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

NCT02198651 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: M14-5002014-001114-26
• Study Type: interventional
• Target: 149
• Locations: 13 countries
• Sites: 69

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.

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

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• 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 Outcomes (37)

• Median Time to Flare

  From Week 4 to Week 40

• Physicians' Assessment of Flare Severity

  At the Flare Week 0 Visit

• Participants' Assessment of Flare Severity

  At the Flare Week 0 Visit

• Percentage of Participants With a Flare

  From Week 4 to Week 40

• Number of Participants Who Regained Clinical Remission in the Open-Label Rescue Arm Over Time

  From Flare Week 0 to Flare Week 16

Study Arms (4)

Adalimumab 40 mg eow

EXPERIMENTAL

40 mg adalimumab administered subcutaneously every other week (eow) from Week 0 to Week 4 (Lead-in Period)

Biological: Adalimumab

Adalimumab Tapering

ACTIVE COMPARATOR

40 mg adalimumab administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)

Biological: Adalimumab

Adalimumab Withdrawal Arm

PLACEBO COMPARATOR

Placebo administered subcutaneously every three weeks from Week 4 to Week 40 (Double-blind Period)

Other: Placebo

Adalimumab 40 mg eow Rescue Arm

EXPERIMENTAL

40 mg adalimumab administered subcutaneously every other week from Flare Week 0 to Flare Week 16 (Open-label Rescue Period)

Biological: Adalimumab

Interventions

Adalimumab BIOLOGICAL

Pre-filled syringe, administered by subcutaneous injection

Also known as: ABT-D2E7, Humira

Adalimumab 40 mg eow; Adalimumab 40 mg eow Rescue Arm; Adalimumab Tapering

Placebo OTHER

Pre-filled syringe, administered by subcutaneous injection in the Double-blind period

Adalimumab Withdrawal Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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.
• 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;
• variables DAS28 (ESR) assessed at Screening \< 2.6, with all components including ESR assessed at Screening.
• 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).
• 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.
• 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.
• Participant must have been able and willing to provide written informed consent and comply with the requirements of this study protocol.

You may not qualify if:

• 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.
• 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).
• Participant had been treated with intra-articular or parenteral corticosteroids within the last four weeks before Screening.
• Participant had undergone joint surgery within 12 weeks of Screening (at joints to be assessed by magnetic resonance imaging (MRI) and/or ultrasound).
• 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)
• Participant had a medical condition precluding a contrast MRI with gadolinium \[e.g. nephrogenic systemic fibrosis, previous anaphylactic/anaphylactoid reaction to gadolinium containing contrast agent, pregnancy or breast feeding, severe renal insufficiency with an estimated Glomerular Filtration Rate (eGFR) below 30 mL/min/1.73m\^2 at Screening, hepato-renal syndrome, severe chronic liver function impairment\]
• 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.

Sponsors & Collaborators

• AbbVie: lead

Study Sites (70)

J Michael Grelier Research /ID# 149772

Tuscaloosa, Alabama, 35406, United States

Location

Westlake Medical Research (WMR) Clinical Trials /ID# 155386

Thousand Oaks, California, 91360-3994, United States

Location

University of Florida /ID# 144851

Jacksonville, Florida, 32209, United States

Location

North Georgia Rheumatology Grp /ID# 155225

Lawrenceville, Georgia, 30045, United States

Location

The Arthritis & Diabetes Clinic, Inc. /ID# 149017

Monroe, Louisiana, 71203, United States

Location

Aa Mrc Llc /Id# 151933

Grand Blanc, Michigan, 48439, United States

Location

North Mississippi Med Clinics /ID# 149443

Tupelo, Mississippi, 38801, United States

Location

Montefiore Medical Center /ID# 155013

The Bronx, New York, 10461, United States

Location

Shanahan Rheuma & Immuno /ID# 148689

Raleigh, North Carolina, 27617, United States

Location

Altoona Ctr Clinical Res /ID# 148448

Duncansville, Pennsylvania, 16635, United States

Location

Low Country Rheumatology, PA /ID# 154198

Summerville, South Carolina, 29486, United States

Location

West Tennessee Research Inst /ID# 148391

Jackson, Tennessee, 38305, United States

Location

Arthritis Centers of Texas /ID# 152843

Dallas, Texas, 75246, United States

Location

Royal Prince Alfred Hospital /ID# 154649

Camperdown, New South Wales, 2050, Australia

Location

Optimus Clinical Research Pty. /ID# 133881

Kogarah, New South Wales, 2217, Australia

Location

John Hunter Hospital /ID# 133884

Newcastle, New South Wales, 2305, Australia

Location

Rheumatology Research Unit /ID# 133883

Maroochydore, Queensland, 4558, Australia

Location

AKH Wien /ID# 133885

Vienna, Vienna, 1090, Austria

Location

St. Joseph's Healthcare /ID# 149233

Hamilton, Ontario, L8N 4A6, Canada

Location

The Arthritis Program Res Grp /ID# 129056

Newmarket, Ontario, L3Y 3R7, Canada

Location

Institut de Rhum. de Montreal /ID# 129055

Montreal, Quebec, H2L 1S6, Canada

Location

Groupe de Recherche en Maladies Osseuses /ID# 129057

Sainte-Foy, Quebec, G1V 3M7, Canada

Location

CIUSSS de l'Estrie - CHUS /ID# 144839

Sherbrooke, Quebec, J1G 2E8, Canada

Location

CHU de la miletrie /ID# 133928

Poitiers, Poitou-Charentes, 86021, France

Location

CHU Amiens Picardie /ID# 144846

Amiens, Somme, 80054, France

Location

Hospital Louis Pasteur /ID# 134708

Chartres, 28630, France

Location

CHU de Grenoble - Albet Michal /ID# 135953

Grenoble, 38043, France

Location

Asklepios Klinik /ID# 129146

Bad Abbach, 93077, Germany

Location

Charité Universitätsmedizin Campus Mitte /ID# 129142

Berlin, 10117, Germany

Location

Immanuel-Krankenhaus /ID# 129143

Buch, 13125, Germany

Location

Krankenhaus Porz am Rhein /ID# 129147

Cologne, 51149, Germany

Location

Rheumaforschungszentrum II /ID# 148554

Hamburg, 20095, Germany

Location

Klinikum der Univ Munich /ID# 129144

Munich, 80337, Germany

Location

Rheumazentrum Ratingen /ID# 129148

Ratingen, 40882, Germany

Location

Rheumatologische Praxis /ID# 151979

Rendsburg, 24768, Germany

Location

University General Hospital "Attikon" /ID# 134709

Athens, Attica, 12462, Greece

Location

General Hospital of Athens /ID# 129202

Athens, 11527, Greece

Location

General UH of Heraklion /ID# 134712

Heraklion, 71110, Greece

Location

Budai Irgalmasrendi Korhaz /ID# 134714

Budapest, 1023, Hungary

Location

Orszagos Reumatologiai es Fizi /ID# 134710

Budapest, 1023, Hungary

Location

Debreceni Egyetem Klinikai Koz /ID# 134715

Debrecen, 4032, Hungary

Location

St Vincent's University Hosp /ID# 129210

Dublin, D04 T6F4, Ireland

Location

AP Romano Umberto I /ID# 132895

Rome, Lazio, 00161, Italy

Location

A.O. Univ Consorziale Policlin /ID# 133932

Bari, 70124, Italy

Location

Azienda Istituto Gaetano Pini /ID# 132964

Milan, 20122, Italy

Location

Fondazione IRCCS Policlinico /ID# 133886

Pavia, 27100, Italy

Location

A.O.U.I. di Verona Policlinico /ID# 132973

Verona, 37134, Italy

Location

Jan van Breemen Instituut /ID# 133887

Amsterdam, 1056 AB, Netherlands

Location

Rijnstate Hospital /ID# 129206

Arnhem, 6815 AD, Netherlands

Location

Medisch Centrum Leeuwarden /ID# 133888

Leeuwarden, 8934 AD, Netherlands

Location

UMC Utrecht /ID# 132896

Utrecht, 3584 CX, Netherlands

Location

Hospital Parc de Salut del Mar /ID# 148670

Barcelona, 08003, Spain

Location

Hosp Sant J. Despi-Moises Brog /ID# 135368

Barcelona, 08906, Spain

Location

Hospital Universitario Basurto /ID# 135529

Bilbao, 48013, Spain

Location

Hosp Clinico Virgen Arrixaca /ID# 137020

El Palmar, 30120, Spain

Location

Hospital General Universitario Gregorio Maranon /ID# 133889

Madrid, 28007, Spain

Location

Hospital Universitario La Paz /ID# 135369

Madrid, 28046, Spain

Location

Hospital Univ De Mostoles /ID# 134489

Móstoles, 28935, Spain

Location

Complejo Hosp Santiago /ID# 133890

Santiago de Compostela, 15706, Spain

Location

Hosp General Univ de Valencia /ID# 134488

Valencia, 46014, Spain

Location

Akademiska Sjukhuset /ID# 148669

Uppsala, Uppsala County, 751 85, Sweden

Location

Uppsala University Hospital /ID# 133891

Uppsala, 75185, Sweden

Location

Vastmanlands Sjukhus /ID# 133892

Västerås, 72189, Sweden

Location

Whipps Cross Univ Hospital /ID# 133893

London, London, City of, E11 1NR, United Kingdom

Location

Guy's and St Thomas' NHS Found /ID# 132965

London, London, City of, SE1 9RT, United Kingdom

Location

Mid Essex Hospitals NHS Trust /ID# 151636

Chelmsford, CM1 7ET, United Kingdom

Location

Western General Hospital /ID# 132966

Edinburgh, EH4 2XU, United Kingdom

Location

Chapel Allerton Hospital /ID# 129208

Leeds, LS7 4SA, United Kingdom

Location

University Hospital Aintree /ID# 132980

Liverpool, L9 7AL, United Kingdom

Location

Queen Alexandra Hospital /ID# 132982

Portsmouth, PO6 3LY, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 32404343 DERIVED

• 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.

  PMID: 29490959 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Arthritis, Rheumatoid; Connective Tissue Diseases; Arthritis

Interventions

Adalimumab

Condition Hierarchy (Ancestors)

Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Global Medical Services
• Organization: AbbVie

abbvieclinicaltrials@abbvie.com

800-633-9110

Study Officials

• AbbVie Inc.

  AbbVie

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2014
• First Posted: July 24, 2014
• Study Start: January 5, 2015
• Primary Completion: May 3, 2018
• Study Completion: August 8, 2018
• Last Updated: June 25, 2019
• Results First Posted: June 25, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR, 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.

Locations

NL (4); US (13); SE (3); CA (5); DE (8); FR (4); HU (3); ES (9); IT (5); GB (7); AU (4); GR (3); IE (1)