Rheumatoid Arthritis
Conditions
Brief summary
This randomized, double-blind, parallel-group study will evaluate the efficacy and safety of RoActemra/Actemra (tocilizumab) in combination with methotrexate versus RoActemra/Actemra monotherapy in patients with rheumatoid arthritis and an inadequate response to methotrexate. All patients will receive RoActemra/Actemra 8 mg/kg intravenously (iv) every 4 weeks plus oral methotrexate for 16 weeks. Patients achieving low disease activity at Week 16 will be randomized to receive a further 12 weeks of RoActemra/Actemra treatment plus either methotrexate or placebo. Anticipated time on study treatment is 28 weeks.
Interventions
DRUGmethotrexate
orally, Week 1 - 16
DRUGplacebo
methotrexate placebo orally, Week 17-28
DRUGtocilizumab [RoActemra/Actemra]
8 mg/kg iv every 4 weeks, 28 weeks
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients, \>/= 18 years of age * Active moderate to severe rheumatoid arthritis (DAS28 \>/= 3.2) at baseline * Currently receiving methotrexate for at least 12 weeks, at a stable oral dose of at least 15 mg/week for at least 6 weeks prior to treatment (Day 1) * Body weight \< 150 kg * Oral corticoids must have been at stable dose for at least 25 out of 28 days prior to baseline; maximum dose 10 mg/day
Exclusion criteria
* Pregnant or nursing women * Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months after baseline * Rheumatic autoimmune disease other than RA * Functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in Rheumatoid Arthritis * Prior history of or current inflammatory joint disease other than RA * Treatment with a biologic agent at any time prior to baseline * Treatment with traditional DMARDs other than methotrexate within 1 month (for leflunomide 3 months) prior to baseline * Intraarticular or parenteral corticosteroids within 6 weeks prior to baseline * Previous treatment with RoActemra/Actemra * History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies * Known active current or history of recurrent infection * History of or currently active primary or secondary immunodeficiency * Active tuberculosis requiring treatment within the previous 3 years * Positive for HIV infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28 | Baseline, Week 16, and Week 28 | The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (erythrocyte sedimentation rate \[ESR\] in millimeters per hour \[mm/hr\]), and general health status (participant global assessment of disease activity using visual analog scale \[VAS\], range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Disease Activity Index (CDAI) <2.8 at Week 28 | Week 28 | CDAI is the sum of tender and swollen joint count based on 28 joints and the participant and physician global disease assessment (VAS 0-10 centimeters \[cm\]). CDAI total score 0-76; higher scores = greater affect due to disease activity. CDAI \<2.8 = clinical remission. |
| Percentage of Participants With Simplified Disease Activity Index (SDAI) <3.3 at Week 28 | 28 weeks | SDAI is calculated by a simple numerical sum of tender and swollen joint count (based on a 28-joint assessment), participant and physician global assessment of disease activity (VAS 0-10 cm), and level of C-reactive protein in milligram per deciliter (mg/dL). SDAI total score 0-86; higher scores = greater affect due to disease activity. SDAI \<3.3 = clinical remission. |
| Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) From Week 16 to Week 28 | Week 16 and Week 28 | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. |
| Percentage of Participants With DAS28 Score Less Than (<) 2.6 at Week 28 | Week 28 | The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (ESR in mm/hr), and general health status (participant global assessment of disease activity using VAS, range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores indicate worsening. DAS28 \<2.6 equals (=) remission. |
| Change in the Quality of Life Questionnaire (SF-12) From Week 16 to Week 28 in Physical Health | Week 16 and Week 28 | Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated a worsening of quality of life. |
| Change From Week 16 to Week 28 in Global Assessment of Disease Activity as Assessed With the Visual Analogue Scale (VAS) Performed by Participant | Week 16 and Week 28 | Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity. The distance from the left edge was measured in mm. |
| Change From Week 16 to Week 28 in Global Assessment of Disease Activity Assessed Using the VAS Performed by the Investigator | Week 16 and Week 28 | Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity. The distance from the left edge was measured in mm. |
| Change in the Quality of Life Questionnaire (Short Form-12 [SF-12]) From Week 16 to Week 28 in Mental Health | Week 16 and Week 28 | Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated decline in health and higher scores indicated improvement in health. |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TCZ + MTX (Not Randomized) Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules orally, at a stable dose (10, 15, 17.5, or 20 mg, no maximum dose was defined) weekly from Week 1 through 16. | 96 |
| TCZ + MTX (Randomized) Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules, orally, at a stable dose (10, 15, 17.5, or 20 mg/week, but no maximum dose was defined), weekly, from Weeks 1 through 24. | 83 |
| TCZ + Placebo (Randomized) Participants received TCZ 8 mg/kg (maximum 800 mg) via IV infusion q4w through Week 24 (total of 7 infusions). Participants also received MTX capsules, orally, at stable dose (10, 15, 17.5, or 20 mg per week, but no maximum dose was defined) weekly, from Weeks 1 through 16 followed by matching placebo capsules, orally, weekly through Week 24. | 82 |
| Total | 261 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 3 | 1 |
| Overall Study | Clinical RA remission | 1 | 0 | 0 |
| Overall Study | Inclusion Error | 2 | 0 | 0 |
| Overall Study | Investigator Decisión | 1 | 0 | 2 |
| Overall Study | Lack of Efficacy | 9 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 | 0 |
| Overall Study | Non-Compliant | 1 | 0 | 0 |
| Overall Study | Positive result for hepatitis B | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 2 | 0 | 0 |
| Overall Study | Sponsor Decision | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 0 | 0 |
Baseline characteristics
| Characteristic | TCZ + MTX (Not Randomized) | TCZ + MTX (Randomized) | TCZ + Placebo (Randomized) | Total |
|---|---|---|---|---|
| Age, Continuous | 52.3 years STANDARD_DEVIATION 13.2 | 50.2 years STANDARD_DEVIATION 12.5 | 51.0 years STANDARD_DEVIATION 12.2 | 51.2 years STANDARD_DEVIATION 12.6 |
| Sex: Female, Male Female | 76 Participants | 62 Participants | 65 Participants | 203 Participants |
| Sex: Female, Male Male | 20 Participants | 21 Participants | 17 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 96 | 20 / 83 | 24 / 82 | 8 / 83 | 4 / 82 |
| serious Total, serious adverse events | 11 / 96 | 0 / 83 | 1 / 82 | 1 / 83 | 4 / 82 |
Outcome results
Primary
Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28
The DAS28 is a combined index for measuring disease activity in rheumatoid arthritis (RA). The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (erythrocyte sedimentation rate \[ESR\] in millimeters per hour \[mm/hr\]), and general health status (participant global assessment of disease activity using visual analog scale \[VAS\], range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
Time frame: Baseline, Week 16, and Week 28
Population: Intent-to-treat (ITT) population: all randomized participants who received at least one dose of study medication and who had at least one efficacy measurement performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TCZ + MTX (Randomized) | Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28 | Baseline | 5.42 units on a scale | Standard Deviation 1.01 |
| TCZ + MTX (Randomized) | Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28 | Week 16 | 1.77 units on a scale | Standard Deviation 0.77 |
| TCZ + MTX (Randomized) | Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28 | Week 28 | 1.82 units on a scale | Standard Deviation 1.18 |
| TCZ + Placebo (Randomized) | Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28 | Baseline | 5.29 units on a scale | Standard Deviation 1.01 |
| TCZ + Placebo (Randomized) | Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28 | Week 16 | 1.96 units on a scale | Standard Deviation 0.76 |
| TCZ + Placebo (Randomized) | Change in Disease Activity Score Based on 28-Joint Count (DAS28) From Week 16 to Week 28 | Week 28 | 1.98 units on a scale | Standard Deviation 1.13 |
p-value: 0.7ANCOVA
Secondary
Change From Week 16 to Week 28 in Global Assessment of Disease Activity as Assessed With the Visual Analogue Scale (VAS) Performed by Participant
Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity. The distance from the left edge was measured in mm.
Time frame: Week 16 and Week 28
Population: ITT Population; only participants with non missing values were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TCZ + MTX (Randomized) | Change From Week 16 to Week 28 in Global Assessment of Disease Activity as Assessed With the Visual Analogue Scale (VAS) Performed by Participant | 1.68 units on a scale | Standard Deviation 23.8 |
| TCZ + Placebo (Randomized) | Change From Week 16 to Week 28 in Global Assessment of Disease Activity as Assessed With the Visual Analogue Scale (VAS) Performed by Participant | 0.56 units on a scale | Standard Deviation 20.42 |
p-value: 0.76995% CI: [-5.526, 7.464]ANCOVA
Secondary
Change From Week 16 to Week 28 in Global Assessment of Disease Activity Assessed Using the VAS Performed by the Investigator
Participants were asked to rate their global assessment of disease activity on a scale ranging from 0=very good to 100=very bad. The scale was represented by a line with 0 at the left edge and 100 at the right edge. The participant was asked to mark the line corresponding to the assessment of their disease activity. The distance from the left edge was measured in mm.
Time frame: Week 16 and Week 28
Population: ITT Population; only participants with non missing values were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TCZ + MTX (Randomized) | Change From Week 16 to Week 28 in Global Assessment of Disease Activity Assessed Using the VAS Performed by the Investigator | 2.71 units on a scale | Standard Deviation 16.96 |
| TCZ + Placebo (Randomized) | Change From Week 16 to Week 28 in Global Assessment of Disease Activity Assessed Using the VAS Performed by the Investigator | 2.85 units on a scale | Standard Deviation 18.48 |
p-value: 0.65595% CI: [-6.573, 4.141]ANCOVA
Secondary
Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) From Week 16 to Week 28
HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.
Time frame: Week 16 and Week 28
Population: ITT Population; only participants with non missing values were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TCZ + MTX (Randomized) | Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) From Week 16 to Week 28 | 0.08 units on a scale | Standard Deviation 0.47 |
| TCZ + Placebo (Randomized) | Change in the Health Assessment Questionnaire Disability Index (HAQ-DI) From Week 16 to Week 28 | 0.00 units on a scale | Standard Deviation 0.52 |
p-value: 0.67495% CI: [-0.119, 0.184]ANCOVA
Secondary
Change in the Quality of Life Questionnaire (SF-12) From Week 16 to Week 28 in Physical Health
Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated a worsening of quality of life.
Time frame: Week 16 and Week 28
Population: ITT Population; only participants with non missing data were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TCZ + MTX (Randomized) | Change in the Quality of Life Questionnaire (SF-12) From Week 16 to Week 28 in Physical Health | 0.48 units on a scale | Standard Deviation 9.49 |
| TCZ + Placebo (Randomized) | Change in the Quality of Life Questionnaire (SF-12) From Week 16 to Week 28 in Physical Health | -2.26 units on a scale | Standard Deviation 8.82 |
p-value: 0.01595% CI: [0.676, 6.076]ANCOVA
Secondary
Change in the Quality of Life Questionnaire (Short Form-12 [SF-12]) From Week 16 to Week 28 in Mental Health
Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. A negative change from baseline indicated decline in health and higher scores indicated improvement in health.
Time frame: Week 16 and Week 28
Population: ITT Population; only participants with non missing values were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TCZ + MTX (Randomized) | Change in the Quality of Life Questionnaire (Short Form-12 [SF-12]) From Week 16 to Week 28 in Mental Health | -2.36 units on a scale | Standard Deviation 10.22 |
| TCZ + Placebo (Randomized) | Change in the Quality of Life Questionnaire (Short Form-12 [SF-12]) From Week 16 to Week 28 in Mental Health | -0.38 units on a scale | Standard Deviation 9.25 |
p-value: 0.20495% CI: [-4.775, 1.03]ANCOVA
Secondary
Percentage of Participants With Clinical Disease Activity Index (CDAI) <2.8 at Week 28
CDAI is the sum of tender and swollen joint count based on 28 joints and the participant and physician global disease assessment (VAS 0-10 centimeters \[cm\]). CDAI total score 0-76; higher scores = greater affect due to disease activity. CDAI \<2.8 = clinical remission.
Time frame: Week 28
Population: ITT Population; only participants with CDAI scores at Weeks 28 were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCZ + MTX (Randomized) | Percentage of Participants With Clinical Disease Activity Index (CDAI) <2.8 at Week 28 | 40.7 percentage of participants |
| TCZ + Placebo (Randomized) | Percentage of Participants With Clinical Disease Activity Index (CDAI) <2.8 at Week 28 | 35.8 percentage of participants |
p-value: 0.518Chi-squared
Secondary
Percentage of Participants With DAS28 Score Less Than (<) 2.6 at Week 28
The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (ESR in mm/hr), and general health status (participant global assessment of disease activity using VAS, range 1-100 mm). DAS28, which uses a 28-joint count, is derived from the original DAS, which includes a 44-swollen joint count. The DAS28 scale ranges from 0 to 10, where higher scores indicate worsening. DAS28 \<2.6 equals (=) remission.
Time frame: Week 28
Population: ITT Population; only participants with Week 28 DAS28 values were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCZ + MTX (Randomized) | Percentage of Participants With DAS28 Score Less Than (<) 2.6 at Week 28 | 82.3 percentage of participants |
| TCZ + Placebo (Randomized) | Percentage of Participants With DAS28 Score Less Than (<) 2.6 at Week 28 | 75.9 percentage of participants |
p-value: 0.328Chi-squared
Secondary
Percentage of Participants With Simplified Disease Activity Index (SDAI) <3.3 at Week 28
SDAI is calculated by a simple numerical sum of tender and swollen joint count (based on a 28-joint assessment), participant and physician global assessment of disease activity (VAS 0-10 cm), and level of C-reactive protein in milligram per deciliter (mg/dL). SDAI total score 0-86; higher scores = greater affect due to disease activity. SDAI \<3.3 = clinical remission.
Time frame: 28 weeks
Population: ITT Population; only participants with SDAI scores at Week 28 were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TCZ + MTX (Randomized) | Percentage of Participants With Simplified Disease Activity Index (SDAI) <3.3 at Week 28 | 35.1 percentage of participants |
| TCZ + Placebo (Randomized) | Percentage of Participants With Simplified Disease Activity Index (SDAI) <3.3 at Week 28 | 28.2 percentage of participants |
p-value: 0.358Chi-squared