Methotrexate in Patients With Early Rheumatoid Arthritis (MTXRA)

August 21, 2023 updated by: Anna Södergren, Region Västerbotten

Efficacy, Tolerability and Preferences of Per Oral or Subcutaneous Methotrexate in Patients With Early Rheumatoid Arthritis - a Randomised Register Based Multicentre Study

Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting the small joints of hands and feet, but may also present with systemic, extraarticular features. The Swedish Rheumatology Quality Register (SRQ) is a nationwide quality register with the aim of continuously improving the treatment and follow-up of patients with rheumatic disease. Using this type of quality registers, it is possible to perform a Registrybased Randomised Clinical Trial (R-RCT), that is a randomised clinical trial this is carried out by screening, recruitment and registration of study data is performed based on information given by a quality register. All patients with newly diagnosed RA are included in SRQ. Treatment options for RA include different types of immunosuppression and corticosteroids as bridging therapy. Methotrexate, a synthetic conventional disease modifying antirheumatic drug (csDMARD), which can be given either orally or subcutaneously, is considered a first-line treatment. Studies have shown the beneficial efficacy and improved quality of life for patients with RA treated with methotrexate, however this is not studied in a setting of unselected patients with newly diagnosed RA in northern Sweden. Moreover, it is not known to what extent patients prefer oral or subcutaneous administration route, or if there are any health economic benefits from either of the two administration routes. Further, changes in gut microbiota is not studied in this setting.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting the small joints of hands and feet, but may also present with systemic, extraarticular features. Pain and stiffness induced by rest, fever, fatigue, and weight loss are common constitutional symptoms. After onset of symptoms the patient most often sees a general practitioner for referral to a rheumatology department. After diagnosis of RA treatment is indicated to start as soon as possible to prevent future disability. Treatment options for RA include different types of immunosuppression and corticosteroids as bridging therapy. Methotrexate (MTX) has been used for decades as the most commonly prescribed synthetic conventional disease modifying antirheumatic drug (csDMARD) in the treatment for RA. MTX can be given either orally or subcutaneously, although the most commonly used route is still per oral, largely due to convenience. Studies have shown the beneficial efficacy and improved quality of life with methotrexate treatment. Although its mechanism of action has not been fully elucidated, current evidence supports that it works by acting as both an antimetabolite (by inhibiting dihydrofolate reductase) and an immunomodulatory agent (by promoting adenosine release, thereby suppressing inflammation). MTX has long been used as a standard of care to treat RA at typically between 7.5 and 30.0 mg/week in a single weekly dose. Methotrexate has a broad spectrum of adverse effects, one of which is the most common is gastrointestinal manifestations. In our clinic, the standard clinical practice is to start with per oral administration and then a switch from oral medication to subcutaneous injections in cases where gastrointestinal adverse effects occur or a failure to reach remission. When given subcutaneously, the bioavailability of methotrexate increases which thereby is thought to enhance the efficacy of methotrexate. A recent metanalysis showed that subcutaneously given MTX therapy has significantly higher odds than single dose weekly oral MTX of achieving reduction in disease activity, with no increased adverse effects. However, this metanalysis also pinpoints the fact that studies in this area is surprisingly few, i.e. this metanalysis is only based on four original publications.

The Swedish Rheumatology Quality Register (SRQ) is a nationwide quality register with the aim of continuously improving the treatment and follow-up of patients with rheumatic disease. SRQ has been granted certification level

1, which is the highest level a national quality register can obtain. Using this type of quality registers, it is possible to perform a Registrybased Randomised Clinical Trial (R-RCT) that are defined as prospective randomised studies that to some extent use registers for their implementation, that is for example a randomised clinical trial carried out by screening, recruitment and registration of study data based on information given in a quality register. Studies have also proposed an effect on gut microbiota both by the RA disease itself as well as by treatment with methotrexate. There is increasing knowledge that the gut microbiota are not only involved in the digestion and absorption of food, but they can also exert a protective function by preventing adherence of pathogenic bacteria to the mucosal layer, and they play a pivotal role in modulating the innate and acquired immunity of the host. Remarkably, gut microbiota exert their effects not only in the intestine but can signal to distant organs in the body, thereby explaining their association with several diseases, including RA. From a clinical perspective, elucidation of the interaction between RA, MTX and the gut microbiota could reduce the costs and harm to patients that is caused by "trial and error" use of drugs with highly variable treatment responses. Patient acceptability is particularly significant in dictating adherence to therapy.

A potential drawback to subcutaneous MTX is patients' fear of needles and/ or the discomfort of selfinjecting; however, this doubt has been strongly reassured with the advent of the widely accepted biologics which require self-injection. Recent studies examined patient preferences for RA treatment in several populations, finding that most participants were willing to accept certain risks of adverse effects to gain potential benefits, however there seem to be a variability in patient preferences for RA treatment, highlighting the importance of incorporating patient input into the treatment approach. Previous studies have mainly focused on patients with established RA, showing that many patients place a high value on treatment benefits over other treatment attributes, including side effects, cost, or route of administration (9) and also an expectance for injections of MTX in patients with long standing RA. However, patient preference studies are scarce in patients with newly diagnosed disease and in our part of the world. For patient preference study a (threshold technique) TT exercise is often used. Here a decisionmaker, typically a patient or physician is presented with a choice between two treatment or healthcare delivery options. One is the reference option that is the baseline against which an alternative is compared. It is often the option associated with the status quo or standard of care. The second is the target option and confers both an incremental benefit and an incremental burden relative to the status quo or standard of care. Once the reference and target options have been identified, the researcher must identify the key attribute of the target option (either a benefit or a burden) that will be used to estimate the strength of preference for the target relative to the reference option. The key attribute can be any attribute for which values can be expressed numerically. The most common key attributes are probability of benefit, risk of harm, waiting time, life expectancy, and cost. When the key attribute is a measure of burden (e.g., risk of harm, waiting time, or cost), the estimated threshold is a measure of the additional burden that exactly offsets the incremental benefit of the target option. If the key attribute is a benefit (e.g., probability of benefit or life expectancy), the estimated threshold is a measure of the minimum additional benefit that the target must provide to offset the incremental burden of that option. After being presented with descriptions of the two options, respondents real-world options with well-known attributes, using all available information in the initial question, including known differences between the options in the value of the key attribute, may provide a direct measure of decision makers' preference between the reference and target options in addition to providing a starting point for estimating the threshold value of the key attribute. If the reference option is chosen in the initial question, the key attribute of the target is made better or more appealing and the question is repeated. If the target is chosen initially, the key attribute of the target is made worse or less appealing and the question is repeated. The process continues until the researcher can identify the threshold level of the key attribute, i.e., the level at which a respondent is indifferent between the reference and target options. The difference between the threshold value of the key attribute and the level of the same attribute in the reference option is a measure of the strength of preference for the target option compared with the reference option. It is a measure of the change in the key attribute that exactly offsets the difference in benefit or burden between the reference and the target options. The threshold can be a specific value or an interval within which the threshold lies. If the tradeoff exercise yields a specific value, then that threshold for each respondent for each trade-off exercise is known. If, however, the trade-off exercise results in a threshold interval, then the researcher has options for how to utilize these data. The researcher can simply report the threshold interval or the proportion of respondents choosing the target option at different threshold intervals. During recent year an increasing interest have been on cost-utility analyses, comparing the cost per quality-adjusted life-year (QALY) of different treatment regimes. However, most studies focus on biologic treatment. The incremental cost for subcutaneous compared to per oral methotrexate is not insignificant, still health economic evaluations comparing these two administration routes, and which administration to recommend, are scarce.

Study Type

Interventional

Enrollment (Estimated)

212

Phase

  • 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 Locations

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

Ages Eligible for Study

16 years to 93 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • The subject has given written consent to participate in the study
  • Diagnosis of rheumatoid arthritis by rheumatologist fulfilling 2010
  • Rheumatoid Arthritis Classification Criteria
  • Indication of methotrexate
  • 18-95 years of age

  • Women of Childbearing Capacity (WOCBC) must:

    1. Comply to use of highly effective contraception methods during the course of the trial.
    2. Have a negative pregnancy test.
  • Male patients included in the study that have fertile female partners must use adequate contraception within their relationship during the same period of time

Exclusion Criteria:

  • Contraindications for methotrexate
  • Previous treatment with any DMARD within the last five years
  • Known or suspected allergies against methotrexate or any other substance in the given medication
  • Anamnestic information on pregnancy, breastfeeding, or planned pregnancy
  • Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation or inability to answer questionnaire in written Swedish
  • Treatment or disease which, according to the investigator, can affect treatment or study results.
  • Fear of needles leading to not being able to use subcutaneous injections
  • For the study in gut microbiota: Use of antibiotics or probiotics within the last 3 months

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: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Per oral
Drug:per oral Methotrexate Tablets dosage 5-30mg once weekly.
Drug: Methotrexate
When accepted inclusion the patient will be included in SRQ, and thereafter randomised for Methotrexate per oral or subcutaneous administration
Active Comparator: Subcutaneous
Drug: subcutaneous Methotrexate Injection dosage 5-30mg once weekly.
Drug: Methotrexate
When accepted inclusion the patient will be included in SRQ, and thereafter randomised for Methotrexate per oral or subcutaneous administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease activity measured as DAS28 over 12 months
Time Frame: 12 months
The primary objective of this study is to study difference in DAS28 (range 0-10, higher value means higher disease activity) over 12 months of follow up in patients with newly diagnosed RA randomized to oral or subcutaneous methotrexate
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease activity measured as DAS28 over 24 months
Time Frame: 24 months
One secondary outcome is to study difference disease activity measured as DAS28 (range 0-10, higher value means higher disease activity) over 24 months of follow up in patients with newly diagnosed RA randomized to oral or subcutaneous methotrexate
24 months
Disease activity measured as DAS28 over 3 months
Time Frame: 3 months
One secondary outcome is to study difference disease activity measured as DAS28 (range 0-10, higher value means higher disease activity) over 3 months of follow up in patients with newly diagnosed RA randomized to oral or subcutaneous methotrexate
3 months
Disease activity measured as DAS28 over 6 months
Time Frame: 6 months
One secondary outcome is to study difference disease activity measured as DAS28 (range 0-10, higher value means higher disease activity) over 6 months of follow up in patients with newly diagnosed RA randomized to oral or subcutaneous methotrexate
6 months
Gut microbiota by sequencing of the microbial 16S rRNA gene
Time Frame: 24 months
At follow up nalysis of gut microbiota composition will be done by sequencing of the microbial 16S rRNA gene.
24 months
Patient preferences
Time Frame: 24 months
To determine the acceptable levels of risks for newly diagnosed patients with RA measured using the threshold technique
24 months
Health economy
Time Frame: 24 months
To determine the health economic aspects including quality of life, measured by EQ5D, of the two administration routes
24 months
Adverse events
Time Frame: 24 months
Number of adverse events in patients with newly diagnosed RA randomized to oral or subcutaneous methotrexate over 24 months
24 months

Collaborators and Investigators

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

Sponsor

Region Västerbotten

Collaborators

Karolinska University Hospital
Uppsala University
Umeå University
Vastra Gotaland Region
Region Stockholm
Danderyd Hospital
Dalarna County Council, Sweden
Jämtland County Council, Sweden
Region Gävleborg
County Council of Norrbotten, Sweden
Västernorrland County Council, Sweden
Sormland County Council, Sweden

Investigators

  • Principal Investigator: Anna Södergren, MD PhD, Region Västerbotten

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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)

April 28, 2022

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

May 11, 2021

First Submitted That Met QC Criteria

April 25, 2022

First Posted (Actual)

April 29, 2022

Study Record Updates

Last Update Posted (Actual)

August 22, 2023

Last Update Submitted That Met QC Criteria

August 21, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MTXRA
  • 2020-000462-41 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual level data may not be made publicly available due to The General Data Protection Regulation (GDPR) and privacy concerns. The data used for this study contain protected health information. Data will available from Umeå University for researchers who meet the criteria for access to confidential data and have entered into a data use agreement. Umeå University has restricted public sharing because they contain identifying patient information.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

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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