An Observational Study of the Impact of RoActemra/Actemra on Fatigue in Patients With Rheumatoid Arthritis (PEPS)

Study Overview
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Brief Summary
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This prospective, observational study will assess the effect of RoActemra/Actemra (tocilizumab) on fatigue in patients with moderate to severe rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARDS) or anti tumor necrosis factor (anti-TNF) drugs. Eligible patients receiving RoActemra/Actemra according to the standard of care will be followed for 4 months.

Official Title
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Pharmacoepidemiological Study of the Impact of Roactemra® Treatment on Fatigue in Rheumatoid Arthritis Patients in a Real Life Setting

Conditions
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Rheumatoid Arthritis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, >/= 18 years of age Moderate to severe rheumatoid arthritis Inadequate response to disease-modifying antirheumatic drugs (DMARDS) or anti-TNF (tumor necrosis factor) drugs Exclusion Criteria: Hypersensitivity to RoActemra/Actemra or any component Active infection Participation in a clinical trial in rheumatoid arthritis

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Tocilizumab<br>Eligible participants receiving tocilizumab according to summary of product characteristics in a real life setting will be observed for 4 months | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Clinically Significant Improvement in Fatigue After 4 Months of Tocilizumab Treatment | Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score assesses self-reported fatigue and its impact upon daily activities and function. It is calculated with 13-item questionnaire on 5-point scale: 0 (not at all) to 4 (very much). The larger the participant's response to the questions (exception of 2 negatively stated), the greater the participants fatigue. For all questions (except for 2 negatively stated), the code is reversed and a new score is calculated as 4 minus the participant's response. The sum of all responses resulted a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the participant's health status. Clinically relevant improvement is defined as a >= 4-point change from Baseline. This was performed using the last observation carried forward (LOCF) method and for participants who completed a FACIT-Fatigue score at Month 4 (completers). | At Month 4 | 
| Number of Participants With Clinically Significant Improvement in Fatigue at Month 4 With Respect to Predictive Factors | Predictive factors of fatigue were taken into account included gender, age, time since initial diagnosis, Erosive RA, disease activity score (DAS, ranging from 0 [no disease activity] to 10 [worsening in disease activity]), erythrocyte sedimentation rate (ESR), anemia, treatment with corticosteroids, doses of corticosteroids, health assessment questionnaire (HAQ, ranging from 0 [without any difficulty] to 60 [worsening or unable to do physical activities]), FACIT-Fatigue score (ranging from 0 [worse score] to 52 [better score]), visual analogue score (VAS) for fatigue, pain, quality of sleep, and global assessment (ranging from 0 [symptom-free and no arthritis symptoms] to 100 [worsening of symptoms and arthritis disease activity]), Short Form 36 (SF36) vitality score (ranging from 0 [worst] to 100 [best]), Hospital Anxiety and Depression Scale (HADS; represented as score </= 7 [no case], 7 to 10 [doubtful case], and > 10 [certain case of HAD]). | At Month 4 | 
| Median Clinically Significant Improvement in C-Reactive Protein as a Predictive Factors After 4 Months of Tocilizumab Treatment | Predictive factors were characteristics of participants that indicated greater or lesser likelihood of responding to a specific treatment regimen. C-reactive protein (CRP) is one of the biomarkers for the diagnosis and assessment of disease activity in RA. | At Month 4 | 
| Mean Clinically Significant Improvement in Tender Joints and Swollen Joints as Predictive Factors After 4 Months of Tocilizumab Treatment | Predictive factors were characteristics of participants that indicated greater or lesser likelihood of responding to a specific treatment regimen. For tender joint count (TJC), a total of 68 joints were assessed. The presence of a tender joint was scored as 1 and absence as 0. Total score is calculated by adding the scores, which is ranging from 0 (best possible score or no tender joint) to 68 (worse possible score or all tender joints). Lower scores indicate no tender joint and higher scores indicate worsening tender joints. For swollen joint count (SJC), a total of 66 joints were assessed. The presence of a tender joint was scored as 1 and absence as 0. Total score is calculated by adding the scores, which is ranging from 0 (best possible score or no swollen joint) to 66 (worse possible score or all swollen joints). Lower scores indicate no swollen joint and higher scores indicate worsening swollen joints. | At Month 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline Disease Characteristics: Mean Disease Duration | Mean disease (rheumatoid arthritis) duration at inclusion was recorded for all participants as baseline disease characteristics. | Baseline (Day [D] 0) | 
| Baseline Disease Characteristics: Number of Participants With Positive Rheumatoid Factor and/or Anti-cyclic Citrullinated Protein Antibodies | Blood was collected for Rheumatoid Factor (RF) at Baseline and was analyzed. RF level was reported in international units/milliliter (IU/mL). All participants were assessed for anti-cyclic citrullinated protein (anti-CCP) antibodies at baseline. Number of participants with a positive RF and/or anti-CCP antibodies were reported as baseline disease characteristics. | Baseline (D0) | 
| Baseline Disease Characteristics: Tender Joint Count and Swollen Joint Count | For tender joint count, a total of 68 joints were assessed. The presence of a tender joint was scored as 1 and absence as 0. Total score is calculated by adding the scores, which is ranging from 0 (best possible score or no tender joint) to 68 (worse possible score or all tender joints). Lower scores indicate no tender joint and higher scores indicate worsening tender joints. For swollen joint count, a total of 66 joints were assessed. The presence of a tender joint was scored as 1 and absence as 0. Total score is calculated by adding the scores, which is ranging from 0 (best possible score or no swollen joint) to 66 (worse possible score or all swollen joints). Lower scores indicate no swollen joint and higher scores indicate worsening swollen joints. Tender joint count and swollen joint count were assessed at baseline and were used as baseline disease characteristics for assessment of rheumatoid arthritis. | Baseline (D0) | 
| Baseline Disease Characteristic: DAS28, Patient's Global Assessment, VAS Pain and HAQ Score as Rheumatoid Arthritis Assessment Parameters | DAS28 is a combined index for measuring disease activity in RA. The index includes swollen (range 0-28) and tender (range 0-28) joint counts, acute phase response (ESR in mm/h), and patient's global assessment of disease activity (measured on a 100-mm visual analog scale, where 0 is no disease activity and 100 is maximum disease activity). The DAS28 scale ranges from 0 to 10, where higher scores indicate worsening disease activity. VAS pain score calculated as 0 to 10 cm; where 0 = no pain, and 10 = worst possible pain. HAQ indicates how the disease affected participant's activities of daily life. It consisted of 20 questions in 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities) rated on a 4-point scale, 0=without any difficulty to 3=unable to do. Sum of scores was divided by number of domains with a score for a total possible score of 0 (best/no difficulties to perform activities) to 3 (worst/ unable to perform activities at all). | Baseline (D0) | 
| Baseline Disease Characteristic: Number of Participants With High Erythrocyte Sedimentation Rate, CRP Level, Anemia, and Unacceptable Patient Acceptable Symptom State Fatigue | High Erythrocyte Sedimentation Rate (ESR) was defined as (1) for participants aged up to 50 years: > 15 mm/h for men and > 20 mm/h for women, and (2) for participants aged over 50 years: > 20 mm/h for men and > 25 mm/h for women. Anemia was defined as plasma hemoglobin level <12 gram per deciliter (g/dL) for women and <13 g/dL for men. The CRP test is evaluated for an acute phase reactant of inflammation. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. Patient-Acceptable Symptom State (PASS) that is defined as the highest level of symptom beyond which participants consider themselves well. PASS is a 1-question assessment of how rheumatoid arthritis has affected participant in last 48 hours. | Baseline (D0) | 
| Baseline Disease Characteristic: Mean FACIT-Fatigue Score and VAS Fatigue Score | FACIT-fatigue score and VAS fatigue score were fatigue assessment parameters. FACIT-Fatigue score assesses self-reported fatigue and its impact upon daily activities and function. It is calculated with 13-item questionnaire on 5-point scale, 0 (not at all) to 4 (very much). The larger the participant's response to the questions (exception of 2 negatively stated), the greater the participants fatigue. For all questions (except for 2 negatively stated), the code is reversed and a new score is calculated as 4 minus the participant's response. The sum of all responses results a total possible score of 0 (worse score) to 52 (better score). VAS fatigue score ranges from 0 (symptom-free and no arthritis symptoms) to 100 (worsening in symptoms and arthritis disease activity). Clinically relevant improvement is defined as >/= 4-point change from Baseline. | Baseline (D0) | 
| Correlation Between Relative Changes From Baseline of FACIT-Fatigue Score and VAS Fatigue to 4 Months of Tocilizumab Treatment | Correlation between FACIT-Fatigue score and VAS fatigue was evaluated for all participants at inclusion and after 4 months of tocilizumab treatment (relative change from baseline) using a linear regression. FACIT-Fatigue score assesses self-reported fatigue and its impact upon daily activities and function. It is calculated with 13-item questionnaire on 5-point scale, 0 (not at all) to 4 (very much). The larger the participant's response to the questions (exception of 2 negatively stated), the greater the participants fatigue. For all questions (except for 2 negatively stated), the code is reversed and a new score is calculated as 4 minus the participant's response. The sum of all responses results a total possible score of 0 (worse score) to 52 (better score). VAS fatigue score ranging from 0 (symptom-free and no arthritis symptoms) to 100 (worsening in symptoms and arthritis disease activity) | From Baseline (D0) to Month (M) 4 | 
| Median Time to Onset of an Improvement of the FACIT-Fatigue Score | The time of onset of a clinically significant improvement of fatigue was defined as the time between the date of the first tocilizumab infusion and the date of the first increase of at least 4 points of the FACIT-Fatigue score (date of questionnaire completion) during 4 months of tocilizumab treatment. FACIT-Fatigue score assesses self-reported fatigue and its impact upon daily activities and function. It is calculated with 13-item questionnaire on 5-point scale, 0 (not at all) to 4 (very much). The larger the participant's response to the questions (exception of 2 negatively stated), the greater the participants fatigue. For all questions (except for 2 negatively stated), the code is reversed and a new score is calculated as 4 minus the participant's response. The sum of all responses results a total possible score of 0 (worse score) to 52 (better score). | Up to Month 4 | 
| Relative Median Change From Baseline in DAS 28 and VAS Patient's Global Assessment to Month 1, Month 2, Month 3, and Month 4 | Relative change from Baseline (BL) in DAS 28 was evaluated for all participants at each evaluation time (on raw data at inclusion; at Month 1, Month 2, Month 3, and Month 4 using a linear regression. DAS-28 and VAS patient's global assessment (PGA) were described as continuous variables for all participants at each evaluation time points (Baseline to M4). DAS 28 ranging from 0 (no disease activity) to 10 (worsening in disease activity) and VAS PGA ranging from 0 (symptom-free and no arthritis symptoms) to 100 (worsening of symptoms and arthritis disease activity), | From Baseline (D0) to M 1, M 2, M 3, and M 4 | 
| Relative Median Change From Baseline in Disease Activity (Tender Joint Count and Swollen Joint Count) to Month 1, Month 2, Month 3, and Month 4 | Relative change (RC) from Baseline (BL) in disease activity included TJC and SJC was evaluated as continuous variables for all participants at each evaluation time points. For tender joint count, a total of 68 joints were assessed. The presence of a tender joint was scored as 1 and absence as 0. Total score is calculated by adding the scores, which is ranging from 0 (best possible score or no tender joint) to 68 (worse possible score or all tender joints). Lower scores indicate no tender joint and higher scores indicate worsening tender joints. For swollen joint count, a total of 66 joints were assessed. The presence of a tender joint was scored as 1 and absence as 0. Total score is calculated by adding the scores, which is ranging from 0 (best possible score or no swollen joint) to 66 (worse possible score or all swollen joints). Lower scores indicate no swollen joint and higher scores indicate worsening swollen joints. | From Baseline (D0) to M 1, M 2, M 3, and M 4 | 
| Relative Median Change From Baseline in ESR to Month 1, Month 2, Month 3, and Month 4 | The correlation between fatigue and ESR value was evaluated for all participants at each evaluation time (on raw data at inclusion; on relative changes at M1 to M4) using a linear regression. ESR values were described as continuous variables for all participants at each evaluation time (Baseline to M4). | From Baseline (D0) to M 1, M 2, M 3, and M 4 | 
| Relative Median Change From Baseline in C - Reacting Protein at Month 1, Month 2, Month 3, and Month 4 | The correlation between fatigue and CRP value was evaluated for all participants at each evaluation time (on raw data at inclusion; on relative changes at M1 to M4) using a linear regression. CRP values were described as continuous variables for all participants at each evaluation time (Baseline to M4). | From Baseline (D0) to M 1, M 2, M 3, and M 4 | 
| Number of Participants Achieving PASS Score at Baseline (Day 0) and Month 4 | A PASS score at Day 0 and Month 4 calculated on participants with acceptable symptom state. PASS is defined as the highest level of symptom beyond which participants consider themselves well. PASS is a 1-question assessment of how rheumatoid arthritis has affected participant in last 48 hours. | Baseline (D0) and Month 4 | 
| Percentage of Participants With FACIT-Fatigue Score, SF36 Vitality Score, and VAS Fatigue at Day 0 and Month 4 | FACIT-Fatigue score (ranging from 0 [worse score] to 52 [better score]), VAS (ranging from 0 [symptom-free and no arthritis symptoms] to 100 [worsening in arthritis disease activity]) and SF36 vitality score (ranging from 0 [worst] to 100 [best]) were calculated at Baseline and Month 4. | Baseline (D0) and Month 4 | 
| Correlations Between Fatigue and Other Participant Reported Outcomes at Day 0 and Month 4 | Fatigue was assessed by FACIT-Fatigue scale (ranging from 0 [worse score] to 52 [better score]) and VAS fatigue (ranging from 0 [symptom-free and no arthritis symptoms] to 100 [worsening of symptoms and arthritis disease activity]). Other participant reported outcomes (PROs) were VAS for pain and quality of sleep (ranging from 0 [symptom-free and no arthritis symptoms] to 100 [worsening in arthritis disease activity]), SF36 vitality score (ranging from 0 [worst] to 100 [best]) and HAD score (calculated using the 14 items and each item was scored 0, 1, 2 or 3 where a score of 3 corresponds to the most anxious/depressed. 7-item depression and 7-item anxiety subscales were summed; each resulting in a total score of 0-21). Correlation between fatigue as assessed by FACIT-Fatigue score or VAS fatigue was evaluated for all participants using a linear regression and were reported for D0 and M4. | Day 0 and Month 4 | 
| Number of Participants for Rheumatoid Arthritis Management With Tocilizumab Treatment up to Month 4 | Participants with tocilizumab treatment were managed according to number of tocilizumab treatment received according to Summary of Product Characteristics recommendations, as 8 mg/kg, dose duration of 1-hour, correct infusion progress; and received DMARD, methotrexate, and corticosteroids concomitantly with tocilizumab during Months 1 to 4. | From Baseline (D0) to M 1, M 2, M 3, and M 4 | 
| Number of Participants With Any Adverse Events and Serious Adverse Events | An Any Adverse Events (AEs) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An Serious Adverse Events (SAEs) is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. | Up to 4 months |