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

Study Overview
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Brief Summary
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This study will compare the efficacy and safety of re-treatment with 2 doses of MabThera (rituximab) in patients with active rheumatoid arthritis (RA) who have previously experienced an inadequate response or intolerance to anti-tumor necrosis factor (anti-TNF) therapies etanercept, infliximab or adalimumab therapy. All patients will receive infusions of 1000 mg intravenous (IV) MabThera on Days 1 and 15; at Week 24 patients who have demonstrated a moderate or good response will be randomized to receive re-treatment with either 1 or 2 additional infusions of 1000 mg IV MabThera. The anticipated time on study treatment is 2+ years, and the target sample size is 100-500 individuals.

Official Title
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A Comparative Study to Assess the Effect of Retreatment With 2 Doses of MabThera on Disease Activity Score in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response or Intolerance to antiTNF-alfa Therapy.(SMART)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients >18 years of age RA for >=6 months Receiving outpatient treatment Ongoing treatment with methotrexate for >=3 months, stable for >=1 month Inadequate response or intolerance to etanercept, infliximab or adalimumab Exclusion Criteria: Previous treatment with MabThera Concurrent treatment with any anti TNF-alfa therapy or biologic therapy Previous treatment with any investigational cell-depleting therapies

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>1000 mg IV rituximab | Drug: rituximab<br>* Arm A: 1000 mg IV (one infusion) every 2 months \nArm B: 2 x 1000 mg IV (2 infusions) every 2 months<br>* Other names: MabThera/Rituxan;|
| Experimental: B<br>2 x 1000 mg IV rituximab | Drug: rituximab<br>* Arm A: 1000 mg IV (one infusion) every 2 months \nArm B: 2 x 1000 mg IV (2 infusions) every 2 months<br>* Other names: MabThera/Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (DAS28-CRP) Area Under the Curve (AUC) at Week 104 | DAS28-CRP was based on joint counts, overall participant assessment, and serum CRP levels (measured in milligrams per liter [mg/L]) at each visit. Joint counts included swollen joint count (SJC) and tender joint count (TJC). Total score range was 0 to 9.4; a higher score indicated more disease activity. DAS28-CRP less than or equal to (≤)3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity, and less than (<)2.6 equals (=) remission. The AUC of all DAS28-CRP values between Day 1 and Week 104 (15 values of protocol visits) was calculated using the trapeze method (AUC between t1 and t2=(t2-t1)*((DAS28-CRP at t1 + DAS28-CRP at t2)/2). The true visit dates were used to calculate the time between 2 DAS28-CRP evaluations. All the AUC were censored at Week 104 (linear extrapolation using the 2 last DAS28-CRP values (Weeks 96 and 104) to obtain the true DAS28-CRP value at the true Week 104). | Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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). | 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). | 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). | 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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. | 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). | 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. | 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. | 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. | 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. | 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. | 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). | 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. | 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). | Baseline, Week 24, 12 and 24 weeks after 1st retreatment |