SMART Study: A Study of Re-treatment With MabThera (Rituximab) in Patients With Rheumatoid Arthritis Who Have Failed on Anti-TNF Alfa Therapy

DAS28-CRP During the Initial Treatment

Mean DAS28-CRP at Week 24 of the Initial Treatment study. DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP ≤3.2 implied low disease activity, \>3.2 to 5.1 implied moderate to high disease activity, and \<2.6=remission.

Time frame: Days 1 and 15, and Weeks 6, 12, and 24

DAS28-CRP and Changes From Baseline to Week 24 in DAS28-CRP by Retreatment Course

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity, \>3.2 to 5.1 implied moderate to high disease activity, and \<2.6=remission.

Time frame: Day 1, 24 weeks following each infusion up to 72 Weeks

Percentage of Participants Achieving Clinical Remission (DAS28-CRP <2.6) or Low Disease Activity (DAS28-CRP ≤3.2)

Percentage of participants with clinical remission and low disease activity as measured by DAS28-CRP for Arm A and Arm B at Week 24 of the Initial Treatment, at 24 weeks after first re-treatment, and at 24 weeks after second retreatment. DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity and \<2.6 = remission.

Time frame: Week 24 of the Initial Treatment, 24 weeks after first retreatment, and 24 weeks after second retreatment

DAS28-CRP AUC Weighted Time

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity, \>3.2 to 5.1 implied moderate to high disease activity, and \<2.6=remission.

Time frame: Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Time to Achieve DAS28-CRP Remission After the First Course

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP \<2.6=remission.

Time frame: Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Time to Achieve DAS28-CRP Remission After Retreatment

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP \<2.6=remission.

Time frame: Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Time to Achieve DAS28-CRP ≤3.2 After the First Course of Treatment

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.

Time frame: Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Time to Achieve DAS28-CRP ≤3.2 After Retreatment

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.

Time frame: Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Duration of DAS28-CRP Remission After the First Course of Treatment

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP \<2.6=remission.

Time frame: Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Duration of DAS28-CRP Remission After Retreatment

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP \<2.6=remission.

Time frame: Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Duration of DAS28-CRP ≤3.2 After the First Course of Treatment

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.

Time frame: Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Duration of DAS28-CRP ≤3.2 After Retreatment

DAS28-CRP was based on joint counts, overall participant assessment, and the serum CRP level at each visit. Joint counts included SJC and TJC using the 28 joints count and CRP (mg/L). Total score range=0 to 9.4; a higher score indicated more disease activity. A DAS28-CRP score of ≤3.2 implied low disease activity.

Time frame: Days 1 and 15, Weeks 6, 12, and 24 and every 8 weeks thereafter through Week 104

Percentage of Participants Achieving American College of Rheumatology 20%, 50%, and 70% Improvement (ACR20/ACR50/ACR70)

ACR20/50/70 response defined as ≥20%, 50%, or 70% improvement, respectively, in TJC and SJC, and ≥20%, 50%, or 70% improvement, respectively, in at least 3 of 5 remaining ACR core measures: Patient Global Assessment of Pain, Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity (on a visual analog scale \[VAS\]); Health Assessment Questionnaire-Disability Index (HAQ-DI); and CRP.

Time frame: Week 24 of the initial treatment, 24 weeks after first retreatment, and 24 weeks after second retreatment

Percentage of Participants Achieving a Response During Initial Treatment by European League Against Rheumatism (EULAR) Category

DAS28-based EULAR response criteria were used to measure individual response as no response, 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 a DAS28 score of ≤3.2; moderate responders = change from baseline \>1.2 with a DAS28 score of \>3.2 to ≤ 5.1 or change from baseline \>0.6 to ≤1.2 with a DAS28 score of ≤5.1; non-responders = change from baseline ≤0.6 or change from baseline \>0.6 and ≤ 1.2 with a DAS28 score of \>5.1.

Time frame: Day 15, Weeks 6, 12, and 24

Percentage of Participants Achieving a Response During Retreatment by EULAR Category

DAS28-based EULAR response criteria were used to measure individual response as no response, 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 a DAS28 score of ≤3.2; moderate responders = change from baseline \>1.2 with a DAS28 score of \>3.2 to ≤ 5.1 or change from baseline \>0.6 to ≤1.2 with a DAS28 score of ≤5.1; non-responders = change from baseline ≤0.6 or change from baseline \>0.6 and ≤ 1.2 with a DAS28 score of \>5.1.

Time frame: Week 24, 24 weeks after 1st retreatment, 24 weeks after 2nd retreatment

Percentage of Participants With Rheumatoid Factor (RF) at 24 Weeks After Treatment

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 international units per milliliter (IU/mL) is considered positive.

Time frame: Week 24 of the initial treatment, 24 weeks after first re-treatment, and 24 weeks after second retreatment

Percentage of Participants With Anti-cyclic Citrullinated Protein (Anti-CCP) Antibodies at 24 Weeks After Treatment

Anti-CCP antibodies are auto antibodies (antibodies directed against 1 or more of an individual's own proteins) that are frequently detected in the blood of rheumatoid arthritis participants. Anti-CCP antibodies value higher than 10 U/mL is considered positive.

Time frame: Week 24 of the initial treatment, 24 weeks after first re-treatment, and 24 weeks after second retreatment

Physician's Global Assessment of Disease Activity

The Physician's Global Assessment of disease activity is assessed on a 0 to 100 millimeter (mm) horizontal VAS by the physician. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Physicians were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high disease activity).

Time frame: Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Patient Global Assessment of Disease Activity

The Patient's Global Assessment of Disease Activity is assessed on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).

Time frame: Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Patient's Global Assessment of Pain

The participants assessed their pain over the past 24 hours on a 0 to 100 mm horizontal VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". Participants were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high pain levels).

Time frame: Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Participant Assessment of Fatigue

Participants were asked to rate their level of fatigue over the last 7 days on a 100-mm VAS. The left-hand extreme of the line equals 0 mm, and is described as "no fatigue" and the right-hand extreme equals 100 mm as "extreme fatigue". Participants were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high levels of fatigue).

Time frame: Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Cortisone Intake AUC (Time- and Weight-Weighted)

All cortisone intakes (in mg) were taken into account (oral, IV \[including the cortisone administration before the rituximab infusion\], intramuscular, and intra-articular).

Time frame: Day 1 (each infusion), Week 24, Week 104

Total Mean Dose of Cortisone Between Week 24 and Week 104

All cortisone intakes were taken into account, including oral, IV (including the cortisone administration before the rituximab infusion), intramuscular and intra-articular.

Time frame: Week 24 to Week 104

HAQ-DI Scores

HAQ-DI: 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.

Time frame: Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Short Form 12 (SF-12) Physical Health Composite Score

Physical and Mental Health Composite Scores of SF-12 were computed using the scores of 12 questions and range from 0 to 100, where a 0 score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.

Time frame: Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

SF-12 Mental Health Composite Score

Mental Health Composite Scores of SF-12 were computed using the scores of 12 questions and range from 0 to 100, where a 0 score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health.

Time frame: Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Medical Outcomes Study Sleep Scale (MOS-Sleep) Composite Sleep Problems 6 (SLP6) Index

The MOS Sleep Scale measures most constructs of sleep. The scale has a battery of questions to measure specific aspects of sleep in participants with co-morbidities. The SLP6 index is comprised of 6 items: provides a summary of sleep problems and contains questions from the sleep disturbance, sleep adequacy, respiratory impairment, and somnolence domains. The SLP6 index score ranges between 0 and 100, with higher values corresponding to more sleep problems.

Time frame: Day 1 and Week 24 of initial treatment, before 1st retreatment, at 1st retreatment, and at 12 and 24 weeks after 1st retreatment

Percentage of Participants Reporting Acceptable Disease Activity Symptom State Assessed Using Patient Acceptable and Unacceptable Symptom State (PASS)

Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of disease activity they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of disease activity they had during the last 48 hours. In the case of missing data, participants who withdrew from the study because of inefficacy or toxicity were considered "unacceptable".

Time frame: Week 24, 12 and 24 weeks after 1st retreatment

Patient Global Assessment of Disease Activity in Participants Reporting Acceptable Symptoms Using PASS

The Patient's Global Assessment of Disease Activity assessed in participants reporting acceptable symptom state using PASS (acceptance to remain for the rest of their lives with the level of disease activity they had during the last 48 hours) on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).

Time frame: Week 24, 12 and 24 weeks after 1st retreatment

Percentage of Participants With Minimum Clinically Important Improvement (MCII) in Disease Activity

Participants were asked how their disease activity had been during the last 48 hours compared to baseline. Those participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse-more disease activity.

Time frame: Week 24, 12 and 24 weeks after 1st retreatment

Change From Baseline in Patient Global Assessment of Disease Activity in Participants With MCII

The Patient's Global Assessment of Disease Activity was assessed in participants reporting MCII on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as "maximum disease activity" (maximum arthritis disease activity). Higher values correspond to worst state of participant (high disease activity).

Time frame: Baseline, Week 24, 12 and 24 weeks after 1st retreatment

Percentage of Participants Reporting Acceptable Symptom State in Functioning Assessed Using PASS

Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of function they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of function they had during the last 48 hours. In the case of missing data, participants who withdrew from the study because of inefficacy or toxicity were considered "unacceptable".

Time frame: Week 24, 12 and 24 weeks after 1st retreatment

HAQ-DI Scores in Participants Reporting Acceptable Function Using PASS

HAQ-DI was assessed in participants reporting acceptable symptom state using PASS (acceptance to remain for the rest of their lives with the level of disease activity they had during the last 48 hours). 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.

Time frame: Week 24, 12 and 24 weeks after 1st retreatment

Percentage of Participants With MCII in Functioning

Participants were asked how their functioning had been during the last 48 hours compared to baseline. Those participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse.

Time frame: Week 24, 12 and 24 weeks after 1st retreatment

Change From Baseline in HAQ-DI in Participants With MCII

HAQ-DI was assessed in participants with MCII. 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.

Time frame: Baseline, Week 24, 12 and 24 weeks after 1st retreatment

Percentage of Participants With Acceptable Symptom State in Pain Assessed Using PASS

Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of pain they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of pain they had during the last 48 hours. In the case of missing data, participants who withdrew from the study because of inefficacy or toxicity were considered "unacceptable".

Time frame: Week 24, 12 and 24 weeks after 1st retreatment

Patient Global Assessment of Pain in Participants Reporting Acceptable Symptoms Using PASS

Patient Global Assessment of Pain assessed in participants reporting acceptable symptom state using PASS (acceptance to remain for the rest of their lives with the level of pain they had during the last 48 hours) on a 0 to 100 mm horizontal VAS by the participant. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". Higher values correspond to worst state of participant (high pain levels).

Time frame: Week 24, 12 and 24 weeks after 1st retreatment

Percentage of Participants With MCII in Pain

Participants were asked how their pain had been during the last 48 hours compared to baseline. Those participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse pain.

Time frame: Week 24, 12 and 24 weeks after 1st retreatment

Change From Baseline in Patient Global Assessment of Pain in Participants With MCII

The participants assessed their pain over the past 24 hours on a 0 to 100 mm horizontal VAS. The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". Participants were asked to mark the line and the distance from the left edge was measured. Higher values correspond to worst state of participant (high pain levels).

Time frame: Baseline, Week 24, 12 and 24 weeks after 1st retreatment