Methotrexate Monitoring Target Trial Emulation

April 3, 2026 updated by: Cynthia Crowson, Mayo Clinic

Safety of Reduced Methotrexate Lab Monitoring: a Population-based, Target Trial Emulation Study

The goal of this retrospective, observational study is to learn more about the risks and benefits of methotrexate lab monitoring. The main question it aims to answer is:

- Is reduced methotrexate lab monitoring non-inferiorly safe when compared to standard lab monitoring?

Differences in end-organ damage and/or death will be compared between participants who have previously been treated with methotrexate for various rheumatic diseases and have undergone varying intervals of methotrexate lab monitoring

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

- Target trial emulation that will include Incident methotrexate users age ≥18 years in the REP between 1/1/2012-12/31/2022 (to allow at least three years follow-up through analysis date 12/31/2025) with ≥2 preceding codes for rheumatic disease

Treatment strategies:

  • Guidelines group: monitor 3+ times in first 0-3 months, 3+ times in 3 to 12 months, and at least once every 4.5 months afterward.
  • Reduced group: monitor 1-2 times in first 0-3 months, 1-2 times in 3 to 12 months, and at least once per year afterward (but not more than once every 4.5 months).
  • Assignment procedures: We will use clone-censor-weighting (CCW) methods to explore the effect of both treatments in each patient. A negative control outcome such as trauma outcomes to assess for uncontrolled confounding.
  • Time zero: start date of incident methotrexate use
  • Follow up: Ends at methotrexate discontinuation (defined as not taking methotrexate for ≥6 months), death, loss to follow-up, or three years after baseline, whichever occurs first.

Data: Laboratory and prescription data were electronically available since 1/1/2010 and fully viewable since 1/1/2012. Therefore, this study will include all adults aged ≥18 years with incident low-dose (≤25mg/week) methotrexate use from 1/1/2012 on. To ensure the population would fall under the purview of the ACR methotrexate monitoring guidelines, we also required ≥2 codes (30 days apart) for a rheumatic condition within two years prior to index date of first methotrexate prescription, which we ascertained by prescription data and confirmed by manual chart review. A rheumatologist previously manually abstracted all methotrexate monitoring-related data including frequency as described previously (Reed et al., unpublished).

Outcomes:

  • Primary outcome is end-organ injury including cirrhosis, severe cytopenia defined by blood product transfusion (RBCs, Plts, G-CSF), or death, all within the follow-up period above. The outcome will be reported as absolute risk per 100 person-years.
  • For cirrhosis we will initially use a published code set of ICD-9 and ICD-10 codes with PPV > 50% and then perform blinded, independent validation of outcome and date by chart review.
  • Sample size/Power Calculation; A parallel, two-group design (where higher Poisson rates are considered worse) will be used to test whether the Group 2 (treatment) Poisson rate is non-inferior to the Group 1 (control) Poisson rate, with a non-inferiority ratio of 1.5 (H0: λ2 / λ1 ≥ 1.5 versus H1: λ2 / λ1 < 1.5). The comparison will be made using a one-sided, two-sample, Poisson regression term Z-test using the variance calculation method with assumed true rates, with a Type I error rate (α) of 0.025. The dispersion is assumed to be 1. To detect a ratio of Poisson event rates (λ2 / λ1) of 1.25 (λ2 = 0.00413, λ1 = 0.0033), with a sample size of 1500 subjects in Group 1 and 1100 subjects in Group 2, with average exposure time 4, the power is 0.08092. The power was computed using PASS 2025, version 25.0.2. Anticipating a 20% dropout rate, 1875 subjects should be enrolled in Group 1, and 1375 in Group 2, to obtain final group sample sizes of 1500 and 1100, respectively.
  • Missing data: Multiple imputation with predictive mean matching will be implemented for baseline data that are assumed missing at random (allows for inclusion of key predictors of both missingness and outcomes).26 Median/modal values of the multiple imputed values will be used for single imputation purposes.

Analysis plan:

  • Estimate per-protocol effect via comparison of outcome under each treatment strategy using CCW estimation approach, adjusting for baseline confounders alone. Under the CCW estimation approach, we will only be able to estimate the per-protocol effect of reduced monitoring.
  • noninferiority margin: We will survey all co-authors and use their mean answer for tolerable increased absolute risk per 100 person-years of end-organ injury or death to justify the benefits of reduced monitoring (e.g., reduced methotrexate avoidance, cost, time, iatrogenic harm) as the noninferiority margin. We will use one-sided alpha of 0.025
  • Normally distributed continuous variables will be compared using t-tests, non-normally distributed continuous variables using the Wilcoxon rank sum tests, and categorical variables using the chi-squared or Fisher's exact tests (for variables with low cell sizes), as appropriate.
  • Sensitivity analyses will be conducted for negative control outcome, patients on methotrexate monotherapy, no preceding cirrhosis, an eGFR of < 45 mL/min, based on creatinine with CKD-EPI equation calculation, defining cytopenia using CIRT definition of Hgb <8, plt <50, or WBC <2.9, serum albumin of < 3.0 g/dL (30g/L)

Study Type

Observational

Enrollment (Actual)

2414

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

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Incident methotrexate users age ≥18 years in the REP between 1/1/2012-12/31/2022 (to allow at least three years follow-up through analysis date 12/31/2025) with ≥2 preceding codes for rheumatic disease

Description

Inclusion Criteria:

  • Incident methotrexate users in rheumatology practice.

Exclusion Criteria:

  • Hypersensitivity to methotrexate
  • Persistent transaminitis 4 weeks prior to study initiation
  • Preexisting severe cytopenias or laboratory evidence consistent with immunodeficiency syndromes
  • Active malignancy
  • Pregnancy
  • Breastfeeding patients

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

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Standard (guidelines) monitoring
The group which has undergone a standard frequency of methotrexate lab monitoring
Diagnostic test: Standard methotrexate lab monitoring
This group will undergo standard or guidelines based frequency of methotrexate lab monitoring, defined as lab monitoring 3+ times in first 0-3 months, 3+ times in 3 to 12 months, and at least once every 4.5 months afterward.
Reduced monitoring
The group which has undergone a reduced frequency of methotrexate lab monitoring compared to the standard group
Diagnostic test: Reduced methotrexate lab monitoring
This group will undergo reduced frequency of methotrexate lab monitoring, defined as lab monitoring 1-2 times in first 0-3 months, 1-2 times in 3 to 12 months, and at least once per year afterward (but not more than once every 4.5 months).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Primary Outcome
Time Frame: From baseline until methotrexate discontinuation, death or loss to follow-up, assessed up to 3 years.

Primary outcome is end-organ injury including cirrhosis, severe cytopenia defined by blood product transfusion (RBCs, Plts, G-CSF), or death, all within the follow-up period above.

The outcome will be reported as absolute risk per 100 person-years
From baseline until methotrexate discontinuation, death or loss to follow-up, assessed up to 3 years.

Collaborators and Investigators

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

Sponsor

Mayo Clinic

Collaborators

National Institute on Aging (NIA)
National Center for Advancing Translational Sciences (NCATS)
Rochester Epidemiology Project

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)

January 1, 2012

Primary Completion (Actual)

December 31, 2025

Study Completion (Actual)

December 31, 2025

Study Registration Dates

First Submitted

March 24, 2026

First Submitted That Met QC Criteria

April 3, 2026

First Posted (Actual)

April 6, 2026

Study Record Updates

Last Update Posted (Actual)

April 6, 2026

Last Update Submitted That Met QC Criteria

April 3, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20-008534
  • UL1TR002377 (U.S. NIH Grant/Contract)
  • AG 058738 (Other Grant/Funding Number: National Institute on Aging (NIA))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

individual clinical trial participant-level data will not be shared

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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