This multicenter, open-label study will evaluate the efficacy and safety of subcutaneously administered RoActemra/Actemra (tocilizumab) as monotherapy or in combination with methotrexate or other non-biologic DMARDs in patients with active rheumatoid arthritis and an inadequate response to non-biologic DMARDs or to one anti-TNF. In Phase 1, all patients will receive RoActemra/Actemra 162 mg subcutaneously (sc) weekly for Weeks 1 to 24, with or without methotrexate or other non-biologic DMARDs. For Part 2, patients who achieve sustained clinical DAS28-ESR remission at Weeks 20 and 24 will be randomized to receive RoActemra/Actemra 162 mg sc either weekly or every 2 weeks for Weeks 24 to 48, with or without methotrexate or other non-biologic DMARDs. Patients who do not achieve sustained clinical remission but achieve low disease activity (DAS-ESR \</= 3.2) will continue the initial treatment of RoActemra/Actemra 162 mg sc weekly for Weeks 24 to 48, with or without methotrexate or other non-biologic DMARDs.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
401
non-biological disease-modifying antirheumatic drugs at stable dose
stable dose
162 mg subcutaneously (SC) qw, Weeks 1-24
162 mg SC qw or q2w, Weeks 24-48
162 mg SC qw, Weeks 24-48
Unnamed facility
Co Leitrim, Ireland
Unnamed facility
Cork, Ireland
Unnamed facility
Dublin, Ireland
Unnamed facility
Dublin, Ireland
Unnamed facility
Limerick, Ireland
Unnamed facility
Waterford, Ireland
Percentage of Participants Achieving Sustained Clinical Remission, Disease Activity Scale 28 - Erythrocyte Sedimentation Rate <26 (DAS28-ESR <2.6) at Week 20 and Week 24
The DAS 28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP) and general health status. For this study ESR was used to calculate the DAS 28 score.
Time frame: Week 20 and Week 24
Mean Change in Disease Activity Score 28 - Erythrocyte Sedimentation Rate(DAS28-ESR)
The DAS 28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP) and general health status. For this study ESR was used to calculate the DAS 28 score.
Time frame: From week 24 up to week 48
Percentage of Patients Allocated in Groups A1 and A2 Who Remain With Clinical Remission Activity (DAS 28 ESR <2.6) up to Week 48
The DAS28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP), and general health status. For this study ESR will be used to calculate the DAS28 score.
Time frame: From week 28 up to week 48
Percentage of Patients Reporting Change in DAS 28 ESR >1.2 Until Week 48
The DAS28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP), and general health status. For this study ESR will be used to calculate the DAS28 score.
Time frame: From week 28 up to week 48
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24
The definition of improvement of ACR core set of outcome measures includes an improvement equal or higher to the 20%, 50%, 70%, 90% compared to Baseline in both Swollen Joint Count (SJC) and Tender Joint Count (TJC) as well as in three out of five additional parameters: Physician's Global Assessment of disease activity VAS, patient's Global Assessment of disease activity VAS, patient's assessment of pain VAS, HAQ-DI, and acute phase reactant (either CRP or erythrocyte sedimentation rate \[ESR\]).
Time frame: From week 2 until week 24
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48
The definition of improvement of ACR core set of outcome measures includes an improvement equal or higher to the 20%, 50%, 70%, 90% compared to Baseline in both Swollen Joint Count (SJC) and Tender Joint Count (TJC) as well as in three out of five additional parameters: Physician's Global Assessment of disease activity VAS, patient's Global Assessment of disease activity VAS, patient's assessment of pain VAS, HAQ-DI, and acute phase reactant (either CRP or erythrocyte sedimentation rate \[ESR\]).
Time frame: From week 28 until week 48
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24
DAS28-based EULAR response criteria were used to measure individual response as good or moderate depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline \>1.2 with DAS28 ≤3.2; moderate responders: change from baseline \>1.2 with DAS28 \>3.2 to ≤5.1 or change from baseline \>0.6 to =\<1.2 with DAS28 ≤5.1.
Time frame: From week 2 until week 24
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48
DAS28-based EULAR response criteria were used to measure individual response as good or moderate depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline \>1.2 with DAS28 ≤3.2; moderate responders: change from baseline \>1.2 with DAS28 \>3.2 to ≤5.1 or change from baseline \>0.6 to =\<1.2 with DAS28 ≤5.1.
Time frame: From week 28 until week 48
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24
Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index was calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. A negative change from baseline indicates an improvement.
Time frame: From baseline to Week 24
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48
Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index was calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. A negative change from baseline indicates an improvement.
Time frame: From week 24 until week 48
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24
Simplified Disease Activity Index (SDAI) is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =\< 3.3 indicates disease remission, \> 3.4 to 11 indicates low disease activity, \> 11 to 26 indicates moderate disease activity, and \> 26 indicates high disease activity.
Time frame: From baseline to Week 24
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48
Simplified Disease Activity Index (SDAI) which is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =\< 3.3 indicates disease remission, \> 3.4 to 11 indicates low disease activity, \> 11 to 26 indicates moderate disease activity, and \> 26 indicates high disease activity.
Time frame: From week 24 until week 48
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24
TCJ is a clinical assessment of 68 joints which are classified as tender/not tender by pressure and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused joints are not be taken into consideration.
Time frame: From baseline to Week 24
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48
TCJ is a clinical assessment of 68 joints which are classified as tender/not tender by pressure and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused joints are not be taken into consideration.
Time frame: From week 24 until week 48
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24
SJC is a clinical assessment of 66 joints classified as swollen/not swollen by pressure and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused joints will not be taken into consideration for swelling.
Time frame: From baseline to Week 24
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48
SJC is a clinical assessment of 66 joints classified as swollen/not swollen by pressure and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused joints will not be taken into consideration for swelling.
Time frame: From week 24 until week 48
Percentages of Patients Who Achieve DAS28-ESR Remission (DAS28 < 2.6) up to Week 48
The DAS 28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP) and general health status. For this study ESR was used to calculate the DAS 28 score.
Time frame: Week 48
Percentages of Patients With Remission (CDAI<2.8) Until Week 24
Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index was calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. A negative change from baseline indicates an improvement.
Time frame: From baseline to Week 24
Percentages of Patients With Remission (CDAI<2.8) Until Week 48
Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index was calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. A negative change from baseline indicates an improvement.
Time frame: From week 28 until week 48
Percentages of Patients With Remission (SDAI<3.3) Until Week 24
Simplified Disease Activity Index (SDAI) is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =\< 3.3 indicates disease remission, \> 3.4 to 11 indicates low disease activity, \> 11 to 26 indicates moderate disease activity, and \> 26 indicates high disease activity.
Time frame: From baseline to Week 24
Percentages of Patients With Remission (SDAI<3.3) Until Week 48
Simplified Disease Activity Index (SDAI) is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =\< 3.3 indicates disease remission, \> 3.4 to 11 indicates low disease activity, \> 11 to 26 indicates moderate disease activity, and \> 26 indicates high disease activity.
Time frame: From week 28 until week 48
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24
The DAS28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP), and general health status. For this study ESR is used to calculate the DAS28 score.
Time frame: From baseline to Week 24
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48
The DAS28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP), and general health status. For this study ESR was used to calculate the DAS28 score.
Time frame: From week 28 until week 48
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24
Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index was calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. A negative change from baseline indicates an improvement.
Time frame: From baseline to Week 24
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48
Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index was calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. A negative change from baseline indicates an improvement.
Time frame: From week 28 until week 48
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24
Simplified Disease Activity Index (SDAI) is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =\< 3.3 indicates disease remission, \> 3.4 to 11 indicates low disease activity, \> 11 to 26 indicates moderate disease activity, and \> 26 indicates high disease activity.
Time frame: From baseline to Week 24
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 48
Simplified Disease Activity Index (SDAI) is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =\< 3.3 indicates disease remission, \> 3.4 to 11 indicates low disease activity, \> 11 to 26 indicates moderate disease activity, and \> 26 indicates high disease activity.
Time frame: From week 28 until week 48
Safety: Number of Patients Reporting Adverse Events up to Week 24
Number of patients reporting any treatment emergent adverse event (TEAE), at least one TEAE of special interest, at least one serious TEAE, at least one TEAE leading to dose modification, at least one TEAE leading to discontinuation up to week 24
Time frame: From baseline to Week 24
Safety: Number of Patients Reporting Adverse Events up to Week 48
Number of patients reporting any treatment emergent adverse event (TEAE), at least one TEAE of special interest, at least one serious TEAE, at least one TEAE leading to dose modification, at least one TEAE leading to discontinuation up to week 48
Time frame: From week 24 until week 48
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 24
Number of patients resulting positive to anti-tocilizumab antibodies test are reported.
Time frame: From baseline to Week 24
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48
Number of patients resulting positive to anti-tocilizumab antibodies test are reported.
Time frame: From week 24 until week 48
Immunogenicity: TCZ Levels up to Week 24
Mean concentrations of TCZ in patients' blood are reported.
Time frame: From baseline to Week 24
Immunogenicity: TCZ Levels at Week 36 and Early Withdrawal Visit
Mean concentrations of TCZ in patients' blood are reported.
Time frame: week 36 and early withdrawal visit
Immunogenicity: SIL-6R Levels up to Week 24
Mean concentration of SIL-6R in patients' blood are reported.
Time frame: From baseline to Week 24
Immunogenicity: SIL-6R Levels at Week 36 and Early Withdrawal Visit
Mean concentration of SIL-6R in patients' blood are reported.
Time frame: Baseline, Week 36 and Early Withdrawal Visit
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24
This patient reported outcome assessment represents the patient's overall assessment of their current disease activity on a 100 mm horizontal VAS. The extreme left end of the line should be described as "no disease activity" (symptom-free and no arthritis symptoms) and the extreme right end as "maximum disease activity" (maximum arthritis disease activity). The line was marked by the participant and the distance from the left edge was recorded and the mean values are reported.
Time frame: From baseline to Week 24
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48
This patient reported outcome assessment represents the patient's overall assessment of their current disease activity on a 100 mm horizontal VAS. The extreme left end of the line should be described as "no disease activity" (symptom-free and no arthritis symptoms) and the extreme right end as "maximum disease activity" (maximum arthritis disease activity). The line was marked by the participant and the distance from the left edge was recorded and the mean values are reported.
Time frame: Baseline, from week 28 until week 48
Assessment of Pain Reported by the Patient (VAS) Until Week 24
This patient reported outcome assessment represents the patient's assessment of his/her current level of pain on a 100 mm horizontal VAS. The extreme left end of the line should be described as "no pain" and the extreme right end as "unbearable pain".
Time frame: From baseline to Week 24
Assessment of Pain Reported by the Patient (VAS) Until Week 48
This patient reported outcome assessment represents the patient's assessment of his/her current level of pain on a 100 mm horizontal VAS. The extreme left end of the line should be described as "no pain" and the extreme right end as "unbearable pain".
Time frame: Baseline, from week 28 until week 48
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24
The Stanford HAQ-DI is a patient-oriented outcome assessment questionnaire specific for RA. It consists of 20 questions referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. To respond to each question, a four-level response (score of 0 to 3 points), with higher scores showing larger functional limitations, was chosen. Scoring was as follows with respect to performance of participant's everyday activities: 0 (equals)=without difficulties; 1=with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. Minimum score was 0, maximum score was 3.
Time frame: From baseline to Week 24
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48
The Stanford HAQ-DI is a patient-oriented outcome assessment questionnaire specific for RA. It consists of 20 questions referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. To respond to each question, a four-level response (score of 0 to 3 points), with higher scores showing larger functional limitations, was chosen. Scoring was as follows with respect to performance of participant's everyday activities: 0 (equals)=without difficulties; 1=with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. Minimum score was 0, maximum score was 3.
Time frame: Baseline, from week 28 until week 48
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24
The symptom-specific measure FACIT-F assesses chronic illness therapy with special emphasis on fatigue in the past 7 days and consists of 5 dimensions: 1) physical well- being, 2) social/family well-being, 3) emotional well-being, 4) functional well-being, and 5) additional concerns. Each of the questions is categorically answered using the scales 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much for a total possible FACIT-F score of 0 to 160. The figures are reversed during score calculations, so that higher score values indicate more favorable conditions.
Time frame: From baseline to Week 24
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48
The symptom-specific measure FACIT-F assesses chronic illness therapy with special emphasis on fatigue in the past 7 days and consists of 5 dimensions: 1) physical well- being, 2) social/family well-being, 3) emotional well-being, 4) functional well-being, and 5) additional concerns. Each of the questions is categorically answered using the scales 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much for a total possible FACIT-F score of 0 to 160. The figures are reversed during score calculations, so that higher score values indicate more favorable conditions.
Time frame: Baseline, from week 28 until week 48
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Unnamed facility
Almada, Portugal
Unnamed facility
Amadora, Portugal
Unnamed facility
Lisbon, Portugal
Unnamed facility
Lisbon, Portugal
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