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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: tocilizumab SC
* Drug: tocilizumab IV
* Drug: placebo to tocilizumab SC
* Drug: placebo to tocilizumab IV
* Drug: Disease-modifying antirheumatic drugs (DMARDs)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tocilizumab SC<br>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<br>* 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.<br>* Other names: RoActemra/Actemra;Drug: placebo to tocilizumab IV<br>* 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.<br>Drug: Disease-modifying antirheumatic drugs (DMARDs)<br>* stable dose as prescribed<br>|
| Experimental: Tocilizumab IV<br>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<br>* Tocilizumab supplied in vials as a sterile solution for 8 mg/kg intravenous infusion every 4 weeks.<br>* Other names: RoActemra/Actemra;Drug: placebo to tocilizumab SC<br>* 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.<br>Drug: Disease-modifying antirheumatic drugs (DMARDs)<br>* stable dose as prescribed<br>|
| Experimental: Tocilizumab SC Then Tocilizumab IV<br>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<br>* 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.<br>* Other names: RoActemra/Actemra;Drug: tocilizumab IV<br>* Tocilizumab supplied in vials as a sterile solution for 8 mg/kg intravenous infusion every 4 weeks.<br>* Other names: RoActemra/Actemra;Drug: placebo to tocilizumab IV<br>* 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.<br>Drug: Disease-modifying antirheumatic drugs (DMARDs)<br>* stable dose as prescribed<br>|
| Experimental: Tocilizumab IV Then Tocilizumab SC<br>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<br>* 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.<br>* Other names: RoActemra/Actemra;Drug: tocilizumab IV<br>* Tocilizumab supplied in vials as a sterile solution for 8 mg/kg intravenous infusion every 4 weeks.<br>* Other names: RoActemra/Actemra;Drug: placebo to tocilizumab SC<br>* 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.<br>Drug: Disease-modifying antirheumatic drugs (DMARDs)<br>* stable dose as prescribed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR20) Response at Week 24 | 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]). | Baseline, 24 weeks | 
| Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments |  | Baseline to up to 3 months after last dose of study drug (approximately up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR50) Response at Week 24 | 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). | Baseline, 24 weeks | 
| Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR70) Response at Week 24 | 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). | Baseline, 24 weeks | 
| Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 24 | 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. | Week 24 | 
| Percentage of Participants Achieving a Decrease of ≥ 0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 24 | 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. | Baseline, 24 Weeks | 
| Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 24 | The percentage of participants who withdrew from the study because they were not responding to treatment with the study drug. | 24 Weeks | 
| Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | 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. | Week 97 | 
| Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 97 | 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. | Week 97 | 
| Percentage of Participants Achieving a Decrease of ≥0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 97 | 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. | Baseline, Week 97 | 
| Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 97 | The percentage of participants who withdrew from the study because they were not responding to treatment with the study drug. | Week 97 | 
| Area Under the Serum Concentration Curve of Tocilizumab After First SC Injection or IV Infusion |  | Week 0: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after first dose | 
| Area Under the Serum Concentration Curve of Tocilizumab at Steady State for SC and IV Treatment |  | Week 20: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after dose. | 
| Minimum Serum Concentration (Cmin) of Tocilizumab |  | Week 0, Week 20: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after dose | 
| Maximum Serum Concentration (Cmax) of Tocilizumab |  | Week 0, Week 20: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after dose | 
| Time to Maximum Serum Concentration (Tmax) of Tocilizumab |  | Week 0, Week 20: at 6 hours (hr), 24 hr, 48 hr, 96 hr, 120 hr and 168 hr after dose | 
| Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 |  | Baseline, Week 25 | 
| Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 |  | Baseline, Week 97 | 
| Percentage of Participants Who Developed Antibodies To Tocilizumab at Week 97 |  | Week 97 |