Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000958583
Ethics application status
Approved
Date submitted
7/08/2015
Date registered
11/09/2015
Date last updated
16/01/2023
Date data sharing statement initially provided
9/07/2021
Date results information initially provided
16/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Is antibiotic treatment effective in the management of chronic low back pain? A clinical trial.
Scientific title
Is antibiotic treatment effective in the management of chronic low back pain in those with disc herniation? A double-blind, randomised, placebo-controlled trial with an economic evaluation.
Secondary ID [1] 287242 0
Nil known
Universal Trial Number (UTN)
U1111-1172-0516
Trial acronym
NA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Low back pain with lumbar disc herniation 295567 0
Condition category
Condition code
Musculoskeletal 295836 295836 0 0
Other muscular and skeletal disorders
Infection 296106 296106 0 0
Studies of infection and infectious agents
Anaesthesiology 296151 296151 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Antibiotic: Amoxycillin clavulanic acid (500/125mg), 1 tablet twice a day for 90 days.

Adherence: Return of unused medication or empty bottles

MRI scans: Two lumbar spine MRI scans will be performed. The first is a screening MRI to determine the presence of lumbar disc herniation and the second is a followup MRI at 12 months. Both MRIs will allow the presence of modic changes to be examined. The MRI scans will performed at Melbourne-based imaging clinics by experienced radiographers/MRI specialists. Participants will be positioned in supine on a plinth which will retract into a cylindrical MRI scanner. The scans will take approximately 40 mins each.
Intervention code [1] 292530 0
Treatment: Drugs
Comparator / control treatment
Placebo: Microcrystalline cellulose placebo tablets, 1 tablet twice a day for 90 days.
Control group
Placebo

Outcomes
Primary outcome [1] 295774 0
Pain Intensity will be assessed with the Low Back Pain Rating Scale and Visual Analogue Scale.
Timepoint [1] 295774 0
- Baseline and 90 days (which is at the start and end of the intervention period)
- 6, 9 and 12 months after commencement of the intervention.
Primary outcome [2] 295775 0
Disability
Roland Morris Disability Questionnaire
Timepoint [2] 295775 0
- Baseline and 90 days (which is at the start and end of the intervention period)
- 6, 9 and 12 months after commencement of the intervention.
Primary outcome [3] 295776 0
Absence from paid/unpaid work
Short Form Health and Labour Questionnaire
Timepoint [3] 295776 0
- Baseline and 90 days (which is at the start and end of the intervention period)
- 6, 9 and 12 months after commencement of the intervention.
Secondary outcome [1] 316505 0
Economic evaluation
Cost questionnaires
The cost questionnaires will include information on all health care utilization due to chronic low back pain, such as the number and type of medical and allied health visits, imaging usage, amount and type of medication (using The Medication Quantification Scale), other care/assistance (ie home-care assistance), and hours of absenteeism from paid and unpaid work. Unit costs of resources will be obtained from the Australian Pharmaceutical Benefits Scheme's manual of costs. The Short form Health and Labour questionnaire, a validated questionnaire which examines work absenteeism in relation to injury or sickness, will allow data on absenteeism from paid work, production losses without absenteeism from paid work and hindrance in the performance of paid and unpaid work to be collected.
Timepoint [1] 316505 0
- Baseline and 90 days (which is at the start and end of the intervention period)
- 6, 9 and 12 months after commencement of the intervention.
Secondary outcome [2] 316610 0
Presence of modic changes
Lumbar spine MRI scans
Timepoint [2] 316610 0
Baseline and 12 months after intervention commenced
Secondary outcome [3] 316611 0
Fear of movement/(re)injury
Tampa scale (17 item)
Timepoint [3] 316611 0
- Baseline and 90 days (which is at the start and end of the intervention period)
- 6, 9 and 12 months after commencement of the intervention.
Secondary outcome [4] 316612 0
Depression/Mood
Beck Depression Inventory
Timepoint [4] 316612 0
- Baseline and 90 days (which is at the start and end of the intervention period)
- 6, 9 and 12 months after commencement of the intervention.
Secondary outcome [5] 327957 0
Global Improvement; Patient's Global Impression of Change Scale.
Timepoint [5] 327957 0
Baseline and 90 days (which is at the start and end of the intervention period) - 6, 9 and 12 months after commencement of the intervention.
Secondary outcome [6] 327958 0
General Health Status; EuroQol (EQ-5D-5L)
Timepoint [6] 327958 0
Baseline and 90 days (which is at the start and end of the intervention period) - 6, 9 and 12 months after commencement of the intervention.

Eligibility
Key inclusion criteria
1 Chronic low back pain (Chronic > 3 months in duration; pain in the region bordered above by the 12th ribs and below by the gluteal folds)
2. Aged 18-60 years
3. Presence of a lumbar disc herniation on MRI
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Specific pathological entities, such as metastasis and osteoporosis; any contra-indication or allergy to antibiotics; antibiotic therapy in the past 3 months; immuno-compromised; osteomyelitis; current pregnancy or lactation; any liver or kidney disease; candidate for spinal surgery; major co-existing illness which may confound assessment of function; inability to provide consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment will be ensured by the use of identical, active placebo, and the use of a central automated allocation procedure, with security in place to ensure allocation data cannot be accessed or influenced by any person.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be performed by a computerised random number generator, that will be held by an independent researcher not involved in other aspects of the trial.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Summary statistics comparing randomized arms at baseline will be tabulated. Intention to treat analyses of primary and secondary continuous outcomes will be performed by linear regression adjusting for the baseline of the outcome variable where relevant. Logistic regression will be performed for binary outcomes. Adjustment for imbalanced baseline factors, including the presence of symptoms other than low back pain, will be performed as supplementary analyses. Analyses of treatment efficacy will be done by blinding individuals at the time of any protocol deviation and developing a model for the probability of deviation, followed by weighted analyses using only the uncensored individuals where the weights are the inverse probability of censoring. This produces estimates of treatment effect as if there was full compliance with the protocol in this RCT and is far preferable to per-protocol analyses based on (unweighted) observed compliance. This RCT is well-placed to model non-compliance with frequent monitoring for adverse events and resultant prognostic information

Sample size for primary outcome measure: With 85 patients in each arm of the trial there will be 90% power to detect a difference of 0.50 standard deviations in our primary outcome measure of pain. For the Low Back Pain rating scale, and assuming a between-person SD of 3.02, a difference of 1.5 units can be detected with 90% power. A clinically significant difference in pain intensity is regarded as being 2 to 3 units. For the secondary aim of assessing whether the effect of antibiotics is dependent on the presence of Modic changes, the relevant power calculation is that for detecting an interaction between antibiotic intervention and Modic status. We anticipate half the patients will demonstrate Modic changes at baseline, and assuming a between person SD of 3.0 in LBP rating scale 2, 85 patients per randomised arm will have 80% power to detect an interaction effect of size 2.6, meaning that the effect of antibiotics in patients with Modic changes is 2.6 units higher than inpatients without Modic changes. The value of 2.6 was observed in Albert et al and therefore there is sufficient power to detect a large antibiotic effect in the Modic changes subgroup compared to little effect if any in other patients. If there is a significant interaction effect between antibiotic effect and Modic changes, this will provide evidence to support the hypothesis that infection is important in the underlying pathogenesis in this subgroup of patients with pain. All analyses will adjust for the baseline value of the relevant outcome variable and this will further increase the power by an amount depending on the size of the baseline to followup correlation in the outcome.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
14/09/2015
Actual
20/01/2016
Date of last participant enrolment
Anticipated
Actual
27/05/2021
Date of last data collection
Anticipated
Actual
26/07/2022
Sample size
Target
170
Accrual to date
Final
170
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 291809 0
Government body
Name [1] 291809 0
National Health and Medical Research Council
Country [1] 291809 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine
Monash University
The Alfred Centre
99 Commercial Road
Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 290501 0
None
Name [1] 290501 0
Address [1] 290501 0
Country [1] 290501 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293326 0
Alfred Ethics Committee
Ethics committee address [1] 293326 0
Alfred Research Ethics Committee
Alfred Hospital
55 Commercial Road
Melbourne 3004
Vic
Ethics committee country [1] 293326 0
Australia
Date submitted for ethics approval [1] 293326 0
Approval date [1] 293326 0
04/03/2015
Ethics approval number [1] 293326 0
526/14

Summary
Brief summary
Low back pain is a major public health problem in Australia, ranking 2nd only to cancer as the leading cause of disability.

While its prevalence is high, with 80% of Australians experiencing low back pain during their lifetime, effective treatments are limited.

In 2013 a study was published which showed that antibiotics were effective in treating a specific type of low back pain involving injury to the disc and oedema of the bone.

The trial was based on the hypothesis that following a disc injury (experienced as acute back pain) a secondary
infection develops in the disc which leads to a chronic, disabling condition.

There has been both immense interest and controversy regarding this trial. While leading, international surgeons suggest that it should be nominated for a Nobel prize, others have called for further research.

To date the results of the trial have not been translated into clinical practice, as there are unanswered questions regarding the approach.

The specific group of patients who need to be targeted is unclear, the effectiveness of this treatment in conjunction with standard care is unknown, and the costs and associated resistance to the antibiotic therapy has not been investigated.

We aim to perform a clinical trial to investigate the effectiveness of antibiotic treatment in a broader group of individuals with chronic low back pain and a disc injury, to determine whether specific Magnetic Resonance Imaging (MRI) changes predict response to this approach, and to
examine the cost-effectiveness and antibiotic resistance of this therapy.

If antibiotics are found to be a cost-effective and safe treatment for some patients with chronic low back pain, this will provide a novel approach for the prevention of long term pain and disability in these individuals.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58710 0
Prof Flavia Cicuttini
Address 58710 0
Monash University
The Alfred Centre
99 Commercial Road
Melbourne VIC 3004
Country 58710 0
Australia
Phone 58710 0
+61 3 9903 0555
Fax 58710 0
+61 3 9903 0556
Email 58710 0
Flavia.Cicuttini@monash.edu
Contact person for public queries
Name 58711 0
Ms Molly Bond
Address 58711 0
Monash University
The Alfred Centre
99 Commercial Road
Melbourne VIC 3004
Country 58711 0
Australia
Phone 58711 0
+61 3 9903 0553
Fax 58711 0
+61 3 9903 0556
Email 58711 0
Molly.Bond@monash.edu
Contact person for scientific queries
Name 58712 0
Dr Donna Urquhart
Address 58712 0
Monash University
The Alfred Centre
99 Commercial Road
Melbourne VIC 3004
Country 58712 0
Australia
Phone 58712 0
+61 3 9903 0555
Fax 58712 0
+61 3 9903 0556
Email 58712 0
Donna.Urquhart@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We plan to do further analysis after the primary trial data is published.


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study protocolUrquhart DM, Rosenfeld JV, van Tulder M, Wluka AE, Leder K, Cheng AC, Forbes AB, Chan P, O'Sullivan R, Liew S, Cicuttini FM. Is antibiotic treatment effective in the management of chronic low back pain with disc herniation? Study protocol for a randomised controlled trial. Trials. 2021 Oct 30;22(1):759. doi: 10.1186/s13063-021-05728-1. jointstudy@monash.edu
Statistical analysis plan  jointstudy@monash.edu Specific information about the statistical analysi... [More Details]
Informed consent form  jointstudy@monash.edu
Ethical approval  jointstudy@monash.edu Specific information about the ethics approval for... [More Details]


Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo NA

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseIs antibiotic treatment effective in the management of chronic low back pain with disc herniation? Study protocol for a randomised controlled trial.2021https://dx.doi.org/10.1186/s13063-021-05728-1
N.B. These documents automatically identified may not have been verified by the study sponsor.