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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 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]

Nil known

Universal Trial Number (UTN)

U1111-1172-0516

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Low back pain with lumbar disc herniation

Condition category

Condition code

Musculoskeletal

Other muscular and skeletal disorders

Infection

Studies of infection and infectious agents

Anaesthesiology

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]

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]

Pain Intensity will be assessed with the Low Back Pain Rating Scale and Visual Analogue Scale.

Timepoint [1]

- 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]

Disability
Roland Morris Disability Questionnaire

Timepoint [2]

- 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]

Absence from paid/unpaid work
Short Form Health and Labour Questionnaire

Timepoint [3]

- 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]

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]

- 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]

Presence of modic changes
Lumbar spine MRI scans

Timepoint [2]

Baseline and 12 months after intervention commenced

Secondary outcome [3]

Fear of movement/(re)injury
Tampa scale (17 item)

Timepoint [3]

- 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]

Depression/Mood
Beck Depression Inventory

Timepoint [4]

- 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]

Global Improvement; Patient's Global Impression of Change Scale.

Timepoint [5]

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]

General Health Status; EuroQol (EQ-5D-5L)

Timepoint [6]

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?

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]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Ethics Committee

Ethics committee address [1]

Alfred Research Ethics Committee
Alfred Hospital
55 Commercial Road
Melbourne 3004
Vic

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

04/03/2015

Ethics approval number [1]

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

Prof Flavia Cicuttini

Address

Monash University
The Alfred Centre
99 Commercial Road
Melbourne VIC 3004

Country

Australia

Phone

+61 3 9903 0555

Fax

+61 3 9903 0556

[email protected]

Contact person for public queries

Name

Molly Bond

Address

Monash University
The Alfred Centre
99 Commercial Road
Melbourne VIC 3004

Country

Australia

Phone

+61 3 9903 0553

Fax

+61 3 9903 0556

[email protected]

Contact person for scientific queries

Name

Donna Urquhart

Address

Monash University
The Alfred Centre
99 Commercial Road
Melbourne VIC 3004

Country

Australia

Phone

+61 3 9903 0555

Fax

+61 3 9903 0556

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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?

Doc. No.	Type	Citation	Email	Other Details
12498	Study protocol	Urquhart 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.	[email protected]
12499	Statistical analysis plan		[email protected]	Specific information about the statistical analysi... [More Details]
12500	Informed consent form		[email protected]
12501	Ethical approval		[email protected]	Specific information about the ethics approval for... [More Details]

Results publications and other study-related documents

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Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Is antibiotic treatment effective in the management of chronic low back pain with disc herniation? Study protocol for a randomised controlled trial.	2021	https://dx.doi.org/10.1186/s13063-021-05728-1

N.B. These documents automatically identified may not have been verified by the study sponsor.

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