Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06289114 |
| Other study ID # |
S-20220005 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2023 |
| Est. completion date |
September 1, 2025 |
Study information
| Verified date |
February 2024 |
| Source |
Hospital of South West Jutland |
| Contact |
Philip R Lage-Hansen, MD |
| Phone |
+4530114582 |
| Email |
philip.rask.lage-hansen3[@]rsyd.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
SUMMARY Background: Several studies have shown physical activity (PA) to be inversely
correlated to disease activity in rheumatoid arthritis (RA) patients. However, it is unclear
whether improved PA leads to lower disease activity or if low disease activity predicts
improved PA in rheumatoid arthritis patients. Furthermore, it is unknown how fibromyalgia
(FM) affects this interaction.
Objective(s): Our primary objective will be to compare the effect of an immediate improvement
in physical activity after one week on the proportion of RA patients achieving low disease
activity after 12 weeks of biological treatment. Furthermore, we will explore whether the
presence of concomitant FM affects this clinical response (i.e., interaction between FM
status and PA response).
Design: A prospective cohort study in the form of a target-trial attempting to address a
causal question comparing the outcome among the participants with an immediate improvement in
physical activity, relative to individuals without.
Setting and patients: Biologically naive RA patients initiating biological treatment are
consecutively enrolled. PA is quantified by accelerometry one week prior to, one week after,
and after 3 months of biological treatment.
Sample size: 100 RA patients starting biological therapy is planned enrolled in the study.
Measurements: RA patients will be divided into two groups depending on their improvement in
physical activity after onset of biological treatment. The percentage of time spent in
moderate-to-vigorously physical activity (MVPA) i.e., the percentage of time a patient is in
motion [walking, running, bicycling, or swimming] is measured prior to, one week, and
approximately 3 months after biological treatment onset, respectively. The MVPA ratio (MVPA
After biological treatment/MVPA Before biological treatment) will divide patients enabling a
contrast between two groups: Those with high improvement considering MVPA (after 1 week; the
upper tertile of MVPA ratio of the sample) and those without. Treatment response (achieving a
disease activity score < 3.2) after approximately 3 months from baseline will be analyzed as
the contrast between groups.
Description:
INTRODUCTION Chronic pain, fatigue and decreased functional ability are challenging for
patients suffering from Rheumatoid Arthritis (RA). Approximately half of this patient
population report significant pain, extensive fatigue, and limitation in activities of daily
living, including workability despite comprehensive anti-inflammatory treatment [1, 2]. RA
patients have an increased risk of cardiovascular disease similar to diabetes patients, and
RA is associated with excess mortality [3, 4]. Physical activity (PA) reduces the
cardiovascular risk through various pathways, including the enhanced activity of endothelial
nitric oxide synthase, increased blood flow and improvements in anti-oxidizing mechanisms
[5]. The fourth leading risk factor for death globally is physical inactivity, responsible
for approximately 6% of deaths [6].
PA has been widely studied in RA, where both self-report questionnaires and performance-based
assessment, such as accelerometry, have been applied [7-18]. The reliability of accelerometry
is well established [19, 20]; however, patient reporting of PA is subject to recall bias and
biased estimation. Studies have demonstrated only a modest association between self-reported
and performance-based measures of PA [9, 16].
Several accelerometry studies of RA patients have been performed with partially conflicting
results. Most studies have proven RA patients to be less physically active than healthy
controls, and only a minority of RA patients seem to fulfill the World Health organization
(WHO) recommendations regarding the level of daily physical activity [7, 10, 13-16, 18].
However, a minority of studies find no differences between RA patients and healthy controls
[12, 17]. Several studies have examined differences in PA among RA patients regarding disease
activity. They all found PA to be inversely correlated to disease activity or score on the
Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) [7, 8, 11, 14, 16, 18].
However, most of these studies do not allow inferences about directions of the observed
relationships given the study design applied. Only two studies (including n=18 and n = 30,
altogether 48 patients) were prospective, leaving this question relatively unanswered [14,
16].
Rationale and Evidence-Based Research Concomitant fibromyalgia (FM) is a chronic pain
syndrome characterized by widespread pain and tenderness, often accompanied by multiple
symptoms from various organ systems. FM has been estimated to be present in between 15 and 20
% of RA patients [21-23]. As for RA, PA studies in FM patients assessed by accelerometry have
concluded that FM patients are less physically active than healthy controls [24-28]. Like RA
patients, only a minority of FM patients fulfill WHO recommendations regarding daily physical
activity, and a former study has shown that RA patients with concomitant FM have higher
disease activity (DAS28-CRP) scores than sole RA patients [29]. To our knowledge, no study
has examined the impact of concomitant FM in RA patients regarding PA measured by
accelerometry and the response to disease-modifying treatment.
Aims and Hypotheses The primary aim of this study is to investigate the prognostic value of
immediate change in PA on treatment response among RA patients initiating their first
biological treatment (according to Danish national treatment guidelines [32]). The main
hypothesis is that treatment response to biological therapy (defined as achieving
DAS28-CRP<3.2 after 12-16 weeks, according to Danish national guideline [32]) can be
predicted from an initial higher increase in objectively measured PA, measured by
accelerometer one week after first biological treatment onset compared to one week before
biological treatment onset.
Secondary aims are to investigate whether the presence of concomitant FM (according to the
2016 criteria for FM), higher levels of CRP (above the median), and excessive fatigue (BRAF ≥
6) affect the possible effect of being PA responder immediately after initiating biological
treatment (i.e., testing the interaction between contextual factor and PA-group). Secondary
hypotheses are that concomitant FM, lower CRP, and excessive fatigue are associated with a
lack of improvement in objective measures of PA.
We also aim to explore the association between objective measures of PA, measures of
self-reported PA, functional ability, and fatigue on standardized diseases-specific
questionnaires. Finally, we want to examine if any differences exist regarding PA measured
one week after initiation of biological therapy compared to 3 months of biological therapy.
Objectives Our primary objective will be to compare the effect of an immediate significant
improvement in the objectively measured physical activity, relative to individuals without,
on the proportion of patients who subsequently achieve low disease activity (DAS28-CRP < 3.2)
after at least 12 weeks in RA patients initiating their first biological treatment.
Furthermore, we will explore whether the presence of:
- Concomitant FM (according to 2016 criteria) affects the clinical response (i.e.,
interaction between FM status and PA response)
- Higher levels of CRP (above the median) affect the clinical response (i.e., the
interaction between CRP status and PA response)
- Excessive fatigue (BRAF ≥ 6) affects the clinical response (i.e., the interaction
between fatigue status and PA response)
Other objectives include:
- Comparisons between objectively measured PA and self-reported PA (through a validated
standardized questionnaire) on the ability to predict treatment response after at least
12 weeks
- To compare the effect of an immediate significant improvement in the objectively
measured physical activity, relative to individuals without, on the proportion of
patients who subsequently achieve ACR 20%, 50%, and 70% response
- To compare the effect of an immediate significant improvement in the objectively
measured physical activity, relative to individuals without, on the proportion of
patients who subsequently achieve enhancement related to patient related outcome
measurements including HAQ-DI, VAS-scores of pain and fatigue.
Study design The study is designed as a prospective cohort study that follows RA patients
from a week before initiation of their biologic agent (baseline; t = 0 weeks) up to the first
outcome assessment after at least 12 weeks from baseline.
Setting and source of data RA patients treated in Esbjerg and OUH rheumatic outpatient
clinics who fulfill nationally endorsed criteria for initiating biological treatment and
where such treatment decisions have been made (by patients treating rheumatologists) are
consecutively invited to participate in the study. If acceptance is achieved and inclusion
and exclusion criteria are satisfied, informed consent will be obtained, and patients will be
enrolled in the study. Patients are planned to be evaluated regarding physical activity
during one week prior to the onset of biological therapy and during the following week after
the onset of biological therapy. After 12-16 weeks, study participants are again evaluated
regarding physical activity and disease activity.
Participants Eligibility criteria: Patients with RA (> 18 years of age) who are to be treated
with a biological agent and who can read and understand Danish. Exclusion criteria: patients
who are physically impaired (patients depending on assistance devices for walking),
pregnancy, patients who have received corticosteroids two weeks prior to and during the
period of the movement measurement, and patients who by virtue of illiteracy or cognitive
impairment are unable to complete the questionnaire.
Variables and Outcome(s) Clinical data include personal data, assessment for concomitant FM
through the FM score according to 2016 criteria for FM [21], PA measurements by
accelerometry, self-reported evaluation of PA, and disease activity scores including
patient-reported outcome measures (PROMs), fatigue evaluation (by Bristol Rheumatoid
arthritis fatigue multidimensional questionnaire [BRAF-MDQ] [34]), clinical assessments, and
laboratory data. PA is measured by accelerometry, where patients' actual physical activity is
quantified. The time the participant is lying, sitting, standing, walking, running,
bicycling, and swimming is recorded for each activity by the sensor during the period of
measurement. The percentage of time a subject exhibit MVPA; that is the percentage of time a
patient is in motion [i.e., walking, running, bicycling, or swimming]) can thereby be
derived. MVPA is measured before, one week after and finally 3 months after initiation of
biological therapy. We will define the MVPA ratio MVPA AFTER / MVPA BEFORE, where "after"
reflects time spent in MVPA one week after onset of biological treatment and "before" refers
to time spend in MVPA one week before biological treatment onset. We define an MVPA ratio >
the upper tertile of the cohort as representing a high MVPA ratio.
Predictors For the primary prognostic model, the primary exposure variable will be the MVPA
ratio measured as MVPA AFTER / MVPA BEFORE reflecting the time spent in MVPA 1 week after and
before onset of biological treatment. Patients will be dichotomized into two groups based on
the upper tertile value of the MVPA ratio. Study participants with improvement corresponding
to the upper tertile of MVPA ratio will be considered "PA Improvers" while other patients
will be considered "PA Failures".
Data sources and measurements A sensor named "SENS motion" will be attached to the patient's
left thigh to evaluate movement. The SENS motion is a small device that measures patients'
actual physical activity. The time the subject is lying, sitting, standing, walking, running,
bicycling, and swimming is recorded for each activity by the sensor during the period of
measurement. In this manner, an overview of patients' actual physical activity is derived
[35, 36].
All enrolled patients are planned to be evaluated regarding movement during three periods
lasting one week each. The "SENS motion" device will be attached to the patients one week
prior to biological treatment onset defining period number one. Period number two is defined
by the time of biological treatment initiation and during the following week. The SENS motion
device will then be detached. At 3 months follow-up, another SENS motion device is attached
to the patient's left thigh, generating data regarding actual movement as earlier explained.
Final data collection is completed 1 week after the scheduled visit to the rheumatic
outpatient clinic and the detachment of the SENS motion devise is performed.
All study subjects will, before attachment of the Sens motion device, fill in the
international physical activity questionnaire (IPAQ), which is a standardized and validated
tool measuring PA [37]. Patients will fill in the questionnaire before initiating biological
therapy, when detachment of the Sens-motion device is performed the first time (after one
week of biological treatment) and at 3 months follow up. Furthermore, all patients will at
enrollment and at 3 months follow-up be evaluated for concomitant fibromyalgia according to
2016 criteria. Before and 12 weeks after initiation of biological therapy, patients fill in
the standard questionnaires used for evaluating treatment response in RA patients and
DAS28-CRP calculations will be performed. The questionnaires include the HAQ-DI and VAS
scores regarding pain, fatigue, and overall wellbeing. Furthermore, for evaluating level of
fatigue more thoroughly, patients will fill in the BRAF-MDQ simultaneously [34]. Finally, all
patients will at inclusion be evaluated regarding potential confounders as outlined earlier.
Based on the percentage of time a patient exhibits MVPA; that is the percentage of time a
patient is in motion (i.e., walking, running, bicycling, or swimming) during one week before
initiating biological therapy and during the following week after onset of biological therapy
(i.e., MVPAAFTER / MVPA BEFORE) patients will be dichotomized in groups based as earlier
explained.
Power and Sample size considerations
Based on earlier studies [14, 16] we expect that patients reaching low disease activity will
show increased time of MVPA, however it is unknown if this will occur within one week of
treatment onset. As earlier explained, no similar studies have ever been performed, why no
formalized power and sample size calculation was performed. However, if we assume that on
average two-thirds of RA patients are responding to biologics (independent of prognostic
phenotype), we have ptotal = 2/3 ptotal = (w1 × p1 + w2 × p2) / (w1 + w2)
Anticipating almost all the patients (say p1=90%) with an immediate response on PA after 1
week (33% of the total sample), will have achieved low disease activity after 12-16 weeks,
that corresponds to p2=55% will achieve low disease activity in the other group (67% of the
sample). From this we have estimated that we would have a reasonable statistical power (>80%)
to detect a difference between the groups if we enroll 60 patients in total (i.e.
corresponding to a n1=20 vs. n2=40). Due to the risk of missing data from the application of
a new device, we decided to aim for including 100 patients in total.
