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A ntibiotics I n M odic changes; The AIM-study

Antibiotic treatment in patients with chronic low back pain and Modic Changes a randomized controlled trial. A ntibiotics I n M odic changes; The AIM-study. Kjersti Storheim, OUS Ullevål And the Norwegian AIM study group. Background.

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A ntibiotics I n M odic changes; The AIM-study

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  1. Antibiotic treatment in patients with chronic low back pain and Modic Changesa randomized controlled trial Antibiotics In Modic changes; The AIM-study • Kjersti Storheim, OUS Ullevål • And the Norwegian AIM study group

  2. Background • Low back pain (LBP) is the number one cause for living with disability globally • Huge expenses • Most patients are viewed within a biopsychosocial model and are not given a patho-anatomical diagnosis • Treatment effects for non-specific LBP are in general small – moderate

  3. Background • Albert et al treated a sub-group of chronic LBP patients with a supposed biomedical source of LBP (Modic Changes) with Amoxicillin for 100 days • The effect was substantially greater than all currently established treatments for chronic LBP • RMDQ during study (range 0-23): baseline, 100 days, 1 year • antibiotic 15, 11, 5.7 • placebo 15, 14, 14 • Leg pain during study (range 0 -10): baseline, 100 days, 1 y • antibiotics 5.3, 3.0, 1.4 • placebo 4.0, 4.3, 4.3 • Lumbar pain during s (range 0 – 10): baseline, 100 days, 1 y • antibiotics 6.7, 5.0, 3.7 • placebo 6.3, 6.3, 6.3

  4. Background • The Danish study may be a potentially important breakthrough in the understanding and management of LBP • Evoked parallels to the discoveries that a chronicHelicobacter pylori infection of the stomach lining causes 80 - 90 % of ulcers

  5. Type 1: Ødem Type 2: Fettomdanning Type 3: Sclerose Modic Changes (MCs) • Visible on MRI-scans only • Classified into type I, II and III • Frequent finding in patients with LBP • Sign risk factor for LBP (Jensen et al 2012, Määttä et al 2015) • The aetiology and pathogenesis is unclear • Mechanical? (the forces acting within the disc)inflammatory reaction • Nucleus tissue entering the vertebrae cause an autoimmune reaction? • MCs occur due to edema surrounding an infected disc? • infection with low virulent anaerobic organisms, mainly the propionibacterium acnes (P.acnes) is found in biopsies from nucleus material • i.e. the infection is in the disc and the MC is a secondary change in the bone due to cytokine and propionic acid production The hypothesis of the Danish study MCs can be treated by antibiotic

  6. Criticism….. • The prevalence of MCs is high • 40-50% in LBP patients • 10-20% in normal populations: • Kjær 2005, Jensen 2009, Jensen 2009, Mättää et al 2015 • Use of antibiotics in a large patient group… • Can cause risky antibiotic side effects in individuals • May spread antibiotic resistance Jensen et al 2008

  7. Criticism…. • The MRI-based selection of patients for antibiotic treatment is not without problems • The type of MCs (especially type I vs. II) has been used to guide on treatment • Albert et al included only patients with type I MCs • low field 0.2 T • The differentiation between type I and II may be less relevant, since the different types of MCs may represent different stages of a common process • Also, there are important challenges when evaluating Modic type • Different observers may report up to twofold different prevalence of MCs (any type) at a specific endplate (e.g. 25% vs. 50%)

  8. Betydning av magnetfeltstyrke • Signalet fra fett og vann avhenger av feltstyrken • Høyt magnetfelt gir kraftigere signal, men også mer artefakter. • T1 og T2 egenskapene er også feltavhengige • Modic type 1 var 3 x hyppigere ved lav feltstyrke • Modic type 3 var 2 x hyppigere ved høy feltstyrke Bendix et al 2012

  9. Criticism….. • It is not clear how nucleus pulposus and/or “infection fluids” leak into the endplates and become manifested as MCs in the bone • Biological material analysed for bacteria is harvested from patients having surgery • we cannot rule out that the bacteria found in the nuclear material may be due to intraoperative contamination rather than infection

  10. No change in the Placebo group • RMDQ : • antibiotic 15, 11, 5.7 • placebo 15, 14, 14 • Leg pain : • antibiotics 5.3, 3.0, 1.4 • placebo 4.0, 4.3, 4.3 • Lumbar pain : • antibiotics 6.7, 5.0, 3.7 • placebo 6.3, 6.3, 6.3

  11. Hence…. • A new RCT should be performed to prevent inappropriate use of antibiotics in a large group of patients based on a single trial.

  12. Aims • The overall aim of the present study is to re-examine the finding that antibiotic treatment can cure patients with chronic LBP and MCs • Further, to add important new knowledge to the research field beyond the Danish RCT • broadening the inclusion criteria to include both patients • with type I and type II MCs • by improving the MRI assessment of MCs • contribute to a clarification of the pathogenesis of MCs by studying gene expression of inflammatory biomarkers • to conduct health economic analysis • to study effect-modifying factors

  13. Methods • Placebo-controlled RCT • Multicenter UNN St.Olavs Hospital Haukeland University Hospital Oslo University Hospital Drammen Hospital Østfold Hospital

  14. Prosjektets organisering Benedicte A Lid Ansgar Espeland PI’s UNN Audny Anke St.Olav Øystein Nygaard HUS Jan Sture Skouen Drammen Anne Froholdt Østfold Lars Grøvle OUS Jens Ivar Brox

  15. Elektronisk datainnsamling

  16. Participating hospitals • OUS Ullevål • Coordinating investigator: John-Anker Zwart • Project managing: Kjersti Storheim • Local (and national) coordinating: Monica Wigemyr (Linda M Pedersen: blood /epigenetics) • Principal Investigator (PI): Jens Ivar Brox (Elina Schistad / Lars CH Bråten / Mads Rolfsen / Bendik Winsvold) • Haukeland US • MR-imaging (Ansgar Espeland / Nils Vetti / Per M Kristoffersen) • Infection medicine (Olav Lutro) / statistician (Jörg Aßmus) • PI: Jan Sture Skouen (Thomas Kadar / Pål Christian Haugland / Tonje Wåle Flørenes / Siv K Claussen)

  17. Participating hospitals (cont) • Drammen hospital • PI: Anne Froholdt (Sigrun Randen / Hilde Presberg) • St.Olavs Hospital • PI: Øystein Nygaard (Gunn Hege Marchand / Vidar Rao / Britt-Elin Lurud / Fredrik Granviken / Hege Andresen) • Sykehuset Østfold • PI: Lars Grøvle (Anne J Haugen / Knut Morten Huneide / Marianne Thorsø / Veronica Sørensen) • Universitetssykehuset Nord-Norge (UNN) • PI: Audny Anke (Terese Fors / Daniel Svendsen / Ingrid Knutsen

  18. Stipendiater • Kliniske problemstillinger • Lars Christian Haugli Bråten (OUS Ullevål) • Kjersti Storheim (hovedveileder) • Radiologiske problemstillinger • Per Martin Kristoffersen (Haukeland) • Ansgar Espeland (hovedveileder) • Epigenetikk / biomolekylært • Maria Dehli Vigeland (OUS Ullevål / UiO) • Benedicte A Lie (hovedveileder) • Biopsier / histologi • Mads Peder Rolfsen (OUS Ullevål) • Christian Hellum (hovedveileder)

  19. Case-control studie: biopsier • Case-control design • Prøver både av ”sykt” og friskt vev • Skivevev • Bein • Radiologi, blodprøver og epigenetikk som i RCT-studien • Svært viktig supplement til RCT’en • Finner vi anaerobe bakterier i skivevev / benvev?

  20. Sikkerhetskomité (DMC) • Lege: Morten Lindbæk • leder Antibiotikasenteret for primærmedisin (ASP). • ASP ble opprettet i 2006 etter initiativ fra Folkehelseinstituttets komité for forebygging og bekjempelse av antibiotikaresistens (Antibiotikakomitéen). • professor ved institutt for allmennmedisin, HELSAM. • Etiker: Lisbeth Thoresen • Avdeling for medisinsk etikk, UiO • Statistiker: Are Hugo Pripp • Avdeling for biostatistikk, epidemiologi og helseøkonomi • Oslo universitetssykehus

  21. Strata for Modic type I / II Tidligere discoperert: JA / NEI

  22. Study interventions • Antibiotic treatment: • Amoxicillin 750 mgx3 for 100 days • Versus placebo • x3 for 100 days Tilvirkes av Kragerø Tablettproduksjon

  23. Target population • Patients from all health regions • Former disc herniation, now MC • Both conservatively and surgically treated patients will be included • If operated on for disc herniation, at least 12 months should have elapsed since surgery • Patients registered in the Norwegian Registry for Spine Surgery operated on for disc herniation and reporting severe LBP pain at 12 months follow-up in the registry, will also be invited.

  24. Inclusion criteria • Aged between 18 and 65 years • LBP of > 6 months duration in the area below the 12th rib and above the gluteal folds with a Numerical Rating Scale (NRS) pain intensity score of  5 • mean of three NRS scales; current LBP, the worst LBP within the last 2 weeks, and usual/mean LBP within the last 2 weeks. • MRI-confirmed lumbar disc herniation within the preceding 2 years • MC type I and/or type II in the vertebral body marrow at the same level as the previously herniated disc. • For patients with former surgery for disc herniation, the MC has to be located at an operated level • Written informed consent

  25. Exclusion criteria • Allergy to penicillin or cefalosporins • Allergy/hypersensitivity to any of the excipients of the study drug • Current pregnancy or lactation • Elevated kidney (creatinine) or hepatic (ALAT/ASAT) values outside normal range • Phenylketonuria (Følling disease) • Mononucleosis or leukaemia • Any specific diagnosis that may explain patient’s low back symptoms (e.g. tumor, fracture, spondyloarthritis, infection, spinal stenosis). • Former low back surgery (L1 – S1) for other reasons than disc herniation (e.g fusion, decompression, disc prosthesis).

  26. Exclusion criteria (cont) • Former surgery for disc herniation, but < 12 months have elapsed since surgery. • Former surgery for disc herniation, but MC located at non-operated level(s) only. • Reservation against intake of gelatine (the capsules contains gelatine, which among other things is produced by ingredients from pigs) • Regular use of glucocorticoids • Regular use of opioids with the exception of codeine and tramadol • Not understanding Norwegian language • Unlikely to adhere to treatment and/ or complete follow-up (e.g ongoing serious psychiatric disease, drug abuse, plans to move) • Antibiotic treatment within the preceding one month before treatment start • Contraindications to MRI (e.g. cardiac pacemaker electrodes, metal implant in eye or brain, claustrophobia). • Unwilling to participate

  27. Outcome measures • Primary outcome • Roland Morris Disability Questionnaire • Secondary outcomes • Lumbar pain and leg pain measured by NRSs • Bothersomeness • Health-related quality of life (EuroQoL-5D) • Days with sick leave • Patient’s satisfaction • Radiological outcomes • Gene expression • Cost-effectiveness • Data will be collected at baseline, during treatment, post-treatment, during follow-up and at 1-year follow-up Baseline variabler: Demografi, etnisitet, subjektive helseplager, distress, fear-avoidance, smertetegning, forventning til effekt Blindingsindex: 100 dager, 1 år Main endpoint

  28. Compliance to the medicine protocol, side-effects, and co-interventions (other pharmaco-logical treatment and non-pharmacological treatment) will also be registered • Safety: • Haematological blood samples, as well as kidney and liver function, will be assessed monthly during the intervention period, together with a short clinical evaluation (for monitoring patients clinical status related to antibiotic intake, not outcome measures).

  29. Tidslinje Behandling slutt = dag 100 Follow-up slutt 1 år etter beh.start Inklusjon = dag 0 Klinisk ktr Dag 33 Klinisk ktr Dag 66 Screening Ny MR Behandlingsperiode Alle som tilfredsstiller alle inkl/ekskl krit og som henvises til nytt MR: MR-studier Ukentlig: Smertemonitorering og Compliance Månedlig helseøkonomi

  30. Når kommer resultatene? • Ca 80 vurdert • 33 startet behandlingen • 14 inkluderbare • Ca 10 henvist til MR etter studieprotokoll • 2 års inklusjonsperiode? • 1-års follow-up

  31. Takk til Penger Egeninnsats

  32. Trial Flow chart

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