Epigenetic and Molecular Biomarkers in Chronic Low Back Pain and Modic Changes

• ClinicalTrials.gov Identifier: NCT03406624
• Recruitment Status: Recruiting
• First Posted: January 23, 2018
• Last Update Posted: April 18, 2024
• Sponsor: Oslo University Hospital
• Collaborators: Haukeland University Hospital; University Hospital, Akershus; Helse Stavanger HF
• Information provided by (Responsible Party): Kjersti Storheim, Oslo University Hospital

Study Description

Brief Summary:

In the present study the investigators aim to examine the presence of bacteria in the disc and Modic Changes (MCs) (bone). A prospective study with 1-year follow-up of two patient populations undergoing elective spinal surgery (spinal fusion or disc herniation surgery) will be conducted. Patients previously operated on at index level will also be included, and evaluated as sub-groups.

The following tissues are collected: dermis, sub-fascial tissue, nucleus pulposus, annulus fibrosus, and endplates. Endplate biopsies are only performed in patients undergoing fusion surgery.

All tissue samples undergoing culturing should be processed within 4 hours of sampling. The time for sampling and culture processing are noted for each sample.In short, 1 mL enrichment broth (Brain Heart Infusion, BHI) is added to each tissue sample and further homogenized using sterile beads or a mortar. In addition, a control sample containing only enrichment broth is included. The control sample also undergoes the homogenization step. Each sample is plated onto three agar plates: blood and chocolate for aerobic culturing and anaerobic medium (HM0 or FAA) anaerobic culturing. The blood and chocolate agar plates and the enrichment broth are incubated in 35oC (5% CO2) and the anaerobic plates are incubated anaerobically for a total of 14 days. On day 3 and 7, the enrichment broth is plated onto a chocolate and an anaerobic agar for aerobic and anaerobic incubation respectively. Aerobic plates are read every 1-2 days and the anaerobic plates are read every 2-3 days. All growth is identified and recorded. Colonies considered relevant are frozen at -80oC.

The pre-specification of microbiological results; significant growth, no growth and probable contamination (< 5 single colonies on primary plate and no growth from enrichement broth or no growth on primary plate, but growth from enrichement broth). Main endpoint for bacteriology is significant growth or no growth. A prespecification of PCR results in the probable contamination group seems to be premature, due to high risk of contamination. We will perform sensitivity analysis as the samples are analyzed, and PCR and histology will be used in combination to determine if a probable contamination should be considered in the significant growth group or in the no growth group. In addition to a pre-specified evaluation of growth or not, microbiologists and the pathologist are blinded to the knowledge of case or control. The clinicians are blinded to the results of aerob/anaerobe cultivation, PCR and histological report. Hence, the decision of no bacterial growth, probable contamination or significant growth cannot be influenced by information of case or control.

Blood-samples are collected to characterize gene expression patterns and related markers to gain insight into molecular mechanisms that may be important for low back pain (LBP) and the development of MCs

Condition or disease	Intervention/treatment
Low Back Pain	Procedure: Biopsy

Detailed Description:

All included patients will be analyzed in the primary analysis, but power analysis was based on secondary- and sub-group analysis.

Planned analysis

Primary analysis:

MC1 and MC2 vs. control (significant growth from disc, yes/no)

Secondary analysis:

MC1 vs. control (significant growth from disc, yes/no)

Exploratory subgroup analyses:

MC1 and MC2 in previously operated vs. control (significant growth from disc, yes/no)

Large MCs vs. control (significant growth from disc, yes/no). Large MCs are defined as MCs with volume ≥ 25% of vertebral body volume or height > 50% of vertebral body height.

MC1 and MC2 vs. control in fusion group (significant growth from vertebral body biopsy, yes/no). Vertebral body biopsies are not performed in the disc herniation group.

Statistics and power:

The main aim of this study is to investigate if the proportions of perioperative biopsies showing significant bacterial growth differ between patients with or without MCs. The null hypothesis is that there is no difference between cases and controls. The alternative hypothesis is that there is a difference.

We calculated the sample size using a two-sided Pearson's chi-squared test with a 5% significance level, and based the calculation on the following estimates:

For the primary analysis, bacterial growth in biopsies from MC1 and MC2 vs controls, we aim to achieve 90% power to detect a between-group difference, based on an estimated difference of bacterial growth in 25% of cases (any MC1 or MC2) vs. 5% of controls (alfa 0.05). Therefore, we plan to analyze at least 100 cases and 50 controls.

For the secondary analysis, bacterial growth of disc biopsies in MC1 vs. control, we aim to achieve 80% power to detect a between-group difference based on an estimated difference of bacterial growth in 25% cases (MC1) vs. 5% of controls (alfa 0.05). We therefore plan to analyze at least 50 cases with MC1.

For the exploratory subgroup analyses, we will not perform a sample size calculation, because smaller sub-groups are more likely to be underpowered.

Study Design

• Study Type: Observational
• Estimated Enrollment: 200 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Epigenetic and Molecular Biomarkers in Chronic Low Back Pain and Modic Changes
• Actual Study Start Date: January 29, 2018
• Estimated Primary Completion Date: May 2024
• Estimated Study Completion Date: May 2024

Groups and Cohorts

Group/Cohort	Intervention/treatment
Spinal fusion with modic changes; Patients scheduled for surgery with lumbar spinal fusion with procedures involving moderate to extensive removal of the disc, and with modic changes seen on MRI at the actual level for surgery	Procedure: Biopsy; Biopsies will be taken from disc and / or endplates during elective lumbar fusion surgery or disc herniation surgery (endplate biopsy is omitted in disc herniation surgery)
Spinal fusion without modic changes; Patients scheduled for surgery with lumbar spinal fusion with procedures involving moderate to extensive removal of the disc, but with no modic changes seen on MRI at the actual level for surgery	Procedure: Biopsy; Biopsies will be taken from disc and / or endplates during elective lumbar fusion surgery or disc herniation surgery (endplate biopsy is omitted in disc herniation surgery)
Disc herniation surgery with modic changes; Patients scheduled for disc herniation surgery, and with modic changes seen on MRI at the actual level for surgery	Procedure: Biopsy; Biopsies will be taken from disc and / or endplates during elective lumbar fusion surgery or disc herniation surgery (endplate biopsy is omitted in disc herniation surgery)
Disc herniation surgery without modic changes; Patients scheduled for disc herniation surgery, but with no modic changes seen on MRI at the actual level for surgery	Procedure: Biopsy; Biopsies will be taken from disc and / or endplates during elective lumbar fusion surgery or disc herniation surgery (endplate biopsy is omitted in disc herniation surgery)

Outcome Measures

Primary Outcome Measures :

1. Microbiological analysis (aerob, anaerob cultivation) [ Time Frame: During surgery ]
2. Histopathology and PCR [ Time Frame: During surgery ]
3. Gene expression profiling [ Time Frame: During surgery ]

Secondary Outcome Measures :

1. Oswestry disability index [ Time Frame: Pre surgery, 3 and 12 months postoperatively ]
   The Oswestry Disability Index (ODI) provides the level of self-reported impairment of activity of daily living due to low back pain. There are 10 items in the ODI, each rated on a Likert scale from 0-5. The total range of possible scores is from 0 -50, which is converted to a percentage ranging from 0-100. The percentage of self-reported disability ranges from 0='no impairment' to 100='complete impairment'.
2. Roland and Morris Disability Questionnaire [ Time Frame: Pre surgery, 3 and 12 months postoperatively ]
   The Roland Morris Questionnaire (RMQ) provides the level of self-reported impairment of activity of daily living due to low back pain. There are 24 items in the RMQ, each answered yes/no on a dichotomous questionnaire. All items answered with "yes" are summarized into a scale ranging from 0='no impairment' to 24='complete impairment'.
3. Low back pain [ Time Frame: Pre surgery, 3 and 12 months postoperatively ]
   Self-reported level of low back pain, measured on a 0 to 10 Likert scale anchored by 0 indicating "no pain" and 10 indicating "unbearable pain".
4. Leg pain [ Time Frame: Pre surgery, 3 and 12 months postoperatively ]
   Self-reported level of leg pain, measured on a 0 to 10 Likert scale anchored by 0 indicating "no pain" and 10 indicating "unbearable pain".
5. Health-related quality of life (EQ-5D) [ Time Frame: Pre surgery, 3 and 12 months postoperatively ]
   EQ-5D, measuring patients health-related quality of life, have 5 dimensions: "Mobility", "Human Autonomy," "Current Daily Activities", "Pain / Discomfort", "Anxiety / Depression" and all dimensions are described by 5 problem levels corresponding to patient response choices. A quality of life score is obtained according to the answers to the questionnaires.
6. Magnetic Resonance Imaging [ Time Frame: Pre surgery and 12 months postoperatively (12 months postoperatively only for patients undergoing lumbar disc herniation surgery ]
   Magnetic Resonance Imaging (MRI): Sagittal T1- and T2 weighted images, axial T2 weighted images, sagittal short tau inversion recovery (STIR) images, sagittal fat-water separation images, sagittal diffusion weighted images (DWI), and sagittal T1 weighted DCE images (only if the patient can receive gadolinium injection). The same MRI protocol and the same type of 1.5 Tesla MRI scanners will be used at all study sites.
7. Blood samples [ Time Frame: Pre surgery and 12 months postoperatively ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Patients will be recruited from orthopaedic outpatient clinics at four university hospitals. They will be asked for participation after being scheduled for surgery with lumbar spinal fusion with procedures involving moderate to extensive removal of the disc (i.e. transforaminal lumbar interbody fusion (TLIF), posterior Lumbar Interbody Fusion (PLIF)) or or disc herniation surgery.

Criteria

Inclusion Criteria:

• Patients scheduled for surgery with lumbar spinal fusion with procedures involving moderate to extensive removal of the disc or disc herniation surgery (for cases: MC seen on MRI at the actual level for surgery, for controls: no MC seen on MRI at the actual level for surgery)
• LBP in the area below the 12th rib and above the gluteal folds
• Age > 18 years
• Written informed consent

Exclusion Criteria:

• Antibiotic treatment within the preceding one month before surgery
• Use of glucocorticoids the preceding month before surgery
• Small dots (i.e. <= 5 mm or height <10% of vertebra) are not included for any cases or control group
• Unwilling to participate
• Contraindications to MRI

Contacts and Locations

Contacts

Contact: Kjersti Storheim, PhD; 22117740 ext 0047; kjersti.storheim@medisin.uio.no

Contact: Mads P Rolfsen, MD; madrol@ous-hf.no

Locations

Norway

Haukeland University Hospital; Recruiting

Bergen, Norway, 5021

Contact: Ivar Austevoll, MD

Sub-Investigator: Frode Rekeland, MD

Akershus University Hospital; Recruiting

Lørenskog, Norway, 1478

Contact: Oliver Grundnes

Sub-Investigator: Filip Dolatowski, MD

Sub-Investigator: Sverre Mjønes, MD

Oslo University Hospital Ullevål; Recruiting

Oslo, Norway, 4950

Contact: Mads P Rolfsen

Stavanger Universitetssjukehus; Recruiting

Stavanger, Norway

Contact: Eric Franssen, MD 51518000 ext 0047 eric.franssen@sus.no

Contact: Heidi Syre 51518000 ext 0047 heidi.syre@sus.no

Sponsors and Collaborators

Oslo University Hospital

Haukeland University Hospital

University Hospital, Akershus

Helse Stavanger HF

Investigators

• Study Director: Smeland, Professor; Oslo University Hospital

More Information

• Responsible Party: Kjersti Storheim, Head of FORMI, Oslo University Hospital
• ClinicalTrials.gov Identifier: NCT03406624
• Other Study ID Numbers: 2015/697
• First Posted: January 23, 2018
• Last Update Posted: April 18, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kjersti Storheim, Oslo University Hospital:

Modic changes; biomarkers; low back pain

Additional relevant MeSH terms:

Back Pain; Low Back Pain; Pain; Neurologic Manifestations