Effects of Etanercept on the Heart, Veins and Thickness of Certain Major Arteries In Ankylosing Spondylitis Patients

Study Overview
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Brief Summary
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Study to assess whether etanercept therapy is able to increase flow-mediated vasodilatation in AS, and whether etanercept can modify the intima-media thickness (IMT) in these patients

Official Title
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Effects of Etanercept on Endothelial Function and Carotid Intima-media Thickness (IMT) in Patients With Active AS

Conditions
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Ankylosing Spondylitis

Intervention / Treatment
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* Drug: etanercept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of AS, as defined by Modified New York Criteria for Ankylosing Spondylitis. AS with active disease as defined by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI, see Attachment 4) >= 4 at screening visit. Patients capable, in the opinion of the investigator, of complying with the treatment schedule and doses throughout the 52 weeks Agreement by male subjects who are not surgically sterile and female subjects who are not surgically sterile or postmenopausal to use reliable methods of birth control for the duration of the study. Ability to self-inject drug or have a designee who can do so. Ability to store injectable test article at 2ºC to 8ºC. Exclusion Criteria: 1. Pregnancy confirmed by test taken at screening in all women except those who were surgically sterile or at least 1 year postmenopausal. Sexually active women of childbearing potential participating in the study must use a medically acceptable form of contraception that needs to be continued for 15 days following discontinuation of the test article.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>etanercept 50 mg/week | Drug: etanercept<br>* etanercept 50 mg/week<br>* Other names: Enbrel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Flow-Mediated Dilatation (FMD) at Week 12 | Brachial artery (BA) FMD equals (=)(maximum diameter minus[-] baseline diameter divided by baseline diameter) times (*) 100 percent (%). Ultrasound images of BA at rest were followed by blood pressure (BP) cuff inflated to at least 50 millimeters of mercury (mm Hg) above participants systolic BP for 5 minutes. Cuff released and reactive hyperaemia was produced. BA was imaged continuously from 30 seconds prior cuff inflation to 2 minutes after cuff deflation. Higher scores indicate improved endothelial function. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Flow-Mediated Dilatation at Weeks 4, 24, 36, and 52 | BA FMD =(maximum diameter -baseline diameter divided by baseline diameter) * 100%. Ultrasound images of BA at rest were followed by BP cuff inflated to at least 50 mm Hg above participants systolic BP for 5 minutes. Cuff released and reactive hyperaemia was produced. BA was imaged continuously from 30 seconds prior cuff inflation to 2 minutes after cuff deflation. Higher scores indicate improved endothelial function. Change: Week x observation minus Baseline observation. | Baseline, Weeks 4, 24, 36, and 52 or Early Termination (ET) | 
| Change From Baseline in Carotid Intima Media Thickness (IMT) at Weeks 12 and 52 | Change in IMT in the distal common carotid arteries (CCA), common bulbs (CB), and internal carotid arteries (ICA) as determined by ultrasound. Higher scores indicate worsening in cardiovascular risk assessment. Change: Week x observation minus Baseline observation. | Baseline, Week 12 and 52 or ET | 
| Change From Baseline Lipid Parameters at Weeks 4, 12, 24, 36 and 52 | Mean Total Cholesterol (TC), Low Density Lipoprotein (LDL) and Triglyceride (TGL) blood concentrations, lower values indicated improvement in cardiovascular risk. Mean High Density Lipoprotein (HDL), higher values indicated improvement in cardiovascular risk. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in Total Serum Homocysteine at Weeks 4, 12, 24, 36 and 52 | Mean serum homocysteine blood concentrations. Lower values of homocysteine indicate improvement in inflammation. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 4, 12, 24, 36 and 52 | ESR is a laboratory test that provides a non-specific measure of inflammation. The test assesses the rate at which red blood cells fall in a test tube. Normal range is 0-30 mm/hour (hr). A higher rate is consistent with inflammation. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in C-Reactive Protein (CRP) at Weeks 4, 12, 24, 36, 52 | CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 4, 12, 24, 36 and 52 | BASDAI a validated self assessment tool to determine disease activity in participant with Ankylosing Spondylitis (AS) using a Visual Analog Scale (VAS) of 0 (none) to 10 (very severe) centimeter (cm). Participant answered 6 questions measuring discomfort, pain and fatigue. Final BASDAI score averages the individual assessments for a final score range of 0-10. Change: Week x observation minus Baseline observation. Higher score indicates greater disability. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36, and 52 or ET | 
| Percentage of Participants With BASDAI 50 Percent (%) Improvement at Weeks 4, 12, 24, 36, and 52 | BASDAI a validated self assessment tool used to determine disease activity in participants with AS. Utilizing a VAS of 0 (none) to 10 cm (very severe), participant's answered 6 questions measuring discomfort, pain and fatigue. BASDAI 50 response defined as at least a 50% improvement (decrease) from baseline in BASDAI. Baseline score - score at observation divided by Baseline score * 100 = greater than or equal to 50%. | Weeks 4, 12, 24, 36, and 52 or ET | 
| Percentage of Participants With Assessment in Ankylosing Spondylitis (ASAS) 20 at Weeks 4, 12, 24, 36, and 52 | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 20 = 20% improvement from baseline and an absolute change greater than or equal to (≥) 10 units on a 0-100 millimeter (mm) scale (0 mm = no disease activity; 100 mm = high disease activity) for ≥ 3 domains, and no worsening in remaining domain. | Week 4, 12, 24, 36, and 52 or ET | 
| Percentage of Participants With ASAS 40 at Weeks 4, 12, 24, 36, and 52 | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 40 = 40% improvement from baseline and an absolute change ≥ 20 units on a 0-100 mm scale (0 mm = no disease activity, 100 mm = high disease activity) for ≥ 3 domains, and no worsening in remaining domain. | Weeks 4, 12, 24, 36, and 52 or ET | 
| Percentage of Participants With ASAS 50 at Weeks 4, 12, 24, 36, and 52 | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 50 = 50% improvement (vs. baseline) and an absolute change ≥ 20 units on a 0-100 mm scale (0 mm = no disease activity, 100 mm = high disease activity) for ≥ 3 domains, and no worsening in remaining domain. | Weeks 4, 12, 24, 36 and 52 or ET | 
| Percentage of Participants With ASAS 70 at Weeks 4, 12, 24, 36, and 52 | ASAS measures symptomatic improvement in Ankylosing Spondylitis (AS) participants ASAS = 4 domains: participant global assessment of disease activity, pain, function, inflammation. ASAS 70 = 70% improvement (vs. baseline) and an absolute change ≥ 20 units on a 0-100 mm scale (0 mm = no disease activity, 100 mm = high disease activity) for ≥ 3 domains, and no worsening in remaining domain. | Weeks 4, 12, 24, 36 and 52 or ET | 
| Percentage of Participants With ASAS 5/6 at Weeks 4, 12, 24, 36, and 52 | ASAS 5/6 consists of 6 domains: the 4 used in ASAS 20 (participant global assessment of disease activity, pain, function, inflammation measured on a 0-100 scale, where 0 = no disease activity and 100=high disease activity) plus spinal mobility and an acute phase reactant, C Reactive Protein (CRP). Achieving ASAS 5/6 requires a 20% improvement compared to baseline in ≥ 5 domains and no worsening in the remaining domain. | Weeks 4, 12, 24, 36 and 52 or ET | 
| Percentage of Participants With ASAS Partial Remission at Weeks 4, 12, 24, 36, and 52 | Partial remission defined as a score of less than 20 units (on a scale of 0-100, where 0 = no disease activity and 100 = high disease activity) in each of the 4 Assessment in Ankylosing Spondylitis (ASAS) domains: participant global assessment of disease activity, pain, function, and inflammation. For scale, 100=high disease activity. | Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 4, 12, 24, 36, and 52 | BASMI is an objective measure of spinal mobility. The BASMI score is composed of 5 measures: cervical rotation, intermalleolar distance, modified Schober's test, lateral flexion and tragus to wall distance. Each measure was scored 0-2 (0=normal mobility, 2=severe reduction) to give a final score ranging 0 to 10. Lower score indicated better spinal mobility. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in BASMI-Cervical Rotation at Weeks 4, 12, 24, 36 and 52 | While in a neutral position, the participant turned the head as far as possible to the right and then to the left. Using a goniometer the degrees of movement were measured. Two measurements on the right and 2 on the left were made. The best of the two measurements for each side (corresponding to the highest value), were then averaged. Higher score indicated greater spinal mobility. Actual rotation ranged from 3.0 to 99.0 degrees. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36, 52 or ET | 
| Change From Baseline in BASMI-Intermalleolar Distance at Weeks 4, 12, 24, 36 and 52 | Measurement in cm of the distance between the medial malleoli when participant was lying supine with knees straight and feet pointed straight up with legs separated as far as possible, 2 attempts were measured. The best of the two measurements which corresponds to the highest value were reported. Higher score indicated greater spinal mobility. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in BASMI-Modified Schober's Test at Weeks 4, 12, 24, 36 and 52 | Measurement in cm of distance between marks originally placed while participant was standing erect 10 cm above and 5 cm below the midpoint of a line that joins the posterior superior iliac spines. Distance between marks was re-measured with participant maximally bent forward, knees fully extended, with supine in full flexion. The measurement was carried out two times and best of the two measurements which corresponds to the highest value were reported. Higher score indicated greater spinal mobility. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in BASMI-Tragus to Wall Distance at Weeks 4, 12, 24, 36 and 52 | Measurement in cm of distance between the tragus and wall from the right and left side while participant was standing with back against the wall; knees straight; scapulae, buttocks, and heels against the wall; with head in a neutral position. Two measurements on the right and 2 on the left were made. The best of the two measurements for each side (corresponding to the smallest value), were then averaged. Higher score indicated greater spinal mobility. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in BASMI-Lateral Flexion at Weeks 4, 12, 24, 36 and 52 | Measurement in cm of distance between participant's middle fingertip and the floor after bending sideways, without bending knees or lifting heels, while attempting to keep shoulders in same place (flexion position). Two measurements on the right and 2 on the left were made. The best of the two measurements for each side (corresponding to the highest value), were then averaged. Higher score indicated greater spinal mobility. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in Occiput-to-Wall Distance at Weeks 4, 12, 24, 36 and 52 | While participant stood with back against the wall and during maximal effort to touch head to the wall, the distance between the occiput (back of head) and the wall was measured. The measurement of two attempts was made and best of the two measurements which corresponds to the highest value were reported. Lower scores indicated improvement in spinal mobility. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 
| Change From Baseline in Chest Expansion at Weeks 4, 12, 24, 36 and 52 | Chest expansion defined as the difference in thoracic circumference during full expiration versus full inspiration, measured in cm at the fourth intercostal space (nipple line) while participant was standing. Measurement taken twice and best of the two measurements (corresponding to the highest value of inspiration and smallest value for expiration), were then averaged. Greater chest circumference indicated improvement in spinal mobility. Change: Week x observation minus Baseline observation. Baseline value was used when present, otherwise valid screening value used as baseline if within 14 days of first test article injection. | Baseline, Weeks 4, 12, 24, 36 and 52 or ET | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IMT evaluation in AS patients treated with etanercept