A Phase 4 interventional study of methylprednisolone and tocilizumab [RoActemra/Actemra] in Rheumatoid Arthritis, sponsored by Hoffmann-La Roche. Completed at 16 sites in Belgium. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2015-01-19.
Sponsored by Hoffmann-La Roche · Phase 4, Interventional, and Treatment
This open-label, single-arm study will assess the use of glucocorticoids (GC) in daily clinical practice and will evaluate the dose reduction of glucocorticoids once low disease activity is achieved in patients with rheumatoid arthritis tre ated with GC and background RoActemra/Actemra (tocilizumab) 8mg/kg intravenously every 4 weeks. In the non-interventional phase, the use of GC in daily clinical Belgian practice will be evaluated and described. This period of maximum 6 mont hs will allow those patients to obtain the inclusion criteria for the secondary interventional phase. In the interventional phase, a systematic GC dose reductio n schedule will be evaluated in patients having achieved low disease activity wh ile receiving the same background therapy with RoActemra/Actemra 8 mg/kg. Methyl prednisolone will be given from a starting dose of >/= 1 mg to \</=20 mg orally d aily and will be tapered down. The anticipated study duration is up to 13 months
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Non-interventional phase
Exclusion Criteria:
Non-interventional \& interventional phase
Drug: methylprednisolone · Drug: tocilizumab [RoActemra/Actemra]
starting dose \>/= 1 mg and \</= 20 mg orally daily, according to dose-reduction schedule
Drug page: Tocilizumab
background therapy: 8 mg/kg iv every 4 weeks
Median GC Dose Taken During the Noninterventional Phase
During the noninterventional phase of the study participants received GC as prescribed by the physician. Doses of all GC administered are expressed as MP equivalents.
Time frame: V1 and V2 (up to 6 months after V1)
Number of Participants With GC Switches During the Noninterventional Phase
During the noninterventional phase of the study, once LDA was achieved, GC was switched to MP tablets.
Time frame: V1 and V2 (up to 6 months after V1)
Type of GC Taken at the End of the Noninterventional Phase
During the noninterventional phase of the study participants received GC as prescribed by the physician.
Time frame: V1 and V2 (up to 6 months after V1)
Percentage of Participants in the Interventional Phase Who Achieved LDA and Discontinued Oral GC Within 20 Weeks
The percentage of participants with rheumatoid arthritis (RA) with LDA was defined as DAS28 ≤3.2, able to discontinue oral GC within 20 weeks and at the latest at V8, confirmed at the Consolidation Visit without loss of clinical response defined as DAS28 (CRP) \>3.2.
Time frame: Visits 3 (7 months), 4 (8 months), 5 (9 months), 6 (10 months), 7 (11 months), and 8 (12 months)
Percentage of Participants Able to Acheive LDA Assessed Using DAS28 While Receiving Oral GC on Background Tocilizumab Treatment During the Noninterventional Phase
DAS28 was calculated from the number of swollen joints and tender joints using the 28-joint count, the CRP and Patient's Global Assessment (PtGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 ≤3.2 and oral GC intake with MP equivalent dose of ≥1 mg and ≤20 mg/day= LDA.
Time frame: V1 and V2 (up to 6 months after V1)
Percentage of Participants Acheiving Remission Assessed Using DAS28 While Receiving Oral GC on Background TocilizumabTreatment During the Noninterventional Phase
DAS28 was calculated from the number of swollen joints and tender joints using the 28-joint count, the CRP and PtGA of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 \<2.6 = remission.
Time frame: V1 and V2 (up to 6 months after V1)
Percentage of Participants With Erosions During the NonInterventional Phase
In RA, the presence, number and size of bone erosions and the number of joints with erosions on conventional radiographs (CRs) are hallmarks for diagnosis, staging and prediction of damage progression and are used for treatment monitoring in randomized controlled studies.
Time frame: V1 and V2 (up to 6 months after V1)
Number of Erosions During the NonInterventional Phase
In RA, the presence, number, and size of bone erosions and the number of joints with erosions on CRs are hallmarks for diagnosis, staging and prediction of damage progression and are used for treatment monitoring in randomized controlled studies.
Time frame: V1 and V2 (up to 6 months after V1)
Percentage of Participants Positive for Rheumatoid Factor (RF) During the Noninterventional Phase
RF is the auto antibody directed against immunoglobulin G (IgG) and its concentration is observed in human serum or plasma. RF value higher than 20 units per milliliter (U/mL) is considered positive.
Time frame: V1 and V2 (up to 6 months after V1)
Percentage of Participants Positive for Anti-cyclic Citrullinated Peptide (Anti-CCP) Antibody During the Noninterventional Phase
Anti-CCP antibodies are important markers of bone erosion in RA. Anti-CCP antibodies were classified as positive if \>7 U/mL.
Time frame: V1 and V2 (up to 6 months after V1)
Health Assessment Questionnaire Disability Index (HAQ-DI) During the Noninterventional Phase
HAQ-DI is a self-reported, valid assessment of functional disability in RA. Assessed based on ability of participants to perform daily activities in 8 categories: dressing, arising, eating, walking, reaching, gripping, hygiene, and carrying out daily activities. HAQ-DI score range: 0-3: without any difficulty=0, with some difficulty=1, with much difficulty=2, unable to do=3. HAQ total scores expressed as overall mean score with range 0-3: 0-0.25=normal functioning; 0.25-0.5=mild functional limitation; 0.5-1=moderate functional limitation; more than 1=significant functional limitation. Timepoint was V2, or before V2 for participants withdrawn before V2.
Time frame: V1 and V2 (up to 6 months after V1)
DAS28-CRP During the Noninterventional Phase
DAS28-CRP was calculated from the swollen joint count (SJC) and tender joint count (TJC) using the 28-joint count and CRP (mg/L). Total score range: 0 to 10, higher score indicated more disease activity. DAS28-CRP ≤3.2=LDA and \>3.2 to 5.1=moderate to high disease activity, and DAS28-CRP \<2.6=remission. Timepoint was V2, or before V2 for participants withdrawn before V2; DAS28-CRP values indicated in the Case Report Form (CRF) were recalculated by the data manager. The recalculated values were used in the statistical analyses.
Time frame: V1 and V2 (up to 6 months after V1)
DAS28-ESR During the Noninterventional Phase
DAS28-ESR was calculated from the SJC and TJC using the 28 joints count and ESR (millimeters per hour \[mm/hr\]). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-ESR ≤3.2=LDA and \>3.2 to 5.1=moderate to high disease activity, and DAS28-ESR \<2.6=remission. Timepoint was V2, or before V2 for participants withdrawn before V2; DAS28-ESR values indicated in the CRF were recalculated by the data manager. The recalculated values were used in the statistical analyses.
Time frame: V1 and V2 (up to 6 months after V1)
Clinical Disease Activity Index (CDAI) During the Noninterventional Phase
The CDAI is the numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGA and Physician Global Assessment (PGA) of disease assessed on 0-100 mm Visual analog scale (VAS); higher scores=greater affection due to disease activity. CDAI total score=0-76. CDAI ≤2.8=disease remission, \>2.8 to 10=LDA, \>10 to 22=moderate disease activity, and \>22=high disease activity.
Time frame: V1 and V2 (up to 6 months after V1)
Median Time Interval Between V1 and V2
The noninterventional phase was planned to last for a maximum of 6 months per participant. The time between V1 and V2 was measured in months.
Time frame: V1 and V2 (up to 6 months after V1)
Median Dose of Tocilizumab During the Noninterventional Phase
Time frame: V1 and V2 (up to 6 months after V1)
Number of Participants With Changes in Tocilizumab Dose During the Noninterventional Phase
The dose of tocilizumab could have been reduced from the recommended 8 mg/kg to 4 mg/kg in participants in the case of adverse events.
Time frame: V1 and V2 (up to 6 months after V1)
Percentage of Participants With Changes in RA Treatment During the Noninterventional Phase
Time frame: V1 and V2 (up to 6 months after V1)
Percentage of Participants Able to Start the GC Reduction Phase at V3
All participants who maintained LDA (defined as DAS28-CRP ≤3.2) from V2 to V3 were included in the interventional phase for reduction of GC.
Time frame: V3 (7 months)
Percentage of Participants Able to Reduce Oral GCs by ≥50 Percent (%) During the Interventional Phase by V9
Time frame: V9 (24 weeks after V3)
Percentage of Participants Able to Discontinue GCs During the Interventional Phase by V9
Time frame: V9 (24 weeks after V3)
Time-Averaged GC Dose Changes During the Interventional Phase
Area Under the Curve (AUC) of GC dose during the interventional phase was determined using the trapezoidal method and was calculated as: AUC = sigma(Ti+1 - Ti) x \[(Di+1+Di)/2\] With Di=dosage at time Ti It corresponds to the total GC dose received between Baseline (visit 3) and visit 9 and has been calculated only for the 30 patients achieving visit 9.
Time frame: V3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
DAS28-CRP During the Interventional Phase
DAS28-CRP was calculated from the SJC and TJC using the 28-joint count and CRP (mg/L). Total score range: 0 to 10, higher score indicated more disease activity. DAS28-CRP) ≤3.2=LDA and \>3.2 to 5.1=moderate to high disease activity, and DAS28-CRP \<2.6=remission. DAS28-CRP values indicated in the CRF were recalculated by the data manager. The cumulative DAS28 (CRP) value (AUC method) was performed using the calculated DAS28. The recalculated values were used in the statistical analyses.
Time frame: V3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
HAQ-DI During the Interventional Phase
HAQ-DI is a self-reported, valid assessment of functional disability in RA. Assessed based on ability of participants to perform daily activities in 8 categories: dressing, arising, eating, walking, reaching, gripping, hygiene, and carrying out daily activities. HAQ-DI score range: 0-3: without any difficulty=0, with some difficulty=1, with much difficulty=2, unable to do=3. HAQ total scores expressed as overall mean score with range 0-3: 0-0.25=normal functioning; 0.25-0.5=mild functional limitation; 0.5-1=moderate functional limitation; more than 1=significant functional limitation. V3, CV, and the change from V3 to CV was determined.
Time frame: Visit 3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
VAS-Physician's Global Assessment of Disease Activity (GDA) During the Interventional Phase
Physician's were asked to determine the overall GDA for each participant using a 100-mm VAS, where 0=no disease activity and 100=maximum disease activity. The physician marked the line corresponding to their assessment and the distance from the left edge was measured. V3, CV, and the change from V3 to CV was determined.
Time frame: V3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
VAS for Pain (VAS-Pain) During the Interventional Phase
Participants were asked to mark the line corresponding to the intensity of their pain on a 100-mm VAS, where 0=no pain and 100=worst possible pain. The distance from the left edge was measured. Change = V3 mean minus CV mean.
Time frame: V3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
SJC and TJC During the Interventional Phase
TJC and SJC were assessed for 28 joints. An assessment of 28 joints for swelling and tenderness was made. Joints were assessed and classified as swollen (1)/not swollen (0) and tender (1)/not tender (0) by pressure and joint manipulation on physical examination for a total score range of 0-28. Higher scores indicated greater disease activity (tenderness/swelling). V3, CV, and the change from V3 to CV was determined.
Time frame: V3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score During the Interventional Phase
FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (not at all) to 4 (very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-F score for a total possible score of 0 (worse score) to 52 (better score). V3, CV, and the change from V3 to CV was determined.
Time frame: V3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
Short-Form 36 (SF-36) Mental Component Score (MCS) and Physical Component Score (PCS) During the Interventional Phase
36-Item Short-Form Health Survey (SF-36) is a standardized survey evaluating 8 aspects of functional health and well-being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as physical and mental component scores (PCS and MCS). Total of 11 variables were analyzed (8 subscales, 2 composite subscales and Question 2 "how would you rate your health in general now?" (range 1= better, 5= worst). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). Higher scores reflect higher quality of life. V3, CV, and the change from V3 to CV was determined.
Time frame: V3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
SF-36 Subscale Scores During the Interventional Phase
SF-36 is a standardized survey evaluating 8 aspects of functional health and well-being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as physical and mental component scores (PCS and MCS). Total of 11 variables were analyzed (8 subscales, 2 composite subscales and Question 2 "how would you rate your health in general now?" (range 1= better, 5= worst). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). Higher scores reflect higher quality of life. V3, CV, and the change from V3 to CV was determined.
Time frame: V3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
CDAI Score During the Interventional Phase
The CDAI is the numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGA and PGA assessed on 0-100 mm VAS; higher scores=greater affection due to disease activity. CDAI total score=0-76. CDAI ≤2.8=disease remission, \>2.8 to 10=LDA, \>10 to 22=moderate disease activity, and \>22=high disease activity. V3, CV, and the change from V3 to CV was determined.
Time frame: V3 (7 months) and CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
Percentage of Participants With LDA or Remission During the Interventional Phase Assessed Using CDAI
The CDAI is the numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGA and PGA assessed on 0-100 mm VAS; higher scores=greater affection due to disease activity. CDAI total score=0-76. CDAI ≤2.8=disease remission and \>2.8 to 10=LDA.
Time frame: Visits 3 (7 months), 4 (8 months), 5 (9 months), 6 (10 months), 7 (11 months), 8 (12 months), and 9 (24 weeks after V3) or CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
Percentage of Participants With LDA or Remission During the Interventional Phase Assessed Using DAS28-CRP
DAS28 calculated from the number of swollen joints (SJC) and tender joints (TJC) using the 28 joint count, the CRP and PtGA of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28-CRP ≤3.2 and oral GC intake with MP equivalent dose of ≥1 mg and ≤20 mg/day=LDA; DAS28 \<2.6 = remission.
Time frame: Visits 3 (7 months), 4 (8 months), 5 (9 months), 6 (10 months), 7 (11 months), 8 (12 months), 9 (24 weeks after V3) or CV (4 weeks after GC-free status, maximum of 24 weeks after V3)
| Milestone | Tocilizumab |
|---|---|
| Started | 68 |
| Completed | 30 |
| Not completed | 38 |
| Withdrew: Adverse event | 8 |
| Withdrew: No lda reached | 5 |
| Withdrew: No lda maintained | 7 |
| Withdrew: Lost to follow-up | 3 |
| Withdrew: Gc free | 1 |
| Withdrew: Withdrawal by subject | 5 |
| Withdrew: Protocol violation | 8 |
| Withdrew: Lack of efficacy | 1 |
During the noninterventional phase of the study participants received GC as prescribed by the physician. Doses of all GC administered are expressed as MP equivalents.
| mg | Tocilizumab |
|---|---|
| Start dose V1 (n=68) | 6 (2 to 40) |
| Start dose (V1) for Interventional phase (n=50) | 6 (2 to 32) |
| Stop dose (V2; n=50) | 4 (1 to 16) |
| Change from start to stop (n=50) | 0 (-24 to 2) |
| Cumulative dose from V1 to V2 (n=45) | 320 (58 to 2688) |
During the noninterventional phase of the study, once LDA was achieved, GC was switched to MP tablets.
| participants | Tocilizumab |
|---|---|
| Number of Participants With GC Switches During the Noninterventional Phase | 0 |
DAS28 was calculated from the number of swollen joints and tender joints using the 28-joint count, the CRP and Patient's Global Assessment (PtGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 ≤3.2 and oral GC intake with MP equivalent dose of ≥1 mg and ≤20 mg/day= LDA.
| percentage of participants | Tocilizumab |
|---|---|
| Percentage of Participants Able to Acheive LDA Assessed Using DAS28 While Receiving Oral GC on Background Tocilizumab Treatment During the Noninterventional Phase | 72.1 |
DAS28 was calculated from the number of swollen joints and tender joints using the 28-joint count, the CRP and PtGA of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28 \<2.6 = remission.
| percentage of participants | Tocilizumab |
|---|---|
| Percentage of Participants Acheiving Remission Assessed Using DAS28 While Receiving Oral GC on Background TocilizumabTreatment During the Noninterventional Phase | 41.2 |
In RA, the presence, number and size of bone erosions and the number of joints with erosions on conventional radiographs (CRs) are hallmarks for diagnosis, staging and prediction of damage progression and are used for treatment monitoring in randomized controlled studies.
| percentage of participants | Tocilizumab |
|---|---|
| V1 (n=57) | 47.4 |
| Between V1 and V2 (n=36) | 41.7 |
In RA, the presence, number, and size of bone erosions and the number of joints with erosions on CRs are hallmarks for diagnosis, staging and prediction of damage progression and are used for treatment monitoring in randomized controlled studies.
| erosions | Tocilizumab |
|---|---|
| V1 (n=11) | 5.1 ± 6.0 |
| Between V1 and V2 (n=6) | 3.2 ± 2.3 |
RF is the auto antibody directed against immunoglobulin G (IgG) and its concentration is observed in human serum or plasma. RF value higher than 20 units per milliliter (U/mL) is considered positive.
| percentage of participants | Tocilizumab |
|---|---|
| V1 (n=39) | 56.4 |
| Between V1 and V2 (n=21) | 52.4 |
Anti-CCP antibodies are important markers of bone erosion in RA. Anti-CCP antibodies were classified as positive if \>7 U/mL.
| percentage of participants | Tocilizumab |
|---|---|
| V1 (n=20) | 75.0 |
| Between V1 and V2 (n=6) | 83.3 |
HAQ-DI is a self-reported, valid assessment of functional disability in RA. Assessed based on ability of participants to perform daily activities in 8 categories: dressing, arising, eating, walking, reaching, gripping, hygiene, and carrying out daily activities. HAQ-DI score range: 0-3: without any difficulty=0, with some difficulty=1, with much difficulty=2, unable to do=3. HAQ total scores expressed as overall mean score with range 0-3: 0-0.25=normal functioning; 0.25-0.5=mild functional limitation; 0.5-1=moderate functional limitation; more than 1=significant functional limitation. Timepoint was V2, or before V2 for participants withdrawn before V2.
| units on a scale | Tocilizumab |
|---|---|
| V1 (n=66) | 1.7 ± 0.6 |
| V2 (n=61) | 1.2 ± 0.7 |
| Change from V1 to V2 (n=60) | -0.5 ± 0.6 |
DAS28-CRP was calculated from the swollen joint count (SJC) and tender joint count (TJC) using the 28-joint count and CRP (mg/L). Total score range: 0 to 10, higher score indicated more disease activity. DAS28-CRP ≤3.2=LDA and \>3.2 to 5.1=moderate to high disease activity, and DAS28-CRP \<2.6=remission. Timepoint was V2, or before V2 for participants withdrawn before V2; DAS28-CRP values indicated in the Case Report Form (CRF) were recalculated by the data manager. The recalculated values were used in the statistical analyses.
| units on a scale | Tocilizumab |
|---|---|
| V1 (n=67) | 5.4 ± 1.0 |
| V2 (n=66) | 2.9 ± 1.1 |
| Change from V1 to V2 (n=65) | -2.5 ± 1.3 |
DAS28-ESR was calculated from the SJC and TJC using the 28 joints count and ESR (millimeters per hour \[mm/hr\]). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-ESR ≤3.2=LDA and \>3.2 to 5.1=moderate to high disease activity, and DAS28-ESR \<2.6=remission. Timepoint was V2, or before V2 for participants withdrawn before V2; DAS28-ESR values indicated in the CRF were recalculated by the data manager. The recalculated values were used in the statistical analyses.
| units on a scale | Tocilizumab |
|---|---|
| V1 (n=62) | 5.8 ± 1.0 |
| V2 (n=52) | 3.3 ± 1.4 |
| Change from V1 to V2 (n=50) | -2.7 ± 1.3 |
The CDAI is the numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGA and Physician Global Assessment (PGA) of disease assessed on 0-100 mm Visual analog scale (VAS); higher scores=greater affection due to disease activity. CDAI total score=0-76. CDAI ≤2.8=disease remission, \>2.8 to 10=LDA, \>10 to 22=moderate disease activity, and \>22=high disease activity.
| units on a scale | Tocilizumab |
|---|---|
| V1 (n=62) | 33.8 ± 12.2 |
| V2 (n=52) | 14.6 ± 10.3 |
| Change from V1 to V2 (n=50) | -20.4 ± 13.7 |
The noninterventional phase was planned to last for a maximum of 6 months per participant. The time between V1 and V2 was measured in months.
| months | Tocilizumab |
|---|---|
| Median Time Interval Between V1 and V2 | 2.3 (0.8 to 5.9) |
| mg/kg | Tocilizumab |
|---|---|
| Median Dose of Tocilizumab During the Noninterventional Phase | 8.0 (8.0 to 8.0) |
The dose of tocilizumab could have been reduced from the recommended 8 mg/kg to 4 mg/kg in participants in the case of adverse events.
| participants | Tocilizumab |
|---|---|
| Number of Participants With Changes in Tocilizumab Dose During the Noninterventional Phase | 1 |
| percentage of participants | Tocilizumab |
|---|---|
| Percentage of Participants With Changes in RA Treatment During the Noninterventional Phase | 15.2 |
All participants who maintained LDA (defined as DAS28-CRP ≤3.2) from V2 to V3 were included in the interventional phase for reduction of GC.
| percentage of participants | Tocilizumab |
|---|---|
| Percentage of Participants Able to Start the GC Reduction Phase at V3 | 87.8 (75.2 to 95.4) |
| percentage of participants | Tocilizumab |
|---|---|
| Percentage of Participants Able to Reduce Oral GCs by ≥50 Percent (%) During the Interventional Phase by V9 | 93.3 (77.9 to 99.2) |
| percentage of participants | Tocilizumab |
|---|---|
| Percentage of Participants Able to Discontinue GCs During the Interventional Phase by V9 | 3.3 (0.1 to 17.2) |
Area Under the Curve (AUC) of GC dose during the interventional phase was determined using the trapezoidal method and was calculated as: AUC = sigma(Ti+1 - Ti) x \[(Di+1+Di)/2\] With Di=dosage at time Ti It corresponds to the total GC dose received between Baseline (visit 3) and visit 9 and has been calculated only for the 30 patients achieving visit 9.
| mg | Tocilizumab |
|---|---|
| Time-Averaged GC Dose Changes During the Interventional Phase | 341.8 ± 364.2 |
DAS28-CRP was calculated from the SJC and TJC using the 28-joint count and CRP (mg/L). Total score range: 0 to 10, higher score indicated more disease activity. DAS28-CRP) ≤3.2=LDA and \>3.2 to 5.1=moderate to high disease activity, and DAS28-CRP \<2.6=remission. DAS28-CRP values indicated in the CRF were recalculated by the data manager. The cumulative DAS28 (CRP) value (AUC method) was performed using the calculated DAS28. The recalculated values were used in the statistical analyses.
| units on a scale | Tocilizumab |
|---|---|
| V3 (n=42) | 2.2 ± 0.7 |
| CV (n=27) | 2.3 ± 0.8 |
| Change from V3 to CV (n=27) | 0.2 ± 0.8 |
HAQ-DI is a self-reported, valid assessment of functional disability in RA. Assessed based on ability of participants to perform daily activities in 8 categories: dressing, arising, eating, walking, reaching, gripping, hygiene, and carrying out daily activities. HAQ-DI score range: 0-3: without any difficulty=0, with some difficulty=1, with much difficulty=2, unable to do=3. HAQ total scores expressed as overall mean score with range 0-3: 0-0.25=normal functioning; 0.25-0.5=mild functional limitation; 0.5-1=moderate functional limitation; more than 1=significant functional limitation. V3, CV, and the change from V3 to CV was determined.
| units on a scale | Tocilizumab |
|---|---|
| V3 (n=41) | 1.0 ± 0.7 |
| CV (n=28) | 0.8 ± 0.7 |
| Change from V3 to CV (n=26) | 0.0 ± 0.4 |
Physician's were asked to determine the overall GDA for each participant using a 100-mm VAS, where 0=no disease activity and 100=maximum disease activity. The physician marked the line corresponding to their assessment and the distance from the left edge was measured. V3, CV, and the change from V3 to CV was determined.
| mm | Tocilizumab |
|---|---|
| V3 (n=40) | 16.6 ± 12.5 |
| CV (n=28) | 16.7 ± 15.9 |
| Change from V3 to CV (n=26) | 3.1 ± 15.4 |
Participants were asked to mark the line corresponding to the intensity of their pain on a 100-mm VAS, where 0=no pain and 100=worst possible pain. The distance from the left edge was measured. Change = V3 mean minus CV mean.
| mm | Tocilizumab |
|---|---|
| V3 (n=43) | 19.9 ± 16.5 |
| CV (n=28) | 24.9 ± 19.0 |
| Change from V3 to CV (n=28) | 6.9 ± 22.4 |
TJC and SJC were assessed for 28 joints. An assessment of 28 joints for swelling and tenderness was made. Joints were assessed and classified as swollen (1)/not swollen (0) and tender (1)/not tender (0) by pressure and joint manipulation on physical examination for a total score range of 0-28. Higher scores indicated greater disease activity (tenderness/swelling). V3, CV, and the change from V3 to CV was determined.
| joints | Tocilizumab |
|---|---|
| SJC V3 (n=43) | 0.9 ± 1.3 |
| SJC CV (n=29) | 0.4 ± 0.9 |
| SJC Change from V3 to CV (n=29) | -0.3 ± 0.8 |
| TJC V3 (n=43) | 0.9 ± 1.2 |
| TJC CV (n=29) | 1.8 ± 2.7 |
| TJC Change from V3 to CV (n=29) | 1.0 ± 2.6 |
FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (not at all) to 4 (very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-F score for a total possible score of 0 (worse score) to 52 (better score). V3, CV, and the change from V3 to CV was determined.
| units on a scale | Tocilizumab |
|---|---|
| V3 (n=37) | 37.5 ± 9.9 |
| CV (n=26) | 35.6 ± 10.8 |
| Change from V3 to CV (n=22) | 8.8 ± 19.0 |
During the noninterventional phase of the study participants received GC as prescribed by the physician.
| percentage of participants | Tocilizumab |
|---|---|
| MP | 70.0 |
| Prednisolone | 28.0 |
| Prednisone | 2.0 |
The percentage of participants with rheumatoid arthritis (RA) with LDA was defined as DAS28 ≤3.2, able to discontinue oral GC within 20 weeks and at the latest at V8, confirmed at the Consolidation Visit without loss of clinical response defined as DAS28 (CRP) \>3.2.
| percentage of participants | Tocilizumab |
|---|---|
| Percentage of Participants in the Interventional Phase Who Achieved LDA and Discontinued Oral GC Within 20 Weeks | 58.1 (42.1 to 73.0) |
36-Item Short-Form Health Survey (SF-36) is a standardized survey evaluating 8 aspects of functional health and well-being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as physical and mental component scores (PCS and MCS). Total of 11 variables were analyzed (8 subscales, 2 composite subscales and Question 2 "how would you rate your health in general now?" (range 1= better, 5= worst). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). Higher scores reflect higher quality of life. V3, CV, and the change from V3 to CV was determined.
| units on a scale | Tocilizumab |
|---|---|
| MCS V3 (n=37) | 47.0 ± 9.9 |
| MCS CV (n=26) | 46.2 ± 9.0 |
| MCS: Change from V3 to CV (n=22) | -4.4 ± 10.6 |
| PCS V3 (n=36) | 42.5 ± 7.6 |
| PCS CV (n=26) | 41.8 ± 8.8 |
| PCS: Change from V3 to CV (n=22) | -2.1 ± 6.4 |
SF-36 is a standardized survey evaluating 8 aspects of functional health and well-being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as physical and mental component scores (PCS and MCS). Total of 11 variables were analyzed (8 subscales, 2 composite subscales and Question 2 "how would you rate your health in general now?" (range 1= better, 5= worst). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). Higher scores reflect higher quality of life. V3, CV, and the change from V3 to CV was determined.
| units on a scale | Tocilizumab |
|---|---|
| Physical functioning V3 (n=36) | 41.52 ± 10.37 |
| Physical functioning CV (n=26) | 41.92 ± 10.44 |
| Change in physical functioning V3 to CV (n=22) | -1.80 ± 6.77 |
| Physical sub-score V3 (n=37) | 40.61 ± 7.53 |
| Physical sub-score CV (n=26) | 39.85 ± 8.23 |
| Change in physical sub-score V3 to CV (n=22) | -2.79 ± 7.68 |
| Bodily pain V3 (n=37) | 45.88 ± 8.35 |
| Bodily pain CV (n=26) | 44.65 ± 9.70 |
| Change in bodily pain V3 to CV (n=22) | -3.21 ± 8.67 |
| General health V3 (n=37) | 43.11 ± 9.42 |
| General health CV (n=26) | 40.82 ± 8.77 |
| Change in general health V3 to CV (n=22) | -3.78 ± 7.35 |
| Vitality V3 (n=37) | 50.51 ± 8.74 |
| Vitality CV (n=26) | 48.91 ± 9.13 |
| Change in vitality V3 to CV (n=22) | -4.37 ± 9.98 |
| Social functioning V3 (n=37) | 45.42 ± 9.63 |
| Social functioning CV (n=26) | 45.58 ± 9.29 |
| Change in social functioning V3 to CV (n=22) | -2.73 ± 9.63 |
| Emotional sub-score V3 (n=37) | 40.59 ± 9.98 |
| Emotional sub-score CV (n=26) | 40.37 ± 10.53 |
| Change in emotional sub-score V3 to CV (n=22) | -2.45 ± 10.29 |
| Mental health V3 (n=37) | 47.14 ± 10.00 |
| Mental health CV (n=26) | 45.94 ± 10.37 |
| Change in Mental health V3 to CV (n=22) | -5.47 ± 10.98 |
The CDAI is the numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGA and PGA assessed on 0-100 mm VAS; higher scores=greater affection due to disease activity. CDAI total score=0-76. CDAI ≤2.8=disease remission, \>2.8 to 10=LDA, \>10 to 22=moderate disease activity, and \>22=high disease activity. V3, CV, and the change from V3 to CV was determined.
| units on a scale | Tocilizumab |
|---|---|
| V3 (n=40) | 5.6 ± 3.8 |
| CV (n=27) | 6.5 ± 5.4 |
| Change from V3 to CV (n=25) | 1.4 ± 5.2 |
The CDAI is the numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, PtGA and PGA assessed on 0-100 mm VAS; higher scores=greater affection due to disease activity. CDAI total score=0-76. CDAI ≤2.8=disease remission and \>2.8 to 10=LDA.
| percentage of participants | Tocilizumab |
|---|---|
| V3 LDA (n=40) | 85.0 |
| V3 Remission (n=40) | 27.5 |
| V4 LDA (n=41) | 82.9 |
| V4 Remission (n=41) | 39.0 |
| V5 LDA (n=38) | 81.6 |
| V5 Remission (n=38) | 47.4 |
| V6 LDA (n=35) | 71.4 |
| V6 Remission (n=35) | 37.1 |
| V7 LDA (n=33) | 75.8 |
| V7 Remission (n=33) | 33.3 |
| V8 LDA (n=31) | 80.6 |
| V8 Remission (n=31) | 38.7 |
| V9 LDA (n=29) | 69.0 |
| V9 Remission (n=29) | 31.0 |
| CV LDA (n=27) | 77.8 |
| CV Remission (n=27) | 33.3 |
DAS28 calculated from the number of swollen joints (SJC) and tender joints (TJC) using the 28 joint count, the CRP and PtGA of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS28-CRP ≤3.2 and oral GC intake with MP equivalent dose of ≥1 mg and ≤20 mg/day=LDA; DAS28 \<2.6 = remission.
| percentage of participants | Tocilizumab |
|---|---|
| V3 LDA (n=42) | 90.5 |
| V3 Remission (n=42) | 73.8 |
| V4 LDA (n=41) | 85.4 |
| V4 Remission (n=41) | 73.2 |
| V5 LDA (n=35) | 88.6 |
| V5 Remission (n=35) | 71.4 |
| V6 LDA (n=35) | 82.9 |
| V6 Remission (n=35) | 62.9 |
| V7 LDA (n=33) | 90.9 |
| V7 Remission (n=33) | 57.6 |
| V8 LDA (n=32) | 87.5 |
| V8 Remission (n=32) | 62.5 |
| V9 LDA (n=30) | 73.3 |
| V9 Remission (n=30) | 56.7 |
| CV LDA (n=27) | 88.9 |
| CV Remission (n=27) | 59.3 |
Collected over Adverse events were recorded throughout the study from V1, 6 months before Interventional phase to CV. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Noninterventional Phase | — | 4/68 (5.9%) | 36/68 (52.9%) |
| Interventional Phase | — | 1/43 (2.3%) | 26/43 (60.5%) |
| Event | Noninterventional Phase | Interventional Phase |
|---|---|---|
| Breast cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/68 | 1/43 |
| Atrial fibrillationCardiac disorders | 1/68 | 0/43 |
| CellulitisInfections and infestations | 1/68 | 0/43 |
| Attempted to commit suicidePsychiatric disorders | 1/68 | 0/43 |
| Neck painMusculoskeletal and connective tissue disorders | 1/68 | 0/43 |
| OsteitisInfections and infestations | 1/68 | 0/43 |
| Event | Noninterventional Phase | Interventional Phase |
|---|---|---|
| BronchitisInfections and infestations | 6/68 | 3/43 |
| HypercholesterolaemiaMetabolism and nutrition disorders | 5/68 | 1/43 |
| Back painMusculoskeletal and connective tissue disorders | 1/68 | 3/43 |
| Oedema peripheralGeneral disorders | 0/68 | 3/43 |
| LeukopeniaBlood and lymphatic system disorders | 1/68 | 3/43 |
| FatigueGeneral disorders | 4/68 | 0/43 |
| PainGeneral disorders | 0/68 | 2/43 |
| LaryngitisInfections and infestations | 0/68 | 2/43 |
| CoughRespiratory, thoracic and mediastinal disorders | 3/68 | 2/43 |
| RhinorrhoeaRespiratory, thoracic and mediastinal disorders | 0/68 | 2/43 |
Safety observational (obs): all participants included in the study who were eligible for the study at Visit (V) 1.
| Age, Continuous(years) | Tocilizumab |
|---|---|
| Mean | 58.0 ± 12.2 |
| Sex: Female, Male(Participants) | Tocilizumab |
|---|---|
| Female | 47 |
| Male | 21 |
The record gives a start of Jan 2011, a primary completion of Mar 2013 and a completion of Mar 2013. It does not say whether these dates are actual or estimated.
Results were first posted in Jan 2015, 1 year 10 months after primary completion.
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Studies of the drugs tested here: Methylprednisolone · Tocilizumab