Clinical trial NCT02198651: 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: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Musculoskeletal and Connective Tissue Diseases
Keywords: Rheumatoid Arthritis
Adalimumab
Taper
Flare
Arthritis
Anti-rheumatic drugs
Remission
Magnetic Resonance Imaging
Ultrasound
Biomarker
Drug Level
Reduced dose
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2014-07-24
Enrollment: 149
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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
timeFrame: From Week 4 to Week 40
measure: Association Between Baseline Bone Marrow Edema RAMRIS Score and Flare up to Week 40 in the Tapering Arm
timeFrame: From Week 4 to Week 40
measure: 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
timeFrame: From Week 4 to Week 40
Secondary outcomes:
measure: Median Time to Flare
timeFrame: From Week 4 to Week 40
measure: Physicians' Assessment of Flare Severity
timeFrame: At the Flare Week 0 Visit
measure: Participants' Assessment of Flare Severity
timeFrame: At the Flare Week 0 Visit
measure: Percentage of Participants With a Flare
timeFrame: From Week 4 to Week 40
measure: Number of Participants Who Regained Clinical Remission in the Open-Label Rescue Arm Over Time
timeFrame: From Flare Week 0 to Flare Week 16
measure: Median Time to Clinical Remission From the Occurrence of Flare
timeFrame: From Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Disease Activity Score 28 (DAS28)
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Clinical Disease Activity Index (CDAI) Score
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Simplified Disease Activity Index (SDAI) Score
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: 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
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline to Week 40 or Final Visit in Magnetic Resonance Imaging (MRI) Synovitis Score
timeFrame: From Week 4 to Week 40 or Final visit
measure: Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Marrow Edema (BME) Score
timeFrame: From Week 4 to Week 40 or Final visit
measure: Mean Change From Double-blind Baseline to Week 40 or Final Visit in Bone Erosions Rheumatoid Arthritis Magnetic Resonance Imaging Scoring System (RAMRIS) Score
timeFrame: From Week 4 to Week 40 or Final Visit
measure: Mean Change From Double-blind Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) Score Over Time
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Number of Participants With Health Assessment Questionnaire- Disability Index (HAQ-DI) Score ≤ 0.5 at Double-blind Baseline and at Week 40
timeFrame: Week 4 and Week 40
measure: Mean Change From Double-blind Baseline in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed During In-office Visits
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Flare Week 0 in Routine Assessment of Patient Index Data (RAPID3) Questionnaire Scores Assessed at Home
timeFrame: Flare Week 0 and Flare Weeks 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15
measure: Mean Change From Double-blind Baseline in Swollen Joint Count 28
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Swollen Joint Count 66
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Tender Joint Count 28
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Tender Joint Count 68
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Participant's Global Assessment of Disease Activity
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Participant's Global Assessment of Rheumatoid Arthritis Pain
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Physician's Global Assessment of Disease Activity
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Morning Stiffness Duration
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Morning Stiffness Severity
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Participant's Assessment of Sleep Disturbance
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Effectiveness Score
timeFrame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Side Effects Score
timeFrame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Convenience Score
timeFrame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction Score
timeFrame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Work Productivity and Activity Impairment (WPAI) Overall Work Impairment and Activity Impairment Scores
timeFrame: At Weeks 4, 28, and 40 and Flare Weeks 0, 10, and 16
measure: Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Physical Component Summary (PCS) Score
timeFrame: At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Short-Form 36 Version 2 Health Survey (SF-36v2) Mental Component Summary (MCS) Score
timeFrame: At Weeks 4, 28, and 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale
timeFrame: At Weeks 4, 16, 28, and 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Serum Levels of C-reactive Protein (CRP)
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
measure: Mean Change From Double-blind Baseline in Serum Levels of Erythrocyte Sedimentation Rate (ESR)
timeFrame: From Week 4 to Week 40 and from Flare Week 0 to Flare Week 16
Other outcomes:
Locations:
city: Tuscaloosa
country: United States
facility: J Michael Grelier Research /ID# 149772
state: Alabama
city: Thousand Oaks
country: United States
facility: Westlake Medical Research (WMR) Clinical Trials /ID# 155386
state: California
city: Jacksonville
country: United States
facility: University of Florida /ID# 144851
state: Florida
city: Lawrenceville
country: United States
facility: North Georgia Rheumatology Grp /ID# 155225
state: Georgia
city: Monroe
country: United States
facility: The Arthritis & Diabetes Clinic, Inc. /ID# 149017
state: Louisiana
city: Grand Blanc
country: United States
facility: Aa Mrc Llc /Id# 151933
state: Michigan
city: Tupelo
country: United States
facility: North Mississippi Med Clinics /ID# 149443
state: Mississippi
city: Bronx
country: United States
facility: Montefiore Medical Center /ID# 155013
state: New York
city: Raleigh
country: United States
facility: Shanahan Rheuma & Immuno /ID# 148689
state: North Carolina
city: Duncansville
country: United States
facility: Altoona Ctr Clinical Res /ID# 148448
state: Pennsylvania
city: Summerville
country: United States
facility: Low Country Rheumatology, PA /ID# 154198
state: South Carolina
city: Jackson
country: United States
facility: West Tennessee Research Inst /ID# 148391
state: Tennessee
city: Dallas
country: United States
facility: Arthritis Centers of Texas /ID# 152843
state: Texas
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital /ID# 154649
state: New South Wales
city: Kogarah
country: Australia
facility: Optimus Clinical Research Pty. /ID# 133881
state: New South Wales
city: Newcastle
country: Australia
facility: John Hunter Hospital /ID# 133884
state: New South Wales
city: Maroochydore
country: Australia
facility: Rheumatology Research Unit /ID# 133883
state: Queensland
city: Vienna
country: Austria
facility: AKH Wien /ID# 133885
state: Wien
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare /ID# 149233
state: Ontario
city: Newmarket
country: Canada
facility: The Arthritis Program Res Grp /ID# 129056
state: Ontario
city: Montreal
country: Canada
facility: Institut de Rhum. de Montreal /ID# 129055
state: Quebec
city: Sainte-foy
country: Canada
facility: Groupe de Recherche en Maladies Osseuses /ID# 129057
state: Quebec
city: Sherbrooke
country: Canada
facility: CIUSSS de l'Estrie - CHUS /ID# 144839
state: Quebec
city: Poitiers
country: France
facility: CHU de la miletrie /ID# 133928
state: Poitou-Charentes
city: Amiens CEDEX 1
country: France
facility: CHU Amiens Picardie /ID# 144846
state: Somme
city: Chartres
country: France
facility: Hospital Louis Pasteur /ID# 134708
city: Grenoble
country: France
facility: CHU de Grenoble - Albet Michal /ID# 135953
city: Bad Abbach
country: Germany
facility: Asklepios Klinik /ID# 129146
city: Berlin-buch
country: Germany
facility: Immanuel-Krankenhaus /ID# 129143
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Campus Mitte /ID# 129142
city: Cologne
country: Germany
facility: Krankenhaus Porz am Rhein /ID# 129147
city: Hamburg
country: Germany
facility: Rheumaforschungszentrum II /ID# 148554
city: Munich
country: Germany
facility: Klinikum der Univ Munich /ID# 129144
city: Ratingen
country: Germany
facility: Rheumazentrum Ratingen /ID# 129148
city: Rendsburg
country: Germany
facility: Rheumatologische Praxis /ID# 151979
city: Athens
country: Greece
facility: University General Hospital "Attikon" /ID# 134709
state: Attiki
city: Athens
country: Greece
facility: General Hospital of Athens /ID# 129202
city: Heraklion
country: Greece
facility: General UH of Heraklion /ID# 134712
city: Budapest
country: Hungary
facility: Budai Irgalmasrendi Korhaz /ID# 134714
city: Budapest
country: Hungary
facility: Orszagos Reumatologiai es Fizi /ID# 134710
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Koz /ID# 134715
city: Dublin
country: Ireland
facility: St Vincent's University Hosp /ID# 129210
city: Rome
country: Italy
facility: AP Romano Umberto I /ID# 132895
state: Lazio
city: Bari
country: Italy
facility: A.O. Univ Consorziale Policlin /ID# 133932
city: Milan
country: Italy
facility: Azienda Istituto Gaetano Pini /ID# 132964
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico /ID# 133886
city: Verona
country: Italy
facility: A.O.U.I. di Verona Policlinico /ID# 132973
city: Amsterdam
country: Netherlands
facility: Jan van Breemen Instituut /ID# 133887
city: Arnhem
country: Netherlands
facility: Rijnstate Hospital /ID# 129206
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden /ID# 133888
city: Utrecht
country: Netherlands
facility: UMC Utrecht /ID# 132896
city: Barcelona
country: Spain
facility: Hospital Parc de Salut del Mar /ID# 148670
city: Barcelona
country: Spain
facility: Hosp Sant J. Despi-Moises Brog /ID# 135368
city: Bilbao
country: Spain
facility: Hospital Universitario Basurto /ID# 135529
city: El Palmar
country: Spain
facility: Hosp Clinico Virgen Arrixaca /ID# 137020
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon /ID# 133889
city: Madrid
country: Spain
facility: Hospital Universitario La Paz /ID# 135369
city: Mostoles
country: Spain
facility: Hospital Univ De Mostoles /ID# 134489
city: Santiago de Compostela
country: Spain
facility: Complejo Hosp Santiago /ID# 133890
city: Valencia
country: Spain
facility: Hosp General Univ de Valencia /ID# 134488
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset /ID# 148669
state: Uppsala Lan
city: Uppsala
country: Sweden
facility: Uppsala University Hospital /ID# 133891
city: Vasteras
country: Sweden
facility: Vastmanlands Sjukhus /ID# 133892
city: London
country: United Kingdom
facility: Whipps Cross Univ Hospital /ID# 133893
state: London, City Of
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Found /ID# 132965
state: London, City Of
city: Chelmsford
country: United Kingdom
facility: Mid Essex Hospitals NHS Trust /ID# 151636
city: Edinburgh
country: United Kingdom
facility: Western General Hospital /ID# 132966
city: Leeds
country: United Kingdom
facility: Chapel Allerton Hospital /ID# 129208
city: Liverpool
country: United Kingdom
facility: University Hospital Aintree /ID# 132980
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital /ID# 132982
Study officials:
affiliation: AbbVie
name: AbbVie Inc.
role: STUDY_DIRECTOR
References:
citation: Emery P, Burmester GR, Naredo E, Sinigaglia L, Lagunes I, Koenigsbauer F, Conaghan PG. Adalimumab dose tapering in patients with rheumatoid arthritis who are in long-standing clinical remission: results of the phase IV PREDICTRA study. Ann Rheum Dis. 2020 Aug;79(8):1023-1030. doi: 10.1136/annrheumdis-2020-217246. Epub 2020 May 13.
citation: Emery P, Burmester GR, Naredo E, Zhou Y, Hojnik M, Conaghan PG. Design of a phase IV randomised, double-blind, placebo-controlled 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) patients (PREDICTRA). BMJ Open. 2018 Feb 28;8(2):e019007. doi: 10.1136/bmjopen-2017-019007.