ANZCTR - Registration

Please note the ANZCTR will be unattended from Friday 20 December 2024 for the holidays. The Registry will re-open on Tuesday 7 January 2025. Submissions and updates will not be processed during that time.

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

Trial registered on ANZCTR

Registration number

ACTRN12617000877381

Ethics application status

Approved

Date submitted

13/06/2017

Date registered

15/06/2017

Date last updated

29/06/2022

Date data sharing statement initially provided

13/12/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

METHODS - A randomised controlled trial of METhotrexate to treat Hand Osteoarthritis
with Synovitis

Scientific title

METHODS - A randomised controlled trial of METhotrexate to treat Hand Osteoarthritis
with Synovitis

Secondary ID [1]

NHMRC Project Grant APP1127981

Universal Trial Number (UTN)

Trial acronym

METHODS

Linked study record

Health condition

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

Hand osteoarthritis with synovitis

Condition category

Condition code

Musculoskeletal

Osteoarthritis

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Methotrexate
- the dose administered: 10 mg weekly for four weeks, followed by 20 mg weekly for the remainder of the study if there is no toxicity as determined at the physician’s discretion (Australian Rheumatology Association Guidelines)
- the duration of administration: 6 months
- the mode of administration: oral tablet

All participants will be prescribed oral folic acid at a minimum dose of 5 mg/week, 6 days/week.

Pill count will be performed at 4 weeks, 3 and 6 months after randomisation to monitor adherence.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Identical placebo tablet, the same duration and mode of administration as the intervention

All participants will be prescribed oral folic acid at a minimum dose of 5 mg/week, 6 days/week

Control group

Placebo

Outcomes

Primary outcome [1]

Reduction in hand pain score assessed using a 100mm Visual Analogue Scale

Timepoint [1]

6 months after randomisation

Secondary outcome [1]

Physical function assessed using Functional Index for Hand Osteoarthritis

Timepoint [1]

3 and 6 months after randomisation

Secondary outcome [2]

Quality of life assessed using Short Form-36

Timepoint [2]

3 and 6 months after randomisation

Secondary outcome [3]

Joint activity assessed using tender and swollen joint count

Timepoint [3]

3 and 6 months after randomisation

Secondary outcome [4]

Grip strength assessed using hand dynamometer

Timepoint [4]

3 and 6 months after randomisation

Secondary outcome [5]

Progression of synovitis assessed using magnetic resonance imaging of hand

Timepoint [5]

6 months after randomisation or end of study

Secondary outcome [6]

Progression of bone marrow lesions assessed using magnetic resonance imaging of hand

Timepoint [6]

6 months after randomisation or end of study

Secondary outcome [7]

Proportion of participants with radiographic progression of hand osteoarthritis assessed using hand x-ray

Timepoint [7]

6 months after randomisation or end of study

Eligibility

Key inclusion criteria

1. Aged 40 - 75 years with symptomatic radiological hand osteoarthritis and synovitis
2. A pain score of greater than or equal to 40mm on a 100mm visual analogue scale and radiological osteoarthritis (Kellgren and Lawrence grade greater than or equal to 2) in at least one joint
3. Evidence of synovitis determined from magnetic resonance imaging with a grade greater than or equal to 1 in at least one joint

Minimum age

40 Years

Maximum age

75 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Concomitant rheumatic disease, inflammatory joint disease, psoriatic arthritis, ankylosing spondylitis, or gout
2. Contraindication to methotrexate (e.g. renal, liver or haematological condition, cancer including skin cancer, serious infections requiring hospitalisation in the last 5 years, known or past infection with HIV, Hepatitis B or C, Tuberculosis, or known lung disease with scarring (any fibrosis or evidence of past tuberculosis exposure on chest x-ray), concurrent regular prednisolone use, taking regular Trimethoprim or Bactrim antibiotics, egg or flu vaccination allergy, women who are pregnant, breast-feeding or trying to become pregnant, or men who father a child)
3. Contraindication to magnetic resonance imaging (e.g. implanted pacemaker, metal sutures, presence of shrapnel or iron filings in the eye, or claustrophobia)
4. Unable to complete informed 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)

numbered containers
central randomisation by computer

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Block randomization will be performed, stratified according to the study site. Randomisation will also utilise gender stratification.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving 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

96 patients (allowing for a 20% dropout) will be sufficient (with 90% power) to detect the clinically significant differences between intervention and control groups in terms of a minimal clinically important difference in VAS pain of 15mm.
An intention-to-treat analysis, including all participants in their randomised groups regardless of their adherence to assigned treatments, will be performed in a blinded fashion. The effect of intervention on pain reduction and other pain and function outcomes measured at multiple time points will be analysed using mixed linear regression models, with a random intercept for participant. For measures only taken at baseline and a single follow-up time point, regression models will omit random intercepts and terms for time. Binary logistic regression will be used to assess the effect of intervention on structural progression at 6 months. The outcome of tender/swollen joint count will be analysed via a Poisson model fit via generalised estimating equations with an exchangeable working correlation structure to account for multiple measurements per participant. If more than 5% of participants are missing their primary outcome, multiple imputation will be applied to account for missing data. Sensitivity analyses will fit outcome regression models additionally adjusted for age, body mass index, and severity of radiographic OA and synovitis if baseline imbalances between randomised groups with respect to these variables are considered clinically important. A sensitivity analysis of the primary outcome will be undertaken to estimate the effect of methotrexate under the assumption of hypothetical complete compliance to treatment.

Recruitment

Recruitment status

Active, not recruiting

Date of first participant enrolment

Anticipated

1/09/2017

Actual

4/04/2018

Date of last participant enrolment

Anticipated

30/07/2021

Actual

8/11/2021

Date of last data collection

Anticipated

31/08/2022

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

SA,TAS,WA,VIC

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

16 Marcus Clarke Street
Canberra, ACT 2600

Country [1]

Australia

Primary sponsor type

University

Name

Monash University

Address

School of Public Health and Preventive Medicine
Monash University
553 St Kilda 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 Hospital Ethics Committee

Ethics committee address [1]

55 Commercial Road
Melbourne, VIC 3004

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/06/2017

Approval date [1]

15/08/2017

Ethics approval number [1]

290/17

Ethics committee name [2]

Tasmania Health & Medical Human Research Ethics Committee

Ethics committee address [2]

Office of Research Services
University of Tasmania
Private Bag 01
Hobart, TAS 7001

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

10/07/2017

Approval date [2]

18/10/2017

Ethics approval number [2]

H0016794

Ethics committee name [3]

Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)

Ethics committee address [3]

Ground Floor, Basil Hetzel Institute for Translational Health Research
28 Woodville Road
Woodville South SA 5011

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

10/07/2017

Approval date [3]

09/10/2018

Ethics approval number [3]

HREC/18/CALHN/458

Ethics committee name [4]

South Metropolitan Health Service Human Research Ethics Committee

Ethics committee address [4]

Education Building, Fiona Stanley Hospital
11 Robin Warren Drive 
Murdoch, WA 6150

Ethics committee country [4]

Australia

Date submitted for ethics approval [4]

10/07/2017

Approval date [4]

12/01/2018

Ethics approval number [4]

RGS0000000573

Summary

Brief summary

Osteoarthritis (OA) is the most common joint disease and frequently involves the hand. Painful hand OA is associated with a significant burden of disease and reduced health-related quality of life. The effect of hand OA on quality of life is comparable to rheumatoid arthritis, but effects considerably more people (prevalence ~40% versus ~1% in older adults). With an ageing population, the burden and health-care costs related to
hand OA will increase. Since no treatment affects disease progression, there is an urgent and unmet need for effective treatment to slow structural disease and reduce symptoms. Only treatments that impact on the underlying biological processes causing hand OA will be able to achieve this.

Hand OA is a heterogeneous condition. A common phenotype is joint swelling (synovitis). Synovitis is present in approximately 50% of people with symptomatic hand OA. Joints in hands with synovitis are 3.5 times more likely to experience joint destruction and radiographic progression than those without synovitis. Drugs used to treat synovitis may offer a novel therapeutic approach for reducing disease burden from hand OA. Recent efforts to examine anti-synovitis therapies in hand OA have been hampered by their application to the general population, rather than the synovitis phenotype. Moreover, previous attempts to examine anti-synovitis therapies examined costly and poorly accepted drugs. Methotrexate (MTX) is a well-established, low-cost drug with a well-described safety profile commonly prescribed as first-line therapy for the treatment of
inflammatory arthritis. Recently, MTX has been shown to improve both synovitis and symptoms in a RCT and open label trial of knee OA. We propose that MTX might be a potential disease modifying OA drug for patients with symptomatic hand OA and synovitis to reduce disease progression and pain.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Flavia Cicuttini

Address

School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne, VIC 3004

Country

Australia

Phone

+ 61 3 9903 0158

Fax

+ 61 3 9903 0556

flavia.cicuttini@monash.edu

Contact person for public queries

Name

Flavia Cicuttini

Address

School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne, VIC 3004

Country

Australia

Phone

+ 61 3 9903 0158

Fax

+ 61 3 9903 0556

flavia.cicuttini@monash.edu

Contact person for scientific queries

Name

Flavia Cicuttini

Address

School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne, VIC 3004

Country

Australia

Phone

+ 61 3 9903 0158

Fax

+ 61 3 9903 0556

flavia.cicuttini@monash.edu

Data sharing statement

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

No/undecided IPD sharing reason/comment

The IPD will be kept confidential. Access to computer or paper-based records with identifiable data is restricted to authorised staff.

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

Source	Title	Year of Publication	DOI
Embase	METHODS - A randomised controlled trial of METhotrexate to treat Hand Osteoarthritis with Synovitis: study protocol for a randomised controlled trial.	2021	https://dx.doi.org/10.1186/s12891-021-04842-0
Embase	Methotrexate to treat hand osteoarthritis with synovitis (METHODS): an Australian, multisite, parallel-group, double-blind, randomised, placebo-controlled trial.	2023	https://dx.doi.org/10.1016/S0140-6736%2823%2901572-6

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

Trial Review

Registering a new trial?

Documents added manually

Documents added automatically