Sedimentation Rate).

  • Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR70) Response at Week 24 [ Time Frame: Baseline, 24 weeks ] [ Designated as safety issue: No ]
    ACR70 response is defined as a ≥ 70% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the five additional ACR core set variables: Patient's Assessment of Pain over the previous 24 hours using a Visual Analog Scale (VAS) where left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions in 8 areas (dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities) answered on a scale of 0=without difficulty to 3=unable to do; and acute-phase reactant (either C-reactive protein or Erythrocyte Sedimentation Rate).

  • Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    The DAS28 (ESR) score is a measure of the subject's disease activity. It is calculated using the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity VAS where left side of the line 0=no disease activity to right side of the line 100=extreme disease activity and ESR. DAS28-(ESR) total scores range from 0 - 10. Remission is defined as achieving a DAS28-ESR score of less than 2.6.

  • Percentage of Participants Achieving a Decrease of ≥ 0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 24 [ Time Frame: Baseline, 24 Weeks ] [ Designated as safety issue: No ]
    The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a participant completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do).HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A decrease indicates improvement.

  • Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 24 [ Time Frame: 24 Weeks ] [ Designated as safety issue: No ]
    The percentage of participants who withdrew from the study because they were not responding to treatment with the study drug.

  • Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 [ Time Frame: Week 97 ] [ Designated as safety issue: No ]
    ACR20, ACR50 and ACR70: ≥20%, ≥50% and ≥70% reduction from baseline for both TJC68 and SJC66, as well as for 3 of 5 additional ACR variables: Patient's Assessment of Pain in last 24 hours using a Visual Analog Scale (VAS) (0=no pain and 100=unbearable pain); Patient's and Physician's Global Assessment of Disease Activity in last 24 hours using a VAS (0=no disease activity and100=maximum disease activity); Health Assessment Questionnaire: 20 questions in 8 areas (dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities) answered on a scale of 0=without difficulty to 3=unable to do; and acute-phase reactant (either CRP or ESR). CRP was used for calculation of ACR. If missing, ESR was used. LOCF was used for missing joint counts, no imputation for other ACR components.

  • Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 97 [ Time Frame: Week 97 ] [ Designated as safety issue: No ]
    The DAS28 (ESR) score is a measure of the subject's disease activity. It is calculated using the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity VAS where left side of the line 0=no disease activity to right side of the line 100=extreme disease activity and ESR. DAS28-(ESR) total scores range from 0 - 10. Remission is defined as achieving a DAS28-ESR score of less than 2.6. LOCF used for tender and swollen joint counts, no imputation used for ESR and Patient's Global Assessment of Disease Activity VAS.

  • Percentage of Participants Achieving a Decrease of ≥0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 97 [ Time Frame: Baseline, Week 97 ] [ Designated as safety issue: No ]
    The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do).HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A decrease indicates improvement. No imputation of missing scores was made other than for missing baseline scores, for which last score prior to baseline will be carried forward. For participants who prematurely withdrew, data collected at withdrawal visit was used and data thereafter is missing.

  • Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 97 [ Time Frame: Week 97 ] [ Designated as safety issue: No ]
    The percentage of participants who withdrew from the study because they were not responding to treatment with the study drug.

  • Area Under the Serum Concentration Curve of Tocilizumab After First SC Injection or IV Infusion [ Time Frame: Week 0: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after first dose ] [ Designated as safety issue: No ]
  • Area Under the Serum Concentration Curve of Tocilizumab at Steady State for SC and IV Treatment [ Time Frame: Week 20: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after dose. ] [ Designated as safety issue: No ]
  • Minimum Serum Concentration (Cmin) of Tocilizumab [ Time Frame: Week 0, Week 20: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after dose ] [ Designated as safety issue: No ]
  • Maximum Serum Concentration (Cmax) of Tocilizumab [ Time Frame: Week 0, Week 20: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after dose ] [ Designated as safety issue: No ]
  • Time to Maximum Serum Concentration (Tmax) of Tocilizumab [ Time Frame: Week 0, Week 20: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after dose ] [ Designated as safety issue: No ]
  • Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 [ Time Frame: Baseline, Week 25 ] [ Designated as safety issue: No ]
  • Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 [ Time Frame: Baseline, Week 97 ] [ Designated as safety issue: No ]
  • Percentage of Participants Who Developed Antibodies To Tocilizumab at Week 97 [ Time Frame: Week 97 ] [ Designated as safety issue: No ]

Enrollment: 1262
Study Start Date: September 2010
Study Completion Date: August 2013
Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tocilizumab SC

Participants received tocilizumab 162 mg subcutaneous (SC) injection weekly plus placebo to tocilizumab intravenous (IV) infusion every 4 weeks for a total of 24 weeks in the double-blind period. Participants continued to receive tocilizumab 162 mg SC injection weekly for a total of 72 weeks in open label extension period.

Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) at a stable dose continued throughout the study.

Drug: tocilizumab SC
Tocilizumab supplied in a single-use pre-filled syringe, with a needle safety device, delivering 162 mg/0.9 mL solution for subcutaneous injection once a week.
Other Name: RoActemra/Actemra
Drug: placebo to tocilizumab IV
Placebo to tocilizumab supplied as a solution in 10 mL vials containing polysorbate 80 and sucrose in water for infusion every 4 weeks for a total of 24 weeks in the double-blind period.
Drug: Disease-modifying antirheumatic drugs (DMARDs)
stable dose as prescribed
Experimental: Tocilizumab IV

Participants received tocilizumab 8 mg/kg infusion (IV) every 4 weeks plus placebo to tocilizumab SC injection weekly for a total of 24 weeks in the double-blind period. Participants continued to receive tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 72 weeks in open label extension period.

Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) at a stable dose continued throughout the study.

Drug: tocilizumab IV
Tocilizumab supplied in vials as a sterile solution for 8 mg/kg intravenous infusion every 4 weeks.
Other Name: RoActemra/Actemra
Drug: placebo to tocilizumab SC
Placebo tocilizumab supplied as a single-use pre-filled syringe with a needle safety device, delivering 0.9 mL sodium chloride for subcutaneous injection once a week for 24 weeks in the double-blind period.
Drug: Disease-modifying antirheumatic drugs (DMARDs)
stable dose as prescribed
Experimental: Tocilizumab SC Then Tocilizumab IV

Participants who received tocilizumab 162 mg subcutaneous (SC) injection weekly plus placebo to tocilizumab IV infusion every 4 weeks for 24 weeks in double blind treatment period switched to tocilizumab 8 mg/kg IV infusion every 4 weeks for a total of 72 weeks in open label extension period.

Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) at a stable dose continued throughout the study.

Drug: tocilizumab SC
Tocilizumab supplied in a single-use pre-filled syringe, with a needle safety device, delivering 162 mg/0.9 mL solution for subcutaneous injection once a week.
Other Name: RoActemra/Actemra
Drug: tocilizumab IV
Tocilizumab supplied in vials as a sterile solution for 8 mg/kg intravenous infusion every 4 weeks.
Other Name: RoActemra/Actemra
Drug: placebo to tocilizumab IV
Placebo to tocilizumab supplied as a solution in 10 mL vials containing polysorbate 80 and sucrose in water for infusion every 4 weeks for a total of 24 weeks in the double-blind period.
Drug: Disease-modifying antirheumatic drugs (DMARDs)
stable dose as prescribed
Experimental: Tocilizumab IV Then Tocilizumab SC

Participants who received tocilizumab 8 mg/kg infusion (IV) every 4 weeks plus placebo to tocilizumab SC injection weekly in double blind treatment period switched to tocilizumab 162 mg SC injection weekly for a total of 72 weeks in open label extension period.

Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) at a stable dose will be continued throughout the study.

Drug: tocilizumab SC
Tocilizumab supplied in a single-use pre-filled syringe, with a needle safety device, delivering 162 mg/0.9 mL solution for subcutaneous injection once a week.
Other Name: RoActemra/Actemra
Drug: tocilizumab IV
Tocilizumab supplied in vials as a sterile solution for 8 mg/kg intravenous infusion every 4 weeks.
Other Name: RoActemra/Actemra
Drug: placebo to tocilizumab SC
Placebo tocilizumab supplied as a single-use pre-filled syringe with a needle safety device, delivering 0.9 mL sodium chloride for subcutaneous injection once a week for 24 weeks in the double-blind period.
Drug: Disease-modifying antirheumatic drugs (DMARDs)
stable dose as prescribed

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult participants, ≥ 18 years of age
  • Rheumatoid arthritis of ≥ 6 months duration, according to American College of Rheumatology (ACR) criteria
  • Swollen joint count (SJC) ≥ 4 (66 joint count), tender joint count (TJC) ≥ 4 (68 joint count) at screening and baseline
  • Inadequate response to current DMARD therapy
  • Permitted DMARDs must be at stable dose for ≥ 8 weeks prior to baseline
  • Oral corticosteroids (≤ 10 mg/day prednisone or equivalent) and NSAIDs (up to maximum recommended dose) must be at stable dose for ≥ 4 weeks prior to baseline

Exclusion Criteria:

  • Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization
  • Rheumatic autoimmune disease other than RA
  • Functional class IV (ACR classification)
  • Diagnosis of juvenile idiopathic arthritis (JIA) or juvenile rheumatoid arthritis (JRA) and/or RA before the age of 16
  • Prior history of or current inflammatory joint disease other than RA
  • Intra-articular or parenteral corticosteroids within 4 weeks prior to baseline
  • Previous treatment with tocilizumab
  • Active current or history of recurrent infection
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01194414

  Show 217 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01194414     History of Changes
Other Study ID Numbers: WA22762  2010-018375-22 
Study First Received: September 1, 2010
Results First Received: January 7, 2013
Last Updated: May 11, 2016
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

ClinicalTrials.gov processed this record on December 02, 2016