Exercise-induced Cardiac Adaptions in Rheumatoid Arthritis Patients During IL-6 vs. TNF Antibody Therapy (RABEX)

Exercise-induced Cardiac Adaptions in Rheumatoid Arthritis Patients During Interleukin-6 vs. Tumor Necrosis Factor Antibody Therapy: a Randomised, Controlled Study.

The present study will investigative the physiological effects of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) on the adaptive changes to exercise in patients with rheumatoid arthritis. The investigators hypothesize that blockage of IL-6 receptors will decrease the cardiac and metabolic adaptations to exercise training compared to the inhibition of TNF. 80 patients will be included in a 12-week investigator blinded randomised exercise training intervention study.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Behavioral: No exercise; Behavioral: Exercise

Detailed Description

80 patients with rheumatoid arthritis who are being treated with either interleukin-6 receptor blockers (IL-6Rb) or tumor necrosis factor inhibitors (TNFi) for a minimum of four months prior to enrollment will be recruited and undergo baseline testing, including examination, biochemistry, ECG, DXA, OGTT, pulmonary function, VO2max, echocardiography, cardiac MRI.

After baseline testing, 40 patients in IL-6 receptor blocker treatment and 40 patients in TNF inhibitor treatment.will be randomly allocated into one group receiving standard of care (control group) or a group performing supervised high-intensity interval training three times a week over a period of 12 weeks. The randomization procedure involves a computer-generated block randomization schedule in a ratio of 1:1 stratified by sex by an independent person. Following the 12-week intervention period, all groups will complete a series of follow-up tests (as baseline testing).

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age >= 18 and <70 years
• Informed consent
• Diagnosed RA based on the 2010 American College of Rheumatology/ EULAR criteria. In biological treatment with either IL-6rB og TNFi over four months prior to enrollment
• Low RA disease activity, based on the Disease Activity Score-28 ESR for Rheumatoid Arthritis (DAS28) <=3.2
• An electrocardiogram without features of left ventricular hypertrophy defined by the European Society of Cardiology

• Females of childbearing potential have to use one or more of the following highly effective methods for contraception in order to be included:

  • Vasectomized partner
  • Bilateral tubal occlusion
  • Sexual abstinence
  • Intrauterine device
  • Hormonal contraception

• Females who are considered to have no childbearing potential are

  • Bilateral tubal ligation
  • Bilateral oophorectomy
  • Complete hysterectomy
  • Postmenopausal defined as 12 months with no menses without an alternative medical cause

Exclusion Criteria:

• Health conditions that prevent participating in the exercise intervention determined by the Project Coordinator
• Subjects who cannot undergo MRI scans (metallic implants or claustrophobia)
• Corticosteroid use per os > 10 mg/day within seven days of study enrollment
• Intramuscular corticosteroid within 3 weeks of the study enrollment
• Grade 2 hypertension (systolic BP > 160 mmHg and/or diastolic BP >100 mmHg) despite the use of antihypertensive drugs.
• Pregnancy
• Subjects with insulin dependent Diabetes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RA patients TNFi Exercise; The patients will be randomized to 12-week supervised exercise training intervention or no exercise training. The exercise training program includes three supervised sessions per week over a 12-week period. The program consists of high intensity endurance training on ergometer bicycles. The intensity will progress throughout the 12 weeks of training. The training consists of 10 minutes of warm up at 40-60% maximum heart rate (HRmax), followed by 25 minutes of high intensity interval training (4 bouts of 4 min at >85% HRmax interspaced by 3 minutes of low intensity training at 40-60% Hrmax) and finally a 5 min cool-down of 50% Hrmax	Behavioral: Exercise; Supervised high-intensity interval training for 12 weeks three times per week. The supervision may be physical or online supervision; Other Names: High intensity interval training
Active Comparator: RA patients TNFi Control; This group will be allocated to "control" and therefore no supervised exercise regimen	Behavioral: No exercise; Control group, therefore no supervised exercise regime
Experimental: RA patients IL-6Rb Exercise; The patients will be randomized to 12-week supervised exercise training intervention or no exercise training. The exercise training program includes three supervised sessions per week over a 12-week period. The program consists of high intensity endurance training on ergometer bicycles. The intensity will progress throughout the 12 weeks of training. The training consists of 10 minutes of warm up at 40-60% maximum heart rate (HRmax), followed by 25 minutes of high intensity interval training (4 bouts of 4 min at >85% HRmax interspaced by 3 minutes of low intensity training at 40-60% Hrmax) and finally a 5 min cool-down of 50% Hrmax	Behavioral: Exercise; Supervised high-intensity interval training for 12 weeks three times per week. The supervision may be physical or online supervision; Other Names: High intensity interval training
Active Comparator: RA patients IL-6Rb Control; This group will be allocated to "control" and therefore no supervised exercise regimen	Behavioral: No exercise; Control group, therefore no supervised exercise regime

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular mass	measured by MRI scan	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visceral adipose tissue mass	measured by MRI scan	12 weeks
Stroke volume	Structural cardiac parameter: measured by MRI scan and echocardiography	12 weeks
Left ventricular and atrial end-diastolic volume	Structural cardiac parameter: measured by MRI scan and echocardiography	12 weeks
LVEF	Functional cardiac parameters: measured by MRI scan and echocardiography	12 weeks
Global longitudinal strain	Functional cardiac parameters: measured by MRI scan and echocardiography	12 weeks
E/A ratio	Functional cardiac parameters: measured by MRI scan and echocardiography	12 weeks
E/é	Functional cardiac parameters: measured by MRI scan and echocardiography	12 weeks
Left ventricular and atrial end-systolic volume	Structural cardiac parameter: measured by MRI scan and echocardiography	12 weeks
Left atrial volume index	Structural cardiac parameter: measured by MRI scan and echocardiography	12 weeks
Interventricular septum thickness	Structural cardiac parameter: measured by MRI scan and echocardiography	12 weeks
Left ventricular posterior wall thickness	Structural cardiac parameter: measured by MRI scan and echocardiography	12 weeks
Aortic and pulmonary distensibility and pulse wave velocity	Functional vascular parameter: measured by MRI	12 weeks
Subcutaneous, visceral and epicardial adipose tissue	Measured by MRI and MR spectroscopy	12 weeks
Intramyocardial triglyceride content	Measured by MRI and MR spectroscopy	12 weeks
Cardiorespiratory fitness	Measured with an incremental VO2 protocol on exercise bike	12 weeks
Dynamic spirometry	Pulmonary function testing	12 weeks
Whole body plethysmography	Pulmonary function testing	12 weeks
Diffusion capacity	Pulmonary function testing	12 weeks
Body composition	Measured by a DXA scan	12 weeks
Oral glucose tolerance test	75g of glucose taken while fasting	12 weeks
Axial accelerometer-based physical activity monitors	Free-living physical activity is measured using axial accelerometer-based physical activity monitors (AX3; Axivity, Newcastle upon Tyne, UK) for a 5-day period	5 days in week 6 of the intervention/control
Dietary intake	Self reported intake of all foods and liquids	3 days in the week 6 of intervention/control
Blood sample	Change in fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol (mmol/L). Following an overnight fast (10 hours), blood samples are collected and processed by a trained laboratory technician and analysed according to standard procedures.	12 weeks
Blood sample	Change in triglycerides (mmol/L). Following an overnight fast (10 hours), blood samples are collected and processed by a trained laboratory technician and analysed according to standard procedures.	12 weeks
RA disease specific outcomes 1	Change in measures of the international Core Outcome Set for rheumatoid arthritis : 66/68 tender and swollen joint count	12 weeks
RA disease specific outcomes 2	Change in visual analogue scale (VAS) pain, VAS physician global assessment, VAS patient global assessment The Visual Analogue Scale (VAS) is a self-report measure consisting simply of a 100 mm horixontal line with a statement at each end representing one extreme (0mm = nothing, 100mm = extreme)	12 weeks
RA disease specific outcomes 3	Change in Health Assessment Questionnaire (HAQ-DI) Total score is between 0-3.0. Increasing scores indicate worse functioning with 0 indicating no functional impairment and 3 indicating complete impairment.	12 weeks
RA disease specific outcomes 4	Change in Short Form 36 (SF-36) Health Survey Questionnaire A 8-scale score within 8 domains.All items are scored so that a high score defines a more favorable health state.	12 weeks
RA disease specific outcomes 5	Change in the composite Disease Activity Score-28 ESR for Rheumatoid Arthritis (DAS28). A DAS28 of greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission	12 weeks
RA disease specific outcomes 6	Change in response criteria will be assessed according the clinical disease activity index (CDAI). The CDAI composite index quantifies disease activity in RA, by utilising four clinical parameters including tender and swollen joints and global assessment from both patient and assessor on a vasual analogue scale. CDAI interpretation score CDAI ≥ 22,1: High Activity CDAI < 22,1 og ≥10,1: Moderate Activity CDAI <10,0 og ≥ 2,9: Low Activity CDAI <2,9: Remission	12 weeks
RA disease specific outcomes 7	Change in response criteria will be assessed according the American College of Rheumatology (ACR 20/50/70) response	12 weeks
RA disease specific outcomes 8	Change in response criteria will be assessed according the European League Against Rheumatism (EULAR none/good/moderate response)	12 weeks

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Regitse Christensen, Center For Physical Activity Research, Rigshospitalet

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Actual): August 10, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: November 16, 2021
• First Submitted That Met QC Criteria: January 28, 2022
• First Posted (Actual): January 31, 2022

Study Record Updates

• Last Update Posted (Estimated): February 2, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: High intensity interval training; Cardiac adaptations; Metabolic adaptations
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: H-21010559

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymised IPD obtained through this study may be provided to qualified researchers upon reasonable request.
• IPD Sharing Time Frame: Requests can be submitted following the publication of the primary outcome, and IPD will be accessible upon reasonable request up to 3 years from that date.
• IPD Sharing Access Criteria: Requests to acces IPD may be provided if a satisfactory research proposal is sent to Simon Jønck (simon.joenck.04@regionh.dk) and Regitse H Christensen (regitse.hoejgaard.Christensen@regionh.dk)
• IPD Sharing Supporting Information Type: SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No