Clinical trial NCT03883568: A 2-year, European Multicentre Study to Describe, Validate, and Predict Phenotypes of Knee Osteoarthritis
Official title: A 2-year Multicentre, EU, Exploratory Study Without Therapeutic Benefit in Patients With Knee Osteoarthritis to Describe, Validate, and Predict Phenotypes of Knee Osteoarthritis by Use of Clinical, Imaging, and Biochemical (Bio)Markers.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Knee Osteoarthritis
Keywords: phenotypes
(bio)markers
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
name: Nordic Bioscience A/S
name: University of Surrey
name: Leiden University Medical Center
name: Complexo Hospitalario Universitario de A Coruña
name: Institut de Recherches Internationales Servier
name: Newcastle University
name: Merck KGaA, Darmstadt, Germany
name: Diakonhjemmet Hospital
name: Assistance Publique - Hôpitaux de Paris
First posted: 2019-03-21
Enrollment: 297
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with tibiofemoral knee osteoarthritis, according to the clinical ACR classification criteria, pre-identified based on demographic (e.g. age), clinical (e.g. Pain NRS) and tissue structure (e.g. radiographic joint space width) parameters.

Brief summary: Rationale: Despite a large and growing disease burden in osteoarthritis (OA), many pharmaceutical companies have abandoned OA drug development. This is mainly due to the lack of appropriate outcome measures that can robustly identify patients that can benefit from a specific therapy. Different phenotypes of OA may benefit from different types of treatment. Therefore, novel markers to identify selected phenotypes of osteoarthritis may encourage drug development.

Objective: To prospectively describe in detail pre-identified progressing phenotypes of patients with knee OA by use of conventional and novel clinical, imaging, and biochemical (bio)markers, and to validate and refine a predictive model for these (and new) progressing phenotypes based on these markers.

Study design: APPROACH is an exploratory, European, five-centre, 2-year prospective follow-up, cohort study, with extensive measurements. In this study patients are treated according to regular care by their own physician with no study related treatment prescribed. Study related diagnostic and/or monitoring procedures are applied to the patients.

Study population: Patients with tibiofemoral knee osteoarthritis, according to the clinical ACR classification criteria, pre-identified based on demographic (e.g. age), clinical (e.g. Pain NRS) and tissue structure (e.g. radiographic joint space width) parameters.

Main study parameters/endpoints: Joint tissue structure based on radiographs, MRI, and biochemical (bio)markers as well as symptoms (pain, function) and quality of life by questionnaires.

Secondary parameters: A multitude of (novel and conventional) clinical, imaging, and biochemical parameters related to osteoarthritis.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The participants will not have any direct benefit from their participation in this study other than that their OA is maximally diagnosed and followed in detail for up to 2 years (screening, baseline, 6 months, 12 months, 24 months).

Detailed description: Patients will stay in the hospital for 4-5 hours per visit (for screening about 30 min) for physical examination, blood draw, MRI scans, radiographs of knees and hands (only at baseline and 24 months), CT scan of the knee (only at baseline and 24 months), low radiation whole body CT scan (only at baseline and 24 months), HandScan (only at baseline and 24 months), motion analysis, and performance based tests. They will be asked to fill out questionnaires about knee, hand and hip osteoarthritis, and about general health and pain. The patient council in the consortium indicated that the load is acceptable. The patient council will be involved in the execution of the study. The assumed risk is minimal for an individual patient and minimal compared to the contribution to the development of knowledge of their disease. These risks include minimal events due to blood sampling itself (such as hematoma or localized bleeding), radiation exposure by radiographic imaging techniques (with a minimal increased healthcare risk), and exposure to MRI techniques (without known risks and without use of contrast agents).

Eligibility criteria: Inclusion Criteria:

1. Informed consent obtained.
2. Ambulatory (able to walk unassisted)
3. At least 18 years of age
4. Capable of understanding the study
5. Capable of writing and reading in local language
6. Predominantly tibiofemoral knee osteoarthritis and satisfy the clinical classification criteria of the American College of Rheumatology (ACR): Knee pain and three of the following criteria: over 50 years age, less than 30 minutes of morning stiffness, crepitus on active motion, bony tenderness, bony enlargement, or no palpable warmth.
7. Highest probability to progress based on the algorithm based on the following parameters:

   * Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire
   * BMI (in recording height and weight)
   * Pain NRS of the index knee at the moment of the screening visit
   * Pain NRS of the index knee during the last week before the screening visit
   * Age
   * Gender
   * KIDA parameters of the index knee, based on standardized weight-bearing (KIDA) radiograph, measured \< 3 months (patients with a Joint Space Width (JSW) \< 2 mm of the index knee will not be included)

   Exclusion Criteria:
8. Not being able to comply to the protocol
9. Participating in a trial with local therapeutic intervention for index knee OA (pharmaceutical or surgical) or systemic Disease Modifying OsteoArthritic Drugs (DMOADs) or potential DMOADs treatments for OA at the same time or within the past 6 months or anticipated in the forthcoming; participation in non-interventional registries or epidemiological studies is allowed.
10. Surgery of the index knee in the past 6 months (to avoid interferences with imaging)
11. Scheduled or expected surgery of the index knee in the next 2 years (to avoid interferences with imaging)
12. Pregnancy (child bearing woman) because of imaging (radiation and MRI, risks)
13. Predominantly patellar femoral knee OA (clinical judgment)
14. The following secondary osteoarthritis of the knee: clinically significant deformities of the lower limbs (varus \>10°, valgus \>10°), septic arthritis, inflammatory joint disease, gout, major chondrocalcinosis (pseudogout), Paget's disease of the bone, ochronosis, acromegaly, haemochromatosis, Wilson's disease, rheumatic symptoms due to malignancies, primary osteochondromatosis, osteonecrosis, osteochondritis dissecans, haemophilia
15. Generalized pain syndrome, for example fibromyalgia
16. Patients with contra indication to MRI or CT
17. Hip replacement or expected hip replacement within 6 months
18. Osteosynthesis material near the knee joint
19. Self-reported severe Intervertebral disc (IVD) degeneration or facet OA

Primary outcomes:
measure: OA structural progression of the index knee
timeFrame: over two years
measure: OA pain progression of the index knee
timeFrame: over two years
Secondary outcomes:
measure: OA progression of the index knee
timeFrame: over two years
measure: OA progression
timeFrame: over two years
Other outcomes:
Locations:
city: Paris
country: France
facility: Saint-Antoine hospital, AP-HP
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Oslo
country: Norway
facility: Diakonhjemmet hospital
city: A Coruña
country: Spain
facility: SERGAS
Study officials:
affiliation: UMC Utrecht
name: Floris PJ Lafeber, PhD
role: STUDY_DIRECTOR
References:
citation: Roemer FW, Jansen M, Marijnissen ACA, Guermazi A, Heiss R, Maschek S, Lalande A, Blanco FJ, Berenbaum F, van de Stadt LA, Kloppenburg M, Haugen IK, Ladel CH, Bacardit J, Wisser A, Eckstein F, Lafeber FPJG, Weinans HH, Wirth W. Structural tissue damage and 24-month progression of semi-quantitative MRI biomarkers of knee osteoarthritis in the IMI-APPROACH cohort. BMC Musculoskelet Disord. 2022 Nov 17;23(1):988. doi: 10.1186/s12891-022-05926-1.
citation: Wirth W, Maschek S, Marijnissen ACA, Lalande A, Blanco FJ, Berenbaum F, van de Stadt LA, Kloppenburg M, Haugen IK, Ladel CH, Bacardit J, Wisser A, Eckstein F, Roemer FW, Lafeber FPJG, Weinans HH, Jansen M. Test-retest precision and longitudinal cartilage thickness loss in the IMI-APPROACH cohort. Osteoarthritis Cartilage. 2023 Feb;31(2):238-248. doi: 10.1016/j.joca.2022.10.015. Epub 2022 Nov 3.
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citation: Angelini F, Widera P, Mobasheri A, Blair J, Struglics A, Uebelhoer M, Henrotin Y, Marijnissen AC, Kloppenburg M, Blanco FJ, Haugen IK, Berenbaum F, Ladel C, Larkin J, Bay-Jensen AC, Bacardit J. Osteoarthritis endotype discovery via clustering of biochemical marker data. Ann Rheum Dis. 2022 May;81(5):666-675. doi: 10.1136/annrheumdis-2021-221763. Epub 2022 Mar 4.
citation: van Helvoort EM, Welsing PMJ, Jansen MP, Gielis WP, Loef M, Kloppenburg M, Blanco F, Haugen IK, Berenbaum F, Bay-Jensen AC, Ladel C, Lalande A, Larkin J, Loughlin J, Mobasheri A, Weinans H, Lafeber F, Eijkelkamp N, Mastbergen S. Neuropathic pain in the IMI-APPROACH knee osteoarthritis cohort: prevalence and phenotyping. RMD Open. 2021 Dec;7(3):e002025. doi: 10.1136/rmdopen-2021-002025.
citation: Taylor J, Dekker S, Jurg D, Skandsen J, Grossman M, Marijnissen AK, Ladel C, Mobasheri A, Larkin J, Weinans H, Kanter-Schlifke I; APPROACH research consortium and APPROACH Principal Investigators. Making the patient voice heard in a research consortium: experiences from an EU project (IMI-APPROACH). Res Involv Engagem. 2021 May 10;7(1):24. doi: 10.1186/s40900-021-00267-0.
citation: van Helvoort EM, van Spil WE, Jansen MP, Welsing PMJ, Kloppenburg M, Loef M, Blanco FJ, Haugen IK, Berenbaum F, Bacardit J, Ladel CH, Loughlin J, Bay-Jensen AC, Mobasheri A, Larkin J, Boere J, Weinans HH, Lalande A, Marijnissen ACA, Lafeber FPJG. Cohort profile: The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) study: a 2-year, European, cohort study to describe, validate and predict phenotypes of osteoarthritis using clinical, imaging and biochemical markers. BMJ Open. 2020 Jul 28;10(7):e035101. doi: 10.1136/bmjopen-2019-035101.