- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03561649
Prediction of Treatment Response at 6 Months by Combinatorial Analysis of Serum Biomarkers in Biotherapy Naive SpA (PRESHUM)
Prediction of Adalimumab Treatment Response at 6 Months by Combinatorial Analysis of Serum Biomarkers in Biotherapy Naive Spondyloarthritis: Pilot Study
The main objective of this trial is to search for biomarkers associated with the success of adalimumab treatment in order to generate an algorithm to predict the response to this treatment at 6 months in spondyloarthritis and to define its metrological properties on this cohort.
The algorithm will allow to better target patients who will have an important benefit/risk ratio for adalimumab treatment.
Study Overview
Detailed Description
The general prevalence of spondyloarthritis (SpA) is 0.5% of the Caucasian population and that of ankylosing spondylitis (AS) is 0.3% in France.
First-line treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) is insufficiently effective in more than half of AS patients in hospitals. These patients are then treated with "anti-tumor necrosis factor alpha" (anti-TNFα). The use of these bio-drugs increasing each year, they become a significant public health and economic challenge. Their development is just beginning, because they are among the largest providers of pharmacy innovations.
The two main cost-drivers appear to be, on the most advanced forms of inflammatory rheumatism, the use of appropriate care structures or services and surgery, especially knee and hip surgery. Among patients treated with biotherapy, clinical practice shows that about one-third (33%) will not respond to selected biopharmaceuticals as these biologics are often prescribed empirically, mainly because of the lack of criteria based on scientific evidence and availability of tools able to predict the response or non-response to these molecules.
Until now, there is no algorithm which can predict the response to biotherapies like adalimumab. The aim of this trial is to search for biomarkers associated with the success of adalimumab treatment in order to generate an algorithm predicting the response to this treatment at 6 months for patients with SpA. This algorithm will be set up from patients' biological and clinical data available after 6 months of adalimumab treatment. A number of 50 patients seems to be statistically sufficient to assess the probability of response or non response to adalimumab in SA with the defined algorithm. A logistic regression model will be used by incorporating the set of available variables.
Then it will be necessary to set up a validation study to determine the metrological properties of the algorithm on an independent cohort.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Belfort, France, 90016
- CH de Belfort
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Besançon, France, 25030
- CHU de Besancon
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Clermont-Ferrand, France, 63003
- CHRU de Clermont-Ferrand
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Saint-Etienne, France, 42055
- CHU de Saint-Etienne
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Échirolles, France, 38434
- CHU de Grenoble
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients with spondyloarthritis validating ASAS or modified New York criteria for which adalimumab treatment is indicated, and performing the pre-biotherapy assessment;
- Between 18 and 70 years old;
- Biotherapy naive;
- Who can be regularly monitored for 6 months;
- Able to take all the treatment;
- Effective contraception for patients of childbearing age (oral contraceptive, intrauterine device, implant, spermicide, surgical sterilization or abstinence) during the study and at least for 5 months after the last injection;
- Able to read and understand the terms of the protocol;
- Having dated and signed the informed consent form of the trial;
- Affiliated to a social security scheme.
Exclusion Criteria:
- Patients having a contraindication to an anti-TNF;
- Surgical operation scheduled during the trial;
- Having difficulty understanding the French language;
- Having impaired upper functions (dementia of Alzheimer type, etc...);
- Psycho-social instability incompatible with regular follow-up (homeless, addictive behavior, history of psychiatric pathology or any other comorbidity which would make a free and informed consent impossible or limit adherence to the protocol);
- Having previously received a biotherapy. There is no other exclusion criteria taking into account prior therapies and the duration of these therapies;
- Described in articles L.1121-5 to L.1121-8 of the Personal Status Code: pregnant, parturient and nursing women; persons in detention by judicial or administrative decision; adults subject to a legal protection order;
- Already participating in interventional research.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Screening
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Adalimumab
Adalimumab is not the experimental study drug. This treatment justifies the inclusion of patients and is used in accordance with its marketing authorization. The patients will be seen as part of their follow-up consultation in Rheumatology. Modality of administration: The baseline visit should take place no more than 4 weeks before the start of adalimumab treatment, 40mg every 2 weeks, subcutaneously, in accordance with Summary of Product Characteristics. At baseline and 6 months follow-up visits, a single blood draw for the biomarker dosage will be added to the standard patient health care follow-up. The clinical examination will also be performed at these two visits, and the clinical response will be assessed after 6 months of adalimumab treatment at M6 follow-up visit. |
This trial will be conducted by rheumatologists who can follow patients with SpA and conduct this trial in good conditions and in accordance with regulatory and legal recommendations.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Measurement of disease activity: AS-DAS (Ankylosing Spondylitis - Disease Activity Score)
Time Frame: 6 months after baseline
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The primary endpoint is the clinically important ASAS response corresponding to a variation in ASDAS CRP ≥ 1.1.
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6 months after baseline
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Measurement of BASDAI response (Bath Ankylosing Spondylitis Disease Activity Index)
Time Frame: 6 months after baseline
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The major clinical ASAS response corresponds to a variation in ASDAS CRP (C-reactive protein) ≥ 2,0 and the major clinical BASDAI 50 response. The BASDAI 50 response means an improvement of the BASDAI score by 50% or more. C-Reactive Protein (CRP) in mg/l and Erythrocyte Sedimentation Rate (ESR) in mm at the first hour. |
6 months after baseline
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Biomarkers analysis for personalized medicine
Time Frame: At baseline and 6 months later
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Blood draw for selected biomarkers analysis (M0): the dosage data will be used to search for biomarkers associated with successful treatment in order to generate an algorithm predicting the response to adalimumab at 6 months, and to define the metrological properties on this cohort. Blood draw for selected biomarkers analysis (M6): we know little about the mechanisms underlying the effect of adalimumab treatment at 6 months in spondyloarthritis, particularly on the biomarker profile. In order to identify possible differences in the profile of selected biomarkers between patients treated with adalimumab at 6 months and biotherapy naive patients (at baseline) and to study the individual variations of the response to this treatment, blood samples will also be collected at 6 months. By using proteomic profiles, the analysis and the comparison of predictive factors at M0 and M6 could be very useful. |
At baseline and 6 months later
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Athan BAILLET, MD, PHD, University Hospital, Grenoble
Publications and helpful links
General Publications
- Baillet A, Trocme C, Berthier S, Arlotto M, Grange L, Chenau J, Quetant S, Seve M, Berger F, Juvin R, Morel F, Gaudin P. Synovial fluid proteomic fingerprint: S100A8, S100A9 and S100A12 proteins discriminate rheumatoid arthritis from other inflammatory joint diseases. Rheumatology (Oxford). 2010 Apr;49(4):671-82. doi: 10.1093/rheumatology/kep452. Epub 2010 Jan 25.
- Trocme C, Marotte H, Baillet A, Pallot-Prades B, Garin J, Grange L, Miossec P, Tebib J, Berger F, Nissen MJ, Juvin R, Morel F, Gaudin P. Apolipoprotein A-I and platelet factor 4 are biomarkers for infliximab response in rheumatoid arthritis. Ann Rheum Dis. 2009 Aug;68(8):1328-33. doi: 10.1136/ard.2008.093153. Epub 2008 Jul 29.
- Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordstrom DC, Blom M. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One. 2012;7(1):e30275. doi: 10.1371/journal.pone.0030275. Epub 2012 Jan 17.
- Baeten D, Kruithof E, Van den Bosch F, Van den Bossche N, Herssens A, Mielants H, De Keyser F, Veys EM. Systematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease? Ann Rheum Dis. 2003 Sep;62(9):829-34. doi: 10.1136/ard.62.9.829.
- Brandt J, Khariouzov A, Listing J, Haibel H, Sorensen H, Grassnickel L, Rudwaleit M, Sieper J, Braun J. Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum. 2003 Jun;48(6):1667-75. doi: 10.1002/art.11017.
- Braun J, de Keyser F, Brandt J, Mielants H, Sieper J, Veys E. New treatment options in spondyloarthropathies: increasing evidence for significant efficacy of anti-tumor necrosis factor therapy. Curr Opin Rheumatol. 2001 Jul;13(4):245-9. doi: 10.1097/00002281-200107000-00001.
- Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-Ihle E, Kellner H, Krause A, Schneider M, Sorensen H, Zeidler H, Thriene W, Sieper J. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet. 2002 Apr 6;359(9313):1187-93. doi: 10.1016/s0140-6736(02)08215-6.
- Braun J, Pham T, Sieper J, Davis J, van der Linden S, Dougados M, van der Heijde D; ASAS Working Group. International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis. 2003 Sep;62(9):817-24. doi: 10.1136/ard.62.9.817.
- Braun J, Sieper J. Biological therapies in the spondyloarthritides--the current state. Rheumatology (Oxford). 2004 Sep;43(9):1072-84. doi: 10.1093/rheumatology/keh205. Epub 2004 Jun 8.
- Claudepierre P, Wendling D, Breban M, Goupillle P, Dougados M. Ankylosing spondylitis, spondyloarthropathy, spondyloarthritis, or spondylarthritis: what's in a name? Joint Bone Spine. 2012 Dec;79(6):534-5. doi: 10.1016/j.jbspin.2012.06.003. Epub 2012 Jul 28. No abstract available.
- Haibel H, Rudwaleit M, Brandt HC, Grozdanovic Z, Listing J, Kupper H, Braun J, Sieper J. Adalimumab reduces spinal symptoms in active ankylosing spondylitis: clinical and magnetic resonance imaging results of a fifty-two-week open-label trial. Arthritis Rheum. 2006 Feb;54(2):678-81. doi: 10.1002/art.21563. No abstract available.
- Hennigan S, Ackermann C, Kavanaugh A. Adalimumab in ankylosing spondylitis: an evidence-based review of its place in therapy. Core Evid. 2008 Jul 31;2(4):295-305.
- Kavanaugh A, Klareskog L, van der Heijde D, Li J, Freundlich B, Hooper M. Improvements in clinical response between 12 and 24 weeks in patients with rheumatoid arthritis on etanercept therapy with or without methotrexate. Ann Rheum Dis. 2008 Oct;67(10):1444-7. doi: 10.1136/ard.2008.094524. Epub 2008 Jun 5.
- Lyngberg KK, Harreby M, Bentzen H, Frost B, Danneskiold-Samsoe B. Elderly rheumatoid arthritis patients on steroid treatment tolerate physical training without an increase in disease activity. Arch Phys Med Rehabil. 1994 Nov;75(11):1189-95. doi: 10.1016/0003-9993(94)90003-5.
- Machado P, Landewe R, Lie E, Kvien TK, Braun J, Baker D, van der Heijde D; Assessment of SpondyloArthritis international Society. Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis. 2011 Jan;70(1):47-53. doi: 10.1136/ard.2010.138594. Epub 2010 Nov 10.
- Madland TM, Larsen A, Brun JG. S100 proteins calprotectin and S100A12 are related to radiographic changes rather than disease activity in psoriatic arthritis with low disease activity. J Rheumatol. 2007 Oct;34(10):2089-92. Epub 2007 Sep 1.
- McIntosh E. The cost of rheumatoid arthritis. Br J Rheumatol. 1996 Aug;35(8):781-90. doi: 10.1093/rheumatology/35.8.781.
- Maksymowych WP. Biomarkers in axial spondyloarthritis. Curr Opin Rheumatol. 2015 Jul;27(4):343-8. doi: 10.1097/BOR.0000000000000180.
- Maksymowych WP, Dougados M, van der Heijde D, Sieper J, Braun J, Citera G, Van den Bosch F, Logeart I, Wajdula J, Jones H, Marshall L, Bonin R, Pedersen R, Vlahos B, Kotak S, Bukowski JF. Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study. Ann Rheum Dis. 2016 Jul;75(7):1328-35. doi: 10.1136/annrheumdis-2015-207596. Epub 2015 Aug 12.
- Mounach A, El Maghraoui A. Efficacy and safety of adalimumab in ankylosing spondylitis. Open Access Rheumatol. 2014 Aug 13;6:83-90. doi: 10.2147/OARRR.S44550. eCollection 2014.
- Pham T, van der Heijde D, Calin A, Khan MA, van der Linden S, Bellamy N, Dougados M; ASAS Working Group. Initiation of biological agents in patients with ankylosing spondylitis: results of a Delphi study by the ASAS Group. Ann Rheum Dis. 2003 Sep;62(9):812-6. doi: 10.1136/ard.62.9.812.
- Trocme C, Gaudin P, Berthier S, Barro C, Zaoui P, Morel F. Human B lymphocytes synthesize the 92-kDa gelatinase, matrix metalloproteinase-9. J Biol Chem. 1998 Aug 7;273(32):20677-84. doi: 10.1074/jbc.273.32.20677.
- Van Den Bosch F, Kruithof E, Baeten D, Herssens A, de Keyser F, Mielants H, Veys EM. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondylarthropathy. Arthritis Rheum. 2002 Mar;46(3):755-65. doi: 10.1002/art.511.
- Wendling D, Claudepierre P, Lohse A, Toussirot E, Breban M. [Therapeutic use of anti-TNF-alpha agents in spondyloarthropathies]. Presse Med. 2003 Oct 4;32(32):1517-24. French.
- Yelin E, Wanke LA. An assessment of the annual and long-term direct costs of rheumatoid arthritis: the impact of poor function and functional decline. Arthritis Rheum. 1999 Jun;42(6):1209-18. doi: 10.1002/1529-0131(199906)42:63.0.CO;2-M.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 38RC17.378
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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