Study setting {9}
As the Copenhagen University Hospital (Rigshospitalet) is the national referral center for patients with mesenteric ischemia, the COMESS study is a single-center trial of a national cohort. The COMESS trial is conducted at the Department of Vascular Surgery, and the Department of Interventional Radiology.
Eligibility criteria {10}
Inclusion Criteria
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Patients with symptomatic CMI of atherosclerotic or atherothrombotic etiology
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Intended endovascular treatment
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Symptoms consistent with CMI (pain, weight loss, diarrhea)
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Significant ostial stenosis (> 50%) of the superior mesenteric artery on CTA
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Significant stenosis on angiography (> 50% or > 15mmHg pressure gradient)
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Patients > 18 years
Exclusion Criteria
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No informed consent
-
Non atherosclerotic cause of Mesenteric Ischemia
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Acute mesenteric ischemia (AMI)
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Signs of acute bowel ischemia, peritonitis, laparotomy, sepsis
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Previous stent treatment in the superior mesenteric artery(ies)
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Target artery lesions > 4cm in length
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Unable to cross lesion with guidewire
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Non-significant stenosis angiographically
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Pregnancy
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Allergies to contrast media or stent materials
Who will take informed consent? {26a}
Patients will be asked to provide informed consent by the project responsible physician or project nurse prior to surgery, in accordance with local and national guidelines upon providing consent, each participant will receive a copy of the informed consent document for their records.
Patients with CMI and AoCMI have variable clinical presentation but are in most cases investigated and treated within one week of referral. Thus, it is difficult to give a standardized inform consent timeline for the study cohort. Some will receive treatment the next morning, others the next week. Subjects are recruited from patients referred for treatment of CMI/AoCMI at the Department of Vascular Surgery, Rigshospitalet.
If, during the screening of referral data by responsible physician and/or nurse, the patient is found eligible for study inclusion, the study nurse/coordinator is contacted (scenario 1). The first contact with the patient will then be by letter or via secure email to inquire if the patient wants more information regarding the trial. If affirmative, participants receive an information letter including study information, (including subjects’ rights in a health science research project) and a written consent form to be signed if the subject decides to participate in the trial. The patient is offered a further information meeting and can choose to have this by telephone or physically. The patient is allowed to have a resource person (e.g. family member, friend or acquaintance) present during this meeting. During this meeting, the patient is informed about the project verbally as well and allowed to ask questions.
Alternatively, due to a subacute scenario (scenario 2), some AoCMI patients are approached by the clinically responsible physician and/or nurse following the first physical contact with the department to inquire if the patient wants more information regarding the trial. If affirmative, participants are handed over the information letter including study information, (including subjects’ rights in a health science research project) and a written consent form to be signed if the subject decides to participate in the trial. The patient is then provided a meeting with the study nurse/physician and informed verbally as well and allowed to ask questions. The patient is allowed to have a resource person (e.g. family member, friend or acquaintance) present during this meeting. If the patient in scenario 2, due to subacute illness, cannot provide informed consent, the patient shall be considered ineligible for the study.
The description of the research project will be given verbally in layman terms and the patient can ask questions. This meeting will take place in the outpatient clinic or department in a quiet room. The verbal information will be accompanied by a briefing of the previously provided written information describing:
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Risks, benefits, complications and unpredictable risks and events to participating
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Alternative treatment options
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That patient data, including confidential and private, is protected but may be accessed by health care personnel involved in the study
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The right to withdraw at any time without supplying a reason
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That decline to participate will be universally accepted and that the patient will receive standard care.
The patient will then be given a minimum of 24 hours being asked again regarding participation. If the patient accepts inclusion, the informed consent is signed. In the subacute scenario (scenario 2) a minimum of 12 hours will be provided before the patient is asked again regarding participation. This reduced time is to avoid unnecessary treatment delay for the patient in a subacute clinical scenario. Patients who decline participation or are not eligible for inclusion are registered in a prospective screening log.
If new information regarding effects, risks, side effects is discovered after inclusion or during study follow up, participants will be promptly informed. In case of study termination, participants will be informed about the cause of termination.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
The participants in the trial will provide separate consent for the storage of residual material in a biobank for future research.
Interventions
Explanation for the choice of comparators {6b}
The evidence for stent treatment of CMI and AoCMI is convincing, yet there are no stents that are primarily indicated for the use in the mesenteric circulation (7, 8). Currently used stents are indicated for renal or iliac use. Furthermore, the use of covered stents (CS) for CMI has increased, partly due to recommendations from vascular societies and extrapolation from their use in other vascular beds (1, 6). Thus, a wide variation of stents are used, and the recent literature on BMS versus CS for arteriosclerotic occlusive disease of the superior mesenteric artery are conflicting (8, 9).
Intervention description {11a}
The procedure will take place in an angiography suite under local anesthesia. Access will primarily be gained from the femoral artery using a 6–8 Fr sheath. An alternate vascular access route, primarily the brachial artery, can be chosen at the operator's discretion. After the target lesion has been crossed with a 0.035 guidewire, a pressure gradient across the lesion will be determined using a mean pressure gradient > 15 mmHg to define significant lesions (5). In the case of an occlusion or near occlusion of the SMA, intra-arterial pressure measurement is omitted as it is not technically measurable. The lesion is then treated based on the pre- and intraoperative imaging. Patients with a significant lesion will then be randomized to either BMS or CS treatment. The treating physician will choose the appropriate stent length and diameter based on pre- and intraoperative imaging. The stent should cover the entire primary lesion and protrude 3-5mm into the aorta to achieve total lesion coverage. Bare metal stent extensions (either balloon expandable or self expandable) can be placed at the discretion of the operator to allow optimal conformity to the target vessel or minimize the risk of target vessel dissections. The stent is dilated to minimum the nominal pressure given by the manufacturer to achieve nominal stent size.
The treatment result is evaluated by standard angiography in two planes and measuring the pressure gradient across the stented segment. Two plane angiography can be substituted by on-table beam CT or angiography in one plane combined with a single x-ray in two planes to determine stent compression. < 30% residual stenosis and/or mean pressure gradient < 15mmHg is considered a treatment success.
All patients will have the balloon catheter used for ballooning the stenosis/occlusion collected. Residual material from the PTA balloon and blood samples from the angioplasty catheter (< 50ml blood) will be collected during the procedure and stored at -80 degrees Celsius in a research biobank until analysis. Peripheral blood samples (< 50ml blood in total) will be collected in connection with PTA treatment, as well as during the yearly outpatient visits (< 50ml) to analyze circulating blood markers.
Follow Up
In this trial patients will attend out-patient visits with clinical exams, blood samples, Duplex ultrasound (DUS) and Quality of life (QoL) questionnaire at six weeks, 12 months, and then annually to 5 years postoperatively. CTA will be performed once at 12 months postoperatively, prior to the scheduled follow up. In case of prohibitive traveling distance to the study site, the follow up DUS at one year and beyond can be omitted from the protocol and replaced by CTA at investigators discretion. As the primary study endpoint is at 1 year, this alteration will not interfere with the conclusions. If there is suspicion of an in stent re-stenosis based on the clinical exam and DUS of the SMA (threshold 412 cm/s) (6), a patient will undergo a CTA. Following evaluation of CTA results and clinical examination, the patient may be offered additional treatment if indicated.
Criteria for discontinuing or modifying allocated interventions {11b}
As randomization takes place during the procedure, the patients can accept inclusion but be excluded during the proposed intervention if the identified arterial lesion is not confirmed to be significant by intraoperative pressure measurement or multiplane angiography. If a patient is excluded perioperatively, the operator will make a determination on whether the procedure continues according to standard treatment or if an alternative approach is deemed necessary.
The patient has the right to withdraw participation at any time without providing a reason. In the event of refusal or withdrawal, the patient will be transitioned to the standard care pathway for treatment.
Strategies to improve adherence to interventions {11c}
All patients included in the COMESS trial will be followed up with clinical exam, blood samples, DUS of the visceral arteries and QOL questionnaire at 6 weeks, 12 months, and then annually to 5 years postoperatively. During this time, information from exams, tests and information will be gathered. CTA is performed at 12 months, and will be done at the local hospital.
Relevant concomitant care permitted or prohibited during the trial {11d}
There is currently no concomitant care that is prohibited during the trial. At the point of discharge from the hospital, patients will be prescribed statins and relevant antiplatelet therapy, unless the patient is already on other pertinent anticoagulant therapy.
Provisions for post-trial care {30}
Patients are covered by general patient insurance (patienterstatningen).
Secondary endpoint(s)
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Secondary stent patency
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Freedom from stent re-stenosis (luminal diameter > 50%)
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Freedom from reintervention
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Overall survival
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Intervention free survival
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Freedom from symptom recurrence
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Proteomics assay signal (balloon) and concentration of established biomarkers (blood samples)
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Quality of life
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Sensitivity and specificity of CTA and US preoperatively and during follow up
Participant timeline {13}
Table 1
Standard participant timeline.
Enrolment | Baseline | 6 week follow up | 12 month follow up | 2 year follow up | 3 year follow up | 4 year follow up | 5 year follow up |
Informed Consent | X | | | | | | |
EQ-5D-5L | X | X | X | X | X | X | X |
SF-36 | X | X | X | X | X | X | X |
Medical history | X | | | | | | |
Physical examination | X | X | X | X | X | X | X |
CT-angiography | X | | X | | | | |
Duplex Ultrasound | X | X | X | X | X | X | X |
Table 2
Modified participant timeline.
Enrolment | Baseline | 6 week follow up | 12 month follow up | 2 year follow up | 3 year follow up | 4 year follow up | 5 year follow up |
Informed Consent | X | | | | | | |
EQ-5D-5L | X | X | X | X | X | X | X |
SF-36 | X | X | X | X | X | X | X |
Medical history | X | | | | | | |
Physical examination | X | | | | | | |
CT-angiography | X | | X | | | | |
Duplex ultrasound | X | X | | | | | |
Telephone Consultation | | X | X | X | X | X | X |
Sample size {14}
In the only study investigating CS vs BMS in CMI (10), a retrospective non-randomized study of 225 patients, patients treated by CS had freedom from restenosis of 92% ± 6% compared to BMS with freedom restenosis of 53% ± 4% (10). This study suffered several limitations that must be considered for a sample size estimation in the present RCT: the velocity cut-off used may overestimate high-grade restenosis, the follow-up was significantly longer in the BMS group and differences in time-dependent outcomes including restenosis must be expected. In addition, a general underreporting of outcomes in both the BMS and the CS arm must be expected in a retrospective study. Therefore, the expected restenosis rates were adjusted to 85% and 60%.
Using dichotomous endpoints (restenosis: Y/N), a two independent sample study, alpha = 0.05, beta = 0.2 and power = 0.8, sample size was estimated to 49 patients in each group (total = 98). With 120 CMI/AoCMI-patients treated yearly in Copenhagen, an estimated inclusion rate of 80% and 20% dropout, a total of 77 CMI patients will be randomized yearly (app 6 pts/month) - and 98 patients are expected included within 18–24 months.
Recruitment {15}
Patients are discussed in a multidisciplinary team (MDT), including vascular surgeons and interventional radiologists after the referring physician has ruled out other gastrointestinal causes. If a consensus decision of CMI or AoCMI is reached and the diagnostic workup and clinical findings support endovascular treatment, the patient is invited to participate in the study.
Assignment of interventions: allocation
Sequence generation {16a}
The process of randomization is done in Research Electronic Data Capture (REDCAP). Randomization will be in blocks of 6 to get equal patient allocation in the two treatment arms in REDCap and accessible only to the physician/research nurse/coordinator performing the randomization.
Concealment mechanism {16b}
Randomization is done in REDCAP, a password secured third party database, and is only accessible to those whom have been granted access to the project.
Implementation {16c}
Randomization is done of blocks of 6. Randomization will be performed on an intention-to-stent basis in the angiosuite once the target lesion has been crossed with a guidewire and the lesion is determined clinically significant by angiography (> 50%) or pressure measurement (> 15mmHg mean gradient). Only the treating team will know the allocation (CS vs BMS).
Assignment of interventions: Blinding
Who will be blinded {17a}
This is a single-blinded study. Patients and the physicians responsible for postoperative care and follow-up will be blinded to treatment allocation, until the process of unblinding
Procedure for unblinding if needed {17b}
The unblinding process occurs at the 12-month follow-up if the patient wishes to be informed. However, in the case of severe adverse events necessitating unblinding before the 12-month follow-up, the project nurse, with access to the patient's treatment allocation, will facilitate the unblinding process.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Personal data concerning the subjects is protected in accordance with the Data Protection Regulation (GDPR - General Data Protection Regulation) and the Data Protection Act as well as the Health Act. Documentation for the research project is submitted to the Capital Region of Denmark's Research List.
Data is stored and analyzed on a secure network drive with secure access only to staff directly involved in the trial conduct in pseudo-anonymized form in accordance with guidelines specified by the Danish Data Protection Agency and the GDPR. Standard blood samples for immediate analysis when monitoring treatment are labelled with subjects' names and CPR numbers, and blood sample responses will appear in the patient record. Other research blood samples for the research biobank are pseudonymized with identification labels.
Research results belong to the trial site, and results are not handed out. The protocol is performed according to the Declaration of Helsinki II, and trial participants may withdraw from the trial at any time without further explanation.
Plans to promote participant retention and complete follow-up {18b}
According to the existing standard of care (SOC), follow up after mesenteric stenting at Rigshospitalet is an outpatient-visit, including clinical examination and DUS at six weeks and 12 months postoperatively. According to guidelines, FU after stenting of mesenteric arteries includes clinical examination and DUS at one month, six months, 12 months, and annually thereafter (9).
In this trial, annual FU outpatient visits until the fifth postoperative year, including DUS, are planned. In addition, a CTA at 12 months has been added to validate the DUS findings. In summary, because of the present study, the participating patient will receive care in better adherence to internationally accepted guidelines using of CS instead of BMS (half of the patients) and yearly FU for five years instead of one year FU only (all patients).
If a patient chooses to not participate in the trial after randomization, patients will receive care according to current SOC.
Data management {19}
Personal data concerning the subjects is protected in accordance with the Data Protection Regulation (GDPR - General Data Protection Regulation) and the Data Protection Act as well as the Health Act. Documentation for the research project is submitted to the Capital Region of Denmark's Research List. The project responsible physician and project nurse are responsible for data management and data entry.
Confidentiality {27}
Data is stored and analyzed on a computer in pseudo-anonymized form in accordance with guidelines specified by the Danish Data Protection Agency and the GDPR. Control blood samples for immediate analysis when monitoring treatment are labelled with subjects' names and CPR numbers, and blood sample responses will appear in the patient record. Other research blood samples for the research biobank are pseudonymized with identification labels.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
The blood sample and tissue residues will constitute a research biobank located at Rigshospitalet, which will be stored for the project's duration until the final analysis plan is available in collaboration with relevant partners at Rigshospitalet. The COMESS research biobank will be discontinued on 01-06-2031. After completing the study, the remaining material is transferred for storage in a biobank for future research, which is reported to the Capital Region's Knowledge Centre for Data Processing and follows the Data Protection Ordinance and the Data Protection Act. The biobank for future research will be established to carry out future supplementary studies and utilize any technological development after renewed approval from relevant authorities. The participants in the experiment give separate consent for the storage of residual material in a biobank for future research.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Outcomes are analyzed on intention to treat basis and secondarily per protocol. Primary outcomes will be analyzed by t-test and overall survival analysis, to estimate the patency at 12 months.
Secondary endpoints will be analyzed by survival analysis techniques, such as Kaplan Meier curve and Log-rank tests. Anova repeated measures will be used to estimate comparison QOL between the two groups, and secondary stent patency. Log rank test will be used to compare the survival rates between groups. Sensitivity and specificity of CTA and US will be analyzed with a logistic regression and receiver operator curves (ROC) analysis.
Interim analysis {21b}
An Interim analysis will be performed in this trial by The Data safety and monitoring committee after inclusion of 1/3 and 2/3 of subjects to validate safety and efficacy of the trial.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Not applicable.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Patients whom are not included in the trial for any reason are kept in a pseudonymized screening log to allow further analysis. Randomization of patients is performed on an intention to stent basis. Analysis of randomized patients will be done on an Intention-to-treat analysis and per-protocol analysis will also be performed.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
All results will be published, positive or negative, and potential funding bodies will have no impact on which results are published. For publication, all data is consolidated, anonymized and individual patients and outcomes not traceable.
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
The trial steering committee has been formed with representatives from the two clinical departments involved. The TSC maintains the overall responsibility and conduct of the trial. The TSC will report annually on recruitment and monitor the recording of data and violations of the protocol. They will also oversee serious adverse events, safety and study viability.
Composition of the data monitoring committee, its role and reporting structure {21a}
The TSC will be responsible for data monitoring activities. 10% of entered data will be monitored for completeness and accuracy. The TSC will meet at least bi-monthly and minutes are archived. Annual meetings with audit of internal monitoring activities and adverse events will take place and result in a recommendation to continue, terminate or modify the trial.
Adverse event reporting and harms {22}
Adverse events will be reported in REDCAP, in addition to adverse events being reported according to the local guidelines. All adverse events will be adjudicated internally on a continuing basis by the study trial steering committee.
Harms
The risk for procedure-related complications related to the use of BMS and CS is, according to a recent observational cohort study, less than 5% and expected to be similar in both arms (5). Most short-term complications are related to vascular access sites (5). Since both stent types require the same size of vascular sheath for introduction into the artery, the expected procedure-related complication rate is the same in both groups. All patients are handled as in-house patients at the Department of vascular surgery and will be carefully monitored according to standard team policy. Medical staff are available 24/7, and all potential complications will be handled by experienced staff.
List of potential complications:
Death
Arterial dissection
Bleeding
Contrast allergy
Radiation risk
CTA at 12 months has been added to validate the DUS findings. The additional radiation exposure to the patient is negligible, with approximately 2–8,6mSv over the five year study period. The natural background exposure in Denmark is around 3mSv annually (12). The added radiation exposure of 2–8,6mSv will increase the cancer risk in the individual patient with 0.08% providing a total lifetime cancer risk to 25.08% from 25%.
Frequency and plans for auditing trial conduct {23}
This trial is in accordance to the local guidelines and GDPR, and Danish Good Clinical Practice GCP guidelines. However, during the trial period, there will be an internal monitoring of the data and included patients.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
If new information regarding effects, risks, side effects is discovered after inclusion or during study follow up, the patient will be informed. If the study is terminated, the study subject is to be informed of the cause of termination.
Dissemination plans {31a}
The trial is registered at clinicaltrials.gov. Results will be published there accordingly as well as manuscripts published in a peer-reviewed journal. All results will be published, positive or negative, and potential funding bodies will have no impact on which results are published. For publication, all data is consolidated, anonymized and individual patients and outcomes not traceable.