Study Comparing The Effect On Disease Activity When Reducing Or Discontinuing Etanercept In Subjects With RA

Study Overview
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Brief Summary
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This study involves Rheumatoid Arthritis patients in regular clinical setting who are already on etanercept treatment and are in remission or in a low disease activity (LDA) state, and is intended to identify parameters that can serve as guidance in clinical settings. This study will consider the clinical and radiographic course in subjects when etanercept treatment is tapered or discontinued, and analyze the subjects' experience of disease worsening and the predictive values of clinical parameters, serum biomarkers and imaging on the clinical and radiographic course in different treatment groups. The effect of re-treatment with etanercept at treatment failure will also be studied.

Official Title
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Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Subjects Who Have Achieved a Stable Low Disease Activity-state (DOSERA)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Etanercept
* Drug: Etanercept
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Subject has a current DAS28 equal to or less than 3.2. Subject is currently receiving treatment with etanercept, either 25 mg twice weekly or 50 mg once weekly, for a minimum of 14 months at baseline Subject is currently receiving oral, sc or intramuscular methotrexate once weekly, 7.5 mg/week to 25 mg/week and at a stable dose for a minimum of 4 months at baseline. Exclusion Criteria: Subject has earlier had an attempt of discontinuing etanercept for reasons of remission or low disease activity state. Subject has received any disease-modifying anti-rheumatic drug, other than methotrexate, within one month before baseline. Subject has had a dose of prednisone (or equivalent) >7.5 mg/day or has received intra-articular, intravenous, intramuscular, or subcutaneous corticosteroid within one month of baseline.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>50mg once weekly + methotrexate | Drug: Etanercept<br>* 50 mg etanercept once weekly + methotrexate<br>|
| Active Comparator: 2<br>25mg once weekly + methotrexate | Drug: Etanercept<br>* 25mg etanercept once weekly + methotrexate<br>|
| Placebo Comparator: 3<br>once weekly + methotrexate | Drug: Placebo<br>* Placebo comparator once weekly + methotrexate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participant Who Were Non-Failures | A participant was considered as non-failure if the calculated DAS28 <=3.2 at all visits or if the calculated DAS28 >3.2, the increase of calculated DAS28 from randomization (Week 0): was <0.6 at all visit or was >=0.6 but <1.2 on no more than 1 consecutive visit. Percentage of participants who were non-failures calculated based on DAS28 and disease progression as determined by investigator or participant. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Treatment Failure (TTF) | TTF (in weeks): (date of failure minus date of randomization) divided by 7. Date of failure was ordinary visit date or extra visit date in case of failure (extra visit was within 2 weeks from the date a participant experienced significant disease progression between visits and wanted to withdraw from Period 2), or date of withdrawal due to disease progression. Participants who did not have a treatment failure were censored at their last evaluation visit. Participants who withdrew from the study prematurely and did not have a treatment failure were censored on the date of their withdrawal. | Randomization (Week 0) up to date of failure, withdrawal due to disease progression or last evaluation visit (Week 48) | 
| Percentage of Participants With Remission or Low Disease Activity (LDA) | Participants who had DAS28 less than or equal to (<=) 3.2 were considered in remission or LDA state. | Baseline (Week -8), Week -4, Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Percentage of Visits During Which Participants Were in Remission or Low Disease Activity State | Participants who had DAS28 <=3.2 were considered in remission or LDA state. Percentage of visits during which a participant was in remission or LDA state was calculated as number of visits in which participant was in remission or LDA divided by total number of visits multiplied by 100. | Randomization (Week 0) up to Week 48 | 
| Disease Activity Score Based on 28-Joint Count (DAS28) at Randomization | DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) 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 implied low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity and less than (<) 2.6=remission. | Randomization (Week 0) | 
| Change From Randomization in Disease Activity Score Based on 28-Joint Count (DAS28) at Week 6, 12, 18, 24, 30, 36, 42, and 48 | DAS28 calculated from SJC and PJC using the 28 joints count, the ESR (mm/hour) 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 <=3.2 = low disease activity, DAS28 >3.2 to 5.1 = moderate to high disease activity and <2.6=remission. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Change From Randomization in Tender Joints Count (TJC) at Week 6, 12, 18, 24, 30, 36, 42, and 48 | Number of tender joints was determined by examining 28 joints and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1. A negative value in change from randomization indicates an improvement. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Change From Randomization in Swollen Joints Count (SJC) at Week 6, 12, 18, 24, 30, 36, 42, and 48 | Number of swollen joints was determined by examination of 28 joints and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1. A negative value in change from randomization indicates an improvement. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Change From Randomization in Physician Global Assessment (PGA) of Disease Activity at Week 6, 12, 18, 24, 30, 36, 42, and 48 | PGA of disease activity was measured on a 0 to 100 millimeter (mm) Visual Analog Scale (VAS), with 0 mm = no disease activity and 100 mm = extreme disease activity. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Change From Randomization in Participant Global Assessment (PtGA) of Disease Activity at Week 6, 12, 18, 24, 30, 36, 42, and 48 | Participants assessed the overall activity of their rheumatoid arthritis (RA) on a 0 to 100 mm VAS, where 0 mm = no disease activity and 100 mm = extreme disease activity. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Participant General Health Visual Analog Scale (VAS) at Randomization | Participants answered in general how would you rate your health over the last 2-3 weeks? Participants responded by using a 0 to 100 mm VAS, where 0 mm = very well and 100 mm = extremely bad. | Randomization (Week 0) | 
| Change From Randomization in Participant General Health Visual Analog Scale (VAS) at Week 6, 12, 18, 24, 30, 36, 42, and 48 | Participants answered in general how would you rate your health over the last 2-3 weeks? Participants responded by using a 0 to 100 mm VAS, where 0 mm = very well and 100 mm = extremely bad. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Participant Pain Visual Analog Scale (VAS) at Randomization | Participants indicated the amount of pain experience during the last 2-3 days by marking a vertical line on 100 mm VAS. Intensity of pain range: 0 = no pain to 100 = pain as bad as it could be. | Randomization (Week 0) | 
| Change From Randomization in Participant Pain Visual Analog Scale (VAS) at Week 6, 12, 18, 24, 30, 36, 42, and 48 | Participants indicated the amount of pain experience during the last 2-3 days by marking a vertical line on 100 mm VAS. Intensity of pain range: 0 = no pain to 100 = pain as bad as it could be. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Change From Randomization in Morning Stiffness Duration at Week 6, 12, 18, 24, 30, 36, 42, and 48 | Duration of morning stiffness: Time elapsed when participant woke up in morning and was able to resume normal activities without stiffness in minutes. The duration of morning stiffness was determined by asking the following questions: 1) Over the last 2 days, when did you wake in the morning? 2) Over the last 2 days, when were you able to resume your normal activities without stiffness? Increase in stiffness duration from randomization represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Change From Randomization in Erythrocyte Sedimentation Rate (ESR) at Week 6, 12, 18, 24, 30, 36, 42, and 48 | ESR is a laboratory test that provides a non-specific measure of inflammation. The test assesses the rate at which red blood cells fall in a test tube. Normal range is 0-30 millimeter per hour (mm/hour). A higher rate is consistent with inflammation. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Change From Randomization in C-Reactive Protein (CRP) Level at Week 6, 12, 18, 24, 30, 36, 42, and 48 | The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. Normal range of CRP is <10 milligram per liter (mg/L). A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. | Randomization (Week 0), Week 6, 12, 18, 24, 30, 36, 42, 48 | 
| Change From Randomization in Modified Total Sharp Score (mTSS) at Week 48 | mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at randomization. An increase in mTSS from randomization represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. | Randomization (Week 0), Week 48 | 
| Magnetic Resonance Imaging (MRI) Findings at Randomization | MRI of hand/wrist of dominant hand scored for signs of synovitis (S-score), bone edema(O-score), bone erosions (E-score) as per outcome measures in RA clinical trials (OMERACT). S-score:0(normal)-3(severe) for distal radioulnar,radiocarpal,intercarpal-carpometacarpal,second-fifth metacarpophalangeal joints, total score(TS)0-21, higher score(HS)=severe synovitis. O-score:0(no volume increment)-3(100% volume increment) in 23 hand/wrist joints, TS 0-69, HS=more edema. E-score:0(no volume occupied by erosion)-10(100% volume occupied by erosion) in 23 hand/wrist joints, TS 0-230, HS=more erosion. | Randomization (Week 0) | 
| Change From Randomization in Magnetic Resonance Imaging (MRI) Findings (S-Score) at Week 12 | MRI of hand/wrist of dominant hand was scored for signs of synovitis (S-score), bone edema (O-score), and bone erosions (E-score) as per OMERACT. S-score: 0 (normal) to 3 (severe) for each of distal radioulnar, radiocarpal, intercarpal-carpometacarpal, second to fifth metacarpophalangeal joints; total score 0 to 21, higher score=severe synovitis. | Randomization (Week 0), Week 12 | 
| Change From Randomization in Magnetic Resonance Imaging (MRI) Findings (O-Score, E-Score) at Week 12 | MRI of hand/wrist of dominant hand was scored for signs of synovitis (S-score), bone edema (O-score), and bone erosions (E-score) as per OMERACT. O-score: 0 (no volume increment) to 3 (100% volume increment) in 23 hand/wrist joints; total score 0 to 69, higher scores=more edema. E-score: 0 (no volume occupied by erosion) to 10 (100% volume occupied by erosion) in 23 hand/wrist joints; total score 0 to 230, higher scores=more erosion. | Randomization (Week 0), Week 12 | 
| Percentage of Participants in Treatment Failure for Each Potentially Predictor Variable at Randomization | Percentage of participants who were treatment failure over 48 weeks as per potentially predictor variables (at randomization) are reported: number of swollen joints/tender joints, DAS28, PGA, PtGA, participant general health VAS, participant pain VAS, clinical disease activity index (CDAI), simplified disease activity index (SDAI), ESR (mm/hour), plasma CRP (mg/L), sensitive serum CRP (mg/L), anti- cyclic citrullinated peptide (anti CCP, units/mL), cartilage oligomeric matrix protein (COMP, units/liter), S-score, O-score, E-score, Joint space narrowing score, erosion score, and mTSS. | Randomization (Week 0) up to Week 48 |