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Trial registered on ANZCTR


Registration number
ACTRN12621000710820
Ethics application status
Approved
Date submitted
30/04/2021
Date registered
8/06/2021
Date last updated
20/11/2023
Date data sharing statement initially provided
8/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Effectiveness of metformin for knee osteoarthritis with obesity - a randomised, double-blind, placebo-controlled trial of a potential disease modifying therapy
Scientific title
Effectiveness of metformin for knee osteoarthritis with obesity - a randomised, double-blind, placebo-controlled trial of a potential disease modifying therapy
Secondary ID [1] 304102 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
knee osteoarthritis 321777 0
obesity 322225 0
Condition category
Condition code
Musculoskeletal 319507 319507 0 0
Osteoarthritis
Diet and Nutrition 319918 319918 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Metformin (oral tablet, up to 2000 mg) once daily over 6 months
Study medication will be initiated at a dose of 500 mg once daily with the evening meal for 2 weeks. The dose will be increased by 500 mg every 2 weeks. Over 6 weeks, the dose of study medication will be titrated to 2000 mg once daily.
Adherence to study medication will be assessed by bottle returns and pill count.
Intervention code [1] 320430 0
Treatment: Drugs
Comparator / control treatment
placebo (with no active ingredients, silicified microcrystalline cellulose, Prosolv) once daily over 6 months
Control group
Placebo

Outcomes
Primary outcome [1] 327376 0
Change in visual analogue scale (VAS) knee pain
Timepoint [1] 327376 0
VAS will be collected at baseline and monthly from 1-6 months after intervention commencement. Change in VAS knee pain from baseline to 6 month is the primary outcome.
Secondary outcome [1] 394847 0
OMERACT-OARSI responder criteria (based on the Western Ontario and McMaster Universities Osteoarthritis Index and visual analogue scale)
Timepoint [1] 394847 0
Data collected at baseline and 6 months after intervention commencement
Secondary outcome [2] 394848 0
Change in knee pain, stiffness and function, assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)
Timepoint [2] 394848 0
Data collected at baseline and 6 months after intervention commencement
Secondary outcome [3] 394849 0
Change in health-related quality of life, assessed by Assessment of Quality of Life (AQoL)
Timepoint [3] 394849 0
Data collected at baseline and 6 months after intervention commencement

Eligibility
Key inclusion criteria
1. Men and women aged over 40 years, with overweight or obesity (body mass index greater than or equal to 25 kg/m2);
2. Knee pain for at least 6 months with a pain score greater than or equal to 40 mm on a 100 mm visual analogue scale (VAS);
3. Meet the American College of Rheumatology clinical criteria for knee osteoarthritis.
Minimum age
40 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Severe radiographic knee osteoarthritis (Kellgren-Lawrence grade 4) or severe knee pain (on standing >80 mm on a 100 mm VAS);
2. Any inflammatory arthritis or significant knee injury;
3. Known or newly diagnosed diabetes requiring anti-hyperglycemic therapy or previous adverse reaction to metformin;
4. Index knee surgery (arthroscopy or open surgery) in the past year;
5. Index knee intra-articular hyaluronic acid injection in the past 6 months or corticosteroid injection in the past 3 months;
6. Use of any investigational drugs or device within 30 days prior to randomisation;
7. Index knee planned joint replacement or arthroscopy in the next 6 months;
8. Other muscular, joint or neurological condition affecting lower limb function;
9. Acute or chronic renal or liver impairment;
10. Other medical condition precluding study participation or relocation;
11. Women who are pregnant, lactating or trying to become pregnant. Use of menopausal hormone therapy or oral contraceptive pill will be permitted so 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 is done with random numbers prepared by a statistician with no involvement in the trial. Study medication is dispensed by The Pharmacy Common. An identical placebo tablet is used.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Central randomisation is done based on computer generated random numbers. Block randomisation is 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
Intention-to-treat analyses of primary and secondary outcomes will be performed. Comparisons between randomised groups of change in knee pain at 6 months will be analyzed using linear regression, adjusting for baseline knee pain. Differences in trajectories of this outcome over time will be examined using linear mixed-effects models with baseline value as the covariate, fixed factors for treatment, time, and treatment x time interaction, and with an unstructured covariance matrix for repeated measures of individuals over time. Sensitivity analyses will be performed for clinically important imbalances in baseline factors using multiple linear regression or mixed models regression, as appropriate. Multiple imputation of missing follow-up measures will be performed as sensitivity analysis, assuming data are missing at random. Subgroup analyses will be performed to examine whether the difference in outcomes between randomised groups varied based on the severity of radiographic knee osteoarthritis. Per-protocol analyses for the primary and secondary endpoints will be conducted as secondary analyses according to the participants’ randomised treatment group restricted to those complying with the protocol and with available outcome measures at 6 month. These will be performed by developing a model for the probability of deviation, followed by inverse probability weighted estimation in the compliers.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
16/06/2021
Actual
20/12/2021
Date of last participant enrolment
Anticipated
31/07/2023
Actual
29/09/2023
Date of last data collection
Anticipated
31/03/2024
Actual
Sample size
Target
102
Accrual to date
Final
107
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 308486 0
Government body
Name [1] 308486 0
National Health and Medical Research Council (NHMRC)
Country [1] 308486 0
Australia
Primary sponsor type
Individual
Name
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] 309334 0
None
Name [1] 309334 0
Address [1] 309334 0
Country [1] 309334 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308438 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 308438 0
Ethics & Research Governance
Level 5, 553 St Kilda Road
Melbourne, VIC 3004
Australia
Ethics committee country [1] 308438 0
Australia
Date submitted for ethics approval [1] 308438 0
26/11/2020
Approval date [1] 308438 0
05/03/2021
Ethics approval number [1] 308438 0
HREC/69306/Alfred-2020 (Local Reference: Project 708/20)
Ethics committee name [2] 308439 0
Monash University Human Research Ethics Committee
Ethics committee address [2] 308439 0
Level 1, Administration Building B (3D)
26 Sports Walk, Clayton Campus
Wellington Rd
Clayton VIC 3800
Australia
Ethics committee country [2] 308439 0
Australia
Date submitted for ethics approval [2] 308439 0
Approval date [2] 308439 0
27/04/2021
Ethics approval number [2] 308439 0
28498

Summary
Brief summary
Osteoarthritis is a leading cause of disability with no cure. Current therapies are limited, with end-stage osteoarthritis treated with costly total joint replacement. There is an urgent unmet need for an effective disease-modifying drug to reduce the burden of the disease. Obesity and obesity-related metabolic and inflammatory factors are risk factors for knee osteoarthritis with people with osteoarthritis at increased risk of cardiovascular disease morbidity and mortality. Metformin, a safe, low-cost, well-tolerated first-line therapy for type 2 diabetes for over 60 years, affects these pathways with evidence from animal and human studies that metformin may reduce pain of knee osteoarthritis and reduce cardiovascular risk. We propose to test this in a randomised double-blind placebo-controlled trial in participants with knee osteoarthritis and obesity.

AIMS: To determine whether metformin reduces knee pain over 6 months compared with placebo in people with knee osteoarthritis who are obese.

PARTICIPANTS: 102 participants with knee osteoarthritis and obesity

INTERVENTION: Metformin (2000 mg) once daily

COMPARATOR: Identical placebo once daily

OUTCOME: Change in knee pain assessed by visual analogue scale at 6 months

SIGNIFICANCE: 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 osteoarthritis in Australia and worldwide. It has very high potential for rapid translation being a safe, easy to use medication with medical practitioners who have repeatedly called for effective treatments for knee osteoarthritis familiar with its use. Metformin has the potential to significantly reduce disease burden and healthcare costs, while improving quality of life and reducing cardiovascular risk in people with knee osteoarthritis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110714 0
Prof Flavia Cicuttini
Address 110714 0
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne VIC 3004
Australia
Country 110714 0
Australia
Phone 110714 0
+61 3 99030158
Fax 110714 0
Email 110714 0
[email protected]
Contact person for public queries
Name 110715 0
Flavia Cicuttini
Address 110715 0
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne VIC 3004
Australia
Country 110715 0
Australia
Phone 110715 0
+61 3 99030158
Fax 110715 0
Email 110715 0
[email protected]
Contact person for scientific queries
Name 110716 0
Flavia Cicuttini
Address 110716 0
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne VIC 3004
Australia
Country 110716 0
Australia
Phone 110716 0
+61 3 99030158
Fax 110716 0
Email 110716 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
EmbaseMetformin for knee osteoarthritis with obesity: study protocol for a randomised, double-blind, placebo-controlled trial.2023https://dx.doi.org/10.1136/bmjopen-2023-079489
N.B. These documents automatically identified may not have been verified by the study sponsor.