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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)

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ClinicalTrials.gov Identifier: NCT02198651
Recruitment Status : Completed
First Posted : July 24, 2014
Results First Posted : June 25, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
AbbVie

Tracking Information
First Submitted Date  ICMJE July 22, 2014
First Posted Date  ICMJE July 24, 2014
Results First Submitted Date  ICMJE April 29, 2019
Results First Posted Date  ICMJE June 25, 2019
Last Update Posted Date June 25, 2019
Actual Study Start Date  ICMJE January 5, 2015
Actual Primary Completion Date May 3, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2019)
  • 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 [ Time Frame: From Week 4 to Week 40 ]
    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.
  • Association Between Baseline Bone Marrow Edema RAMRIS Score and Flare up to Week 40 in the Tapering Arm [ Time Frame: From Week 4 to Week 40 ]
    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.
  • 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 [ Time Frame: From Week 4 to Week 40 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 22, 2014)
  • Hand and wrist synovitis rheumatoid arthritis magnetic resonance imaging (MRI) scoring system (RAMRIS) score [ Time Frame: At Week 4 ]
    Synovitis is 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.
  • Bone Marrow Edema (BME) RAMRIS score [ Time Frame: At Week 4 ]
    Bone edema in each bone is 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%
  • Composite of Hand, Wrist and BME RAMRIS scores [ Time Frame: At Week 4 ]
    The composite score is the sum of synovitis and bone edema scores.
  • Flare occurrence [ Time Frame: From Week 4 to Week 40 ]
    Flare is defined as an increase from double blind (db) 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].
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2019)
  • Median Time to Flare [ Time Frame: From Week 4 to Week 40 ]
    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.
  • Physicians' Assessment of Flare Severity [ Time Frame: At the Flare Week 0 Visit ]
    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.
  • Participants' Assessment of Flare Severity [ Time Frame: At the Flare Week 0 Visit ]
    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.
  • Percentage of Participants With a Flare [ Time Frame: From Week 4 to Week 40 ]
    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].
  • Number of Participants Who Regained Clinical Remission in the Open-Label Rescue Arm Over Time [ Time Frame: From Flare Week 0 to Flare Week 16 ]
    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.
  • Median Time to Clinical Remission From the Occurrence of Flare [ Time Frame: From Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Disease Activity Score 28 (DAS28) [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Clinical Disease Activity Index (CDAI) Score [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Simplified Disease Activity Index (SDAI) Score [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • 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 [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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).
  • Mean Change From Double-blind Baseline to Week 40 or Final Visit in Magnetic Resonance Imaging (MRI) Synovitis Score [ Time Frame: From Week 4 to Week 40 or Final visit ]
    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.
  • Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Marrow Edema (BME) Score [ Time Frame: From Week 4 to Week 40 or Final visit ]
    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%.
  • Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Erosions Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score [ Time Frame: From Week 4 to Week 40 or Final Visit ]
    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.
  • Mean Change From Double-blind Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) Score Over Time [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Number of Participants With Health Assessment Questionnaire- Disability Index (HAQ-DI) Score ≤ 0.5 at Double-blind Baseline and at Week 40 [ Time Frame: Week 4 and 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.
  • Mean Change From Double-blind Baseline in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed During In-office Visits [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Flare Week 0 in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed at Home [ Time Frame: Flare Week 0 and Flare Weeks 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15 ]
    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.
  • Mean Change From Double-blind Baseline in Swollen Joint Count 28 [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Swollen Joint Count 66 [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Tender Joint Count 28 [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Tender Joint Count 68 [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Participant's Global Assessment of Disease Activity [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Participant's Global Assessment of Rheumatoid Arthritis Pain [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Physician's Global Assessment of Disease Activity [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Morning Stiffness Duration [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Morning Stiffness Severity [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Participant's Assessment of Sleep Disturbance [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Effectiveness Score [ Time Frame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Side Effects Score [ Time Frame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Convenience Score [ Time Frame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction Score [ Time Frame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment and Activity Impairment Scores [ Time Frame: At Weeks 4, 28, and 40 and Flare Weeks 0, 10, and 16 ]
    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.
  • Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Physical Component Summary (PCS) Score [ Time Frame: At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Mental Component Summary (MCS) Score [ Time Frame: At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale [ Time Frame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Serum Levels of C-reactive Protein (CRP) [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
  • Mean Change From Double-blind Baseline in Serum Levels of Erythrocyte Sedimentation Rate (ESR) [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2014)
  • Time to flare [ Time Frame: From Week 4 to Week 40 ]
    Flare is defined as an increase from db Baseline in DAS28 [ESR] of > 0.6 AND DAS28 [ESR] > 2.6, OR an increase in DAS28 (ESR) of ≥ 1.2 irrespective of the resulting DAS28 [ESR].
  • Flare severity [ Time Frame: From Week 4 to Week 40 ]
    It is assessed using Likert scale 0-10.
  • Proportion of subjects who regain clinical remission in the Open-Label Rescue Arm over time [ Time Frame: From Flare Week 0 to Flare Week 16 ]
    Remission defined as DAS28 (ESR) < 2.6 and defined as DAS28 (ESR) decrease >1.2 if DAS28 (ESR) was less than 2.6 at flare
  • Time to regain clinical remission in the Open-Label Rescue Arm [ Time Frame: From Flare Week 0 to Flare Week 16 ]
    Clinical remission is defined as DAS28 [ESR] < 2.6 and defined as DAS28 (ESR) decrease > 1.2 if DAS28 [ESR] was less than 2.6 at flare.
  • Proportion of subjects who achieve low disease activity in the Open-Label Rescue Arm over time [ Time Frame: From Flare Week 0 to Flare Week 16 ]
    Low disease activity defined as DAS28 (ESR) < 3.2
  • Change in DAS28 (ESR) [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    Assessed by the change in DAS28 (ESR) from Week 4 to Week 40 and Flare Week 0 to Flare Week 16 in the Open-Label Rescue Arm.
  • Proportion of subjects maintaining clinical remission throughout the study [ Time Frame: From Week 4 to Week 40 ]
    Clinical remission defined by DAS, SDAI and CDAI: DAS28 Erythrocyte sedimentation rate (ESR) < 2.6; SDAI ≤ 3.3; CDAI ≤ 2.8)]
  • Change in MRI synovitis [ Time Frame: From Week 4 to Week 40 or Final visit ]
    Synovitis is 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.
  • Change in Health Assessment Questionnaire - Disability Index (HAQ-DI) over time in the open-label rescue arm [ Time Frame: From Flare Week 0 to Flare Week 16 ]
    Assessed by the HAQ-DI which has 8 sections and 2-3 questions per section. Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). The scores are summed and divided by 8.
  • Proportion of subjects with HAQ-DI normal [ Time Frame: From Week 4 to Week 40 ]
    HAQ-DI ≤ 0.5 is considered to be normal.
  • Change in RAPID 3 scores assessed during in-office visits [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    Assessed by RAPID-3 questionnaire which includes a subset of core variables found in the multi-dimensional HAQ, a patient global assessment for pain and a patient global assessment for health.
  • Change in RAPID 3 at home assessments [ Time Frame: From Flare Week 0 to Flare Week 16 ]
    Assessed weekly by RAPID-3 questionnaire which includes a subset of core variables found in the multi-dimensional HAQ, a patient global assessment for pain and a patient global assessment for health.
  • Change in Treatment Satisfaction Questionnaire for Medication (TSQM) in the open-label rescue arm [ Time Frame: From Week 4 to Week 40 and Flare Week 0 to Flare Week 16 ]
    Assessed by the TSQM questionnaire for medication which gathers patient evaluation of the effectiveness, side effects and convenience of the medication through 14 questions.
  • Change in Work Productivity and Activity Impairment (WPAI) [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    Assessed by the WPAI containing questions related with employment status, the number of missed work hours, the number of working hours and productivity related questions.
  • Change in Short Form-36 (SF-36) [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    Assessed by SF-36 survey questionnaire containing 11 questions directed to patients related to their health and well being.
  • Change in Functional Assessment of Chronic Illness Therapy - fatigue (FACIT-fatigue) [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    Assessed by the FACIT-fatigue questionnaire evaluating standardized statements related with fatigue in rated in a scale from 0-4.
  • Clinical Disease Activity Index (CDAI) [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    CDAI is evaluated by the sum of 28 tender joint count, 28 swollen joint count, physician global assessment and patient global assessment.
  • Change in Simplified Disease Activity Index (SDAI) [ Time Frame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16 ]
    SDAI is evaluated by the sum of 28 tender joint count, 28 swollen joint count, physician global assessment, patient global assessment and c-reactive protein.
  • Change in BME [ Time Frame: From Week 4 to Week 40 or Final visit ]
    Bone edema in each bone is 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%
  • Change in erosions RAMRIS scores [ Time Frame: From Week 4 to Week 40 ]
    Bone erosions in each bone (wrists: carpal bones, distal radius, distal ulna, metacarpal bases; MCP joints: metacarpal heads, phalangeal bases) is 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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)
Brief 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.
Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Rheumatoid Arthritis
  • Musculoskeletal and Connective Tissue Diseases
Intervention  ICMJE
  • Biological: Adalimumab
    Pre-filled syringe, administered by subcutaneous injection
    Other Names:
    • ABT-D2E7
    • Humira
  • Other: Placebo
    Pre-filled syringe, administered by subcutaneous injection in the Double-blind period
Study Arms  ICMJE
  • Experimental: Adalimumab 40 mg eow
    40 mg adalimumab administered subcutaneously every other week (eow) from Week 0 to Week 4 (Lead-in Period)
    Intervention: Biological: Adalimumab
  • Active Comparator: Adalimumab Tapering
    40 mg adalimumab administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)
    Intervention: Biological: Adalimumab
  • Placebo Comparator: Adalimumab Withdrawal Arm
    Placebo administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)
    Intervention: Other: Placebo
  • Experimental: Adalimumab 40 mg eow Rescue Arm
    40 mg adalimumab administered subcutaneously every other week from Flare Week 0 to Flare Week 16 (Open-label Rescue Period)
    Intervention: Biological: Adalimumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 6, 2018)
149
Original Estimated Enrollment  ICMJE
 (submitted: July 22, 2014)
334
Actual Study Completion Date  ICMJE August 8, 2018
Actual Primary Completion Date May 3, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Canada,   France,   Germany,   Greece,   Hungary,   Ireland,   Italy,   Netherlands,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02198651
Other Study ID Numbers  ICMJE M14-500
2014-001114-26 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html
Responsible Party AbbVie
Study Sponsor  ICMJE AbbVie
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: AbbVie Inc. AbbVie
PRS Account AbbVie
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP