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Trial registered on ANZCTR


Registration number
ACTRN12617000877381
Ethics application status
Approved
Date submitted
13/06/2017
Date registered
15/06/2017
Date last updated
13/12/2018
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] 292186 0
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 303660 0
Condition category
Condition code
Musculoskeletal 303049 303049 0 0
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: 2 years
- 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, 6, 12, 18, and 24 months after randomisation to monitor adherence.
Intervention code [1] 298345 0
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] 302421 0
Proportion of participants with radiographic progression of hand osteoarthritis assessed using hand x-ray
Timepoint [1] 302421 0
24 months after randomisation
Primary outcome [2] 302422 0
Reduction in knee pain score assessed using a 100mm Visual Analogue Scale
Timepoint [2] 302422 0
24 months after randomisation
Secondary outcome [1] 335939 0
Physical function assessed using Functional Index for Hand Osteoarthritis


Timepoint [1] 335939 0
3, 6, 12, 18, and 24 months after randomisation
Secondary outcome [2] 335941 0
Quality of life assessed using Short Form-36
Timepoint [2] 335941 0
3, 6, 12, 18, and 24 months after randomisation
Secondary outcome [3] 335942 0
Joint activity assessed using tender and swollen joint count
Timepoint [3] 335942 0
3, 6, 12, 18, and 24 months after randomisation
Secondary outcome [4] 335943 0
Grip strength assessed using hand dynamometer
Timepoint [4] 335943 0
3, 6, 12, 18, and 24 months after randomisation
Secondary outcome [5] 335944 0
Progression of synovitis assessed using magnetic resonance imaging of hand
Timepoint [5] 335944 0
24 months after randomisation
Secondary outcome [6] 335990 0
Progression of bone marrow lesions assessed using magnetic resonance imaging of hand
Timepoint [6] 335990 0
24 months after randomisation

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
Gender
Both males and females
Can healthy volunteers participate?
No
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
125 patients (allowing for a 20% dropout over 24 months) will be sufficient to detect the
clinically significant differences between intervention and control groups in terms of (1) a 50% relative reduction in radiographic progression, and (2) a minimum clinically important difference in VAS pain of 18mm.
An intention-to-treat analysis will be performed in a blinded fashion. We will use binary logistic regression analyses to determine progression of radiographic disease. Pain reduction will be analysed using ANCOVA with adjustment for the baseline measure or ranked based techniques in case of major violations from normality. Covariates will include age, gender, body mass index and baseline severity of radiographic osteoarthritis and
synovitis. Multiple imputation will be used to account for missing data. A sensitivity analysis will be undertaken to estimate the effect of methotrexate under the assumption of hypothetical complete compliance to treatment by applying a twostage least squares instrumental variables approach.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 296724 0
Government body
Name [1] 296724 0
National Health and Medical Research Council
Address [1] 296724 0
16 Marcus Clarke Street
Canberra, ACT 2600
Country [1] 296724 0
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] 295694 0
None
Name [1] 295694 0
Address [1] 295694 0
Country [1] 295694 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297949 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 297949 0
55 Commercial Road
Melbourne, VIC 3004
Ethics committee country [1] 297949 0
Australia
Date submitted for ethics approval [1] 297949 0
26/06/2017
Approval date [1] 297949 0
15/08/2017
Ethics approval number [1] 297949 0
290/17
Ethics committee name [2] 297950 0
Tasmania Health & Medical Human Research Ethics Committee
Ethics committee address [2] 297950 0
Office of Research Services
University of Tasmania
Private Bag 01
Hobart, TAS 7001
Ethics committee country [2] 297950 0
Australia
Date submitted for ethics approval [2] 297950 0
10/07/2017
Approval date [2] 297950 0
18/10/2017
Ethics approval number [2] 297950 0
H0016794
Ethics committee name [3] 297951 0
Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)
Ethics committee address [3] 297951 0
Ground Floor, Basil Hetzel Institute for Translational Health Research
28 Woodville Road
Woodville South SA 5011
Ethics committee country [3] 297951 0
Australia
Date submitted for ethics approval [3] 297951 0
10/07/2017
Approval date [3] 297951 0
09/10/2018
Ethics approval number [3] 297951 0
HREC/18/CALHN/458
Ethics committee name [4] 297952 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [4] 297952 0
Education Building, Fiona Stanley Hospital
11 Robin Warren Drive
Murdoch, WA 6150
Ethics committee country [4] 297952 0
Australia
Date submitted for ethics approval [4] 297952 0
10/07/2017
Approval date [4] 297952 0
12/01/2018
Ethics approval number [4] 297952 0
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 75554 0
Prof Flavia Cicuttini
Address 75554 0
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne, VIC 3004
Country 75554 0
Australia
Phone 75554 0
+ 61 3 9903 0158
Fax 75554 0
+ 61 3 9903 0556
Email 75554 0
flavia.cicuttini@monash.edu
Contact person for public queries
Name 75555 0
Prof Flavia Cicuttini
Address 75555 0
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne, VIC 3004
Country 75555 0
Australia
Phone 75555 0
+ 61 3 9903 0158
Fax 75555 0
+ 61 3 9903 0556
Email 75555 0
flavia.cicuttini@monash.edu
Contact person for scientific queries
Name 75556 0
Prof Flavia Cicuttini
Address 75556 0
School of Public Health and Preventive Medicine
Monash University
553 St Kilda Road
Melbourne, VIC 3004
Country 75556 0
Australia
Phone 75556 0
+ 61 3 9903 0158
Fax 75556 0
+ 61 3 9903 0556
Email 75556 0
flavia.cicuttini@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
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 other documents available
Summary results
No Results