A Phase 4 Trial Assessing the ImPact of Residual Inflammation Detected Via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Subjects

Rheumatoid Arthritis Clinical Trial

— PREDICTRA  

Official title:

A Phase 4 Trial Assessing the ImPact of Residual Inflammation Detected Via Imaging TEchniques, Drug Levels and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Subjects (PREDICTRA)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02198651
• Other study ID #: M14-500
• Secondary ID: 2014-001114-26
• Status: Completed
• Phase: Phase 4
• Start date: January 5, 2015
• Est. completion date: August 8, 2018

Study information

• Verified date: June 2019
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of the study was to investigate the association between residual disease activity at Baseline as detected by Magnetic Resonance Imaging (MRI) and the occurrence of flares in participants with rheumatoid arthritis (RA) randomized to an adalimumab dose tapering regimen controlled by adalimumab withdrawal.

Description:

This was a Phase 4, multicenter, randomized, double-blind, parallel-group study. The study included a Screening period of up to 28 days (unless extended with justification approved by study-designated physician), a 4-week Lead-In Period with open label (OL) 40 mg adalimumab administered subcutaneously (sc) every other week (eow), and a randomized 36-week double-blind period with 40 mg adalimumab sc every 3 weeks (q3wks; tapering arm) or placebo sc q3wks (withdrawal arm). Participants were randomized in a 5:1 ratio (tapering arm: withdrawal arm) after confirmation of meeting the disease activity score (DAS) criteria. Participants who experienced a protocol-defined flare at any time were to enter a rescue arm with OL 40 mg adalimumab administered sc eow for 16 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 149
• Est. completion date: August 8, 2018
• Est. primary completion date: May 3, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Participant had a diagnosis of rheumatoid arthritis (RA) as defined by the 1987 revised American College of Rheumatology (ACR) classification criteria and/or the ACR /European League Against Rheumatism (EULAR) 2010 classification criteria (any duration since diagnosis).

2. Participant must have met the following criteria:

• Must have been treated with adalimumab 40 mg subcutaneously every other week (sc eow) for at least 12 months prior to Week 0 Visit

• Must have been treated with concomitant methotrexate (MTX) at a stable dose (oral, sc or intramuscular (im) at any dose) for at least 12 weeks prior to Week 0 Visit or if not on MTX, must have been treated with other allowed conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) at a stable dose for at least 12 weeks prior to Week 0 Visit or if not treated with csDMARDs must maintain this regimen for at least 12 weeks prior to Week 0 Visit.

3. Participant must be in sustained clinical remission based on the following:

• At least one documented 4 or 3 (if Patient's Global Assessment ; PGA is not available) variables Disease Activity Score 28 Erythrocyte sedimentation rate (DAS28 ESR) or DAS28 C-reactive protein (CRP) < 2.6 (or calculated based on documented components of the DAS28) in the participant's chart 6 months or longer prior to the Screening Visit;

• 4 variables DAS28 (ESR) assessed at Screening < 2.6, with all components including ESR assessed at Screening.

4. If participant was receiving concomitant allowed csDMARDs (in addition or not to MTX) the dose must have been stable for at least 12 weeks prior to the Week 0 Visit (e.g., chloroquine, hydroxychloroquine, sulfasalazine, gold formulations [including auranofin, gold sodium thiomalate, and aurothioglucose] and/or leflunomide).

5. If participant was receiving concomitant oral corticosteroids, prednisone or equivalent must have been < 10 mg/day and the dose must have been stable for at least 4 weeks prior to the Week 0 Visit.

6. If participant was receiving concomitant non-steroidal anti-inflammatory drugs (NSAIDs), tramadol or other equivalent opioids and/or non-opioid analgesics, the dose and/or therapeutic scheme must have been stable for at least 4 weeks prior to the Week 0 Visit.

7. Participant must have been able and willing to provide written informed consent and comply with the requirements of this study protocol.

Exclusion Criteria:

1. Any 4 or 3 (if PGA is not available) variables DAS28 (ESR) or DAS28 (CRP) (or calculated based on documented components of the DAS28) assessed within 6 months prior to the Screening Visit = 2.6.

2. Participant was on an additional concomitant biological disease-modifying anti-rheumatic drug (bDMARD) (including but not limited to abatacept, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab or tocilizumab).

3. Participant had been treated with intra-articular or parenteral corticosteroids within the last four weeks before Screening.

4. Participant had undergone joint surgery within 12 weeks of Screening (at joints to be assessed by magnetic resonance imaging (MRI) and/or ultrasound).

5. Participant had a medical condition precluding an MRI (e.g. magnetic activated implanted devices - cardiac pace-maker, insulin pump, neuro stimulators, etc. and metallic devices or fragments or clips in the eye, brain or spinal canal and in the hand/wrist undergoing MRI)

6. Participant had a medical condition precluding a contrast MRI with gadolinium [e.g. nephrogenic systemic fibrosis, previous anaphylactic/anaphylactoid reaction to gadolinium containing contrast agent, pregnancy or breast feeding, severe renal insufficiency with an estimated Glomerular Filtration Rate (eGFR) below 30 mL/min/1.73m^2 at Screening, hepato-renal syndrome, severe chronic liver function impairment]

7. Participant had been treated with any investigational drug of chemical or biologic nature within a minimum of 30 days or five half-lives (whichever is longer) of the drug prior to the Screening Visit.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Connective Tissue Diseases
• Inflammation
• Musculoskeletal and Connective Tissue Diseases
• Rheumatoid Arthritis

Intervention

Biological:
• Adalimumab
Pre-filled syringe, administered by subcutaneous injection

Other:
• Placebo
Pre-filled syringe, administered by subcutaneous injection in the Double-blind period

Locations

Country	Name	City	State
Australia	Royal Prince Alfred Hospital /ID# 154649	Camperdown	New South Wales
Australia	Optimus Clinical Research Pty. /ID# 133881	Kogarah	New South Wales
Australia	Rheumatology Research Unit /ID# 133883	Maroochydore	Queensland
Australia	John Hunter Hospital /ID# 133884	Newcastle	New South Wales
Austria	AKH Wien /ID# 133885	Vienna	Wien
Canada	St. Joseph's Healthcare /ID# 149233	Hamilton	Ontario
Canada	Institut de Rhum. de Montreal /ID# 129055	Montreal	Quebec
Canada	The Arthritis Program Res Grp /ID# 129056	Newmarket	Ontario
Canada	Groupe de Recherche en Maladies Osseuses /ID# 129057	Sainte-foy	Quebec
Canada	CIUSSS de l'Estrie - CHUS /ID# 144839	Sherbrooke	Quebec
France	CHU Amiens Picardie /ID# 144846	Amiens CEDEX 1	Somme
France	Hospital Louis Pasteur /ID# 134708	Chartres
France	CHU de Grenoble - Albet Michal /ID# 135953	Grenoble
France	CHU de la miletrie /ID# 133928	Poitiers	Poitou-Charentes
Germany	Asklepios Klinik /ID# 129146	Bad Abbach
Germany	Charité Universitätsmedizin Campus Mitte /ID# 129142	Berlin
Germany	Immanuel-Krankenhaus /ID# 129143	Berlin-buch
Germany	Krankenhaus Porz am Rhein /ID# 129147	Cologne
Germany	Rheumaforschungszentrum II /ID# 148554	Hamburg
Germany	Klinikum der Univ Munich /ID# 129144	Munich
Germany	Rheumazentrum Ratingen /ID# 129148	Ratingen
Germany	Rheumatologische Praxis /ID# 151979	Rendsburg
Greece	General Hospital of Athens /ID# 129202	Athens
Greece	University General Hospital "Attikon" /ID# 134709	Athens	Attiki
Greece	General UH of Heraklion /ID# 134712	Heraklion
Hungary	Budai Irgalmasrendi Korhaz /ID# 134714	Budapest
Hungary	Orszagos Reumatologiai es Fizi /ID# 134710	Budapest
Hungary	Debreceni Egyetem Klinikai Koz /ID# 134715	Debrecen
Ireland	St Vincent's University Hosp /ID# 129210	Dublin
Italy	A.O. Univ Consorziale Policlin /ID# 133932	Bari
Italy	Azienda Istituto Gaetano Pini /ID# 132964	Milan
Italy	Fondazione IRCCS Policlinico /ID# 133886	Pavia
Italy	AP Romano Umberto I /ID# 132895	Rome	Lazio
Italy	A.O.U.I. di Verona Policlinico /ID# 132973	Verona
Netherlands	Jan van Breemen Instituut /ID# 133887	Amsterdam
Netherlands	Rijnstate Hospital /ID# 129206	Arnhem
Netherlands	Medisch Centrum Leeuwarden /ID# 133888	Leeuwarden
Netherlands	UMC Utrecht /ID# 132896	Utrecht
Spain	Hosp Sant J. Despi-Moises Brog /ID# 135368	Barcelona
Spain	Hospital Parc de Salut del Mar /ID# 148670	Barcelona
Spain	Hospital Universitario Basurto /ID# 135529	Bilbao
Spain	Hosp Clinico Virgen Arrixaca /ID# 137020	El Palmar
Spain	Hospital General Universitario Gregorio Maranon /ID# 133889	Madrid
Spain	Hospital Universitario La Paz /ID# 135369	Madrid
Spain	Hospital Univ De Mostoles /ID# 134489	Mostoles
Spain	Complejo Hosp Santiago /ID# 133890	Santiago de Compostela
Spain	Hosp General Univ de Valencia /ID# 134488	Valencia
Sweden	Akademiska Sjukhuset /ID# 148669	Uppsala	Uppsala Lan
Sweden	Uppsala University Hospital /ID# 133891	Uppsala
Sweden	Vastmanlands Sjukhus /ID# 133892	Vasteras
United Kingdom	Mid Essex Hospitals NHS Trust /ID# 151636	Chelmsford
United Kingdom	Western General Hospital /ID# 132966	Edinburgh
United Kingdom	Chapel Allerton Hospital /ID# 129208	Leeds
United Kingdom	University Hospital Aintree /ID# 132980	Liverpool
United Kingdom	Guy's and St Thomas' NHS Found /ID# 132965	London	London, City Of
United Kingdom	Whipps Cross Univ Hospital /ID# 133893	London	London, City Of
United Kingdom	Queen Alexandra Hospital /ID# 132982	Portsmouth
United States	Montefiore Medical Center /ID# 155013	Bronx	New York
United States	Arthritis Centers of Texas /ID# 152843	Dallas	Texas
United States	Altoona Ctr Clinical Res /ID# 148448	Duncansville	Pennsylvania
United States	Aa Mrc Llc /Id# 151933	Grand Blanc	Michigan
United States	West Tennessee Research Inst /ID# 148391	Jackson	Tennessee
United States	University of Florida /ID# 144851	Jacksonville	Florida
United States	North Georgia Rheumatology Grp /ID# 155225	Lawrenceville	Georgia
United States	The Arthritis & Diabetes Clinic, Inc. /ID# 149017	Monroe	Louisiana
United States	Shanahan Rheuma & Immuno /ID# 148689	Raleigh	North Carolina
United States	Low Country Rheumatology, PA /ID# 154198	Summerville	South Carolina
United States	Westlake Medical Research (WMR) Clinical Trials /ID# 155386	Thousand Oaks	California
United States	North Mississippi Med Clinics /ID# 149443	Tupelo	Mississippi
United States	J Michael Grelier Research /ID# 149772	Tuscaloosa	Alabama

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  France,  Germany,  Greece,  Hungary,  Ireland,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Association Between Baseline Hand and Wrist Synovitis Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score and Flare up to Week 40 in the Tapering Arm	Synovitis was assessed in three wrist regions (the distal radioulnar joint; the radiocarpal joint; the intercarpal and carpometacarpal joints) and in each Metacarpophalangeal joint (MCP) joint. The first carpometacarpal joint and the first MCP joint are not scored. The scale is 0-3. Score 0 is normal, and 1-3 (mild, moderate, severe) are by thirds of the presumed maximum volume of enhancing tissue in the synovial compartment. Flare is defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of > 0.6 AND DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of = 1.2 irrespective of the resulting DAS28 [ESR]. The association between baseline hand and wrist synovitis RAMRIS score and occurrence of rheumatoid arthritis flare up to Week 40 in the Tapering arm was examined using logistic regression, and the 95% confidence interval of the odds ratio was calculated.	From Week 4 to Week 40
Primary	Association Between Baseline Bone Marrow Edema RAMRIS Score and Flare up to Week 40 in the Tapering Arm	Bone marrow edema in each bone was scored separately. The scale is 0-3 based on the proportion of bone with edema, as follows—0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100%. Flare is defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of > 0.6 AND DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of = 1.2 irrespective of the resulting DAS28 [ESR]. The association between baseline bone marrow edema rheumatoid arthritis MRI scoring system (RAMRIS) score and occurrence of rheumatoid arthritis flare up to Week 40 in the Tapering arm was examined using logistic regression, and the 95% confidence interval of the odds ratio was calculated.	From Week 4 to Week 40
Primary	Association Between a Composite of Baseline Hand and Wrist Synovitis and Bone Marrow Edema RAMRIS Scores and Flare up to Week 40 in the Tapering Arm	The composite score is the sum of the baseline hand and wrist synovitis and bone marrow edema RAMRIS scores. Flare is defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of > 0.6 AND DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of = 1.2 irrespective of the resulting DAS28 [ESR]. The association between the composite baseline hand and wrist synovitis score and baseline bone marrow edema rheumatoid arthritis MRI scoring system (RAMRIS) score and occurrence of rheumatoid arthritis flare up to Week 40 in the Tapering arm was examined using logistic regression, and the 95% confidence interval of the odds ratio was calculated.	From Week 4 to Week 40
Secondary	Median Time to Flare	Time to flare was defined as the number of weeks from the date of the first dose of study drug in the Double-blind period to the date of flare.	From Week 4 to Week 40
Secondary	Physicians' Assessment of Flare Severity	Physicians rated the severity of flare at the Flare Week 0 visit from 0 (not severe) to 10 (very severe). The number of participants within each level of flare severity is presented.	At the Flare Week 0 Visit
Secondary	Participants' Assessment of Flare Severity	Participants rated the severity of flare at the Flare Week 0 visit from 0 (not severe) to 10 (very severe). The number of participants within each level of flare severity is presented.	At the Flare Week 0 Visit
Secondary	Percentage of Participants With a Flare	Flare was defined as an increase from Double-blind Baseline in DAS (Disease Activity Score) 28 erythrocyte sedimentation rate (ESR) of > 0.6 AND DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of = 1.2 irrespective of the resulting DAS28 [ESR].	From Week 4 to Week 40
Secondary	Number of Participants Who Regained Clinical Remission in the Open-Label Rescue Arm Over Time	The Disease Activity Score 28 (DAS28) is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, the erythrocyte sedimentation rate (ESR; mm/hour), and the participant's assessment of global disease activity (on a visual analog scale [VAS] from 0 to 10 cm) are included in the DAS28 (ESR) score. Scores on the DAS28 range from 0 to 10; higher scores indicate more disease activity. Clinical remission was defined as DAS28 (ESR) < 2.6.	From Flare Week 0 to Flare Week 16
Secondary	Median Time to Clinical Remission From the Occurrence of Flare	The Disease Activity Score 28 (DAS28) is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, the erythrocyte sedimentation rate (ESR; mm/hour), and the participant's assessment of global disease activity (on a visual analog scale [VAS] from 0 to 10 cm) are included in the DAS28 (ESR) score. Scores on the DAS28 range from 0 to 10; higher scores indicate more disease activity. Clinical remission was defined as DAS28 (ESR) < 2.6. Time to clinical remission was defined as the number of weeks from the occurrence of flare to the first date of clinical remission.	From Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Disease Activity Score 28 (DAS28)	The Disease Activity Score 28 (DAS28) is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, the erythrocyte sedimentation rate (ESR; mm/hour), and the participant's assessment of global disease activity (on a visual analog scale [VAS] from 0 to 10 cm) are included in the DAS28 (ESR) score. Scores on the DAS28 range from 0 to 10; higher scores indicate more disease activity. Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Clinical Disease Activity Index (CDAI) Score	The CDAI is a validated measure of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, global health assessed by the participant on a visual analogue scale from 0 to 10 (cm), and global health assessed by an investigator on a visual analogue scale from 0 to 10 (cm) were included in the CDAI score. Scores on the CDAI range from 0 to 76; higher scores indicate more disease activity. Negative values indicate improvement from the Double-blind baseline score.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Simplified Disease Activity Index (SDAI) Score	The SDAI is a validated measure of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, global health assessed by the participant on a visual analogue scale from 0 to 10 (cm), global health assessed by an investigator on a visual analogue scale from 0 to 10 (cm), and serum levels of C-reactive protein levels (mg/dL) were included in the SDAI score. Scores on the SDAI range from 0 to 86; higher scores indicate more disease activity. Negative values indicate improvement from the Double-blind baseline score.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Number of Participants Maintaining Clinical Remission Defined By DAS28 (ESR) < 2.6, SDAI = 3.3, and CDAI = 2.8 at Each Visit By Treatment Arm	The maintenance of clinical remission after regaining remission during the Open-label rescue period was defined as either Disease Activity Score 28 (DAS28 ESR) < 2.6, Simplified Disease Activity Index (SDAI) score = 3.3, or Clinical Disease Activity Index (CDAI) score = 2.8).	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline to Week 40 or Final Visit in Magnetic Resonance Imaging (MRI) Synovitis Score	Synovitis was assessed in three wrist regions (the distal radioulnar joint; the radiocarpal joint; the intercarpal and carpometacarpal joints) and in each Metacarpophalangeal joint (MCP) joint. The first carpometacarpal joint and the first MCP joint are not scored. The scale is 0-3. Score 0 is normal, and 1-3 (mild, moderate, severe) are by thirds of the presumed maximum volume of enhancing tissue in the synovial compartment.	From Week 4 to Week 40 or Final visit
Secondary	Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Marrow Edema (BME) Score	Bone edema in each bone was scored separately. The scale is 0-3 based on the proportion of bone with edema, as follows—0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100%.	From Week 4 to Week 40 or Final visit
Secondary	Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Erosions Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score	Bone erosions in each bone (wrists: carpal bones, distal radius, distal ulna, metacarpal bases; MCP joints: metacarpal heads, phalangeal bases) were scored separately. The scale is 0-10, based on the proportion of eroded bone compared to the ''assessed bone volume'', judged on all available images—0: no erosion; 1: 1-10% of bone eroded; 2; 11-20%, etc.	From Week 4 to Week 40 or Final Visit
Secondary	Mean Change From Double-blind Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) Score Over Time	The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a participant-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. The minimal clinically important difference (MCID) defined for the HAQ-DI is = 0.22.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Number of Participants With Health Assessment Questionnaire- Disability Index (HAQ-DI) Score = 0.5 at Double-blind Baseline and at Week 40	The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a participant-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. The number of participants with HAQ-DI score = 0.5 (considered to be normal) was recorded.	Week 4 and Week 40
Secondary	Mean Change From Double-blind Baseline in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed During In-office Visits	The RAPID3 is an activity index derived from the Multi-dimensional Health Assessment Questionnaire (MD-HAQ). It includes an assessment of physical function, a pain Visual Analog Scale (VAS), and a participant global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 30 where higher scores represent severe disease. Negative values indicate improvement from the Double-blind baseline score.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Flare Week 0 in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed at Home	The RAPID3 is an activity index derived from the Multi-dimensional Health Assessment Questionnaire (MD-HAQ). It includes an assessment of physical function, a pain Visual Analog Scale (VAS), and a participant global assessment of disease activity VAS. The total RAPID3 score ranges from 0 to 30 where higher scores represent severe disease. Negative values indicate improvement from the Double-blind baseline score.	Flare Week 0 and Flare Weeks 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15
Secondary	Mean Change From Double-blind Baseline in Swollen Joint Count 28	Twenty-eight joints, excluding hip joints, were assessed for swelling by physical examination. Swelling of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with swelling) to 28 (worst possible score/28 joints with swelling). Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Swollen Joint Count 66	Sixty-six joints were assessed for swelling by physical examination. Swelling of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with swelling) to 66 (worst possible score/66 joints with swelling). Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Tender Joint Count 28	Twenty-eight joints were assessed for tenderness by physical examination. Pain or tenderness of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with tenderness) to 28 (worst possible score/28 joints with tenderness). Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Tender Joint Count 68	Sixty-eight joints were assessed for tenderness by physical examination. Pain or tenderness of each joint was classified as present (1) or absent (0), for a total possible score of 0 (0 joints with tenderness) to 68 (worst possible score/68 joints with tenderness). Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Participant's Global Assessment of Disease Activity	Participants rated the severity of their rheumatoid arthritis symptoms and how well they were doing during the last 24 hours by placing a vertical mark on a line with a range of 0 (very well) to 100 mm (very poorly). Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Participant's Global Assessment of Rheumatoid Arthritis Pain	Participants rated the severity of their rheumatoid arthritis pain in the past week by placing a vertical mark on a line with a range of 0 (no pain) to 100 mm (severe pain). Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Physician's Global Assessment of Disease Activity	Physicians assessed participants' current rheumatoid arthritis disease activity at the time of the visit (independent of the participant's self-assessment) by placing a vertical mark on a line with a range of 0 (very low) to 100 mm (very high). Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Morning Stiffness Duration	The duration of morning stiffness was reported by participants as the average daily length during the past week in minutes (from time of awaking to time of maximal improvement). Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Morning Stiffness Severity	Morning stiffness severity was assessed by a numeric rating-scale (NRS). Participants rated the severity of morning stiffness during the past week from 0 to 10 with 0 representing "not severe" and 10 "very severe". Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Participant's Assessment of Sleep Disturbance	Participants rated the severity of their sleep disturbance in the past week by placing a vertical mark on a line with a range of 0 (sleep is no problem) to 100 mm (sleep is a major problem). Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Effectiveness Score	Participants completed the 14-item Treatment Satisfaction Questionnaire for Medication (TSQM; Version 1.4) to assess satisfaction with their current rheumatoid arthritis treatment over the previous 2-3 weeks or since the last time that they took the medication. The TSQM consists of fourteen items over four domains (effectiveness, side effects, convenience, and global satisfaction). The 14 questions are answered either with yes/no or by means of a five or seven stage scale (ranging from very unsatisfied to satisfied). TSQM Scale scores for each domain range from 0 to 100 and higher scores represent higher satisfaction. Negative values indicate worsening from baseline.	At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Side Effects Score	Participants completed the 14-item Treatment Satisfaction Questionnaire for Medication (TSQM; Version 1.4) to assess satisfaction with their current rheumatoid arthritis treatment over the previous 2-3 weeks or since the last time that they took the medication. The TSQM consists of fourteen items over four domains (effectiveness, side effects, convenience, and global satisfaction). The 14 questions are answered either with yes/no or by means of a five or seven stage scale (ranging from very unsatisfied to satisfied). TSQM Scale scores for each domain range from 0 to 100 and higher scores represent higher satisfaction. Negative values indicate worsening from baseline.	At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Convenience Score	Participants completed the 14-item Treatment Satisfaction Questionnaire for Medication (TSQM; Version 1.4) to assess satisfaction with their current rheumatoid arthritis treatment over the previous 2-3 weeks or since the last time that they took the medication. The TSQM consists of fourteen items over four domains (effectiveness, side effects, convenience, and global satisfaction). The 14 questions are answered either with yes/no or by means of a five or seven stage scale (ranging from very unsatisfied to satisfied). TSQM Scale scores for each domain range from 0 to 100 and higher scores represent higher satisfaction. Negative values indicate worsening from baseline.	At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction Score	Participants completed the 14-item Treatment Satisfaction Questionnaire for Medication (TSQM; Version 1.4) to assess satisfaction with their current rheumatoid arthritis treatment over the previous 2-3 weeks or since the last time that they took the medication. The TSQM consists of fourteen items over four domains (effectiveness, side effects, convenience, and global satisfaction). The 14 questions are answered either with yes/no or by means of a five or seven stage scale (ranging from very unsatisfied to satisfied). TSQM Scale scores for each domain range from 0 to 100 and higher scores represent higher satisfaction. Negative values indicate worsening from baseline.	At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment and Activity Impairment Scores	The Work Productivity and Activity Impairment (WPAI) questionnaire for general health is a validated tool in rheumatoid arthritis consisting of 6 questions, based on participant recall of the previous 7 days. WPAI assesses work time missed due to illness (absenteeism), impairment at work due to health (presenteeism), overall work impairment due to health (an aggregate measure of both absenteeism and presenteeism), and total non-occupational activity impairment due to health. WPAI scores are expressed as impairment percentages, with higher scores indicating worse outcomes. A negative change from baseline indicates improvement.	At Weeks 4, 28, and 40 and Flare Weeks 0, 10, and 16
Secondary	Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Physical Component Summary (PCS) Score	The SF-36v2 is a non-disease specific Health Related Quality of Life (HRQoL) instrument. The SF-36v2 comprises 36 total items (questions) targeting a subject's functional health and well-being in 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health) with a recall period of four weeks. Domain scores are aggregated into a Physical Component Summary (PCS) score and a Mental Component Summary (MCS) score. SF-36v2 scores for each domain and PCS/MCS range from 0-100: higher scores indicate a better state of health and a decrease from baseline represents worsening.	At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Mental Component Summary (MCS) Score	The SF-36v2 is a non-disease specific Health Related Quality of Life (HRQoL) instrument. The SF-36v2 comprises 36 total items (questions) targeting a subject's functional health and well-being in 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health) with a recall period of four weeks. Domain scores are aggregated into a Physical Component Summary (PCS) score and a Mental Component Summary (MCS) score. SF-36v2 scores for each domain and PCS/MCS range from 0-100: higher scores indicate a better state of health and a decrease from baseline represents worsening.	At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale	The FACIT-Fatigue questionnaire is a participant questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions on a scale from 'not at all' (0) to 'very much' (4). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue subscale score ranges from 0 to 52, where higher scores represent less fatigue. A negative change from baseline indicates worsening.	At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Serum Levels of C-reactive Protein (CRP)	C-Reactive Protein (CRP; mg/L) was measured from blood samples as a marker for inflammation. Higher levels are indicative of more inflammation. Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Secondary	Mean Change From Double-blind Baseline in Serum Levels of Erythrocyte Sedimentation Rate (ESR)	Erythrocyte sedimentation rate (ESR; mm/hour) indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. Negative values indicate improvement from baseline.	From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16

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