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Trial registered on ANZCTR


Registration number
ACTRN12624000063516p
Ethics application status
Submitted, not yet approved
Date submitted
17/12/2023
Date registered
25/01/2024
Date last updated
25/01/2024
Date data sharing statement initially provided
25/01/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
METHODS-Extend – An open-label pragmatic trial to determine the efficacy and patient acceptability of methotrexate for hand osteoarthritis over 12 months.
Scientific title
METHODS-Extend – An open-label pragmatic trial to determine the efficacy and patient acceptability of methotrexate for hand osteoarthritis over 12 months.
Secondary ID [1] 311109 0
None
Universal Trial Number (UTN)
Trial acronym
METHODS-Extend
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hand osteoarthritis 332265 0
Condition category
Condition code
Musculoskeletal 328980 328980 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 four weeks, and then increased to 25mg 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: 12 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, 6, 9 and 12 months to monitor adherence.
Intervention code [1] 327561 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 336769 0
Change in pain at 12 months
Timepoint [1] 336769 0
12 months post commencement of intervention
Secondary outcome [1] 429635 0
Change in pain at 6 months
Timepoint [1] 429635 0
6 months post commencement of intervention
Secondary outcome [2] 429636 0
Change in hand function at 6 months and 12 months
Timepoint [2] 429636 0
6 and 12 months post commencement of intervention
Secondary outcome [3] 429637 0
Radiographic progression at 12 months
Timepoint [3] 429637 0
12 months post commencement of intervention
Secondary outcome [4] 430626 0
Change in hand function at 6 and 12 months
Timepoint [4] 430626 0
6 and 12 months post intervention
Secondary outcome [5] 430627 0
Change in hand function at 6 months and 12 months
Timepoint [5] 430627 0
6 and 12 months post commencement of intervention
Secondary outcome [6] 430628 0
General health outcome at 6 and 12 months
Timepoint [6] 430628 0
6 and 12 months post commencement of intervention
Secondary outcome [7] 430629 0
Quality of lfe at 6 and 12 months
Timepoint [7] 430629 0
6 and 12 months post commencement of intervention

Eligibility
Key inclusion criteria
1. Aged 40 - 75 years
2. Pain in the hand joints for most days in the last 6 weeks and a pain score of at least 40 on a 100 mm visual analogue scale (VAS) in the last 7 days, hand osteoarthritis that fulfilled the American College of Rheumatology criteria, and radiological osteoarthritis (Kellgren and Lawrence grade greater than or equal to 2) in at least one joint.
Minimum age
40 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) concomitant rheumatic disease, inflammatory joint disease, psoriatic arthritis, ankylosing spondylitis, gout, psoriasis, or suspected chondrocalcinosis; positive rheumatoid factor or anti-cyclic citrullinated peptides, elevated C-reactive protein of > 2X upper limit of normal.
(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 human immunodeficiency virus, hepatitis B or C, tuberculosis, or known lung disease with scarring (any fibrosis or evidence of past tuberculosis exposure on chest x-ray), taking regular trimethoprim or trimethoprim/sulfamethoxazole antibiotics, egg or flu vaccination allergy]
(3) unable to complete informed consent
(4) women who are pregnant, breast-feeding or trying to become pregnant, or men who planned to father a child
(5) excessive alcohol intake

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
We plan to recruit 150 patients with hand OA. We anticipate that about 70% will have had treatment with methotrexate for 6 months or longer so or about 100 patients. To examine determinants for response to methotrexate we will have 80% power to detect an odds ratio of 2.0 or more with alpha error of 5% where the prevalence of the risk factors examined is 20% or more. Assuming that MTX will be associated with a 50% relative reduction in radiographic progression, then with 50 participants per arm, we will have 80% power, with alpha = 0.05, 2-sided significance, to show this effect.

Statistical analyses
Analyses will be conducted in Stata v16 or later. 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, BMI and baseline severity of radiographic OA and synovitis.

1. To identify those most likely to respond or oral methotrexate.
Subgroup analyses and logistic regression analyses will be performed to determine whether the following are predictors of response to methotrexate: age, sex, menopausal status (including time from menopause), duration of symptoms, presence of erosive disease (yes/no), presence of MCP joint OA and severity of radiological OA.

2. To determine whether use of methotrexate for 6 months or longer results in less joint damage.
We will examine radiographs on those on methotrexate and those not on methotrexate. The proportion on methotrexate who progress will be compared to those who progress not on methotrexate.
We will examine whether less amount of pain (based on reduction in the total pain score calculated from pain score from 3monthly VAS pain score) is associated with less radiological progression and the effect of MTX on this.

These data will be used to develop a treatment algorithm for use on MTX in hand OA based on identification of those most likely to respond and optimal duration of effect.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/01/2024
Actual
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
150
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 315366 0
Government body
Name [1] 315366 0
National Health and Medical Research Council
Country [1] 315366 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] 317426 0
None
Name [1] 317426 0
Address [1] 317426 0
Country [1] 317426 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 314283 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 314283 0
55 Commercial Road, Melbourne, VIC 3004
Ethics committee country [1] 314283 0
Australia
Date submitted for ethics approval [1] 314283 0
22/11/2023
Approval date [1] 314283 0
Ethics approval number [1] 314283 0

Summary
Brief summary
Hand osteoarthritis (OA) is a disabling condition impeding activity of daily living leading to pain, functional impairment, and reduced quality of life. The age-standardised prevalence of hand OA in the general population is 44·2% in women and 37·7% in men. Despite the high prevalence and significant disease burden, there is no effective therapy for hand OA.

Hand OA is a heterogeneous condition. The inflammatory phenotype is a commonly encountered clinical phenotype, characterized by joint swelling (synovitis). The presence of synovitis being associated with joint pain and structural progression. Therefore, synovitis has the potential to be a target for treatment in hand OA.

Methotrexate is a well-established, low-cost, and effective treatment for inflammatory arthritis with a well-described safety profile. In our previous METHODS study (a randomized, double-blind, placebo-controlled trial to determine the effect of 20 mg methotrexate once weekly on reducing pain and improving function in patients with symptomatic hand OA and synovitis over 6 months, ACTRN12617000877381), we showed that methotrexate would reduce pain and stiffness over 6 months compared to placebo in patients with hand OA and synovitis. But there are still a number of unknown questions regarding the use of methotrexate, including how long we need to treat those with hand OA with methotrexate; is there a group that are more likely to respond; and does response to treatment predict less joint damage. Thus, we conducted this METHODS-Extend open label study to address those queries.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 131054 0
Prof Flavia Cicuttini
Address 131054 0
School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road, Melbourne, VIC 3004
Country 131054 0
Australia
Phone 131054 0
+61 3 9903 0158
Fax 131054 0
Email 131054 0
[email protected]
Contact person for public queries
Name 131055 0
Flavia Cicuttini
Address 131055 0
School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road Melbourne, VIC 3004
Country 131055 0
Australia
Phone 131055 0
+61 3 9903 0158
Fax 131055 0
Email 131055 0
[email protected]
Contact person for scientific queries
Name 131056 0
Flavia Cicuttini
Address 131056 0
School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Road Melbourne, VIC 3004
Country 131056 0
Australia
Phone 131056 0
+61 3 9903 0158
Fax 131056 0
Email 131056 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified data
When will data be available (start and end dates)?
Following completion of the study (Jan 2026)
Available to whom?
On request to journals and researchers
Available for what types of analyses?
To journals for confirmation of results and researchers for collaborations.
How or where can data be obtained?
On request to PI.


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
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