Study setting {9}
The trial will be conducted in 10 centers in the UK over 36 months. 340 patients will be recruited.
Asymptomatic patients will be identified for inclusion at the time of their clinic appointment while symptomatic or rupture patients will be identified for inclusion at the time of presentation. Patients that present on an urgent or emergency basis will be required to provide written informed consent, after either reading the patient information leaflet or it being read to them by an individual independent of the trial team and the patient’s family.
The expected recruiting sites are:
- Leeds Teaching Hospitals NHS Trust
- Manchester University NHS Foundation Trust
- Liverpool University Hospitals NHS Trust
- University Hospital Derby
- North Bristol NHS Foundation Trust
- Frimley Health NHS Foundation Trust
- Imperial Healthcare NHS Trust, London
- Guy’s and St Thomas’ NHS Foundation Trust, London
- University Hospital Southampton
- Brighton and Sussex University Hospitals
Eligibility criteria {10}
Below are the inclusion and exclusion criteria of the ARIA trial.
Inclusion Criteria:
- Clinical diagnosis of AAA or TAAA suitable for endovascular treatment, as determined by CT imaging and a local treating team multidisciplinary review.
- Patient is confirmed fit for endovascular repair as determined by the operating team
- CT imaging must be in accordance with Cydar EV: Instructions for Use
- Written informed consent (patients lacking capacity or unable to speak English will not be enrolled)
- Age 18 years and above at the time of consent
Exclusion Criteria:
- Patients unable to provide written informed consent
Who will take informed consent? {26a}
Written informed consent will be obtained by the Principal Investigator or designee at each site, following explanation of the trial procedures. Discussions about trial participation may take place during an in-person consultation or remotely, i.e. during a telephone or video consultation. The Participant Information Sheet can be sent by post or email ahead of the in-person or remote consultation. Full consent will be given in writing and the signed original consent forms will be retained on site. Randomisation will only take place once the completed consent form has been received and countersigned.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
No additional consent will be undertaken as part of this trial.
Interventions
Explanation for the choice of comparators {6b}
The control comparator used in the ARIA trial will be endovascular aortic aneurysm repair using X-ray fluoroscopy imaging, which represents the reference standard in England.
Intervention description {11a}
Patients in the intervention arm of the ARIA trial will undergo endovascular aneurysm repair guided by Cydar-EV. Cydar EV provides tools to:
• Import and visualise CT data
• Segment and annotate vascular anatomy from CT data
• Place and edit virtual guidewires and measure lengths on them
• Make measurements of anatomical structures on planar sections of the CT data
• Produce an operative plan from measurements and segmentation of preoperative vessel anatomy
• Overlay planning information such as preoperative vessel anatomy onto live fluoroscopic images, aligned based on the position of anatomical features present in both
• Non-rigidly transform the visualisation of anatomy when intra-operative vessel deformation is observed
• Post-operatively review data relating to procedures where the system was used
Intervention Training
Training on the Cydar-EV product will be as per the Cydar CE marking and Quality Assurance procedures.
Intervention Delivery
Procedures will be performed under local, regional or general anaesthesia (likely ratio: 1:1:8). Procedures can be undertaken using either a mobile C-arm in a surgical operating theatre, a dedicated fixed fluoroscopy set, or in a hybrid operating room. Patients may go to the ward, HDU or ITU following the procedure, according to local protocol. Routine pre-operative CT aortic imaging will be used to determine general suitability for endovascular repair, including assessment of landing zones for fixation and sealing, and procedure type and device selection.
Criteria for discontinuing or modifying allocated interventions {11b}
Cross-over to Cydar EV from standard care will only be permitted in the context of a procedure duration greater than 8 hours or where the patient is in extremis and the surgeon believes that using the Cydar technology may be beneficial to complete the procedure. In these circumstances, the Cydar equipment may be used at the discretion of the operating surgeon and this information must be captured in the reporting system.
Strategies to improve adherence to interventions {11c}
Reasons for non-compliance could include Cydar EV device failure, internet failure, surgeon error, failure to communicate correct randomisation allocation to the surgeon, cross-over, and failure to upload images to Cydar EV, or a non-Cydar-trained surgeon performs the procedure. The patient could impact compliance if they express a wish to withdraw between randomisation and surgical procedure or in the event of death.
Relevant concomitant care permitted or prohibited during the trial {11d}
There is no restriction on concomitant care during the trial.
Provisions for post-trial care {30}
Post-trial care will follow routine NHS practice in each centre. In centres where ultrasound imaging is used as the 4–12-week follow-up and/or at one year, these patients will be required to undergo one additional CT angiography. This deviation from standard care has been noted in the application for ethical approval for the study.
Outcomes {12}
Primary Outcome
Primary efficacy parameter of the study is procedure duration, measured as the time between insertion of the first wire (after percutaneous access achieved, if applicable) at the beginning of the endovascular procedure to the last frame of the completion angiogram. This will be recorded (in minutes) at the time of the procedure by the local research team.
Secondary Outcomes
- Procedural efficiency:
- Anaesthetic duration – the time between the beginning of induction and the end of emergence. This will be documented at the time of the procedure by the local research team in minutes.
- X-ray dose per procedure –fluoroscopy time (FT) (seconds), dose area product (DAP) (Gy.cm2) and cumulative air kerma (CAK) (mGy) should be recorded and documented at the time of the procedure by the local research team. The imaging system used should also be recorded.
- Contrast dose per procedure – the volume (ml) and concentration (mgI/ml) of the iodinated contrast material used should be recorded by the local research team at the time of the procedure in minutes.
- Consumable use in the operating theatre for endovascular aortic aneurysm repair – name of device, unit and quantity used, blood products used; details to be completed by nurse in the operating theatre or research nurse at the time of the procedure.
- Technical success:
- Proximal and distal seal zone at least 10mm and no evidence of endoleak. This will be documented by the imaging CoreLab team on review of the CT images acquired post-operatively and at 4-12 weeks and at 52 weeks.
- Patient outcomes:
- Length of ITU/HDU admission – date and time from admission to date and time of discharge from ITU/HDU; documented by the local research team during the time of admission; ITU and HDU admissions should be documented separately
- Postoperative length of hospital stay – date of procedure to date of discharge from hospital (nights); documented by the local research team during the time of admission.
- 30-day mortality – death of the participant within 30 days of the primary procedure; documented by the local research team; to include date of death (dd/mm/yy) and cause.
- Re-intervention – any procedure open surgical or endovascular undertaken within one year of the primary endovascular aortic aneurysm repair procedure (binary outcome). The type, timing and number of procedures should also be recorded by the local research team.
- Adverse events – hospitalisation for any reason within one year of the primary endovascular aortic aneurysm repair; the type of event should be documented and classified as one of the following: musculoskeletal, urological, neurological, ophthalmological, cardiovascular, gastro-intestinal, hepato-pancreato-biliary, dermatological or other by the local research team, with information captured to understand if linked to re-intervention. For each hospitalisation the following should also be captured:
- Day case, Elective, Non-elective
- Length of hospital stay - date of admission to date of discharge (nights)
- Length of ITU/HDU admission (if applicable) - date and time from admission to date and time of discharge from ITU/HDU
- Quality of life – differences in quality of life between intervention and the comparator group, and changes in quality of life post-surgery will be measured using data from the patient-completed EQ5D-3L (15) instrument. EQ-5D-3L is a validated measure of health-related quality of life, consisting of a five-dimension health status classification system and a separate visual analogue scale. EQ-5D-3L data will be obtained through face-to-face or telephone interview with the participant at baseline, pre-discharge, 4-12 weeks and at 12-months follow up.
- Cost effectiveness, as assessed by:
- Total resource use and costs
- Quality-Adjusted Life Years (QALYs) - Quality of life will be measured by the EQ-5D-3L instrument as described above. In order to be used in the calculation of quality‐adjusted life years (QALYs), the EQ-5D-3L dimension scores will be converted to utilities using the relevant value set for England. Quality-adjusted life years (QALYs) gained in both groups, over the time horizon of the trial, will be calculated using the area under the curve method.
- Incremental cost per QALY
Participant timeline {13}
Figure 4 lays out the trial participant time line of enrolment, intervention and assessment.
Sample size {14}
There is no known minimum clinically important difference (MCID) and part of the aim of the study is to better characterise the clinical benefit to patients. The study is therefore powered on the basis of a minimum economically meaningful difference. Previous work at Duke (11) reported data on the primary outcome, procedure time, and found a mean difference of 22.5 minutes (17%) for patients with an abdominal aortic aneurysm treated with Cydar-EV 109.6 (34.2) and standard 2D fluoroscopy imaging 132.1 (69.2) minutes. This is a meaningful difference in the NHS context as this time reduction per case would allow four rather than three EVAR procedures to be performed per day, which is a productivity increase of 33% at the same capacity. The SD for procedure time increases with the mean and so we have assumed a t-test for ratio of means 1.2 (fold change), assuming a lognormal distribution for the calculations. Therefore, a sample size of 153 patients per arm with a 1:1 allocation ratio (2 x 153 = 306) would give us 90% power at the 2-sided 5% significance level to detect this difference (PASS 15 Power Analysis and Sample Size Software (2017)). Since our primary outcome measure requires the procedure to be completed, we need to inflate the sample size for possible: i. loss post randomisation, pre-procedure (est 7.5%); and ii. on-table death and cross-overs (where surgeons may use the intervention in a control arm patient (see section 4.5) and additional assistance is required to complete the operation) (est 2.5%). These inflate the sample size to 170 per arm. The final randomisation target is therefore 2 x 170 = 340. The Duke data also showed using Cydar-EV in TAAA showed larger reductions in operating time than for AAA. We have powered on the more conservative difference since the relative proportions of AAA/TAAA patients anticipated in our proposed trial is unknown.
Recruitment {15}
Evidence-based site selection was used to confirm the eligibility of each centre to participate in the trial using volumes of endovascular repair of infra-renal and thoraco-abdominal aortic aneurysms listed on the National Vascular Registry, as well as a record of satisfactory patient outcomes and strong clinical engagement. During the trial, the team will maintain regular contact with the sites, undertake regular site visits, ensure there are adequate numbers of randomisers at sites and that Cydar EV is installed in as many rooms as required. These will be supplemented by in person local Principal Investigator and Research Nurse meetings where site teams can hear the experience of other sites and problems and tips and tricks to ensure strong participant recruitment can be shared.
Assignment of interventions: allocation
Sequence generation {16a}
Once baseline assessments are complete, participants will be randomized in a 1:1 ratio using the method of minimisation. Randomisation is at the patient level and is performed using a web-based bespoke randomisation system set up by the King’s Clinical Trials Unit (KCTU) at King’s College London. Randomisation is minimised by the following factors:
- Surgeon
- Procedure urgency: emergency or elective
- Procedure type: simple (repair of infra-renal aneurysm +/- internal iliac embolisation) or complex (all other types of AAA and TAAA repair, to include branched and fenestrated devices)
The procedure is as follows: On receipt of the baseline questionnaire, the Trial Coordinator electronically submits details of each participant to the CTU. This includes participant ID number, site, initials and date of birth. The system immediately notifies the relevant study nurse and records the randomisation outcome. The Trial Coordinator does not receive the randomisation outcome.
Concealment mechanism {16b}
Minimisation will incorporate a random component to assure allocation concealment.
Implementation {16c}
Patients will be enrolled in the ARIA trial by the local trial team at each of the participating sites as per the described consenting procedure. The allocation sequence generation will be implemented via the Kings College Trial Unit (KCTU) web-based randomisation system. The randomisation of participants will be performed post-consent, after checking their eligibility. The signed consent form will be made available for the operating team to review, along with the randomisation result. Participants will be randomised to Cydar-EV image fusion for guidance or standard imaging techniques in a ratio of 1:1 post-consent and confirmation of eligibility.
Randomisation procedure
Study site staff delegated to undertake the randomisation procedure will generate a unique Patient Identification Number (PIN) using the Elsevier MACRO EDC system and randomise the patient using the KCTU web-based randomisation system.
Assignment of interventions: Blinding
Who will be blinded {17a}
Due to the nature of the intervention, it is not possible to blind all members of the trial team. Table 1 lays out the blinding status of the research team in this study.
Procedure for unblinding if needed {17b}
Emergency unblinding is not required in this study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Source Data Worksheets
Sites will be provided with source data worksheets containing the relevant data required to be transcribed to the MACRO EDC system and the randomisation system. Training will be provided by the ARIA Trial Manager.
CT Aorta Image reading
CT imaging data will be uploaded to the ARIA trial image analysis virtual CoreLab, which is a cloud-based system. Images will be read in a blinded manner by two readers, with more than five years of experience of aortic image analysis and with experience of aortic endovascular surgical planning. They will securely log into the cloud-based Cydar vault where the CT image data will be housed, and analyse the pre- and post-operative CTs to determine technical success. Data from this analysis will be entered onto a part of the MACRO EDC system inaccessible to sites. Twenty image data sets will be used to assess the inter- and intra- observer repeatability coefficients for the variables in the CT read protocol.
Plans to promote participant retention and complete follow-up {18b}
Participants will be seen in routine NHS follow up clinics. If visits have not been scheduled by the end of the week 4-12 and week 52 visit windows, the study site staff will contact the participants by telephone to collect the EQ-5D (telephone version) and follow-up data, and attempts will continue to schedule a follow up visit. Data will be collected and entered, even if follow up clinic assessments are outside the optimal visit windows and the date noted.
Data management {19}
Data entry
Authorised staff at sites will transcribe baseline and follow up data from the source data worksheets. A full audit trail of data entry and any subsequent changes to entered data will be automatically date and time stamped, alongside information about the user making the entry/changes within the system.
Security (EDC)
Systems access will be strictly restricted through user-specific passwords to the authorised research team members. Participant initials and partial date of birth (mm/yyyy) will be entered into the systems. Hospital number, email address, participant names and addresses, and full postcodes will not be entered into the EDC system. Trial sites will maintain a master patient log linking participant identifiers to study numbers. No data will be entered unless a participant has signed a consent form to participate in the trial.
Data Quality Processes
At the database design stage, validations will be programmed into the systems to minimise data entry errors by querying the data entered in real time with sites. The CI team will undertake appropriate reviews of the entered data, in consultation with the project analyst, where appropriate for the purpose of data cleaning and will request amendments to the MACRO EDC system data as required. No data will be amended independently of the study site responsible for entering the data. No data can be amended in the randomisation system, however CI or delegate (e.g. Trial Manager) may request King’s Clinical Trials Unit to add notes against individual participant entries to clarify data entry errors. Any errors should be reported by site staff to the Trial Manager as soon as possible once they are detected. The trial manager will onward report errors to KCTU and retain records in the TMF. Site monitoring visits will be conducted by the Trial Manager.
Confidentiality {27}
When consent forms are signed, a copy will be provided to the patient, a copy will be filed in the medical records and the original will be retained in the Investigator Site File. Participant initials and date of birth will be entered into the study database, but no more identifying information will be collected outside the recruiting study site. Within site, an Investigator Site File will be maintained by the site PI. Participants will be fully identifiable within these files.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
There are no biological specimens that will be taken as part of this trial.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The analyses will be carried out according to the statistical analysis plan written before any outcome data are inspected. A CONSORT diagram will describe the patient flow and exclusions. Baseline demographic and clinical data will be summarised by randomisation trial arm.
Statistical methods for primary outcome
As the primary outcome is procedure duration and we envisage 7.5% loss of patients between randomisation and procedure, the primary analysis will be a per-protocol (PP) analysis based on procedure time. The primary analysis will be conducted after completion of first follow-up (at 4-12 weeks) which will include procedure time as well as the secondary outcome data available at this time. Sensitivity analysis with multiple imputation for missing data will also be conducted alongside the per-protocol analysis. No significance tests will be performed for baseline comparison. The primary outcome measure is likely to have a skewed distribution and therefore if necessary and possible the data will be normalised using an appropriate transformation. The data will then be analysed using linear regression techniques with stratification (minimisation) factors included as covariates. If a suitable transformation cannot be found the data will be analysed using quantile regression to allow us to include the addition of the stratification factors as covariates.
Statistical Methods for secondary outcomes
A similar analysis will be undertaken for the secondary outcomes including quality of life scores. Binary outcomes will be compared between arms using logistic regression adjusting for stratification factors. Outcomes will be reported as adjusted differences in means (or median) or odds ratios for continuous and binary data respectively. All tests will be two sided and will be assessed at the 5 % significance level. Safety outcomes will be reported as patient proportions and rates within and between arms with 95 % confidence intervals using exact methods where appropriate.
Interim analyses {21b}
There will be no planned formal interim analyses of the primary and secondary outcomes. However, we will conduct further analyses of secondary outcomes at the completion of 52 weeks follow-up for all the patients.
Methods for additional analyses (e.g. subgroup analyses) {20b}
We will use data collected during this study for further analyses investigating the following topics:
- Image analysis – A CoreLab will perform imaging analysis of technical outcomes and anatomy as seen on the 2 post operative CTs.
- Health economic analysis will be performed to examine the cost effectiveness of the Cydar EV system. This will include an analysis of the systems efficiency that the Cydar EV system may allow.
- Quality of life between the two groups will be assessed using the area under the curve method.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Compliance with intervention will be recorded in the source data worksheets and transcribed to the EDC system. Reasons for non-compliance would include device failure, surgeon error or failure to communicate correct randomisation allocation to the surgeon. The patient could only impact compliance if they express a wish to withdraw between randomisation and surgical procedure. Missingness will be reported and reasons for missingness explored. Although a low percentage of missing data is anticipated a sensitivity analysis of the primary outcome will be undertaken in order to assess the impact of the exclusion of participants with missing intraoperative data in the primary analysis. In this view of the sample size, a modelling approach will be taken rather than multiple imputation.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The Investigator(s) will permit trial-related monitoring, audits and REC review by providing the Sponsor(s), and REC direct access to source data and other documents (e.g. patients’ case sheets, blood results, imaging reports, trial protocol, statistical code, and etc).
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The trial will be coordinated through the KCTU with the CI being supported by the Trial Management Group (TMG) who are made of the following members; Cydar Lead Investigator, KCTU Operations Director, KCTU Data Centre Lead, KCTU Senior Statistician, KCTU Junior Statistician, KCTU Trial Manager, Trial Health Economist, Cydar Project Manager and the KCL Clinical Research Fellow. The TMG is responsible for the study co-ordination, data quality and budget management. The TMG members will meet at least monthly throughout the trial. The CI will chair the TMG. Minutes will be taken by the trial manager and retained in the TMF. The TMG will review recruitment to the study across all study sites and will take appropriate action in the event the study recruitment rate is lower than anticipated.
The TSC is an executive committee, reporting to the funder (NIHR) and the sponsor. Independent members will be independent of both the Sponsor organisations and of any recruiting study sites. The terms of reference of the TSC will be agreed at the first meeting, prior to start of recruitment. Meetings will be scheduled approximately 2 weeks after each Data Monitoring Committee (DMC) meeting. Minutes will be taken by the trial manager and retained in the TMF. The trial manager will prepare reports to the TSC. The trial may be prematurely discontinued by the Co-Sponsors or Chief Investigator on the recommendation of the Trial Steering Committee.
Composition of the data monitoring committee, its role and reporting structure {21a}
The data monitoring committee (DMC) will be composed of three independent members; a statistician and two clinicians. The DMC is an advisory committee, reporting to the Trial Steering Committee. They will receive a report of recruitment, serious and non-serious adverse events and a summary of accumulated clinical data from the trial statistician, and will meet in person or by telephone. The DMC will meet at least annually during the study, approximately 2 weeks prior to the TSC. Members will be independent of the Sponsor organisations and of any recruiting study sites. The DMC will work to the DAMOCLES guidance and a DMC charter will be agreed at the first meeting outlining responsibilities, reporting, meeting frequency, documentation and other matters. The trial statistician will prepare reports for the DMC.
Adverse event reporting and harms {22}
Adverse events will be categorised as per the medicines for human use (Clinical Trials) regulations 2004 and amended regulations 2006.Where any adverse event occurs the relationship with the investigational product will be assessed to determine the relationship and be judged as; definitively, probably, possibly, unlikely, not related or not assessable. All SAEs, SARs and SUSARs will be reported immediately (and certainly no later than 24hrs) by the Investigator to KCTU.The Chief Investigator will report relevant SAE’s to the ethics committee.
Frequency and plans for auditing trial conduct {23}
Monitoring of this trial will ensure compliance with Good Clinical Practice and will be managed by the Trial Manager at King’s College London. The Investigators will permit trial-related monitoring, audits, REC review, and regulatory inspections by providing the Sponsors, Regulators and REC direct access to source data and other documents (e.g. patients’ case sheets, blood results, imaging reports, trial protocol, statistical code, and etc). KCTU will prepare a monitoring plan for approval by the TMG. Recruiting study sites will have a Site Initiation Visit prior to recruitment of the first participant and regular site visits thereafter to verify the data.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
The Trial Manager will be responsible for preparing and submitting protocol amendments to the ethics committee and the HRA, and circulating updated document versions to recruiting study sites, co-applicants, the TMG, TSC and DMC and (where relevant) the funder. Site investigators will be responsible for communicating relevant information to study participants.
Dissemination plans {31a}
The primary analysis will be conducted after completion of first follow-up (at 4-12 weeks) which will include procedure time as well as the secondary outcome data available at this time, and published in a peer reviewed open source medical journal as early as possible. The 52 week secondary outcomes will be published in a further paper when all outcome data collection is complete. Recruiting sites will be informed of the results and will be asked to disseminate the findings to participants. Patient groups will be informed of the results for dissemination among their members. The sharing dataset will be passed to the trial Chief Investigator by the analyst and all future data sharing will be managed as per the Head contract and associated collaboration agreements.