Clinical Trial Results:
A National, Open-Label, Single-Arm, Phase IIIb Study to Evaluate the Efficacy of Weekly Tocilizumab Subcutaneous, Administered as Monotherapy or in Combination With Methotrexate and/or Other DMARDs in Rheumatoid Arthritis (RA) Patients
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Summary
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EudraCT number |
2013-001569-17 |
Trial protocol |
IT |
Global end of trial date |
05 Jul 2016
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Results information
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Results version number |
v2(current) |
This version publication date |
28 Jun 2017
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First version publication date |
06 Nov 2016
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ML28699
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01941940 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
F. HoffmannLa Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
Roche Trial Information Hotline, F. HoffmannLa Roche AG, 41 61 6878333, global.trial_information@roche.com
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Scientific contact |
Roche Trial Information Hotline, F. HoffmannLa Roche AG, 41 61 6878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
05 Jul 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Jul 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess the efficacy of subcutaneous (SC) tocilizumab administered in monotherapy or in combination with methotrexate (MTX) and/or other nonbiological disease modifying antirheumatic drugs (DMARDs) using Clinical Disease Activity Index (CDAI) over time up to Week 24, including onset of action at Week 2.
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Protection of trial subjects |
The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP). Approval from the Independent Ethics Committee/Institutional Review Board (IEC/IRB) was obtained before study start and was documented in a letter to the Investigator specifying the date on which the committee met and granted the approval. The Sponsor also obtained approval from the relevant Competent Authority prior to starting the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Sep 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Italy: 227
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Worldwide total number of subjects |
227
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EEA total number of subjects |
227
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
177
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From 65 to 84 years |
49
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85 years and over |
1
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||
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Pre-assignment
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Screening details |
Out of a total of 288 participants screened, 60 participants were excluded due to screening failure and 1 participant did not receive study treatment based on investigator’s decision. Thus, total 227 participants were included in the study. | ||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||
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Arms
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Arm title
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Tocilizumab | ||||||||||||||||||||||
Arm description |
Tocilizumab at a fixed dose of 162 milligrams (mg) was administered as SC injection alone or along with methotrexate and/or other non-biological DMARDs irrespective of body weight, once every week for a total of 52 weeks. After 52-weeks of treatment, at the discretion of the treating physician, participants could continue the study treatment with SC tocilizumab until it became commercially available in Italy (maximum up to 638 days). | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
Tocilizumab
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Investigational medicinal product code |
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Other name |
RoActemra
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Tocilizumab at a fixed dose of 162 mg as SC injection was administered once every week.
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Baseline characteristics reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
Tocilizumab at a fixed dose of 162 milligrams (mg) was administered as SC injection alone or along with methotrexate and/or other non-biological DMARDs irrespective of body weight, once every week for a total of 52 weeks. After 52-weeks of treatment, at the discretion of the treating physician, participants could continue the study treatment with SC tocilizumab until it became commercially available in Italy (maximum up to 638 days). | ||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
Tocilizumab at a fixed dose of 162 milligrams (mg) was administered as SC injection alone or along with methotrexate and/or other non-biological DMARDs irrespective of body weight, once every week for a total of 52 weeks. After 52-weeks of treatment, at the discretion of the treating physician, participants could continue the study treatment with SC tocilizumab until it became commercially available in Italy (maximum up to 638 days). | ||
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End point title |
Change From Baseline in CDAI at Week 24 [1] | ||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: tender joint count (TJC) and swollen joint count (SJC) based on a 28-joint assessment, patient's global assessment of disease activity (PtGDA) and physician global assessment of disease activity (PGDA) assessed on 0-10 centimeters (cm) visual analogue scale (VAS). Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score less than or equal to (</=) 2.8 indicates disease remission, greater than (>) 2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure.
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End point type |
Primary
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End point timeframe |
Baseline, Week 24
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to EudraCT database limitations it is not possible to add statistical analysis in a single arm study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in CDAI at Week 20 [2] | ||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure.
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End point type |
Primary
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End point timeframe |
Baseline, Week 20
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were only planned for this analysis. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in CDAI at Week 16 [3] | ||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure.
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End point type |
Primary
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End point timeframe |
Baseline, Week 16
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were only planned for this analysis. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in CDAI at Week 12 [4] | ||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure.
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End point type |
Primary
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End point timeframe |
Baseline, Week 12
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were only planned for this analysis. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in CDAI at Week 8 [5] | ||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure.
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End point type |
Primary
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End point timeframe |
Baseline, Week 8
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were only planned for this analysis. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in CDAI at Week 4 [6] | ||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure.
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End point type |
Primary
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End point timeframe |
Baseline, Week 4
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were only planned for this analysis. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in CDAI at Week 2 [7] | ||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 indicates disease remission, >2.8 to 10 indicates low disease activity, >10 to 22 indicates moderate disease activity, and >22 indicates high disease activity. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure.
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End point type |
Primary
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End point timeframe |
Baseline, Week 2
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to EudraCT database limitations it is not possible to add statistical analysis in a single arm study. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants Achieving Clinical Remission According to CDAI up to Week 52 | ||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. Higher scores represent greater affectation due to disease activity. CDAI total score = 0-76. CDAI score </=2.8 during any two consecutive visits, not including the baseline visit indicates disease remission. Analysis was performed on FAS.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 52 (Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 38, and 52)
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| No statistical analyses for this end point | |||||||
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End point title |
Change from Baseline in Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (DAS28-ESR) at Weeks 2, 24, and 52 | ||||||||||||||||
End point description |
DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hour) and PtGDA assessed on 0-10 cm VAS. Higher scores indicate greater affectation due to disease activity. DAS28-ESR total score= 0-9.4. DAS28-ESR </=3.2 indicates low disease activity, DAS28-ESR >3.2 to 5.1 indicates moderate to high disease activity, and DAS28-ESR </=3.2 indicates remission. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 2, 24, and 52
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 24, and 52 | ||||||||||||||||
End point description |
SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and C-reactive protein (CRP) in milligrams per deciliter (mg/dL). Higher scores indicate greater affectation due to disease activity. SDAI total score = 0-86. 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. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 2, 24, and 52
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage of Participants With an American College of Rheumatology 20% (ACR20), 50% (ACR50), and 70% (ACR70) Response | ||||||||||||||||||||||||||
End point description |
The ACR 20, 50, and 70 responses: greater than or equal to (>/=) 20 percent (%), 50%, and 70% improvement in TJC and SJC (28 assessed joints), and 20%, 50%, 70% improvement in 3 of the following 5 criteria, respectively: 1) PGDA, 2) PtGDA, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP or ESR at each visit. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
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End point type |
Secondary
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End point timeframe |
Weeks 2, 24, and 52
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Percentage of Participants With European League Against Rheumatism (EULAR) Response Based on DAS28 | ||||||||||||||||||||||||||
End point description |
The DAS28-based EULAR response criteria were used to measure individual response as none, good, and 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; non-responders: change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28 >5.1. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 2, 24, and 52
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Change From Baseline in Total TJC at Weeks 2, 24, and 52 | ||||||||||||||||||||||||
End point description |
TJC was defined as the total number of painful joints based on 68-joint assessment (TJC-68) and 28-joint assessment (TJC-28). Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 2, 24, and 52
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change From Baseline in Total SJC at Weeks 2, 24, and 52 | ||||||||||||||||||||||||
End point description |
SJC was defined as the total number of swollen joints based on 66-joint assessment (SJC-66) and 28-joint assessment (SJC-28). Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
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End point type |
Secondary
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End point timeframe |
Baseline, Weeks 2, 24, and 52
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Association Between Disease Activity Parameters: DAS28-ESR and CDAI, Assessed Using Correlation Coefficient | ||||||||||||||
End point description |
DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the ESR in mm/hour and PtGDA. DAS28-ESR total score= 0-9.4. Higher scores indicate greater affectation due to disease activity. The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. CDAI total score = 0-76. Higher scores represent greater affectation due to disease activity. Correlation coefficient for relationship between DAS28-ESR and CDAI at different time points is reported. Correlation coefficient value range= -1 to 1. Higher positive value indicates greater positive relationship and higher negative value indicates greater negative relationship. Analysis was performed on FAS; Here, 'n' signifies the number of participants evaluable at specified time point.
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End point type |
Secondary
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End point timeframe |
Weeks 2, 24, 52
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| Notes [8] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Association Between Disease Activity Parameters: DAS28-ESR and SDAI, Assessed Using Correlation Coefficient | ||||||||||||||
End point description |
DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the ESR in mm/hour and PtGDA. DAS28-ESR total score= 0-9.4. Higher scores indicate greater affectation due to disease activity. SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and CRP in mg/dL. SDAI total score= 0-86. Higher scores indicate greater affectation due to disease activity. Correlation coefficient for relationship between DAS28-ESR and SDAI at different time points is reported. Correlation coefficient value range= -1 to 1. Higher positive value indicates greater positive relationship and higher negative value indicates greater negative relationship. Analysis was performed on FAS; Here, 'n' signifies the number of participants evaluable at specified time point.
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End point type |
Secondary
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End point timeframe |
Weeks 2, 24, 52
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| Notes [9] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Association Between Disease Activity Parameters: CDAI and SDAI, Assessed Using Correlation Coefficient | ||||||||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. CDAI total score = 0-76. Higher scores represent greater affectation due to disease activity. SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and CRP in mg/dL. SDAI total score= 0-86. Higher scores indicate greater affectation due to disease activity. Correlation coefficient for relationship between CDAI and SDAI at different time points is reported. Correlation coefficient value range= -1 to 1. Higher positive value indicates greater positive relationship and higher negative value indicates greater negative relationship. Analysis was performed on FAS; Here, 'n' signifies the number of participants evaluable at specified time point.
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End point type |
Secondary
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End point timeframe |
Weeks 2, 24, 52
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| Notes [10] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Association Between Disease Activity Parameter (DAS28-ESR) and Treatment Response Parameters (ACR20, ACR50, and ACR70), Assessed Using Regression Coefficient | ||||||||||||||||||||||||||
End point description |
DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the ESR in mm/hour and PtGDA. DAS28-ESR total score= 0-9.4. The ACR 20, 50, and 70 responses: >/=20%, 50%, and 70% improvement in TJC and SJC, and 20%, 50%, 70% improvement in 3 of the following 5 criteria, respectively: 1) PGDA, 2) PtGDA, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP at each visit. Regression coefficients for relationship between DAS28-ESR and ACR responses (ACR20, ACR50, and ACR70) at different time points are reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship. Analysis was performed on FAS; Here, 'n' = number of participants evaluable at specified time point.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||
End point timeframe |
Weeks 2, 24, 52
|
||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||
| Notes [11] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
|
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End point title |
Association Between Disease Activity Parameter (DAS28-ESR) and Treatment Response Parameter (EULAR), Assessed Using Regression Coefficient | ||||||||||||||
End point description |
DAS28-ESR is calculated from the TJC and SJC based on a 28-joint assessment, the ESR in mm/hour and PtGDA. DAS28-ESR total score= 0-9.4. EULAR response criteria (based on DAS28 score): 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); Non-responders (change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28 >5.1). Regression coefficient for relationship between DAS28-ESR and EULAR Good response at different time points is reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship. Analysis was performed on FAS; Here, 'n' signifies the number of participants evaluable at specified time point.
|
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End point type |
Secondary
|
||||||||||||||
End point timeframe |
Weeks 2, 24, 52
|
||||||||||||||
|
|||||||||||||||
| Notes [12] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||||||||||
End point title |
Association Between Disease Activity Parameter (CDAI) and Treatment Response Parameters (ACR20, ACR50, and ACR70), Assessed Using Regression Coefficient | ||||||||||||||||||||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. CDAI total score = 0-76. The ACR 20, 50, and 70 responses: >/=20%, 50%, and 70% improvement in TJC and SJC, and 20%, 50%, 70% improvement in 3 of the following 5 criteria, respectively: 1) PGDA, 2) PtGDA, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP at each visit. Regression coefficients for relationship between CDAI and ACR responses (ACR20, ACR50, and ACR70) at different time points are reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship. Analysis was performed on FAS; Here, 'n' = number of participants evaluable at specified time point.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||
End point timeframe |
Weeks 2, 24, 52
|
||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||
| Notes [13] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
|||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||
|
|||||||||||||||
End point title |
Association Between Disease Activity Parameter (CDAI) and Treatment Response Parameter (EULAR), Assessed Using Regression Coefficient | ||||||||||||||
End point description |
The CDAI is a numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS. CDAI total score = 0-76. EULAR response criteria (based on DAS28 score): 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); Non-responders (change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28 >5.1). Regression coefficient for relationship between CDAI and EULAR Good response at different time points is reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship. Analysis was performed on FAS; Here, 'n' signifies the number of participants evaluable at specified time point.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Weeks 2, 24, 52
|
||||||||||||||
|
|||||||||||||||
| Notes [14] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||||||||||
End point title |
Association Between Disease Activity Parameter (SDAI) and Treatment Response Parameters (ACR20, ACR50, and ACR70), Assessed Using Regression Coefficient | ||||||||||||||||||||||||||
End point description |
SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and CRP in mg/dL. SDAI total score= 0-86. The ACR 20, 50, and 70 responses: >/=20%, 50%, and 70% improvement in TJC and SJC, and 20%, 50%, 70% improvement in 3 of the following 5 criteria, respectively: 1) PGDA, 2) PtGDA, 3) participant's assessment of pain, 4) participant's assessment of functional disability via a health assessment questionnaire, and 5) CRP at each visit. Regression coefficients for relationship between SDAI and ACR responses (ACR20, ACR50, and ACR70) at different time points are reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship. Analysis was performed on FAS; Here, 'n' = number of participants evaluable at specified time point.
|
||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||
End point timeframe |
Weeks 2, 24, 52
|
||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||
| Notes [15] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
|||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||
|
|||||||||||||||
End point title |
Association Between Disease Activity Parameter (SDAI) and Treatment Response Parameter (EULAR), Assessed Using Regression Coefficient | ||||||||||||||
End point description |
The SDAI is a numerical sum of 5 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGDA and PGDA assessed on 0-10 cm VAS and CRP in mg/dL. SDAI total score= 0-86. EULAR response criteria (based on DAS28 score): 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); Non-responders (change from baseline </=0.6 or change from baseline >0.6 and </=1.2 with DAS28 >5.1). Regression coefficient for relationship between SDAI and EULAR Good response at different time points is reported. Regression coefficient value range= not defined (any negative or positive value is possible). Higher positive value indicates greater extent of positive relationship and higher negative value indicates greater extent of negative relationship. Analysis was performed on FAS; Here, 'n' signifies the number of participants evaluable at specified time point.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Weeks 2, 24, 52
|
||||||||||||||
|
|||||||||||||||
| Notes [16] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||
End point title |
Percentage of DMARDs Dose Reductions and/or Discontinuation Events by Reasons | ||||||||||||||||||
End point description |
Percentage of DMARDs dose reduction and/or discontinuation events is reported by different reasons. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants with DMARDs dose reductions and/or discontinuation.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline up to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [17] - Total number of DMARDs dose reduction and/or discontinuation events = 148 |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||||
End point title |
Percentage of Non-DMARDs Dose Reductions and/or Discontinuation Events by Reasons | ||||||||||||||||||
End point description |
Percentage of non-DMARDs dose reduction and/or discontinuation events is reported by different reasons. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants with non-DMARDs dose reductions and/or discontinuation.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline up to Week 52
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [18] - Total number of non-DMARDs dose reduction and/or discontinuation events = 547 |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in PtGDA VAS Score at Weeks 2, 24, and 52 | ||||||||||||||||
End point description |
Participants answered the following question: "Considering all the ways your arthritis affects you, how are you feeling today." Participants responded by using a 0 - 100 millimeter (mm) VAS, where 0 mm = very well and 100 mm = very poorly. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Weeks 2, 24, and 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in PGDA VAS Score at Weeks 2, 24, and 52 | ||||||||||||||||
End point description |
The physician assessed participant's current disease activity on a 0-100 mm VAS, where 0 mm = no disease activity and 100 mm = maximum disease activity. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Weeks 2, 24, and 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Participant Pain VAS Score at Weeks 2, 24, and 52 | ||||||||||||||||
End point description |
Participants assessed their pain using a 0-100 mm VAS. Intensity of pain range (over past week): 0 mm = no pain to 100 mm = worst possible pain. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Weeks 2, 24, and 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 24, and 52 | ||||||||||||||||
End point description |
HAQ-DI is a 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. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Weeks 2, 24, and 52
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Missed Working Days Assessed Using Short Form-Health and Labor Questionnaire (SF-HLQ) Score at Weeks 24 and 52 | ||||||||||||
End point description |
The SF-HLQ assessed productivity losses related to health problems in individuals with paid or unpaid work and consisted of three modules (absenteeism from paid work, production losses without absenteeism from paid work and hindrance in the performance of paid and unpaid work). Any missed working days or number of worked days with reduced efficiency during the last month were reported. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Weeks 24 and 52
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Total Score at Weeks 2, 24, and 52 | ||||||||||||||||
End point description |
FACIT total score is sum of Functional Assessment of Cancer Therapy-General (FACT-G) score and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; additional concerns) score. FACT-G is a core questionnaire that evaluates quality of life (QoL) in cancer population. FACT-G consists of 27 questions grouped in 4 domains of general health-related QoL: physical well-being, social/family well-being, emotional well-being, and functional well-being; each item ranges from 0 (not at all) to 4 (very much). FACT-G score ranges between 0-108. FACIT-F is a 13-item questionnaire that evaluates self-reported fatigue and its impact upon daily activities. Each item ranges from 0 (Not at all) to 4 (Very much). The sum of all responses result in the FACIT total score with a total possible range of 0 (better score) to 160 (worse score). Negative change from baseline represents a better QoL. Analysis was performed on FAS; Here, 'n'=number of participants evaluable at specified time point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Weeks 2, 24, and 52
|
||||||||||||||||
|
|||||||||||||||||
| Notes [19] - 'Number of Subjects Analysed' = number of participants evaluable for this outcome measure. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||
End point title |
Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) at Weeks 24 and 52 | ||||||||||||||
End point description |
PSQI is a questionnaire with 18 questions to assess sleep quality. The 18 questions are distributed to 7 elements (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction). A participant indicates how frequently each item was experienced on a scale from 0 to 3. The global score is the sum score of all 7 elements and ranges from 0-21 with higher values indicating worse sleep quality. A score of >/=5 indicates poor sleepers. Per-protocol analysis set (PPAS) included all participants in FAS without any major protocol violation and who completed 24 weeks of treatment period. 'Number of Subjects Analysed' = participants evaluable for this outcome; 'n' = participants evaluable at specified time point.
|
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End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline, Weeks 24 and 52
|
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|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
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End point title |
Treatment Compliance, as Assessed Using Participant Diary Cards and Return Records | ||||||||||||
End point description |
Treatment Compliance was calculated as (total actual doses taken for the period) / (total planned or prescribed dose for the period) x 100. Analysis was performed on FAS; Here, 'Number of Subjects Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
|
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End point type |
Secondary
|
||||||||||||
End point timeframe |
Weeks 24 and 52
|
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|
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| No statistical analyses for this end point | |||||||||||||
|
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End point title |
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) of Special Interest | ||||||||
End point description |
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are AEs occurring between the first dose of study drug and up to 28 days after the last dose that were absent before treatment or that worsened relative to pre-treatment state. Following AEs were considered as AEs of special interest: anaphylactic reaction, hypersensitivity, stress cardiomyopathy, Gilbert’s syndrome, gastrointestinal perforation, injection site erythema, injection site hypersensitivity, injection site irritation, injection site pruritus, arthritis bacterial, cellulitis, klebsiella infection, oral candidiasis, pneumonia, skin infection, vulvovaginal candidiasis, alanine aminotransferase increased, hepatic enzyme increased, brain neoplasm malignant, and urticaria. Analysis was performed on FAS.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline up to 95 weeks
|
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|
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| No statistical analyses for this end point | |||||||||
|
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End point title |
Percentage of Participants With Anti-therapeutic Antibodies (ATA) to Tocilizumab | ||||||||||||||||||||||||||||
End point description |
Percentage of participants with positive results for ATA against tocilizumab at different time points is reported. Analysis was performed on FAS; Here, 'n' signifies the number of participants evaluable at specified time points.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 12, 24, 38, 52, at 8 weeks after last dose (up to Week 60), at early withdrawal (up to Week 52), at Follow-up Visits 1 (Week 64), 2 (Week 76), and 3 (Week 88)
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
|
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End point title |
Mean Tocilizumab Concentration | ||||||||||||||||||||||
End point description |
Analysis was performed on FAS; Here 'n' signifies the number of participants evaluable at specified time point.
|
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End point type |
Secondary
|
||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 12, 24, 38, 52, at early withdrawal (up to Week 52), at Follow-up Visit 2 (Week 76)
|
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|
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| No statistical analyses for this end point | |||||||||||||||||||||||
|
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End point title |
Mean Soluble Interleukin-6 Receptor (sIL-6R) Concentration | ||||||||||||||||||||||
End point description |
Analysis was performed on FAS; Here 'n' signifies the number of participants evaluable at specified time point.
|
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End point type |
Secondary
|
||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 12, 24, 38, 52, at early withdrawal (up to Week 52), at Follow-up Visit 2 (Week 76)
|
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|
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| No statistical analyses for this end point | |||||||||||||||||||||||
|
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 up to approximately 95 weeks
|
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Adverse event reporting additional description |
FAS; TEAEs are adverse events occurring between the first dose of study drug and up to 28 days after the last dose that were absent before treatment or that worsened relative to pre-treatment state.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
|
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Reporting groups
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Reporting group title |
Tocilizumab
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Reporting group description |
Tocilizumab at a fixed dose of 162 mg was administered as SC injection alone or along with methotrexate and/or other non-biological DMARDs irrespective of body weight, once every week for a total of 52 weeks. After 52-weeks of treatment, at the discretion of the treating physician, participants could continue the study treatment with SC tocilizumab until it became commercially available in Italy (maximum up to 638 days). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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15 May 2014 |
In the original protocol, onsite visits in the period from Week 24 to Week 52 were scheduled every 14 weeks (Week 24, Week 38, and Week 52). After Week 52, if participants continued the study treatment until tocilizumab became commercially available in Italy, on site assessments were expected every 3 months. During the above-mentioned study period, monthly telephone calls contacts were added to the schedule of assessments in order to collect details on any AE and changes in concomitant medications between an on-site visit and the next one. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
