A Study of Glucocorticoid Use to Evaluate Systematic Methylprednisolone Reduction in Patients With Rheumatoid Arthritis on Background RoActemra/Actemra (Tocilizumab) (ACT-ALONE)

Study Overview
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Brief Summary
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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

Official Title
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An Open-label, Single-arm Study to Describe Glucocorticoid Use in Rheumatoid Arthritis Patients Treated With Tocilizumab in Daily Clinical Practice and to Evaluate Systematic Glucocorticoid Dose Reduction Once Low Disease Activity is Reached (ACT-ALONE)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: methylprednisolone
* Drug: tocilizumab [RoActemra/Actemra]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-interventional phase Adult patients, >/=18 years of age Moderate to severe active rheumatoid arthritis defined as Disease Activity Score using 28-joint count (DAS28) >/=5.1 Patients with inadequate clinical response to a current treatment with 2 or more non-biologic disease-modifying anti-rheumatic drugs (DMARDs), one of them being methotrexate (MTX) optimally administered during a period of more than 3 months or inadequate response to a current anti-TNF therapy Current use of oral glucocorticoids started at least 4 weeks prior to enrolment Interventional phase Patients enrolled in the non-interventional phase Patients with low disease activity defined as DAS28 </=3.2 at Visit 2 Use of oral glucocorticoids with methylprednisolone equivalent dose of >/=1mg and </=20mg/day at Visit 2 Exclusion Criteria: Non-interventional & interventional phase Rheumatic autoimmune disease other than rheumatoid arthritis, or significant systemic involvement secondary to rheumatoid arthritis Functional class IV as defined by the American College of Rheumatology (ACR) Classification of Functional Status in rheumatoid arthritis Prior history or current inflammatory joint disease other than rheumatoid arthritis (e.g. gout)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: methylprednisolone<br>* starting dose >/= 1 mg and </= 20 mg orally daily, according to dose-reduction schedule<br>Drug: tocilizumab [RoActemra/Actemra]<br>* background therapy: 8 mg/kg iv every 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | Visits 3 (7 months), 4 (8 months), 5 (9 months), 6 (10 months), 7 (11 months), and 8 (12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | V1 and V2 (up to 6 months after V1) | 
| Median Dose of Tocilizumab During the Noninterventional Phase |  | 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. | V1 and V2 (up to 6 months after V1) | 
| Percentage of Participants With Changes in RA Treatment During the Noninterventional Phase |  | 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. | V3 (7 months) | 
| Percentage of Participants Able to Reduce Oral GCs by ≥50 Percent (%) During the Interventional Phase by V9 |  | V9 (24 weeks after V3) | 
| Percentage of Participants Able to Discontinue GCs During the Interventional Phase by V9 |  | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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) |