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Antibiotics In Modic Changes (AIM)

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ClinicalTrials.gov Identifier: NCT02323412
Recruitment Status : Completed
First Posted : December 23, 2014
Last Update Posted : November 14, 2018
Sponsor:
Collaborators:
Haukeland University Hospital
St. Olavs Hospital
University Hospital of North Norway
Drammen sykehus
Sykehuset Ostfold
Information provided by (Responsible Party):
Kjersti Storheim, Oslo University Hospital

Brief Summary:
Low-back pain (LBP) is the single leading cause for disability worldwide, affects all age groups and has increased from 58 million years lived with disability (YLDs) in 1990 to 83 million YLDs in 2010. The burden is accordingly substantially higher than previously assessed, causing activity limitation and work absence with subsequently enormous economic burden. Norwegian expenses reach at least NOK 24 billions annually whereof a substantial part is hospital costs. The research project responds to this challenge and aim to conduct a multicenter randomized placebo-controlled trial, complemented by a study of epigenetic and molecular biomarkers, to re-examine the finding of a recent randomized controlled trial that antibiotic treatment can cure patients with chronic low back pain (LBP), a former disc herniation and present Modic Changes (MCs). The hypothesis is that MCs is caused by low virulent anaerobic organisms in the disc. Investigators also want to add important new knowledge to the research field beyond the only former RCT by broadening the inclusion criteria to include both patients with type I and type II MCs, improving the MRI assessment of MCs, further clarifying the pathogenesis of MCs by studying genetic variability, gene and protein expression of inflammatory biomarkers, and conducting health economic analysis.

Condition or disease Intervention/treatment Phase
Low Back Pain Modic Changes Type I or II Seen on MRI Drug: Amoxicillin (Amoksicillintrihydrat) Drug: Placebo Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Antibiotic Treatment in Patients With Chronic Low Back Pain and Modic Changes: a Randomized Double-blind Placebo Controlled Trial
Actual Study Start Date : June 2015
Actual Primary Completion Date : September 21, 2018
Actual Study Completion Date : November 6, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Amoxicillin
Amoxicillin (Amoksicillintrihydrat) tablets 750 mg 1x3 for 100 days (oral intake). The tablets will be encapsulated in Capsugel DB-caps AAel Swedish orange.
Drug: Amoxicillin (Amoksicillintrihydrat)
Amoxicillin tablets 750 mg 1x3 for 100 days (oral intake).
Other Name: Amimox "Meda"

Placebo Comparator: Placebo
Placebo capsules for 100 days of daily (1x3), oral intake. The placebo tablets will also be encapsulated in Capsugel DB-caps AAel Swedish orange.
Drug: Placebo
Placebo tablets 1x3 for 100 days (oral intake).




Primary Outcome Measures :
  1. Roland Morris Disability Questionnaire [ Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), 6, 9 and 12 months after start of treatment. ]
    Self-reported disease-specific disability evaluated by the Roland Morris Disability Questionnaire (RMDQ, scale 0-24, Norwegian translation) from baseline to one year (12 months) follow-up in patients with chronic LBP and MCs type I or II adjacent to a previously herniated disc. The effect will be evaluated in the whole sample (hypothesis A) and in MC type I and II sub-groups (hypothesis B and C). RMDQ will also be evaluated from baseline to post-treatment and used in health economic analysis and in relation to MRI. Primary endpoint of the study is change in RMDQ from baseline to one year (12 months) after start of intervention.


Secondary Outcome Measures :
  1. Oswestry Disability Index [ Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment. ]
    Disease-specific disability (Oswestry Disability Index; ODI, version 2.0, the Norwegian translation). Scale range 0-100.

  2. Lumbar pain [ Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), 6, 9 and 12 months after start of treatment, and weekly during the treatment period. ]
    Numeric Rating Scale (NRS: 0-10); mean of three NRS scales; current LBP, the worst LBP within the last 2 weeks, and usual/mean LBP within the last 2 weeks (at baseline, post-treatment and at one year after start of treatment). Will also be monitored weekly during the intervention period, and the the wording "last 2 weeks" will then be replaced by "the last week".

  3. Health-related quality of life [ Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment. ]
    EuroQoL-5D-5L (version 2.0) (will also be used for health-economic analysis).

  4. STIR signal on MRI [ Time Frame: Evaluated 6-2 weeks before start of intervention and 12-13 months after start of treatment. ]
    Short tau inversion recovery (STIR) signal (intensity and extent) of Modic Changes on 1.5 Tesla MRI scanner. Of practical reasons; the follow-up MRI is taken between 12 and 13 months after treatment start (i.e. 12 to 14 months after baseline MRI).

  5. Leg pain [ Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment. ]
    Numeric Rating Scale (NRS: 0-10); leg pain last week.

  6. Number of hours with low back pain during the last 4 weeks [ Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment. ]
    Number of days during the last 28 days (4 weeks) the participant had experienced LBP (0-28 days), and, on an typical day, how many of the hours awake they experienced LBP (0-16 h). The number of days and hours are multiplied (a 0-448 scale).

  7. Global perceived effect [ Time Frame: Evaluated post-treatment (100 days after start of intervention), and 12 months after start of treatment. ]
    7-point Likert scale; The patients compare their baseline status with their status at one-year follow-up and post-treatment.

  8. Patient's satisfaction [ Time Frame: Evaluated post-treatment (100 days after start of intervention), and 12 months after start of treatment. ]
    5-point Likert scale; patients rate satisfaction with treatment / care at one-year follow-up and post-treatment.

  9. Days with sick leave [ Time Frame: Evaluated monthly during the whole 12-months study period. ]
    Self-reported by patients; how many days patients were on sick-leave last month (if patients are sick listed; degree / % sick listed will also be registered). Will be registered at baseline and monthly during the whole one-year study period

  10. Longitudinal changes in gene (RNA) and protein expression [ Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment. ]
    Total RNA will be isolated from whole blood samples using Tempus Spin RNA Isolation Kits (Applied Biosystems) and changes in gene expression will be assessed using reverse transcriptase quantitative real-time PCR (RT-qPCR). Protein expression in serum will be examined by enzyme-linked immunosorbent assay (ELISA). Investigators will also examine epigenetic patterns by investigating methylation alterations from before to after antibiotic treatment. In addition, investigators will also study genetic variations. Genomic DNA will be isolated from whole blood samples and genotyped by TaqMan methodology. Will be registered at baseline, monthly during the intervention period, and at one-year follow-up.


Other Outcome Measures:
  1. Symptom-specific well-being [ Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment. ]
    A core item from the Core Item Measures Index (COMI) for low back pain (5 point Lickert scale), 1 = very satisfied, 5 = very dissatisfied

  2. Work status [ Time Frame: Evaluated monthly during the whole 12-months study period. ]
    The following alternatives will be registered: On sick leave (if yes; % sick listed), Rehabilitation, Disability pension, Homemaker, Unemployed, Student. Will be registered at baseline and monthly during the whole one-year study period.

  3. Co-interventions [ Time Frame: Evaluated monthly during the whole 12-months study period. ]
    Other pharmacological treatments (ATC-coded by principal investigator during intervention period, self-reported by patients during follow-up) and on-pharmacological treatments (number of visits to a general practitioner, physical or manual therapist, medical specialist, social worker, and alternative therapist, number of days of hospitalization and/or rehabilitation). Will be registered at baseline and monthly during the whole study period.

  4. Constant pain [ Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment. ]
    Patients will be asked if their low back pain is constant, or vary during the day (respond categories: the low back pain is constant / the low back pain vary during the day)

  5. Adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: At all visits (0,1,2,3 and 12 months) ]
    We will report the incidence of adverse events (AEs) and serious adverse events (SAEs) from inclusion to 1-year follow-up in the two intervention groups in the safety population, according to Consort guidelines on reporting of harms in randomized trials. Adverse events are recorded from baseline to 1-year follow-up and will be coded at all follow-up times (0,1,2,3 and 12 months) using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 in accordance with medDRA-coding.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Patients from all health regions in Norway referred to the participating hospitals will be screened for eligibility. Both conservatively and surgically treated patients (i.e. operated on for disc herniation > 12 months prior to inclusion) will be included. In addition, patients registered in the Norwegian Registry for Spine Surgery operated on for disc herniation and reporting severe LBP pain at one-year follow-up in the registry, will be invited.

Inclusion Criteria

  • Age 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 ³ 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

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).
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02323412


Locations
Norway
Oslo University Hospital Ullevål
Oslo, Norway, 0407
Sponsors and Collaborators
Oslo University Hospital
Haukeland University Hospital
St. Olavs Hospital
University Hospital of North Norway
Drammen sykehus
Sykehuset Ostfold
Investigators
Study Chair: Kjersti Storheim, PhD Oslo University Hospital
  Study Documents (Full-Text)

Documents provided by Kjersti Storheim, Oslo University Hospital:
Statistical Analysis Plan  [PDF] November 1, 2018


Publications:
Responsible Party: Kjersti Storheim, Head of section, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT02323412     History of Changes
Other Study ID Numbers: 2014/12701
First Posted: December 23, 2014    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018

Keywords provided by Kjersti Storheim, Oslo University Hospital:
Low back pain
Chronic
Modic Changes
MRI
epigenetics
antibiotics
randomized placebo controlled trial

Additional relevant MeSH terms:
Back Pain
Low Back Pain
Pain
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Anti-Bacterial Agents
Amoxicillin
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents