Ignite Creation Date:
2024-05-06 @ 8:11 PM
Last Modification Date:
2024-10-26 @ 3:22 PM
Study NCT ID:
NCT06289114
Status:
RECRUITING
Last Update Posted:
2024-03-01
First Post:
2024-02-23
Brief Title:
Predictive Utility of a Short-term Improvement in Objectively Measured Physical Activity in Rheumatoid Arthritis PUSIPA
Sponsor:
Hospital of South West Jutland
Organization:
Hospital of South West Jutland
Study Overview
Official Title:
Predictive Utility of a Short-Term Improvement in Objectively Measured Physical Activity in Rheumatoid Arthritis Patients Initiating Biologics A Prospective Cohort Study
Status:
RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PUSIPA
Brief 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
Objectives 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 ie 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 ie 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 treatmentMVPA 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 32 after approximately 3 months from baseline will be analyzed as the contrast between groups
Objectives 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 ie 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 ie 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 treatmentMVPA 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 32 after approximately 3 months from baseline will be analyzed as the contrast between groups
Detailed 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 n18 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-CRP32 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 ie 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 32 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 ie interaction between FM status and PA response
Higher levels of CRP above the median affect the clinical response ie the interaction between CRP status and PA response
Excessive fatigue BRAF 6 affects the clinical response ie 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 Outcomes 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 ie 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 patients 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 patients 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 ie walking running bicycling or swimming during one week before initiating biological therapy and during the following week after onset of biological therapy ie 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 23 ptotal w1 p1 w2 p2 w1 w2
Anticipating almost all the patients say p190 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 p255 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 ie corresponding to a n120 vs n240 Due to the risk of missing data from the application of a new device we decided to aim for including 100 patients in total
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 n18 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-CRP32 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 ie 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 32 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 ie interaction between FM status and PA response
Higher levels of CRP above the median affect the clinical response ie the interaction between CRP status and PA response
Excessive fatigue BRAF 6 affects the clinical response ie 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 Outcomes 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 ie 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 patients 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 patients 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 ie walking running bicycling or swimming during one week before initiating biological therapy and during the following week after onset of biological therapy ie 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 23 ptotal w1 p1 w2 p2 w1 w2
Anticipating almost all the patients say p190 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 p255 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 ie corresponding to a n120 vs n240 Due to the risk of missing data from the application of a new device we decided to aim for including 100 patients in total
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None