Antibiotic treatment In patients with chronic low back pain and Modic changes (the AIM study): study protocol for a randomised controlled trial

Kjersti Storheim, Ansgar Espeland, Lars Grøvle, Jan Sture Skouen, Jörg Aßmus, Audny Anke, Anne Froholdt, Linda M Pedersen, Anne Julsrud Haugen, Terese Fors, Elina Schistad, Olav Lutro, Gunn Hege Marchand, Thomas Kadar, Nils Vetti, Sigrun Randen, Øystein Petter Nygaard, Jens Ivar Brox, Margreth Grotle, John-Anker Zwart, Kjersti Storheim, Ansgar Espeland, Lars Grøvle, Jan Sture Skouen, Jörg Aßmus, Audny Anke, Anne Froholdt, Linda M Pedersen, Anne Julsrud Haugen, Terese Fors, Elina Schistad, Olav Lutro, Gunn Hege Marchand, Thomas Kadar, Nils Vetti, Sigrun Randen, Øystein Petter Nygaard, Jens Ivar Brox, Margreth Grotle, John-Anker Zwart

Abstract

Background: A previous randomised controlled trial (RCT) of patients with chronic low back pain (LBP) and vertebral bone marrow (Modic) changes (MCs) on magnetic resonance imaging (MRI), reported that a 3-month, high-dose course of antibiotics had a better effect than placebo at 12 months' follow-up. The present study examines the effects of antibiotic treatment in chronic LBP patients with MCs at the level of a lumbar disc herniation, similar to the previous study. It also aims to assess the cost-effectiveness of the treatment, refine the MRI assessment of MCs, and further evaluate the impact of the treatment and the pathogenesis of MCs by studying genetic variability and the gene and protein expression of inflammatory biomarkers.

Methods/design: A double-blinded RCT is conducted at six hospitals in Norway, comparing orally administered amoxicillin 750 mg, or placebo three times a day, over a period of 100 days in patients with chronic LBP and type I or II MCs at the level of a MRI-confirmed lumbar disc herniation within the preceding 2 years. The inclusion will be stopped when at least 80 patients are included in each of the two MC type groups. In each MC type group, the study is designed to detect (β = 0.1, α = 0.05) a mean difference of 4 (standard deviation 5) in the Roland Morris Disability Questionnaire score between the two treatment groups (amoxicillin or placebo) at 1-year follow-up. The study includes cost-effectiveness measures. Blood samples are assessed for security measures and for possible inflammatory mediators and biomarkers at different time points. MCs are evaluated on MRI at baseline and after 12 months. A blinded intention-to-treat analysis of treatment effects will be performed in the total sample and in each MC type group.

Discussion: To ensure the appropriate use of antibiotic treatment, its effect in chronic LBP patients with MCs should be re-assessed. This study will investigate the effects and cost-effectiveness of amoxicillin in patients with chronic LBP and MCs at the level of a disc herniation. The study may also help to refine imaging and characterise the biomarkers of MCs.

Trial registration: ClinicalTrials.gov, ID: NCT02323412 . Registered on 21 November 2014.

Keywords: Antibiotics; Chronic low back pain; Modic change; Randomised controlled trial.

Conflict of interest statement

Authors’ information

Not applicable.

Ethics approval and consent to participate

Ethical approval embracing all six participating hospitals has been obtained from The Regional Committees for Medical Research Ethics in Norway (REC South East, reference number 2014-2029) and the Norwegian Medicines Agency (SLV, reference number 14/01368-11, EudraCT Number: 2013-004505-14). The trial was registered at ClinicalTrials.gov (NCT02323412) prior to starting recruitment. Patients are being informed about the risks and possible benefits of the study. The participation in this study is voluntary. Written informed consent is being obtained from all patients.

Consent for publication

All participants consent to the publication of results, given adequate anonymisation. All data will be analysed with respect for confidentiality. This information is included in the written informed consent.

Competing interests

None of the authors have any competing interests to declare.

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Figures

Fig. 1
Fig. 1
Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) flow chart. Magnetic resonance imaging (MRI). (1) Baseline MRI according to the study protocol can be a maximum of 4 weeks old when treatment starts. A follow-up MRI is taken between 12 and 13 months after treatment start (i.e., 12 to 14 months after baseline MRI); (2) For safety: haematological parameters (leucocytes, thrombocytes, eosinophils, haemoglobin (Hb) and hematocrit (Ht)) and measures of kidney (creatinine) and liver function (ASAT/ALAT), every month or more frequently if clinically indicated. For scientific purposes: glucose, white cell counts and C-reactive protein (CRP) for further safety monitoring and evaluation of inflammatory mechanisms and genetics/epigenetics; (3) Blood pressure, pulse, auscultation of heart and lungs (safety); (4) Age, gender, Body Mass Index (BMI), ethnicity, marital status, educational level, work status, physical work load, leisure time activity, smoking habits, subjective health complaints, emotional distress, fear-avoidance beliefs, low back pain (LBP) history/duration (including previous treatment, e.g., surgery for disc herniation, physiotherapy, chiropractic), expectations about treatment effect, pain drawing; (5) Pain provocation tests (springing test, active flexion/extension of the lumbar spine) and neurological tests (muscle strength, toe-heel walking, sensibility, reflexes, straight-leg raising, i.e., Lasegue test/reverse Lasegue test); (6) Roland Morris Disability Questionnaire, also collected 6 and 9 months after start of treatment; (7) Pain monitoring (LBP intensity) weekly during treatment period, and at 6 and 9 months after start of treatment; (8) Oswestry Disability Index, leg pain, hours with low back pain during the last 4 weeks, symptom-specific well-being, health-related quality of life, sick leave, short tau inversion recovery (STIR) signal of Modic changes; (9) Patient’s satisfaction with treatment (5-point Likert scale) and global perceived effect (7-point Likert scale); (10) Patients are asked to report which study medicine they think they received (antibiotics/placebo/unsure); (11) Co-interventions (concomitant medication and non-pharmacological treatments) and sick-listing is monitored monthly also during the follow-up period (100 to 365 days) for health-economical calculations; (12) Embraces patients from two participating hospitals. At day 0, faeces are collected before the first tablet is administered; (13) Containers and capsules delivered to local ‘Sykehusapotek’ at each participating hospital for return capsule count, registering of accountability in electronic systems and destruction of the returned study drug

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