Methotrexate, Blood Pressure and Arterial Function in Rheumatoid Arthritis

February 24, 2025 updated by: Arduino Mangoni, Flinders University
The investigators will study the effects of methotrexate on blood pressure, arterial stiffness and endothelial function in patients with rheumatoid arthritis.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
124

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Australia
    • South Australia
      • Bedford Park, South Australia, Australia, 5042
        • Southern Adelaide Local Health Network

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Group 1
Newly 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 .
Drug: Methotrexate
See arm descriptions
Active Comparator: Group 2
Newly 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.
Drug: Sulfasalazine
See arm description
Experimental: Group 3
RA 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.
Drug: Methotrexate
See arm descriptions
Active Comparator: Group 4
RA 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.
Drug: Other DMARDs
See arm

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in peripheral systolic blood pressure
Time Frame: Change from baseline peripheral systolic blood pressure at 6 months
Change in peripheral systolic blood pressure
Change from baseline peripheral systolic blood pressure at 6 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in peripheral and central blood pressure
Time Frame: Change from baseline peripheral and central blood pressure at 6 months
Change in peripheral and central blood pressure
Change from baseline peripheral and central blood pressure at 6 months
Change in arterial stiffness
Time Frame: Change from baseline pulse wave velocity at 6 months
Change in pulse wave velocity
Change from baseline pulse wave velocity at 6 months
Change in arterial wave reflection
Time Frame: Change from baseline augmentation index at 6 months
Change in augmentation index
Change from baseline augmentation index at 6 months
Change in adenosine
Time Frame: Change from baseline adenosine concentrations at 6 months
Change in adenosine concentrations
Change from baseline adenosine concentrations at 6 months
Change in arginine metabolites
Time Frame: Change from baseline ADMA concentrations at 6 months
Change in ADMA concentrations
Change from baseline ADMA concentrations at 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Flinders University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
medac GmbH
University of South Australia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 16, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 16, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 18, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 25, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 24, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • HREC/17/SAC/46

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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