Coeliac Artery Release or Sham Operation

Study Overview
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Brief Summary
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In patients with Median Arcuate Ligament Syndrome (MALS), significant external compression of the coeliac artery (CA) by the median arcuate ligament (MAL) increasing mucosal ischemia (1,2) is assumed to cause chronic disabling postprandial abdominal pain, weight loss, and consequently lethargy and social deprivation (3,8). The majority of these patients have had a long medical journey before the diagnosis MALS is considered resulting in a substantial burden of disease and high healthcare and societal costs. Although a Systematic Review have shown a sustainable symptom relief of 68% and a significant and durable improvement of quality of life after surgical treatment for MALS (4), there is still no (inter)national consensus on the existence and treatment of MALS (1, 5, 6, 7). Two recent guidelines (3, 8) concluded that patients with MALS might be considered for surgical CA release (Recommendation 25 GRADE 2D; expert agreement 96%, Terlouw 2020). To end the ongoing debate and to enable the development of evidence-based guidelines for the management of MALS, both guideline committees recommend to perform a blinded, randomised controlled trial comparing a CA release with a sham operation. The proposed Coeliac Artery Release or Sham Operation study will either underline the usefulness of eCAR as a minimal invasive (cost)effective treatment for MALS or it will prohibit a meaningless intervention in patients with disabling abdominal symptoms. If the CARoSO study proves that the treatment of MALS by eCAR is effective, to 490 patients with chronic disabling abdominal symptoms per year can be treated in the Netherlands. Effective treatment of MALS is expected to result in mean health gain of 6.05 Quality Adjusted Life Years (QALYs)/patient and has the potency to reduce the substantial productivity loss and healthcare consumption caused by MALS, resulting in a saving up to M€4.3/year. The outcome of the CARoSO study will be translated into strong recommendations in the coming updates of the relevant (inter)national multidisciplinary guidelines and will be adapted in daily practice.

Detailed Description
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The involved professions and the patient representatives unanimously recommend as primary endpoint for this study the proposed disease specific outcome measure: symptom relief measured on a VAS and PGI-I scale. This clinical outcome parameter can be reliable assessed within 6 months after the CA release (1, 9, 10). A two years follow up is suggested to extinguish the positive effect of attention in the diagnostic phase (11). This study design allows for patient and observer blinding and for the sham group the eCAR approach is still feasible if the CARoSO outcome support this without applying additional scar tissue. A sham operation without skin incisions results in unblinding for the patient and the observer and thus undermines the basis of the evidential value of this study. There are no known cases where irreversible damage such as the intestinal infarction has occurred due to not treating this condition. Possible risks of not treating are continuous (pain) complaints and weight loss. The patients who undergo the sham operation and who still have complaints after unblinding of the study and proven effectivity of eCAR can still undergo the endoscopic AC release.

Official Title
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Coeliac Artery Release or Sham Operation in Patients Suspected of the Median Arcuate Ligament Syndrome

Conditions
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Mesenteric Ischemia, Median Arcuate Ligament Syndrome, Dunbar Syndrome, Coeliac Artery Compression, Celiac Artery Compression Syndrome

Intervention / Treatment
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* Procedure: Endoscopic Coeliac Artery Release (eCAR)
* Procedure: Sham Operation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a consensus diagnosis of MALS based on a multidisciplinary discussion in the two Dutch expert centers for Mesenteric Ischemia (Medisch Spectrum Twente and Erasmus Medical Centre). The multidisciplinary team contains of a vascular surgeon, gastroenterologist, radiologist as recommended in the guidelines. Typical complaints: post-prandial pain and at least two of the following: dietary modification, unexplained weight loss, unexplained diarrhea. Eccentric stenosis of ≥70% of the AC at the medial arcuatum ligament, demonstrated by two imaging techniques (duplex, MRA, CTA or DSA), including at least an inspiration and expiration CTA with 1mm sections. (Definition percent stenosis according to ECST 1998 formula: % stenosis = (1 - [diameter at the site of stenosis/estimated original diameter at the site of the stenosis]) x 100). Ultrasound Abdomen without other more common abnormalities. Gastroscopy-duodenoscopy without abnormalities, unless appropriate for mucosal ischemia. Exclusion Criteria: Patient not suitable for endoscopic AC release (e.g. previous surgery in the operating area). Pregnancy. Previous (endovascular) intervention of the visceral arteries. A significant stenosis in the superior or in the inferior mesenteric artery.

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
Interventional Model Description: A nationwide randomized placebo-controlled patient and observer blinded clinical superiority trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: endoscopic Coeliac Artery Release (eCAR)<br>Patients randomized in the Intervention Group. | Procedure: Endoscopic Coeliac Artery Release (eCAR)<br>* Endoscopic Coeliac Artery Release (eCAR); The Median Arcuate Ligament will be cleaved via an endoscopic retroperitoneal approach using a 4 trocar technique described in detail by van Petersen (12). To rule out learning curves and procedural variation all the procedures will be performed by two experienced eCAR surgeons in the MST-Dutch Expert Centre of Gastrointestinal Ischemia. All procedures will be videotaped. Both eCAR surgeons will not be involved in the follow up procedures.<br>|
| Sham Comparator: Sham Operation<br>Patients randomized in the Sham group. | Procedure: Sham Operation<br>* The sham operation consists of making 4 incisions up to the fascia similar to endoscopic AC release (eCAR). After 60 to 75 minutes of general anesthesia, in accordance with the average operating time of eCAR, the sham operation is ended. This study design allows for patient and observer blinding and for the sham group the eCAR approach is still feasible if the CARoSO outcome support this without applying additional scar tissue.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients with significant reduction in abdominal symptoms on a VAS scale | The change in abdominal symptoms is measured with a composite primary end point (CPE) at 6 months after randomization existing of o the daily visual analogue scale (VAS) for abdominal pain every day for seven days, the patients is asked to indicate the average abdominal pain of the past 24 hours on a VAS, this calculates the average VAS for that week. The PGI-I consists of one question about the change in symptoms compared to before surgery indicated on a 7-point Likert scale with the possible answers: very much improved, greatly improved, somewhat improved,  no change, slightly deteriorated, greatly deteriorated and very much worse. - A significant reduction in abdominal symptoms at 6 months after randomization is defined as an o a reduction in mean abdominal pain VAS (0-100) of ≥50% compared to baseline | 6 months after randomization | 
| The number of patients with significant reduction in abdominal symptoms. | The change in abdominal symptoms is measured with a composite primary end point (CPE) at 6 months after randomization o much improved or very much improved symptoms on the PGI-I (12) (7-point Likert Scale). The PGI-I consists of one question about the change in symptoms compared to before surgery. | 6 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Abdominal pain measured with mean abdominal pain VAS endpoint) | Visual Analogue Scale from 0-100 | Preoperative and 3, 6, 12 and 18 months after operation | 
| Change in complaints measured with the PGI-I | PGI-I on a 7-point Likert Scale | 3, 6, 12 and 18 months after operation | 
| Abdominal pain measured with worst abdominal pain VAS |  | Preoperative and 3, 6, 12, 18 and 24 months after operation | 
| HR-QoL measured with the EQ-5D-5L | Visual Analogue Scale from 0-100 | Preoperative and 3, 6, 12, 18 and 24 months after operation | 
| HR-QoL measured with the SF-12 | SF-12 from 0-100 | Preoperative and 3, 6, 12, 18 and 24 months after operation | 
| Productivity loss measured with the iPCQ (Productivity Costs Questionnaire) | Measured in euro per patient | 3, 6 and 24 months after randomization | 
| Healthcare consumption measured with the iMCQ | Measured in euro per patient | 3, 6 and 24 months after operation | 
| Cost-utility ratio (ICUR) of AC release compared to a sham operation | Cost per additional QALY in 6 months | 3, 6 and 24 months after operation | 
| The number of anatomically successful procedures, defined as ≤30% stenosis (diameter permeated lumen/diameter artery*100) measured with a CTa/MRa | Amount of anatomically succesful procedures | 6 months after operation | 
| The number of days until return to a normal diet |  | 24 months after operation | 
| Weight | Kilograms | Preoperative and 3, 6, 12 and 18 months after operation | 
| Success of blinding | By asking the patient in which treatment group they were randomzied | 3, 6, 12, 18 and 24months after operation | 
| Complications classified in the Clavien-Dindo classification | Questionnaire | 30 days after operation | 
| Percentage of patients undergoing additional PTA or other surgical treatment | Percentage of patients | 24 months after operation | 
| QoL measured by WHO-QoL Bref | Scale 0-100 | Preoperative and 3, 6, 12, 18 and 24 months after operation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MALS, Mesenteric ischaemia, Quality of Life, Coeliac Artery Release, Sham Operation, Healthcare Costs