Real-World Emulation of the SWEFOT Trial (SWEFOT-RWEM)

September 22, 2021 updated by: Thomas Frisell, Karolinska Institutet

Comparison of Infliximab With Sulfasalazine/Hydroxychloroquine Initiated After Methotrexate by Rheumatoid Arthritis Patients Treated in Clinical Practice (Real-World Emulation of SWEFOT Trial)

This study will compare rheumatoid arthritis (RA) patients who have been treated in clinical practice with either infliximab or a combination of sulfasalazine and hydroxychloroquine, after having an active disease despite treatment with methotrexate for at least one month. To establish which patients respond to treatment, DAS28-ESR measurements (disease activity score using 28 joints and erythrocyte sedimentation rate) taken at treatment start and nine months thereafter, and the EULAR (European League Against Rheumatism) definition of a "good response" will be employed.

The purpose of the study is to verify if the same conclusion could be reached using data from patients treated in real world clinical practice as in a previous randomized controlled trial comparing the two treatment strategies (SWEFOT -- ClinicalTrials.gov Identifier: NCT00764725).

Inclusion criteria similar to the ones used in the emulated trial will be applied.

In real clinical practice, patients who receive infliximab may have more severe RA and may also differ in other ways from patients receiving sulfasalazine and hydroxychloroquine. To be able to compare the proportions of responders under each treatment in this "real-world" setting, the data will be re-weighted, so that patient characteristics become balanced between treatment groups.

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

This observational study is designed to verify if the results of a previously conducted randomized controlled trial (SWEFOT -- ClinicalTrials.gov Identifier: NCT00764725) could be replicated with observational data, by emulating the trial protocol as close as possible.

Thus, early rheumatoid arthritis (RA) patients who initiated treatment with infliximab or a combination of sulfasalazine and hydroxychloroquine after at least 30 days of methotrexate will be identified in the Swedish Rheumatology Quality register (SRQ) linked to other Swedish national registers and will be compared. Similar inclusion/exclusion criteria to the ones used in SWEFOT will be applied. Also, in keeping with SWEFOT, the primary outcome is the proportion of patients with a "good EULAR response", measured nine months after study treatment initiation and considering patients who discontinued treatment before this point "non-responders" (i.e. "non-responder imputation" - regardless of the reason for discontinuation). For the combination of sulfasalazine and hydroxychloroquine the start of the second drug in the combination will be considered the study treatment initiation.

Since treatment assignment is not random in observational data, inverse probability of treatment weighting will be applied to balance patient characteristics between treatment cohorts, making them comparable (i.e. exchangeable). For each observation (i.e. patient), the probability of receiving the treatment actually received, conditional on a prespecified list of potential confounders will be estimated by logistic regression modelling and will be used to calculate a weight. Potential confounders included in the model are chosen based on knowledge about factors influencing treatment allocation and observed differences in such characteristics between treatment groups. The list of confounders includes: sex, age, country of origin, year of treatment start, duration of RA at treatment start, rheumatoid factor, disease activity at treatment start measured via: DAS28-ESR (disease activity score using 28 joints and erythrocyte sedimentation rate), CDAI (clinical disease activity index), number of swollen and tender joints, pain assessment (measured on a visual analogue scale) and HAQ-DI (health assessment questionnaire disability index), use of NSAIDs and of glucocorticoids, history of: cancer, diabetes, acute coronary syndrome, stroke, venous thromboembolism, peripheral vascular disease, obstructive respiratory disease, anaemia, psoriasis, neuropathies, pain, osteoporosis, depression or anxiety, joint surgery, retinopathy and hospitalized infections, the number of days spent in hospital within 5 years before treatment start, smoking status.

All data included in this study is extracted from Swedish national registers. In these registers, data is collected routinely, prospectively and independently from any study. Thus, data on baseline characteristics was collected before treatment initiation, while outcome data was recorded after treatment initiation.

The proportion of responders in each group and the ratio between proportions will be estimated using a weighted generalized linear model, specifying a binomial distribution for the dependent variable and a logarithmic identity function. Before analysis, missing data (covariates and outcome) will be imputed using fully conditional specification multiple imputation after non-responder imputation. All data-analysis (from weights estimation to responder-ratio estimation) will be conducted separately in each imputed data-set, the results being subsequently pooled using Rubin's rules.

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.
Observational

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.
509

Contacts and Locations

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

Study Locations

  • Sweden
      • Stockholm, Sweden
        • Karolinska Institutet, Department of Medicine Solna, Clinical Epidemiology Unit

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

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Adult patients with rheumatoid arthritis as recorded in the Swedish Rheumatology Quality register (main data source), who initiated one of the two study treatments (infliximab or sulfasalazine + hydroxychloroquine). All eligible patients were included in the study (without any subsequent selection).

Description

Inclusion criteria:

  • Have started methotrexate less than 540 days after RA debut.
  • Have used methotrexate for more then 30 days but less than 540 days before study treatment start.
  • Have a baseline DAS28-ESR of more than 3.2 at study treatment start.
  • Were residents of Sweden within 5 years before study treatment start

Exclusion criteria:

  • Have used other DMARDs (antirheumatic drugs) than methotrexate before treatment start
  • Have initiated study treatments later than May 2020

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

  • Observational Models: Cohort
  • Time Perspectives: Other

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
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.
Infliximab initiators
Rheumatoid arthritis patients initiating infliximab after treatment with methotrexate for a minimum of 30 days.
Biological: Infliximab
Initiation of infliximab in any dose and frequency of administration. Could be discontinued for safety reasons and replaced by etanercept.
Other Names:
  • Flixabi, Inflectra, Remicade, Remsima, Zessly
Sulfasalazine + Hydroxychloroquine initiators
Rheumatoid arthritis patients initiating sulfasalazine and hydroxychloroquine after treatment with methotrexate for a minimum of 30 days.
Drug: Sulfasalazine + Hydroxychloroquine
Initiation of sulfasalazine and hydroxychloroquine not more than 180 days apart, in any dose and frequency of administration. Any one of the two drugs could be discontinued. while continuing the other, or both could be replaced by cyclosporine, for safety reasons.
Other Names:
  • Salazopyrin (sulfasalazine), Plaquenil (hydroxychloroquine)

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
Good EULAR Response
Time Frame: 9 months after study treatment initiation
The proportion of patients remaining on treatment and achieving a "good EULAR response" defined as a DAS28-ESR ≤ 3.2 at evaluation and a decrease > 1.2 units compared to the value at treatment initiation.
9 months after study treatment initiation

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
Good or Moderate EULAR Response
Time Frame: 9 months after study treatment initiation
The proportion of patients remaining on treatment and achieving a "good or moderate EULAR response" defined as a DAS28-ESR ≤ 5.1 at evaluation and a decrease > 0.6 units compared to the value at treatment initiation, or a DAS28-ESR > 5.1 at evaluation and a decrease > 1.2 units compared to treatment start.
9 months after study treatment initiation

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.
Karolinska Institutet

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.
Harvard Medical School (HMS and HSDM)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Thomas Frisell, PhD, Karolinska Institutet

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)

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.
January 12, 2006

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.
November 16, 2020

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.
November 16, 2020

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).
September 10, 2021

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.
September 10, 2021

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.
September 21, 2021

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.
September 28, 2021

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.
September 22, 2021

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.
September 1, 2021

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.
  • SWEFOT-RWEM

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

There is not a plan to make IPD available

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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