Our trial is planned to be conducted in West China Hospital, Chengdu, China. This study was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University (approval number: 2021-212) on 11 March 2021. The trial was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2100046734) on 27 May, 2021. NEONATAL trial is a prospective, single center, paralleled, non-inferiority, single-blind trial, randomized controlled trial (allocation ratio 1:1). The present protocol was written according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement for study protocols of clinical trials . The SPIRIT flow Diagram is shown as Figure 1, and the SPIRIT Checklist is added in Additional file 1. Table 1 shows the schedule of enrollment, interventions, and assessments.
Patients at least 18 years old who are diagnosed with AIOD (Rutherford classification from 2 to 6) will be screened for study recruitment. The inclusion and exclusion criteria are showing in Table 2.
Assignment of interventions
In our trial, the included patients were randomly allocated at 1:1 ratio to CBE stenting group or CSE stenting group. The allocation sequence was computer generated by a biostatistician within sex and 5-year age groups in blocks of ten, and stratification was performed by numbers of treatable legs. As for patients who required intervention in bilateral iliac arteries, the randomization was performed according to the treated arteries. The study nurse in the operating room will prepare the sealed, opaque, consecutively numbered envelopes, and informed the surgeon of the allocation results before intervention. Both study nurse and biostatistician were not involved in the perioperative management of patients. The outcome assessors and data analysts will be blinded to the interventions.
Details of intervention
Prior to the endovascular intervention, informed consent (see Additional file 2) will be obtained from all participants by investigators. The included patients will receive the same perioperative management, including antiplatelet drugs, statin usage, and blood controls. Both common femoral arteries and sometimes left brachial artery will be used for access. Whether to adopt percutaneous or cutdown access route will be determined by the surgeons. After obtaining the arterial access, 0.5mg/kg of unfractionated heparin will be administered. Fluro-opaque ruler will be used to record location and extent of the lesion. Both intraluminal and subintimal recanalization of iliac lesions will be allowed. After the successful passage of the guidewire, the target lesion will be predilated with downsized balloon in CBE group, and with equal-sized balloon in CSE group. During actual intervention, the allocated choice of covered stents may be modified according to intraoperative findings, for instance, the length of lesions did not match the stents. Multiple stents are required when needed and multiple stents edges should overlap by at least 10mm. Furthermore, additional bare metal stents can be added in both groups, according the discretion of surgeons. Post dilation balloon will be performed within the stented segment, with less than 10 % oversizing. A final angiography will be performed after the intervention in both groups, with the use of the same angles and magnifications used at the baseline angiograms.
Postoperative management include a dual antiplatelet regimen for three months, involving 100 mg of aspirin once a day plus 75 mg of clopidogrel once a day. Clopidogrel is not required if a participant is taking warfarin, other direct thrombin inhibitors, factor Xa inhibitors) or low molecular weight heparin will be used according to physician’s recommendation. anticoagulants therapy will be discontinued when other surgical procedure is required and then the participant is to resume anticoagulants therapy as soon as possible after the surgery. Drug side effects will be checked and monitored at outpatient visit or telephone follow up. According to comprehensive surgeon’s recommendation, drug therapy will be discontinued. Clinical follow-up will be planned at 1, 6, 12, 24 and 36 months to evaluate clinical outcomes.
CBE and CSE Stent
The CBE stent used in our trial is BARD® LIFESTREAM™ Covered Stent, a permanently stent used to maintain patency of common or external iliac artery. The stent is a balloon-expandable stent with expanded polytetrafluoroethylene (ePTFE) encapsulated between two layers (inner and outer). The implant is pre-mounted on an over-the-wire balloon catheter that acts as the delivery system. The configurations of BARD® LIFESTREAM™ Covered Stent offered 16, 26, 37, 38 and 58 mm in length and 5 to 12 mm in diameter. The stents can be overlapped if the target lesion exceeds the longest available length of stent.
GORE® VIABAHN™ self-expandable covered stent is the only CSE stent adopted in our trial, it consists of two main components: intravascular covered stent and catheter-based delivery system. The stent consists of self-expanding nickel-titanium alloy stent combined with ePTFE intracavity coated, which is offered in lengths of 25, 50 and 100 mm and in diameters of 5 to 11,12 mm in the configurations.
Follow up and outcomes of interest
All included patients will be followed up in outpatient clinics at 1 month, 6months, 12-months, 24-months, and 36-months after initial intervention. Patients who fail to come back will be followed up on telephone. Trained researcher will collect the outcomes of interest, blinded to the intervention groups. All participants have the right to withdraw from the study at any time for any reason. The principal investigators also have the right to withdraw patients from the study if subjects break the protocol.
The primary end point of this study is target lesion revascularization (TLR) (TLR is defined as the first revascularization procedure (e.g. PTA, atherectomy, etc.) of the target lesion(s)) assessed at 12months after the intervention.
The following secondary end points of this study are collected at 1-, 6-, 12-, 24- and 36 months post-index procedure:
(1) stent and/or surgical related mortality; (2) all-cause mortality; (3) amputation-free survival; (4) acute limb ischemia rate;(5) major adverse cardiovascular and cerebrovascular events (MACCE); (6) target vessel revascularization (TVR), (TVR is defined as the first revascularization procedure (e.g. PTA, stenting, surgical bypass, etc.) in the target vessel(s)); (7) primary patency (the loss of primary patency is defined as target lesion(s) is determined to be > 50% stenosis or TLR/TLR needed in follow up); (8) primary assisted patency (the loss of primary assisted patency is defined as target lesion(s) is determined to be > 50% stenosis after TLR); (9) secondary patency (the loss of secondary patency is defined as target lesion(s) is determined to be > 50% stenosis after endovascular procedure or surgical bypass TVR).
Data collection and management
Importantly, the investigators will be urged to follow up on patients by telephone contacts. Data will be collected as detailed as possible. Collected data lists will be stored in Monitoring committee and will be made available to the third-party regulatory body upon request.
Sample size calculation
We calculated the sample size for this study based on the results of previous studies[4; 13]. As is reported previously in AIOD patients, the 9-month primary patency of CBE stent (BARD®LIFESTREAM™ Stent) was 89.1%, while the 9-month primary patency of the CSE stent (GORE® VIABAHN™ stent) was estimated to be 82.2% based on VIASTAR Trial [14; 15]. In the present study, we hypothesized that the primary patency of CBE stent is not inferior to that of CSE stent, the predetermined noninferiority margin on risk difference scale (δ) is set as 10 % between treatment groups. There was clinical consensus that this non-inferiority margin would be acceptable if safety is maintained and patients are treated more easily, regardless of stent classification . The power analysis is based on a Choi et al. Trials (2016) 17: 302 Page 5 of 10 non-inferiority principle. The type I error rate is 0.05, the power of the test is set as 80%, and the randomization ratio is set as 1:1. After accounting for a 15 % dropout rate. it was calculated that 53 lesions per group are needed for a total of 106 lesions.
In order to achieve adequate participant enrolment, we recruit patients by putting up posters or advertising on the Internet, furthermore, we actively recruit patients from outpatient department and emergency department.
Data collection and management
Two investigators use a pre-identified and unified case report form (CRF) to record the data of included patients independently. Both received training for data collection. Demographics, comorbidities, and prescriptions of cardiovascular drugs were recorded from patient chart. Imaging anatomic parameters were measured from picture archiving and communication system (PACS). Laboratory results were collected from laboratory information system (LIS).
As for data management, two investigators retrieved data from CRF and recorded in two identical electronic form, and cross check is performed to ascertain the accuracy of data. We also set range checks for data values.
R studio Version 1.2.1335 (http://www.R-project.org) and Empower (www.empowerstats.com, X&Y solutions, Inc., Boston, MA) were utilized for statistical analysis. Categorical data are expressed as numbers and rate, while continuous data are expressed as means ± standard deviation (SD) if they are normally distributed, or median (interquartile range [IQR]) vice versa. Student’s t test or Mann-Whitney U test is used for univariate analysis of continuous data, and the χ2 test or Fischer’s exact test is used for categorical data. For primary analyses, multivariate logistic regression is adopted to calculate adjusted odds ratios (OR) and 95% confidence interval (95% CI) for short-term outcomes. Cox proportional hazard regression analysis is used to generate adjusted hazard ratio (HR) and corresponding 95% CI for long-term outcomes. The primary and secondary end points will be analyzed in the modified intention-to-treat analysis, which includes all subjects undergo randomization and subsequent interventions. Sensitivity analyses of primary and secondary endpoints are performed in the per-protocol population, based on the treatment actually received. The noninferiority margin was set at 10 percentage points for the absolute difference between groups. If the standard of noninferiority was reached, the primary and secondary outcomes were subsequently tested for superiority (P<0.05). Noninferiority will be considered proven if conclusions drawn from the intention-to-treat and per protocol analyses are consistent.
Further pre-specified subgroup analyses will be carried out in the following subgroups: TASC II C-D lesions versus A-B lesions, occlusion versus stenosis. Adjustment analyses for primary and secondary endpoints were performed based on the Hochberg method . Multiple imputation was used to handle missing data.
Monitoring committee consists of biostatisticians, surgeons, investigators, and nurses who neither be involved in the conduct of this study, nor financial and professional interests. Annual monitoring will be conducted by Monitoring committee. Monitoring committee will provide feedback to investigators and vascular surgeon as soon as there are any problems. Ethics committee and monitoring committee will have access to check the collected data and question the rationality of the study protocol before, during, and after the trial. Classical interim analyses are performed by an independent statistician who will be a person other than the regular study statistician. The trial will be terminated when one treatment group is significantly superior or inferior to the other treatment group. The final decisions regarding study modifications or stop rest with both ethics committee and monitoring committee. All serious adverse events (SAEs) must be reported as soon as possible. The SAE form contains the following information: identification of the subject, attending surgeon, description of the SAE (event, beginning and duration, severity, outcome, treatment, or interventions taken). To maintain the quality and safety of trial, unblinding occur only in exceptional circumstances when knowledge of the actual treatment is essential for further management of the subject.
All substantial amendments will be notified to the Ethics Committee on Biomedical Research, monitoring committee and the upstream authorities. Non-substantial amendments will not be notified to the monitoring committee and the upstream authorities, but will be recorded and filed by the sponsor. Update informed Consent forms will be sent to new patients after amendments.