Rheumatoid Arthritis
Conditions
Brief summary
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.
Interventions
DRUGtocilizumab 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.
DRUGtocilizumab IV
Tocilizumab supplied in vials as a sterile solution for 8 mg/kg intravenous infusion every 4 weeks.
DRUGplacebo 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.
DRUGplacebo 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.
stable dose as prescribed
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR20) Response at Week 24 | Baseline, 24 weeks | 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 | Baseline to up to 3 months after last dose of study drug (approximately up to 2 years) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 24 | 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. |
| Percentage of Participants Achieving a Decrease of ≥ 0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 24 | Baseline, 24 Weeks | 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 | 24 Weeks | 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 | 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. |
| Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 97 | 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. |
| Percentage of Participants Achieving a Decrease of ≥0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 97 | Baseline, 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. |
| Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 97 | Week 97 | The percentage of participants who withdrew from the study because they were not responding to treatment with the study drug. |
| Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR50) Response at Week 24 | Baseline, 24 weeks | 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). |
| 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 | — |
| 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 | — |
| Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR70) Response at Week 24 | Baseline, 24 weeks | 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). |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Colombia, France, Germany, Guatemala, Hong Kong, Italy, Lithuania, Mexico, New Zealand, Peru, Philippines, Poland, Puerto Rico, Romania, Russia, Singapore, South Africa, Spain, Thailand, United Kingdom, United States
Participant flow
Recruitment details
A total of 1262 participants at 209 centers in 25 countries were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) at a stable dose beginning at least 8 weeks prior to baseline were a requirement of the study. | 631 |
| 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.
Non-biologic disease-modifying anti-rheumatic drugs (DMARDs) at a stable dose beginning at least 8 weeks prior to baseline were a requirement of the study. | 631 |
| Total | 1,262 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 24 Weeks Double Blind Period | Adverse Event | 28 | 40 | 0 | 0 |
| 24 Weeks Double Blind Period | Anaphylaxis or Hypersensitivity Reaction | 2 | 1 | 0 | 0 |
| 24 Weeks Double Blind Period | Death | 0 | 1 | 0 | 0 |
| 24 Weeks Double Blind Period | Insufficient Therapeutic Response | 11 | 8 | 0 | 0 |
| 24 Weeks Double Blind Period | Lost to Follow-up | 2 | 1 | 0 | 0 |
| 24 Weeks Double Blind Period | Other | 0 | 1 | 0 | 0 |
| 24 Weeks Double Blind Period | Physician Decision to Withdraw Subject | 0 | 5 | 0 | 0 |
| 24 Weeks Double Blind Period | Pregnancy | 2 | 2 | 0 | 0 |
| 24 Weeks Double Blind Period | Protocol Violation | 5 | 3 | 0 | 0 |
| 24 Weeks Double Blind Period | Subject/legal Guardian Decision | 9 | 5 | 0 | 0 |
| 72 Weeks Open Label Extension | Adverse Event | 35 | 21 | 2 | 12 |
| 72 Weeks Open Label Extension | Anaphylaxis or Hypersensitivity Reaction | 1 | 1 | 0 | 0 |
| 72 Weeks Open Label Extension | Death | 1 | 2 | 0 | 2 |
| 72 Weeks Open Label Extension | Insufficient Therapeutic Response | 9 | 11 | 2 | 3 |
| 72 Weeks Open Label Extension | Lost to Follow-up | 4 | 3 | 2 | 1 |
| 72 Weeks Open Label Extension | Other | 2 | 1 | 0 | 0 |
| 72 Weeks Open Label Extension | Physician Decision to Withdraw Subject | 3 | 5 | 0 | 0 |
| 72 Weeks Open Label Extension | Pregnancy | 1 | 3 | 1 | 1 |
| 72 Weeks Open Label Extension | Protocol Violation | 0 | 0 | 0 | 1 |
| 72 Weeks Open Label Extension | Randomized but not Treated | 3 | 5 | 0 | 0 |
| 72 Weeks Open Label Extension | Subject/legal Guardian Decision | 20 | 14 | 1 | 6 |
Baseline characteristics
| Characteristic | Tocilizumab SC | Tocilizumab IV | Total |
|---|---|---|---|
| Age, Continuous | 52.7 years STANDARD_DEVIATION 12.35 | 52.8 years STANDARD_DEVIATION 12.53 | 52.7 years STANDARD_DEVIATION 12.44 |
| Sex: Female, Male Female | 520 Participants | 521 Participants | 1041 Participants |
| Sex: Female, Male Male | 111 Participants | 110 Participants | 221 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 488 / 631 | 430 / 631 | 29 / 48 | 118 / 186 |
| serious Total, serious adverse events | 88 / 631 | 80 / 631 | 6 / 48 | 21 / 186 |
Outcome results
Primary
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 \[ESR\]).
Time frame: Baseline, 24 weeks
Population: Per Protocol Population included all randomized participants who received study drug and had no major protocol violations. Last Observation Carried Forward was used for missing joint counts, no imputation for other ACR components. CRP will be used primarily for calculation of the ACR response. If missing, the ESR will be used for that participant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR20) Response at Week 24 | 69.4 Percentage of participants |
| Tocilizumab IV | Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR20) Response at Week 24 | 73.4 Percentage of participants |
Primary
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)
Population: The safety population includes all participants who received at least one dose of study drug, whether re-randomized or not, and who had at least one post-dose safety assessment. Data are included from double blind and open label (OL) periods in the SC and IV arms but only from the OL period in IV-SC and SC-IV switch arms.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tocilizumab SC | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Adverse Events (AEs) | 91.6 percentage of participants |
| Tocilizumab SC | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Clinically Significant Laboratory Assessments | 37.7 percentage of participants |
| Tocilizumab SC | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Serious Adverse Events (SAEs) | 13.9 percentage of participants |
| Tocilizumab IV | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Clinically Significant Laboratory Assessments | 28.2 percentage of participants |
| Tocilizumab IV | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Serious Adverse Events (SAEs) | 12.7 percentage of participants |
| Tocilizumab IV | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Adverse Events (AEs) | 87.8 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Clinically Significant Laboratory Assessments | 25.0 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Adverse Events (AEs) | 81.3 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Serious Adverse Events (SAEs) | 12.5 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Serious Adverse Events (SAEs) | 11.3 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Adverse Events (AEs) | 86.6 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants With Adverse Events, Serious Adverse Events and Clinically Significant Laboratory Assessments | Clinically Significant Laboratory Assessments | 19.4 percentage of participants |
Secondary
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
Population: Pharmacokinetic-Evaluable Population included all participants who provided at least one evaluable PK sample were included in the pharmacokinetic analysis (PK) analysis. Here, number of participants analyzed who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tocilizumab SC | Area Under the Serum Concentration Curve of Tocilizumab After First SC Injection or IV Infusion | 1444 microgram*hour/milliliter (mcg*hr/mL) | Standard Deviation 839 |
| Tocilizumab IV | Area Under the Serum Concentration Curve of Tocilizumab After First SC Injection or IV Infusion | 30988 microgram*hour/milliliter (mcg*hr/mL) | Standard Deviation 9114 |
Secondary
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.
Population: Pharmacokinetic-Evaluable Population included all participants who provided at least one evaluable PK sample were included in the pharmacokinetic analysis (PK) analysis. Here, number of participants analyzed who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tocilizumab SC | Area Under the Serum Concentration Curve of Tocilizumab at Steady State for SC and IV Treatment | 7542 μg*hr/mL | Standard Deviation 3989 |
| Tocilizumab IV | Area Under the Serum Concentration Curve of Tocilizumab at Steady State for SC and IV Treatment | 41304 μg*hr/mL | Standard Deviation 15104 |
Secondary
Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25
Time frame: Baseline, Week 25
Population: The ITT-PK population includes all participants who were eligible for the ITT population and provided at least 1 evaluable PK sample in the double blind or open label periods. Here, number of participants analyzed who were evaluable for this outcome measure and 'n' indicates number of participants who were evaluated at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab SC | Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 | Baseline (n=493, 359, 46, 186) | 39.04 picogram/milliliter (pg/mL) | Standard Deviation 55.456 |
| Tocilizumab SC | Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 | Change at Week 25 (n=385, 280, 33, 149) | 34.42 picogram/milliliter (pg/mL) | Standard Deviation 110.842 |
| Tocilizumab IV | Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 | Change at Week 25 (n=385, 280, 33, 149) | 52.61 picogram/milliliter (pg/mL) | Standard Deviation 507.157 |
| Tocilizumab IV | Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 | Baseline (n=493, 359, 46, 186) | 52.48 picogram/milliliter (pg/mL) | Standard Deviation 240.964 |
| Tocilizumab SC Then Tocilizumab IV | Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 | Change at Week 25 (n=385, 280, 33, 149) | 37.54 picogram/milliliter (pg/mL) | Standard Deviation 93.464 |
| Tocilizumab SC Then Tocilizumab IV | Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 | Baseline (n=493, 359, 46, 186) | 62.18 picogram/milliliter (pg/mL) | Standard Deviation 125.081 |
| Tocilizumab IV Then Tocilizumab SC | Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 | Baseline (n=493, 359, 46, 186) | 50.07 picogram/milliliter (pg/mL) | Standard Deviation 161.045 |
| Tocilizumab IV Then Tocilizumab SC | Change From Baseline in Serum Interleukin-6 (IL-6) Concentration at Week 25 | Change at Week 25 (n=385, 280, 33, 149) | 44.12 picogram/milliliter (pg/mL) | Standard Deviation 136.955 |
Secondary
Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97
Time frame: Baseline, Week 97
Population: The ITT-PK population includes all participants who were eligible for the ITT population and provided at least 1 evaluable PK sample in the double blind or open label periods. Here, number of participants analyzed who were evaluable for this outcome measure and 'n' indicates number of participants who were evaluated at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab SC | Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 | Baseline (n=504, 366, 46, 186) | 44.53 nanogram/milliliter (ng/mL) | Standard Deviation 35.47 |
| Tocilizumab SC | Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 | Change at Week 97 (n=416, 296, 37,157) | 601.52 nanogram/milliliter (ng/mL) | Standard Deviation 222.141 |
| Tocilizumab IV | Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 | Change at Week 97 (n=416, 296, 37,157) | 575.75 nanogram/milliliter (ng/mL) | Standard Deviation 244.398 |
| Tocilizumab IV | Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 | Baseline (n=504, 366, 46, 186) | 45.72 nanogram/milliliter (ng/mL) | Standard Deviation 40.219 |
| Tocilizumab SC Then Tocilizumab IV | Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 | Baseline (n=504, 366, 46, 186) | 44.71 nanogram/milliliter (ng/mL) | Standard Deviation 13.068 |
| Tocilizumab SC Then Tocilizumab IV | Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 | Change at Week 97 (n=416, 296, 37,157) | 569.60 nanogram/milliliter (ng/mL) | Standard Deviation 213.588 |
| Tocilizumab IV Then Tocilizumab SC | Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 | Baseline (n=504, 366, 46, 186) | 43.28 nanogram/milliliter (ng/mL) | Standard Deviation 16.197 |
| Tocilizumab IV Then Tocilizumab SC | Change From Baseline in Serum Soluble Interleukin-6 Receptor (sIL-6R) Concentration at Week 97 | Change at Week 97 (n=416, 296, 37,157) | 586.50 nanogram/milliliter (ng/mL) | Standard Deviation 226.915 |
Secondary
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
Population: Pharmacokinetic-Evaluable Population included all participants who provided at least one evaluable PK sample were included in the PK analysis. Here, number of participants analyzed who were evaluable for this outcome measure and 'n' indicates number of participants who were evaluated at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab SC | Maximum Serum Concentration (Cmax) of Tocilizumab | Week 0 (after first dose) (n=17, 16) | 14.7 mcg/mL | Standard Deviation 8.74 |
| Tocilizumab SC | Maximum Serum Concentration (Cmax) of Tocilizumab | Week 20 (n=13, 13) | 52.7 mcg/mL | Standard Deviation 27.3 |
| Tocilizumab IV | Maximum Serum Concentration (Cmax) of Tocilizumab | Week 0 (after first dose) (n=17, 16) | 180 mcg/mL | Standard Deviation 40.1 |
| Tocilizumab IV | Maximum Serum Concentration (Cmax) of Tocilizumab | Week 20 (n=13, 13) | 233 mcg/mL | Standard Deviation 117 |
Secondary
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
Population: Pharmacokinetic-Evaluable Population included all participants who provided at least one evaluable PK sample were included in the PK analysis. Here, number of participants analyzed who were evaluable for this outcome measure and 'n' indicates number of participants who were evaluated at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab SC | Minimum Serum Concentration (Cmin) of Tocilizumab | Week 0 (after first dose) (n=17, 16) | 7.48 micrgram/milliliter (mcg/mL) | Standard Deviation 4.91 |
| Tocilizumab SC | Minimum Serum Concentration (Cmin) of Tocilizumab | Week 20 (n=13, 13) | 35.7 micrgram/milliliter (mcg/mL) | Standard Deviation 16.2 |
| Tocilizumab IV | Minimum Serum Concentration (Cmin) of Tocilizumab | Week 0 (after first dose) (n=17, 16) | 6.65 micrgram/milliliter (mcg/mL) | Standard Deviation 6.05 |
| Tocilizumab IV | Minimum Serum Concentration (Cmin) of Tocilizumab | Week 20 (n=13, 13) | 16.0 micrgram/milliliter (mcg/mL) | Standard Deviation 10.3 |
Secondary
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.
Time frame: Baseline, 24 Weeks
Population: Participants from the Per Protocol Population (all randomized participants who received study drug and had no major protocol violations) with data available for analysis. No imputation of missing scores will be made other than for missing baseline scores, for which last score prior to defined protocol baseline time window will be carried forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants Achieving a Decrease of ≥ 0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 24 | 65.2 Percentage of participants |
| Tocilizumab IV | Percentage of Participants Achieving a Decrease of ≥ 0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 24 | 67.4 Percentage of participants |
Secondary
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.
Time frame: Baseline, Week 97
Population: ITT Population included all participants who completed double blind period and were re-randomized at Week 24 and received at least one dose of study drug. Here, number of participants analyzed is the participants for whom parameter was collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants Achieving a Decrease of ≥0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 97 | 72.4 percentage of participants |
| Tocilizumab IV | Percentage of Participants Achieving a Decrease of ≥0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 97 | 69.1 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants Achieving a Decrease of ≥0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 97 | 56.4 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants Achieving a Decrease of ≥0.3 in the Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline to Week 97 | 71.0 percentage of participants |
Secondary
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).
Time frame: Baseline, 24 weeks
Population: Per Protocol Population included all randomized participants who received study drug and had no major protocol violations. Last Observation Carried Forward was used for missing joint counts, no imputation for other ACR components. CRP will be used primarily for calculation of the ACR response. If missing, the ESR will be used for that participant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR50) Response at Week 24 | 47.0 Percentage of participants |
| Tocilizumab IV | Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR50) Response at Week 24 | 48.6 Percentage of participants |
Secondary
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).
Time frame: Baseline, 24 weeks
Population: Per Protocol Population included all randomized participants who received study drug and had no major protocol violations. Last Observation Carried Forward was used for missing joint counts, no imputation for other ACR components. CRP will be used primarily for calculation of the ACR response. If missing, the ESR will be used for that participant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR70) Response at Week 24 | 24.0 Percentage of participants |
| Tocilizumab IV | Percentage of Participants Achieving an American College of Rheumatology Criteria (ACR70) Response at Week 24 | 27.9 Percentage of participants |
Secondary
Percentage of Participants Who Developed Antibodies To Tocilizumab at Week 97
Time frame: Week 97
Population: The safety population includes all participants who received at least one dose of study drug, whether re-randomized or not, and who had at least one post-dose safety assessment. Here, 'n' indicates number of subjects in the safety population tested by screening assay at any time point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants Who Developed Antibodies To Tocilizumab at Week 97 | 1.3 percentage of participants |
| Tocilizumab IV | Percentage of Participants Who Developed Antibodies To Tocilizumab at Week 97 | 1.0 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants Who Developed Antibodies To Tocilizumab at Week 97 | 0.0 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants Who Developed Antibodies To Tocilizumab at Week 97 | 0.5 percentage of participants |
Secondary
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.
Time frame: 24 Weeks
Population: Per Protocol Population included all randomized participants who received study drug and had no major protocol violations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 24 | 1.8 Percentage of participants |
| Tocilizumab IV | Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 24 | 0.9 Percentage of participants |
Secondary
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.
Time frame: Week 97
Population: ITT Population included all participants who completed double blind period and were re-randomized at Week 24 and received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 97 | 1.7 percentage of participants |
| Tocilizumab IV | Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 97 | 3.0 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 97 | 4.2 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants Who Withdrew Because of Lack of Therapeutic Response at Week 97 | 1.6 percentage of participants |
Secondary
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.
Time frame: Week 97
Population: Re-Randomized Intent-to-Treat Population (ITT Population) included all participants who completed double blind period and were re-randomized at Week 24, received at least 1 dose of study drug. Here, number of participants analyzed is the participants for whom parameter was collected.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tocilizumab SC | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR20 | 83.6 percentage of participants |
| Tocilizumab SC | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR50 | 65.4 percentage of participants |
| Tocilizumab SC | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR70 | 44.8 percentage of participants |
| Tocilizumab IV | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR20 | 83.3 percentage of participants |
| Tocilizumab IV | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR50 | 62.5 percentage of participants |
| Tocilizumab IV | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR70 | 42.0 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR20 | 82.5 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR50 | 57.5 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR70 | 37.5 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR50 | 67.3 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR70 | 47.3 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants With American College of Rheumatology Criteria (ACR20, ACR50, ACR70) at Week 97 | ACR20 | 88.5 percentage of participants |
Secondary
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.
Time frame: Week 24
Population: Participants from the Per Protocol Population (randomized participants who received study drug and had no major protocol violations) with data available for analysis. Missing SJC and TJC will be imputed using the last post-baseline value for the patient (LOCF). No imputation for missing ESR or patient's global assessment of disease activity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 24 | 38.4 Percentage of participants |
| Tocilizumab IV | Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 24 | 36.9 Percentage of participants |
Secondary
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.
Time frame: Week 97
Population: ITT Population included all participants who completed double blind period and were re-randomized at Week 24 and received at least one dose of study drug. If ESR=0 then ESR=1 is substituted into the DAS28 calculation to enable a non-missing DAS28 score. Here, number of participants analyzed is the participants for whom parameter was collected.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab SC | Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 97 | 53.4 percentage of participants |
| Tocilizumab IV | Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 97 | 46.4 percentage of participants |
| Tocilizumab SC Then Tocilizumab IV | Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 97 | 50.0 percentage of participants |
| Tocilizumab IV Then Tocilizumab SC | Percentage of Participants With Disease Activity Score 28 (DAS28) Remission at Week 97 | 55.6 percentage of participants |
Secondary
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
Population: Pharmacokinetic-Evaluable Population included all participants who provided at least one evaluable PK sample were included in the PK analysis. Here, number of participants analyzed who were evaluable for this outcome measure and 'n' indicates number of participants who were evaluated at specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tocilizumab SC | Time to Maximum Serum Concentration (Tmax) of Tocilizumab | Week 0 (after first dose) (n=17, 16) | 74 hour (hr) |
| Tocilizumab SC | Time to Maximum Serum Concentration (Tmax) of Tocilizumab | Week 20 (n=13, 13) | 70 hour (hr) |
| Tocilizumab IV | Time to Maximum Serum Concentration (Tmax) of Tocilizumab | Week 0 (after first dose) (n=17, 16) | 6 hour (hr) |
| Tocilizumab IV | Time to Maximum Serum Concentration (Tmax) of Tocilizumab | Week 20 (n=13, 13) | 6 hour (hr) |