Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001453875
Ethics application status
Approved
Date submitted
13/09/2021
Date registered
25/10/2021
Date last updated
17/01/2023
Date data sharing statement initially provided
25/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Metformin for low back pain: A clinical trial to examine the effectiveness of metformin for chronic low back pain.
Scientific title
Metformin for low back pain: A double blind, randomised controlled trial to examine the effectiveness of metformin for chronic low back pain in adults.
Secondary ID [1] 305275 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
low back pain 323596 0
Condition category
Condition code
Musculoskeletal 321139 321139 0 0
Other muscular and skeletal disorders
Anaesthesiology 321339 321339 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is metformin (up to 2000mg) taken once daily with the evening meal as an oral tablet. It will be initiated at a dose of 500 mg once daily for 2 weeks and then increased by 500 mg every 2 weeks. Over 6 weeks, the dose of study medication will be titrated to 2000 mg once daily. Treatment will be provided for 4 months, including the 6 week titration period. Adherence to study medication will be assessed by bottle returns and pill count.
Intervention code [1] 321696 0
Treatment: Drugs
Comparator / control treatment
The placebo is silicified microcrystalline cellulose with no active ingredient (Prosolv) to be taken as 1 tablet per day for 4 months. The placebo will be identical size, colour, coating and packaging to metformin.
Control group
Placebo

Outcomes
Primary outcome [1] 328930 0
Change in current level of pain intensity assessed by the visual analogue scale (VAS).
Timepoint [1] 328930 0
Data collected at baseline and 4 months after intervention commencement
Secondary outcome [1] 400888 0
Change in low back disability assessed using the Roland Morris Disability Questionnaire.
Timepoint [1] 400888 0
Data collected at baseline and 4 months after intervention commencement
Secondary outcome [2] 400890 0
Change in physical activity level assessed using the International Physical Activity Questionnaire (long form).
Timepoint [2] 400890 0
Data collected at baseline and 4 months after intervention commencement
Secondary outcome [3] 401551 0
Change in narcotic use will be collected using medication diaries.
Timepoint [3] 401551 0
Data collected at baseline and 4 months after intervention commencement.

Eligibility
Key inclusion criteria
We will recruit individuals aged 18-65 years with chronic low back pain. Chronic low back pain will be defined as pain localised below the lower border of the rib cage and above the gluteal folds that has been present for more than 3 months. A minimum pain score of 30 or more on a 100mm visual analogue scale in the previous week will be required for inclusion.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants with any of the following will be excluded:
(i) specific pathological entities, such as cauda equina syndrome, infection, metastasis,
(ii) major co-existing illness or co-morbidity
(iii) other significant musculoskeletal or chronic pain conditions (e.g. fibromyalgia),
(iv) patients with any history of psychosis,
(v) patients with any diagnosed mental health condition,
(v) acute or chronic renal or liver impairment,
(vi) known or newly diagnosed diabetes requiring anti-hyperglycemic therapy or previous adverse reaction to metformin;
(vii) use of any investigational drugs or device within 30 days prior to randomisation;
(viii) surgery in the previous 12 months or planned surgery or invasive procedures over the course of the trial
(ix) inability to provide informed consent,
(x) pregnancy, planning to become pregnant within 12 months or breastfeeding.
We will also exclude individuals who are using narcotics and have an oral morphine equivalence of 100mg or more daily.
Use of menopausal hormone therapy or oral contraceptive pill will be permitted as long as the dose has been stable for at least 30 days prior to study entry.

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)
Central randomisation will be performed with random numbers prepared by a statistician with no involvement in the trial. Study medication will be dispensed by Syntro Health. An identical placebo tablet will be used.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation will be based on computer generated random numbers. Block randomisation will be performed.
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 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analyses will be based on intention-to-treat. Summary statistics comparing randomized arms at baseline will be tabulated. Continuous outcomes will be analysed using ANCOVA, and logistic regression will be performed for binary outcomes, with adjustments for baseline measurements where appropriate. Assessment of homogeneity of treatment effects at 4 months will be assessed using generalised estimating equations (GEE) to allow for repeated assessments of individuals. Multiple imputation by chained equations will be used to impute missing 4 month data for primary and secondary outcomes by treatment arm using prognostic baseline and post-baseline measures. The percentages of individuals with side-effects will be calculated based on treatment, and differences between groups at baseline, and 4 months will be tested using chi-squared tests and GEE for repeated measures respectively. Analyses of treatment efficacy will be performed by developing a model for non-compliance, followed by weighted analyses using only participants who fully complied, applying weights defined as the inverse probability of compliance. This estimates the treatment effect that would be observed under full compliance with the protocol which is preferable to per-protocol analyses based on (unweighted) observed compliance. Stata version 15 (StataCorp) will be used for all analyses and P values <0.05 will be considered significant.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
25/11/2021
Actual
4/05/2022
Date of last participant enrolment
Anticipated
25/11/2023
Actual
Date of last data collection
Anticipated
25/03/2024
Actual
Sample size
Target
124
Accrual to date
47
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 309645 0
Government body
Name [1] 309645 0
National Health and Medical Research Council (NHMRC)
Country [1] 309645 0
Australia
Primary sponsor type
University
Name
Prof Flavia Cicuttini
Address
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne VIC 3004
Australia
Country
Australia
Secondary sponsor category [1] 310662 0
None
Name [1] 310662 0
Address [1] 310662 0
Country [1] 310662 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309416 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 309416 0
Ethics & Research Governance
Level 5, 553 St Kilda Road
Melbourne, VIC 3004
Australia
Ethics committee country [1] 309416 0
Australia
Date submitted for ethics approval [1] 309416 0
Approval date [1] 309416 0
27/07/2021
Ethics approval number [1] 309416 0
392/21 HREC/76721/Alfred-2021
Ethics committee name [2] 309433 0
Monash University Human Research Ethics Committee
Ethics committee address [2] 309433 0
Level 1, Administration Building B (3D)
26 Sports Walk, Clayton Campus
Wellington Rd
Clayton VIC 3800
Australia
Ethics committee country [2] 309433 0
Australia
Date submitted for ethics approval [2] 309433 0
15/09/2021
Approval date [2] 309433 0
29/09/2021
Ethics approval number [2] 309433 0
30607

Summary
Brief summary
Low back is the leading cause of disability globally. Despite this, effective treatments are limited and narcotic use is alarmingly high. Metformin is a widely prescribed, safe and low-cost medication been used clinically for over 50 years as first-line therapy for type 2 diabetes. Recent evidence has shown that metformin can inhibit the mTOR pathway which is a major contributor to pain hypersensitivity, while human clinical studies show preliminary evidence that metformin may reduce pain in individuals with chronic low back pain. A randomised clinical trial is urgently needed to determine if metformin is effective in the management of individuals with chronic low back pain.

AIMS: To examine the efficacy of metformin compared to placebo on pain intensity over 4 months in individuals with chronic LBP.

HYPOTHESIS: We hypothesize that metformin will be more effective in reducing pain in individuals with chronic low back pain compared with a placebo.

PARTICIPANTS: 124 participants with chronic low back pain.

INTERVENTION: Metformin (2000 mg) once daily

COMPARATOR: Identical placebo once daily

OUTCOME: Change in back pain intensity at 4 months

SIGNIFICANCE: Given the large and growing burden of low back pain and it associated costs, this trial has the potential to deliver enormous health, economic, and social benefits. The repositioning of metformin, a cheap, safe, old drug for this new indication, offers an unprecedented opportunity to significantly and immediately impact the management of low back pain globally.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114082 0
Prof Flavia Cicuttini
Address 114082 0
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne VIC 3004
Australia
Country 114082 0
Australia
Phone 114082 0
+61 3 9903 0553
Fax 114082 0
Email 114082 0
[email protected]
Contact person for public queries
Name 114083 0
Ms Molly Bond
Address 114083 0
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne VIC 3004
Australia
Country 114083 0
Australia
Phone 114083 0
+61 3 9903 0553
Fax 114083 0
Email 114083 0
[email protected]
Contact person for scientific queries
Name 114084 0
A/Prof Donna Urquhart
Address 114084 0
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne VIC 3004
Australia
Country 114084 0
Australia
Phone 114084 0
+61 3 9903 0553
Fax 114084 0
Email 114084 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIMetformin for low back pain: study protocol for a randomised, double-blind, placebo-controlled trial2024https://doi.org/10.1016/j.ocarto.2024.100486
N.B. These documents automatically identified may not have been verified by the study sponsor.