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Rheumatoid ArthritisPhase 4NCT03254589

Methotrexate, Blood Pressure and Arterial Function in Rheumatoid Arthritis

A Phase 4 study testing Methotrexate, Sulfasalazine and Other DMARDs in people with Rheumatoid Arthritis and Stiffness, Aortic, run by Flinders University at 1 site in Australia.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The investigators will study the effects of methotrexate on blood pressure, arterial stiffness and endothelial function in patients with rheumatoid arthritis. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Methotrexate, Sulfasalazine and Other DMARDs
Could I receive a placebo?
No, everyone receives an active treatment
How many people
124 participants
Where
1 siteAustralia
Study dates
1 Oct 2017to 31 Dec 2023
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patient with rheumatoid arthritis according to EULAR/ACR 2010 criteria.
  • Age ≥18 years.
  • Written informed consent, dated and signed before initiating any study-related procedure.

Who cannot join

  • Contraindication to MTX or sulfasalazine.
  • Patient who cannot be followed during 6 months.
  • Active alcohol or substance abuse within the last 12 months.
  • Participation in a clinical trial within 3 months prior to the start of the study.
  • Body mass index >35 Kg/m2.
  • Secondary causes of hypertension.
Show all 25Show fewer
  • Grade 2 (moderate) or 3 (severe) hypertension: clinic blood pressure >160/100 mm Hg.
  • Resistant hypertension: clinical blood pressure ≥140/90 mm Hg despite concurrent use of three antihypertensive agents of different classes, one of which is a diuretic.
  • Clinical systolic blood pressure <100 mm Hg or history of symptomatic orthostatic hypotension.
  • Cardiovascular event, procedure, or hospitalization for unstable angina with the last 6 months.
  • Atrial fibrillation.
  • Heart failure.
  • Treatment with nitrates.
  • Estimated glomerular filtration rate (eGFR) <45 mL/min.
  • Diagnosis of polycystic kidney disease.
  • Glomerulonephritis treated with or likely to be treated with immunosuppressant drugs
  • Uncontrolled diabetes with HbA1c >9.0% (>75 mmol/mol).
  • Uncontrolled dyslipidaemia with total serum cholesterol >7.5 mmol/L or triglycerides >5.6 mmol/L.
  • Clinical diagnosis of dementia, treatment with medications for dementia or, in the opinion of the study staff, the participant is cognitively unable to follow the protocol.
  • Other medical, psychiatric, or behavioural factors that in the judgment of the study staff may interfere with study participation.
  • Cancer diagnosed and treated within the past 2 years that, in the judgment of the study staff, would compromise a participant's ability to comply with the protocol and complete the study.
  • Any organ transplant.
  • Pregnancy, currently trying to become pregnant, or of child bearing potential and not using birth control.
  • Significant illness within 2 weeks of study start.
  • Patients with an unstable active medical condition that could impair evaluation of study results.

Trial locations and contacts

1 site in 1 country.

Australia1 site

  • Southern Adelaide Local Health Network

    Bedford Park, South Australia, 5042

Other trials in Australia

About this study

The investigators will study the effects of methotrexate on blood pressure, arterial stiffness and endothelial function in patients with rheumatoid arthritis.

Read the detailed description

Patients with rheumatoid arthritis have an increased risk of stroke and heart attack when compared to the rest of the population. Recent studies have shown that methotrexate, a disease-modifying antirheumatic drug (DMARDs) commonly prescribed for rheumatoid arthritis, reduces this risk. However, the mechanisms responsible for the protective effects of methotrexate on the heart and the brain are unknown.

The investigators have recently completed an observational study in participants with rheumatoid arthritis treated with either methotrexate or with other DMARDs. Participants on methotrexate had lower blood pressure and 'healthier' blood vessels than participants treated with other DMARDs. These differences were maintained over a period of 8 months. These results suggest that methotrexate lowers blood pressure and exerts salutary effects on blood vessels, which might explain the reduced risk of stroke and heart attack with this drug. However, the observational nature of this study does not allow establishing a clear cause-effect relationship between methotrexate treatment and the observed changes in blood pressure and blood vessels.

In order to address this issue, the investigators will recruit participants that have been recently diagnosed with rheumatoid arthritis and are about to start treatment with either methotrexate (Group 1) or another DMARD (Group 2). Then, the investigators will assess their blood pressure and blood vessels for 6 months. The investigators will use an injectable (subcutaneous) form of methotrexate because this might provide better effects on blood pressure and blood vessels. The investigators will also study a third group (Group 3) of rheumatoid arthritis participants already on treatment (> 1 year) with oral methotrexate, with or without other DMARDs. They will be switched to subcutaneous methotrexate, but continuing all their other medications, for 6 months to see whether the subcutaneous form can further reduce blood pressure and provide additional salutary effects on blood vessels. Finally, the investigators will study a fourth group (Group 4) of participants with rheumatoid arthritis already on treatment (> 1 year) with DMADRs other than methotrexate who will continue with the same medications for 6 months, to assess possible fluctuations in blood pressure and blood vessel markers over time.

Each participant will attend three study visits (baseline, 1 and 6 months), each lasting between 60 and 90 min.

Being tested
Methotrexate, Sulfasalazine, Other DMARDs
Keywords
Methotrexate, Rheumatoid arthritis, Blood pressure, Arterial stiffness, Cardiovascular risk
Medical subject headings
Arthritis, Rheumatoid

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MethotrexateDrug

    See arm descriptions

  • SulfasalazineDrug

    See arm description

  • Other DMARDsDrug

    See arm

Study groups in NCT03254589
Study groupRoleWhat they receive
Group 1ExperimentalNewly diagnosed RA patients started on subcutaneous MTX - open randomisation vs. sulfasalazine. In this group, use of NSAIDs, steroids, and/or other DMARDs, is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice .
Receives: Drug: Methotrexate
Group 2Active comparatorNewly diagnosed RA patients started on sulfasalazine - open randomisation vs. subcutaneous MTX. In this group, use of NSAIDs, steroids, and/or other DMARDs (except MTX), is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.
Receives: Drug: Sulfasalazine
Group 3ExperimentalRA patients on long-term treatment (> 1 year) with oral MTX, with or without other DMARDs, NSAIDs and/or steroids, switched to subcutaneous MTX (same dose). In these patients, treatment with other DMARDs, NSAIDs and/or steroids will continue. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.
Receives: Drug: Methotrexate
Group 4Active comparatorRA patients on stable treatment (> 1 year) with other (non-MTX) DMARDs, with or without NSAIDs and/or steroids, and continued on the same treatment. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.
Receives: Drug: Other DMARDs

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in peripheral systolic blood pressure

    Change in peripheral systolic blood pressure

    Measured: Change from baseline peripheral systolic blood pressure at 6 months

Secondary outcomes (5)

  1. Change in peripheral and central blood pressure

    Change in peripheral and central blood pressure

    Measured: Change from baseline peripheral and central blood pressure at 6 months

  2. Change in arterial stiffness

    Change in pulse wave velocity

    Measured: Change from baseline pulse wave velocity at 6 months

  3. Change in arterial wave reflection

    Change in augmentation index

    Measured: Change from baseline augmentation index at 6 months

  4. Change in adenosine

    Change in adenosine concentrations

    Measured: Change from baseline adenosine concentrations at 6 months

  5. Change in arginine metabolites

    Change in ADMA concentrations

    Measured: Change from baseline ADMA concentrations at 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Aug 2017
  2. Study start1 Oct 2017
  3. Primary completion31 Dec 2023
  4. Study completion31 Dec 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
124 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03254589
Sponsor's protocol ID
HREC/17/SAC/46
Status last verified
Feb 2025
First submitted
16 Aug 2017
Last updated
26 Feb 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Mangoni AA, Wiese MD, Woodman RJ, Sotgia S, Zinellu A, Carru C, Hulin JA, Shanahan EM, Tommasi S. A controlled comparative study of the effects of methotrexate and pharmacogenetic factors on arterial blood pressure and arterial stiffness in patients with rheumatoid arthritis. Ann Med. 2025 Dec;57(1):2539311. doi: 10.1080/07853890.2025.2539311. Epub 2025 Jul 31.

    PubMed 40742006

  • Mangoni AA, Wiese MD, Woodman RJ, Sotgia S, Zinellu A, Carru C, Hulin JA, Shanahan EM, Tommasi S. Methotrexate, blood pressure and arterial function in rheumatoid arthritis: study protocol. Future Cardiol. 2024;20(13):671-683. doi: 10.1080/14796678.2024.2411167. Epub 2024 Oct 10.

    PubMed 39387403

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Methotrexate, Sulfasalazine and Other DMARDs in people with Rheumatoid Arthritis and Stiffness, Aortic, run by Flinders University at 1 site in Australia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in peripheral systolic blood pressure (time frame: Change from baseline peripheral systolic blood pressure at 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03254589, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2025.

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