Rheumatoid Arthritis
Conditions
Brief summary
This 3 arm randomized open label study will evaluate the safety, tolerability and efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis, who have had inadequate response to or are unable to tolerate DMARDs. The protocol incorporates risk mitigation strategies developed in partnership with the FDA to manage known and potential risks associated with the treatment of tocilizumab. Patients will be randomized to receive tocilizumab either 4 mg/kg intravenous (iv) or 8 mg/kg iv with concomitant non-biologic DMARDs, or 8 mg/kg iv without concomitant non-biologic DMARDs, every 4 weeks, for a total of 6 infusions. The anticipated time on study treatment is 3-12 months, and the target sample size is 500-1000 individuals.
Interventions
DRUGtocilizumab [RoActemra/Actemra]
8 mg/kg intravenous every 4 weeks for 24 weeks
DRUGNonbiologic DMARDs of investigator's choice
Nonbiologic disease-modifying antirheumatic drugs (DMARDs) As prescribed
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* adult patients, \>=18 years of age; * moderate to severe active rheumatoid arthritis for \>6 months; * inadequate clinical response or unable to tolerate current or prior biologic or non-biologic Disease-modifying antirheumatic drug (DMARD) therapy; * Swollen joint count (SJC) \>/=4 and Tender joint count (TJC) \>/=4 * body weight \</=150kg * current permitted non-biologic DMARDs must be on stable dose for \>/= 7 weeks prior to baseline;
Exclusion criteria
* history of autoimmune disease or inflammatory joint disease other than rheumatoid arthritis; * functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in rheumatoid arthritis; * treatment with rituximab within 6 months before screening; * intraarticular corticosteroids within 8 weeks or intramuscular (im)/ intravenous (iv) corticosteroids within 12 weeks prior to screening; * known active current or history of recurrent infections, or any major episode of infection requiring hospitalization or treatment with iv antibiotics within 4 weeks of screening, or oral antibiotics within 2 weeks prior to screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing at Least One Serious Adverse Event (SAE) During the 24 Week Treatment Period | 24 Weeks | An SAE was any adverse event that at any dose fulfilled at least one of the following criteria: * Was fatal (results in death) * Was life-threatening * Required in-patient hospitalization or prolongation of existing hospitalization * Resulted in persistent or significant disability/incapacity * Was a congenital anomaly/birth defect * Was medically significant or required intervention to prevent one or other of the outcomes listed above. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | 24 Weeks | Non-serious adverse Events of Special interest include: * Serious/Medically Significant Hepatic Events * Spontaneous /Serious Bleeding * Malignant Neoplasms |
| Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Weeks 8,16,24 | Clinical Remission is defined as a Disease Activity Score 28 \[DAS28\] \< 2.6. The DAS28 is a combined index for measuring disease activity in RA. The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. |
| Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Baseline, Weeks 8,16,24 | The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response C-reactive protein (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A score of \< 2.6 represents clinical remission, a score of ≤ 3.2 represents low disease activity, and a score of \> 5.1 represents high disease activity. The Change from Baseline to Weeks 8, 16 and 24 is reported. |
| Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Baseline, Weeks 8,16,24 | The ACR response rates ACR20, ACR50, and ACR70 are defined as ≥20%, ≥50%, and ≥70% improvement from baseline, respectively, in: 1. Swollen Joint Count (66 joints) and Tender Joint Count (68 joints) and 2. At least 3 of the following 5 assessments: * Patient's global assessment of pain-Visual Analog Scale (VAS) * Patient global assessment of disease activity-(VAS) * Physician global assessment of disease activity-(VAS) * Patient assessment of disability (physical function scale of the Multidimensional Health Assessment Questionnaire) * Acute phase response C-Reactive Protein (CRP) |
| Percentage of Participants Experiencing Serious Adverse Events of Special Interest | 24 Weeks | Serious Adverse Events of Special interest include: * Serious infections including opportunistic infections * Complications of diverticulitis (including lower gastrointestinal \[GI\] perforations) * Myocardial infarction/acute coronary syndrome * Stroke * Spontaneous or serious bleeding * Malignant neoplasms |
| Number of Participants Having Their Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Weeks 12, 16, and 20 | Weeks 12,16, 20 | Dosage of Tocilizumab 4 mg/kg could be increased to 8 mg/kg at the discretion of the investigator based on assessment of the patient's benefit-risk after Week 12. |
| Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Baseline, Weeks 8,16,24 | The RAPID3 is a combined index derived from the Multidimensional Health Assessment Questionnaire that includes physical function score, pain Visual Analog Scale (VAS), and global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 10 where higher scores represent worse outcomes. A negative change from baseline indicates improvement. |
| Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Baseline, Weeks 8,16,24 | The fatigue VAS is a single-item, patient-reported outcome that measures the severity of the fatigue over the past week. Patients rate their fatigue on a scale of 0 (fatigue is no problem) to 100 (fatigue is a major problem). Higher scores represent higher disease activity and a negative change from baseline indicates improvement. |
| Percentage of Participants With Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Week 8 | Baseline, Week 8 | Dosage could be increased from 4 mg/kg Tocilizumab to 8 mg/kg due to failure to achieve 20% improvement from baseline in swollen and tender joint counts. |
Countries
United States
Participant flow
Pre-assignment details
1129 patients were screened for the study. Of these 1129 patients, 886 patients were enrolled and 243 patients were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Tocilizumab 8 mg/kg Monotherapy Participants received Tocilizumab 8 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusions for 24 weeks. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase. | 138 |
| Tocilizumab 4 mg/kg + DMARD Participants received Tocilizumab (TCZ) 4 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusion plus non-biologic disease-modifying antirheumatic drug (DMARD) of the investigator's choice for 24 weeks. Participants not achieving a 20% improvement from baseline in tender and swollen joint counts at Week 8 were to have their dosage increased to 8 mg/kg, per protocol. Beginning at Week 12 dosage increase to 8 mg/kg was at the discretion of the investigator. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase. | 364 |
| Tocilizumab 8 mg/kg + DMARD Participants received Tocilizumab 8 mg/kg as a 60 minute intravenous infusion every 4 weeks for a total of 6 infusion plus non-biologic disease-modifying antirheumatic drug (DMARD) of the investigator's choice for 24 weeks. The dosage could be decreased to 4 mg/kg for safety reasons at the investigator's discretion. Participants who completed the 24 week treatment period were offered the option of entering a long-term extension phase. | 381 |
| Total | 883 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 24 Week Treatment Period | Administrative/Other | 5 | 6 | 1 |
| 24 Week Treatment Period | Adverse event or intercurrent illness | 11 | 32 | 17 |
| 24 Week Treatment Period | Death | 0 | 2 | 0 |
| 24 Week Treatment Period | Failure to return | 4 | 5 | 5 |
| 24 Week Treatment Period | Insufficient therapeutic response | 6 | 9 | 15 |
| 24 Week Treatment Period | Other protocol violation | 1 | 1 | 2 |
| 24 Week Treatment Period | Refused treatment/did not cooperate | 3 | 2 | 1 |
| 24 Week Treatment Period | Violation of selection criteria at entry | 1 | 0 | 2 |
| 24 Week Treatment Period | Withdrew consent | 6 | 3 | 15 |
| Long-term Extension Period | Administrative | 1 | 2 | 2 |
| Long-term Extension Period | Adverse Event | 1 | 11 | 10 |
| Long-term Extension Period | Death | 0 | 0 | 1 |
| Long-term Extension Period | Failure to return | 0 | 2 | 3 |
| Long-term Extension Period | Insufficient therapeutic response | 3 | 2 | 2 |
| Long-term Extension Period | Protocol Violation | 0 | 1 | 1 |
| Long-term Extension Period | Refused treatment/did not cooperate | 1 | 6 | 4 |
Baseline characteristics
| Characteristic | Tocilizumab 8 mg/kg Monotherapy | Tocilizumab 4 mg/kg + DMARD | Tocilizumab 8 mg/kg + DMARD | Total |
|---|---|---|---|---|
| Age Continuous | 53.5 years STANDARD_DEVIATION 12.63 | 55.6 years STANDARD_DEVIATION 11.92 | 54.0 years STANDARD_DEVIATION 12.11 | 54.6 years STANDARD_DEVIATION 12.13 |
| Sex: Female, Male Female | 110 Participants | 273 Participants | 296 Participants | 679 Participants |
| Sex: Female, Male Male | 28 Participants | 91 Participants | 85 Participants | 204 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 63 / 138 | 185 / 364 | 189 / 381 |
| serious Total, serious adverse events | 11 / 138 | 45 / 364 | 40 / 381 |
Outcome results
Primary
Percentage of Participants Experiencing at Least One Serious Adverse Event (SAE) During the 24 Week Treatment Period
An SAE was any adverse event that at any dose fulfilled at least one of the following criteria: * Was fatal (results in death) * Was life-threatening * Required in-patient hospitalization or prolongation of existing hospitalization * Resulted in persistent or significant disability/incapacity * Was a congenital anomaly/birth defect * Was medically significant or required intervention to prevent one or other of the outcomes listed above.
Time frame: 24 Weeks
Population: Safety Population. Patients were included in the TCZ dose group according to the first infusion they actually received. Patients were assigned as using a nonbiologic DMARD if they took at least 1 dose of nonbiologic DMARD during the treatment period. Patients who did not take at least 1 dose of nonbiologic DMARD were considered as on monotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing at Least One Serious Adverse Event (SAE) During the 24 Week Treatment Period | 5.8 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing at Least One Serious Adverse Event (SAE) During the 24 Week Treatment Period | 8.0 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing at Least One Serious Adverse Event (SAE) During the 24 Week Treatment Period | 8.4 Percentage of Participants |
Secondary
Change From Baseline in DAS28 Score at Weeks 8, 16 and 24
The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response C-reactive protein (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. A score of \< 2.6 represents clinical remission, a score of ≤ 3.2 represents low disease activity, and a score of \> 5.1 represents high disease activity. The Change from Baseline to Weeks 8, 16 and 24 is reported.
Time frame: Baseline, Weeks 8,16,24
Population: Intent-to-treat includes participants who received at least one dose of study drug. Patients were included in the treatment group to which they were randomized or assigned, regardless of the treatment actually received. n in each of the categories is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Week 24 (n=126, 286, 302) | -2.03 Score on a scale | Standard Deviation 1.384 |
| Tocilizumab 8 mg/kg Monotherapy | Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Week 8 (n=147, 337, 334) | -1.75 Score on a scale | Standard Deviation 1.213 |
| Tocilizumab 8 mg/kg Monotherapy | Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Week 16 (n=127, 317, 304) | -2.07 Score on a scale | Standard Deviation 1.406 |
| Tocilizumab 4 mg/kg + DMARD | Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Week 24 (n=126, 286, 302) | -1.81 Score on a scale | Standard Deviation 1.264 |
| Tocilizumab 4 mg/kg + DMARD | Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Week 8 (n=147, 337, 334) | -1.00 Score on a scale | Standard Deviation 1.189 |
| Tocilizumab 4 mg/kg + DMARD | Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Week 16 (n=127, 317, 304) | -1.66 Score on a scale | Standard Deviation 1.244 |
| Tocilizumab 8 mg/kg + DMARD | Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Week 24 (n=126, 286, 302) | -1.94 Score on a scale | Standard Deviation 1.38 |
| Tocilizumab 8 mg/kg + DMARD | Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Week 16 (n=127, 317, 304) | -1.87 Score on a scale | Standard Deviation 1.322 |
| Tocilizumab 8 mg/kg + DMARD | Change From Baseline in DAS28 Score at Weeks 8, 16 and 24 | Week 8 (n=147, 337, 334) | -1.54 Score on a scale | Standard Deviation 1.187 |
Secondary
Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24
The fatigue VAS is a single-item, patient-reported outcome that measures the severity of the fatigue over the past week. Patients rate their fatigue on a scale of 0 (fatigue is no problem) to 100 (fatigue is a major problem). Higher scores represent higher disease activity and a negative change from baseline indicates improvement.
Time frame: Baseline, Weeks 8,16,24
Population: Intent-to-treat population includes all participants who received at least 1 dose of study drug. Patients were included in the treatment group to which they were randomized or assigned, regardless of the treatment actually received. n in each of the categories is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Week 24 (n=135, 307, 312) | -15.85 Score on a scale | Standard Deviation 26.881 |
| Tocilizumab 8 mg/kg Monotherapy | Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Week 16 (n=138, 329, 317) | -19.38 Score on a scale | Standard Deviation 26.639 |
| Tocilizumab 8 mg/kg Monotherapy | Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Week 8 (n=156, 350, 344) | -13.17 Score on a scale | Standard Deviation 25.584 |
| Tocilizumab 4 mg/kg + DMARD | Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Week 24 (n=135, 307, 312) | -16.73 Score on a scale | Standard Deviation 26.261 |
| Tocilizumab 4 mg/kg + DMARD | Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Week 8 (n=156, 350, 344) | -10.06 Score on a scale | Standard Deviation 25.349 |
| Tocilizumab 4 mg/kg + DMARD | Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Week 16 (n=138, 329, 317) | -14.00 Score on a scale | Standard Deviation 26.282 |
| Tocilizumab 8 mg/kg + DMARD | Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Week 16 (n=138, 329, 317) | -15.58 Score on a scale | Standard Deviation 25.802 |
| Tocilizumab 8 mg/kg + DMARD | Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Week 8 (n=156, 350, 344) | -13.33 Score on a scale | Standard Deviation 24.95 |
| Tocilizumab 8 mg/kg + DMARD | Change From Baseline in Fatigue Visual Analogue Scale (VAS) at Weeks 8, 16, and 24 | Week 24 (n=135, 307, 312) | -16.07 Score on a scale | Standard Deviation 26.321 |
Secondary
Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24
The RAPID3 is a combined index derived from the Multidimensional Health Assessment Questionnaire that includes physical function score, pain Visual Analog Scale (VAS), and global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 10 where higher scores represent worse outcomes. A negative change from baseline indicates improvement.
Time frame: Baseline, Weeks 8,16,24
Population: Intent-to-treat population includes all participants who received at least 1 dose of study drug. Patients were included in the treatment group to which they were randomized or assigned, regardless of the treatment actually received. n in each of the categories is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Week 24 (n=134, 306, 308) | -1.83 Score on a scale | Standard Deviation 1.978 |
| Tocilizumab 8 mg/kg Monotherapy | Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Week 16 (n=138, 325, 315) | -1.97 Score on a scale | Standard Deviation 2.068 |
| Tocilizumab 8 mg/kg Monotherapy | Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Week 8 (n=156, 348, 343) | -1.60 Score on a scale | Standard Deviation 1.803 |
| Tocilizumab 4 mg/kg + DMARD | Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Week 24 (n=134, 306, 308) | -1.61 Score on a scale | Standard Deviation 1.972 |
| Tocilizumab 4 mg/kg + DMARD | Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Week 8 (n=156, 348, 343) | -1.10 Score on a scale | Standard Deviation 1.848 |
| Tocilizumab 4 mg/kg + DMARD | Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Week 16 (n=138, 325, 315) | -1.42 Score on a scale | Standard Deviation 1.896 |
| Tocilizumab 8 mg/kg + DMARD | Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Week 16 (n=138, 325, 315) | -1.46 Score on a scale | Standard Deviation 1.897 |
| Tocilizumab 8 mg/kg + DMARD | Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Week 8 (n=156, 348, 343) | -1.28 Score on a scale | Standard Deviation 1.733 |
| Tocilizumab 8 mg/kg + DMARD | Change From Baseline in Routine Assessment Patient Index Data (RAPID3) Score at Weeks 8, 16, and 24 | Week 24 (n=134, 306, 308) | -1.46 Score on a scale | Standard Deviation 1.962 |
Secondary
Number of Participants Having Their Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Weeks 12, 16, and 20
Dosage of Tocilizumab 4 mg/kg could be increased to 8 mg/kg at the discretion of the investigator based on assessment of the patient's benefit-risk after Week 12.
Time frame: Weeks 12,16, 20
Population: Safety population includes participants who received at least one dose of study drug. n in each of the categories is the number of participants previously on 4mg/kg + DMARD and receiving a dose at the current visit. Patients were assigned as using a nonbiologic DMARD if they took at least 1 dose of nonbiologic DMARD during the treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Number of Participants Having Their Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Weeks 12, 16, and 20 | Week 12 (n=183) | 41 Participants |
| Tocilizumab 8 mg/kg Monotherapy | Number of Participants Having Their Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Weeks 12, 16, and 20 | Week 16 (n=138) | 18 Participants |
| Tocilizumab 8 mg/kg Monotherapy | Number of Participants Having Their Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Weeks 12, 16, and 20 | Week 20 (n=119) | 5 Participants |
Secondary
Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24
The ACR response rates ACR20, ACR50, and ACR70 are defined as ≥20%, ≥50%, and ≥70% improvement from baseline, respectively, in: 1. Swollen Joint Count (66 joints) and Tender Joint Count (68 joints) and 2. At least 3 of the following 5 assessments: * Patient's global assessment of pain-Visual Analog Scale (VAS) * Patient global assessment of disease activity-(VAS) * Physician global assessment of disease activity-(VAS) * Patient assessment of disability (physical function scale of the Multidimensional Health Assessment Questionnaire) * Acute phase response C-Reactive Protein (CRP)
Time frame: Baseline, Weeks 8,16,24
Population: Intent-to-treat population includes all participants who received at least one dose of study drug. Patients were included in the treatment group to which they were randomized or assigned, regardless of the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 16 ACR20 responders | 46.6 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 8 ACR50 responders | 14.7 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 16 ACR50 responders | 23.3 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 16 ACR70 responders | 7.4 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 8 ACR70 responders | 4.3 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 24 ACR50 responders | 24.5 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 24 ACR20 responders | 47.9 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 24 ACR70 responders | 7.4 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 8 ACR20 responders | 40.5 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 24 ACR70 responders | 8.8 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 16 ACR50 responders | 19.9 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 8 ACR70 responders | 3.3 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 16 ACR70 responders | 8.6 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 8 ACR50 responders | 11.9 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 24 ACR20 responders | 44.8 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 8 ACR20 responders | 37.8 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 16 ACR20 responders | 43.9 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 24 ACR50 responders | 24.3 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 24 ACR70 responders | 10.3 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 8 ACR20 responders | 40.8 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 8 ACR50 responders | 16.8 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 8 ACR70 responders | 5.6 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 16 ACR20 responders | 45.3 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 24 ACR20 responders | 49.7 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 16 ACR50 responders | 22.3 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 16 ACR70 responders | 9.8 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving American College of Rheumatology (ACR) (ACR20/50/70) Responses at Weeks 8, 16, and 24 | Week 24 ACR50 responders | 27.1 Percentage of Participants |
Secondary
Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24
Clinical Remission is defined as a Disease Activity Score 28 \[DAS28\] \< 2.6. The DAS28 is a combined index for measuring disease activity in RA. The index includes tender joint count (TJC) -28 joints and swollen joint count (SJC)-28 joints, acute phase response (CRP) and general health status. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
Time frame: Weeks 8,16,24
Population: Intent-to-treat population includes participants who received at least one dose of study drug. Patients were included in the treatment group to which they were randomized or assigned, regardless of the treatment actually received. n in each of the categories is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Week 16 (n=127, 317, 304) | 15.7 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Week 8 (n=147, 337, 334) | 8.8 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Week 24 (n=126, 286, 302) | 19.8 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Week 16 (n=127, 317, 304) | 17.4 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Week 8 (n=147, 337, 334) | 6.8 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Week 24 (n=126, 286, 302) | 20.6 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Week 8 (n=147, 337, 334) | 12.9 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Week 24 (n=126, 286, 302) | 25.2 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Achieving Clinical Remission at Weeks 8, 16, and 24 | Week 16 (n=127, 317, 304) | 22.0 Percentage of Participants |
Secondary
Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest
Non-serious adverse Events of Special interest include: * Serious/Medically Significant Hepatic Events * Spontaneous /Serious Bleeding * Malignant Neoplasms
Time frame: 24 Weeks
Population: Safety Population. Patients were included in the TCZ dose group according to the first infusion they actually received. Patients were assigned as using a nonbiologic DMARD if they took at least 1 dose of nonbiologic DMARD during the treatment period. Patients who did not take at least 1 dose of nonbiologic DMARD were considered as on monotherapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Spontaneous/Serious Bleeding | 4.3 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Serious/Medically Significant Hepatic Events | 0 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Malignant Neoplasms | 0 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Spontaneous/Serious Bleeding | 3.3 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Serious/Medically Significant Hepatic Events | 0 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Malignant Neoplasms | 0.3 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Serious/Medically Significant Hepatic Events | 0.3 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Malignant Neoplasms | 0.3 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing Non-serious Adverse Events of Special Interest | Spontaneous/Serious Bleeding | 7.3 Percentage of Participants |
Secondary
Percentage of Participants Experiencing Serious Adverse Events of Special Interest
Serious Adverse Events of Special interest include: * Serious infections including opportunistic infections * Complications of diverticulitis (including lower gastrointestinal \[GI\] perforations) * Myocardial infarction/acute coronary syndrome * Stroke * Spontaneous or serious bleeding * Malignant neoplasms
Time frame: 24 Weeks
Population: Safety Population. Patients were included in the TCZ dose group according to the first infusion they actually received. Patients were assigned as using a nonbiologic DMARD if they took at least 1 dose of nonbiologic DMARD during the treatment period. Patients who did not take at least 1 dose of nonbiologic DMARD were considered as on monotherapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Serious Infections (including opportunistic) | 2.9 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Gastrointestinal Perforations and Related Events | 0 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Myocardial Infarction/Acute Coronary Syndrome | 0 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Stroke | 0 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Spontaneous/Serious Bleeding | 0 Percentage of Participants |
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Malignant Neoplasms | 0 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Malignant Neoplasms | 0 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Serious Infections (including opportunistic) | 3.6 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Stroke | 0.3 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Spontaneous/Serious Bleeding | 0.3 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Gastrointestinal Perforations and Related Events | 0.8 Percentage of Participants |
| Tocilizumab 4 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Myocardial Infarction/Acute Coronary Syndrome | 0 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Gastrointestinal Perforations and Related Events | 0 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Myocardial Infarction/Acute Coronary Syndrome | 0.3 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Malignant Neoplasms | 0.3 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Stroke | 0 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Serious Infections (including opportunistic) | 3.9 Percentage of Participants |
| Tocilizumab 8 mg/kg + DMARD | Percentage of Participants Experiencing Serious Adverse Events of Special Interest | Spontaneous/Serious Bleeding | 0.3 Percentage of Participants |
Secondary
Percentage of Participants With Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Week 8
Dosage could be increased from 4 mg/kg Tocilizumab to 8 mg/kg due to failure to achieve 20% improvement from baseline in swollen and tender joint counts.
Time frame: Baseline, Week 8
Population: Safety Population. Patients were included in the TCZ dose group according to the first infusion they actually received. Patients were assigned as using a nonbiologic DMARD if they took at least 1 dose of nonbiologic DMARD during the treatment period. Patients who did not take at least 1 dose of nonbiologic DMARD were considered as on monotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tocilizumab 8 mg/kg Monotherapy | Percentage of Participants With Tocilizumab Dose Increased From 4 mg/kg to 8 mg/kg at Week 8 | 39.9 Percentage of Participants |