Rheumatoid Arthritis (RA)
Conditions
Keywords
TNF inhibitors, csDMARDs, Disease activity, Mean-time weighted
Brief summary
The goal is to investigate whether a strategy of attempting to discontinue of MTX or LEF (and restart when necessary) in RA patients treated with an optimal dose (allowed dose or lower, tapered to the maximum, or according to patient preference) TNFi is not worser to a continuation of combination therapy. The study will also examine the disease-related effects of treatment that attempts to discontinue MTX or LEF, how patients experience it, its safety, and its impact on medication usage and healthcare costs. The main outcome is the difference between treatments in average disease activity over 24 months. The study will compare whether disease activity remains similar between patients who attempt to discontinue MTX or LEF and those who continue combination therapy. Patients will be followed for 24 months with scheduled hospital visits at baseline, after 3, 6, 12, 18, and 24 months, remote visits, and additional visits for disease flares. X-rays of the hands and feet will be taken at baseline and after 24 months. During some visits, additional blood samples will be taken to measure inflammation markers and medication levels.
Detailed description
Rationale Rheumatoid arthritis (RA) is a long-term inflammatory disease that causes joint pain, swelling, and stiffness. Many patients are treated with a combination of medications to control inflammation. These usually include a biological medicine called a TNF inhibitor (TNFi) and another medicine, methotrexate (MTX) or leflunomide (LEF). Although this combination treatment is effective, patients often experience side effects (such as gastro-intestinal complaints and fatigue), require frequent blood tests, and may experience treatment fatigue from taking multiple medications. Patients would therefore prefer to reduce their medication. The safe reduction of TNFi treatment has been studied before. It is still unclear whether patients can safely discontinue MTX or LEF when their disease is well controlled. This study investigates whether attempting to discontinue MTX or LEF while using a TNF inhibitor is no worse than continuing combination treatment in terms of disease activity, with the hope of reducing side effects, the need for monitoring, and healthcare costs. Objective The objective is to investigate whether a strategy of attempting to discontinue of MTX or LEF (and restart when necessary) in RA patients treated with an optimal dose (allowed dose or lower, tapered to the maximum, or according to patient preference) TNFi is not worser to a continuation of combination therapy. The study will also examine the disease-related effects of treatment that attempts to discontinue MTX or LEF, how patients experience it, its safety, and its impact on medication usage and healthcare costs. Main trial endpoints The main endpoint is the difference between treatments in average disease activity over 24 months. The study will compare whether disease activity remains similar between patients who attempt to discontinue MTX or LEF and those who continue combination therapy. Secondary trial endpoints Other study outcomes include the proportion of patients in the discontinuation strategy group using MTX/LEF and/or a TNFi after 24 months, and differences between treatments in patient-reported outcomes, joint damage measured by X-ray, blood levels of TNF inhibitors, safety and cost-effectiveness. Trial design This study is being conducted in multiple hospitals. A total of 202 patients with RA will be randomly assigned to stopping MTX/LEF or continuation of combination therapy and followed for 24 months. Two-thirds of the patients will attempt to discontinue MTX or LEF (discontinuation group), and one-third will continue using the combination treatment (continuation group). Trial population Adult patients aged 18 years and older with RA are eligible to participate if their disease has low disease activity for at least six months during treatment with a TNFi in combination with MTX or LEF. Interventions In this study, we examine the difference between two groups: the discontinuation group and the continuation group. In the discontinuation group, patients immediately stop taking MTX or LEF and use only the TNFi at a stable dose. When disease activity increases, MTX or LEF can be restarted at the previous dose. If necessary, temporary treatment, such as glucocorticoids, can be administered. In the continuation group, patients continue using combination therapy with MTX or LEF and a TNFi at stable doses. In both groups, the goal is to maintain a stable dose of the TNFi throughout the study. Dosage adjustments or switching to a different biologic drug are permitted if disease activity increases or if side effects occur. These decisions are made by the treating rheumatologist in consultation with the patient. During the 24-month study, patients continue to receive regular care, including six-monthly check-ups and laboratory tests. An additional study visit takes place after 3 months to detect changes in disease activity at an early stage. In addition, remote visits (by telephone) will take place at 9, 15 and 21 months. Additional visits can be scheduled if a disease flare is suspected.
Interventions
DRUGStrategy to attempt discontinuation of MTX or LEF (and restart when necessary)
Participants will discontinue their csDMARD (MTX or LEF) immediately following randomization and continue TNFi monotherapy at their current stable dose.
DRUGContinuation of MTX or LEF
Participants will aim to continue combination therapy with csDMARD (MTX or LEF) and TNFi at their current stable doses.
Sponsors
Sint Maartenskliniek
ZonMw: The Netherlands Organisation for Health Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a 24-month multicentre, randomized, controlled, open-label, non-inferiority strategy trial. A total of 202 patients with RA in sustained LDA on TNFi plus csDMARD will be randomized 2:1 (csDMARD discontinuation strategy : csDMARD continuation strategy).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years. * Diagnosis of RA, according to the 2010 ACR/EULAR and/or 1987 RA classification criteria or clinical diagnosis by a rheumatologist. * Stable disease activity for ≥ 6 months, defined as DAS28-CRP ≤ 2.9 or DAS28-CRP ≤ 3.5 combined with clinical judgment of LDA. * Current combination therapy consisting of TNFi and either MTX or LEF. * TNFi administration at a stable dose (at an optimal dose, defined as the authorized dose or lower and being maximally tapered, because of prior disease flare or patient preference) for ≥6 months prior to screening, during which LDA is maintained for ≥6 months. * MTX or LEF administration at a stable dose for ≥3 months prior to screening. * Ability to comply with all study procedures, visits and follow-up assessments. * Written informed consent provided prior to any study-related procedure.
Exclusion criteria
* A previous attempt within the last 12 months prior to screening to taper or discontinue MTX or LEF that required reintroduction or dose increase of the csDMARD due to a disease flare. * Current MTX or LEF treatment for other indications than RA. * Current treatment with prednisolone (equivalent) of \> 5 mg per day. * Current severe comorbidity or serious life-shortening condition that could interfere with adherence to the study protocol or completion of the 24-month follow-up period. * Women that are pregnant, breast feeding or considering pregnancy during the study period (MTX and LEF are contraindicated in pregnancy and breastfeeding). * Inability to comply with the study procedures, visits, or follow-up assessments. * Inability or unwillingness to provide informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The between-group difference in mean time-weighted DAS28-CRP during 24 months of follow-up. | At 24 months of follow-up. | The between-group difference in mean time-weighted DAS28-CRP during 24 months of follow-up. A mean time-weighted DAS28-CRP is chosen to balance the limitations of assessing disease activity at a single timepoint with solely considering the occurrence of flare. The time-weighted DAS28-CRP consists of a weighted average of a patient's DAS28-CRP scores, calculated using the trapezoid method and weighed by the time interval between measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Between-group difference in disease activity | At 3, 6, 12, 18 and 24 months of follow-up. | Disease activity measured by DAS28-CRP at 3, 6, 12, 18 and 24 months. |
| Between-group difference at specific timepoint disease activity | At 3, 6, 12, 18 and 24 months of follow-up. | Proportion of patients in remission (DAS28-CRP ≤ 2.4) or LDA (DAS28-CRP ≤ 2.9) at 3, 6, 12, 18, and 24 months. |
| Between-group difference in PROM | At baseline and 3, 6, 12, 18 and 24 months of follow-up and flare-visits. | Fatigue and pain are measured by the Numeric Pain Rating Scale (NRS 0-10), where the minimum value is 0 and the maximum value is 10, meaning higher scores indicate a worse outcome of greater pain intensity and more severe fatigue. This scale is administered at baseline, 3, 6, 12, 18, and 24 months, as well as at flare visits. |
| Between-group difference in radiographic progression | At 24 months of follow-up. | Radiographic joint damage is measured by the change between baseline and 24 months in the Simple Erosion Narrowing Score (SENS), where the minimum value is 0 and the maximum value is 86, meaning higher scores indicate a worse outcome of more severe joint destruction and progression of structural damage. |
| Between-group difference in physical functioning | At baseline and 3, 6, 12, 18 and 24 months of follow-up and flare-visits. | Physical functioning is measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI), where the minimum value is 0 and the maximum value is 3, meaning higher scores indicate a worse outcome of greater functional disability and impairment. This questionnaire is administered at baseline, 3, 6, 12, 18, and 24 months, as well as at flare visits. |
| Between-group difference in quality of life | At baseline and 3, 6, 12, 18 and 24 months of follow-up and flare-visits. | Health-related quality of life is measured by the Euro Quality of Life 5-Dimensions 5-Levels (EQ-5D-5L) questionnaire, where the minimum value is 0 or 1 (0 for the visual analogue scale and 5 for the level sum scores) and the maximum value is 5 or 100 (5 for the level sum scores and 100 for the visual analogue scale), meaning higher scores indicate a worse outcome of better overall health status. This questionnaire is administered at baseline, 3, 6, 12, 18, and 24 months, as well as at flare visits. |
| Between-group difference in pharmacokinetic and immunogenicity parameters | At baseline and 3 and 24 months of follow-up. | TNFi and ADA serum levels at baseline, 3 (csDMARD discontinuation group only), and 24 months. |
| Between-group difference in flares | At 24 months of follow-up. | Proportion of patients relapsing/restarting combination therapy over 24 months. |
| Between-group difference in safety | At 24 months of follow-up. | Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) using the Common Terminology Criteria for Adverse Events version 5 (CTCAEv5) over 24 months. |
| Between-group difference in medication use | At 24 months of follow-up. | Proportion of patients in the csDMARD discontinuation group using a csDMARD and/or TNFi at 24 months. |
Countries
Netherlands
Contacts
CONTACTAlfons den Broeder, Dr.
CONTACTSophie Marie Gerritsen, MSc.
Outcome results
None listed