Study setting {9}
This study is intended to be conducted in 20 research institutes in China. Details are as follows: Peking University Third Hospital; Nanjing First Hospital, Nanjing Medical University; Gansu Provincial People's Hospital; Xiamen Heart Center, Xiamen University; Tongji Hospital, Huazhong University of Science and Technology; People's Hospital of Wuhan University; The First Affiliated Hospital of Xi'an Jiaotong University; Beijing Anzhen Hospital, Capital Medical University; Union Hospital; Fujian Medical University; Xiamen Heart Center, Xiamen University;
Gansu Provincial People’s Hospital; First Hospital, Shantou University; Cangzhou Central Hospital; First Hospital, Hebei Medical University; First Hospital, Zhengzhou University; Tongji Hospital, Tongji Medical University; Hospital of Jiangnan University; Xuzhou Central Hospital
Tianjin Chest Hospital; General Hospital, Tianjin Medical University.
Eligibility criteria {10}
Eligible patients should meet all of the inclusion criteria and conform to none of the exclusion criteria shown in Table 1. The medical teams should be trained in the study devices and their supporting systems to avoid mistakes in therapeutic strategies. Coronary angiography and PCI should be performed by experienced physicians according to the standard operating procedure (SOP). All study centers should have appropriate conditions for this trial, including eligible staffing and training, a well-equipped laboratory in good working order and sufficient number of subjects.
Who will take informed consent? {26a}
Potential patients will first receive study information and if they agree to participate, research physicians will meet with them, solve remaining problems and obtain their informed consents. Informed consent materials are available from the corresponding author on request.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Participants will be notified in the informed consent form that their study data will be collected and may be used in possible research and analysis in the future.
Interventions
Explanation for the choice of comparators {6b}
The control group will receive provisional T-stenting technique with DES, which is recommended by 2018 European Guidelines for Revascularization and European Bifurcation Club for bifurcation lesion treatment[1,2]. DES must be a bare metal stent (biodegradable stent not allowed) that has been approved for marketing in China with a medical device registration certificate. The stent platform should be a cobalt-chromium alloy, cobalt-nickel alloy or stainless-steel platform. Carried drug should be everolimus, Zotarolimus or rapamycin. There is no restriction on polymer matrix coatings, DES manufacturers or brands.
Intervention description {11a}
Non-target lesions (if exist) are recommended to handle first before treating target lesions. When non-target and target lesions are located in the same vessel, it’s required that no more than one non-target lesion needs operation, namely the total number of non-target lesions treated during hospitalization for this study (emergency PCI counted as past history and excluded) should not exceed two. The treating order, approach and results should be strictly recorded. Then guidewires will be placed in both main and branch vessels for pre-dilation. A successful pre-dilation conforms to the following: (1) stenosis of the main vessel ≤30% after pre-dilation; (2) No coronary artery dissection or National Heart, Lung, and Blood Institute (NHLBI) classification type A/B/C dissection. After the main vessel is successfully pre-dilated, participants will receive either DCB or DES treatment.
For DCB group, the branch vessel will then be pre-dilated. The recommended balloon-to-vessel diameter ratio is (0.8~1):1. Next deliver DCBs to the branch and main vessel sequentially for kissing balloon inflation (KBI). The suggested inflation time of DCBs is 45~60s. A successful dilation satisfies all of the following requirements: angiographic visual residual stenosis of the main vessel ≤50% after dilation; thrombolysis in myocardial infarction (TIMI) grade 3 flow; no coronary artery dissection or NHLBI classification type A/B/C dissection. If one of these situations exists, remedial stenting should be performed based on investigators’ clinical judgment: (1) immediate postoperative angiographic visual residual stenosis of the main vessel >30%; (2) stenosis of the branch vessel opening > 90%; (3) TIMI flow grade of the branch vessel decreases; (4) severe intraoperative dissection of the main or branch vessel (NHLBI classification type D/E/F).
The study device in the DCB group is the RESTORE® DCB, a dual-lumen coronary balloon dilation catheter that allows for rapid change. With a semi-compliant balloon and two x-ray-opaque markers, one proximal and one distal, it can be positioned under x-ray fluoroscopy. The balloon coating is composed of a degradable ammonium shellac salt-paclitaxel complex (1:1 mixture) and the active ingredient paclitaxel (3 ug/mm2) can prohibit smooth muscle cell proliferation, thus lowering risk of restenosis. The RESTORE® DCB has the following advantages: First, the three-layer balloon prevents premature drug elution before it reaches the target lesion, therefore it has lower coating loss rate (30% vs. 80% for its counterpart). Second, drug is released efficiently (within 30~60s) and absorbed completely without polymer formation. Third, no stenting enables rapid healing. Finally, the coating technology is more advanced and no paclitaxel particles appear under the microscope.
For DES group, following a successful pre-dilation of the main vessel, whether to pre-dilate the branch vessel depends on degree of involvement of the branch vessel opening. Next, implant a DES in the main vessel and proximal optimization technique (POT) is advised. If there is no risk of branch vessel occlusion, no further operation is needed, otherwise re-wiring and KBI should be performed in the branch vessel under any of these conditions: (1) severe stenosis (> 90%) of the branch vessel opening; (2) TIMI flow grade of the branch vessel decreases; (3) severe branch vessel dissection (NHLBI classification type D/E/F). If one of the following situations exists after KBI, branch vessel stenting should be performed: (1) branch vessel remains at risk of occlusion determined by the operator; (2) severe stenosis (> 90%) of the branch vessel opening; (3) TIMI flow grade of the branch vessel decreases; (4) severe branch vessel dissection (NHLBI classification type D/E/F).
The study flowchart is shown in Figure 1.
Criteria for discontinuing or modifying allocated interventions {11b}
Patients can withdraw from the trial at any time according to their will. Besides, in order to protect participants’ health and life, investigators may implement decisions deviating from the protocol, which must be promptly reported to the medical device clinical study administration and the study sponsor as well as the ethics committee (EC) should be informed. Criteria for discontinuing or modifying allocated interventions include: (1) subjects withdraw themselves; (2) subjects violate the protocol; (3) subjects are lost to follow-up; (4) the informed consent process is incomplete; (5) adverse events (AEs) or severe adverse events (SAEs) happen; (6) moral, ethics and other issues regarded inappropriate for continuing research.
Strategies to improve adherence to interventions {11c}
Interventions in both groups are designed to promote subject health as much as possible and can be adjusted to participants’ willing. Adherence to the protocol is monitored by specialised personnel.
Relevant concomitant care permitted or prohibited during the trial {11d}
Before, during and after PCI, participants should receive antiplatelet or anticoagulation medications. Table 2 shows the suggested medication regimen. The type, dose and duration of specific drug treatments may be adjusted to participant safety and clinical situations.
Possible intraoperative complications, such as coronary artery dissection, coronary artery spasm, acute coronary closure, balloon rupture and so on will be treated in accordance with standard management.
Table 2. Recommended medication regimen for participants receiving PCI.
Provisions for post-trial care {30}
Participants suffering harm from trial participation will be provided compensation.
Outcomes {12}
The first primary endpoint is the target lesion failure (TLF) rate at 12 months postoperatively, including cardiac death, target vessel myocardial infarction (MI) and target lesion revascularization (TLR). The second primary endpoint is clinical net event rates at 12 months postoperatively, including cardiac death, target vessel MI, TLR and Bleeding Academic Research Consortium (BARC) type 2/3/5 bleeding.
The secondary endpoints include the following:
- Device success: devices are successfully delivered to lesions for use and withdrawal;
- Technical success: postoperative angiography shows < 30% and < 50% residual stenosis in the main and branch vessel separately with TIMI grade 3 flow;
- TLF at 1 and 6 months and 2 and 3 years postoperatively;
- TLR and target vessel revascularization (TVR) at 1, 6 and 12months and 2 and 3 years postoperatively, including PCI re-stenting, balloon dilation, rotational atherectomy or atherectomy and coronary artery bypass graft (CABG);
- PCI duration: the time from inserting the guiding catheter to its removing;
- Duration of postoperative dual antiplatelet therapy;
- BARC type 2/3/5 bleeding at 1, 6 and 12months and 2 and 3 years postoperatively;
- Academic Research Consortium (ARC)-defined stent thrombosis at 1, 6 and 12months and 2 and 3 years postoperatively, including definite and probable stent thrombosis in the acute, subacute, late and very late stage.
Participant timeline {13}
Schedule of enrolment, interventions, assessments and visits for participants is shown in Table 3. Participants who don’t use the study device will not be included in primary endpoint analysis, but a one-month postoperative safety follow-up is still needed. For participants treated with the study device followed by other therapies (e.g., stenting), follow-up should be completed according to the protocol.
Sample size {14}
Sample size calculation in this trial is based on the noninferiority hypothesis followed by the superiority hypothesis. The statistical significance level is set at 2.5% unilaterally and the power is set at 80%. The subjects will be randomly grouped in a 1:1 ratio. The maximum drop-out rate is 5%. According to literature reports and experts’ judgement [5], the estimated TLF rates at 12 months postoperatively for the study and control group are 7% and 10% respectively. The noninferiority threshold is set at 3%. Considering the above parameters, 714 subjects will be required. Sample size formula:
If the noninferiority hypothesis is met, the superiority hypothesis will be tested. The clinical net event rates at 12 months postoperatively are estimated to be 7.5% and 13% in the study and control group separately. Other parameters are the same as above, therefore, the total number of subjects required is 1000. Sample size formula:
Recruitment {15}
Potential subjects will be strictly examined and judged according to the protocol to ensure their eligibility for this trial. Distribute the number of enrolments in each center as evenly as possible and adjust the final enrolments to the reality. The final enrollments in any of the centers should not exceed 50% of the total number of participants. The recruitment is expected to last 30 months.
Assignment of interventions: allocation
Sequence generation {16a}
Interactive Web Response System (IWRS) is used to generate the allocation sequence randomly.
Concealment mechanism {16b}
Participants and operators will be informed the allocation upon randomization.
Implementation {16c}
IWRS is utilized by researchers to generate the allocation sequence and participants are accordingly assigned to either the experimental or the control group.
Assignment of interventions: Blinding
Who will be blinded {17a}
The outcome assessor will be blinded to avoid bias. Participants and operators will not be blinded, as the interventions between the two groups are different. In the statistical analyses for this clinical trial, data will be analyzed using a blinded approach, with the statistician remaining blind to subgroups.
Procedure for unblinding if needed {17b}
In this single-masking trial, the outcome assessor will be blinded and unblinding is not applicable.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Participants’ data at baseline, during and within 24 hours after operation and at discharge should be collected. Follow-up data at 1, 6 and 12 months and 2 and 3 years postoperatively will also be recorded by investigators or qualified professionals authorized by investigators. Specific items to be collected are shown in Table 3.
Besides, during critical intervention periods, the following angiographic results should be carefully documented: (1) ≥2 preoperative orthogonal views of lesions (as reference views); (2) positioning images of DCB or DES before dilation (If balloon positioning image before dilation is not available, a replacement will be required after balloon dilation.); (3) images of catheter head during angiography and operation; (4) two postoperative images with the same projection angle as the preoperative one; (5) follow-up images with the same projection angle as the postoperative one. Meanwhile, intravascular ultrasound (IVUS) and optical coherence tomography (OCT) data should be collected as much as possible for centralized quantitative coronary analysis (QCA) by specialized technicians in the angiographic core laboratory. Main parameters obtained by QCA include: reference vessel diameter (RVD), minimum lumen diameter (MLD), diameter degree of stenosis (DS), immediate lumen gain, late lumen loss and whether restenosis exists. Device and technical success, and PCI duration will be assessed immediately after operation.
Other details to be recorded include: types of angiographic and guiding catheters, brands, lengths and labeled diameters of balloons or stents and maximum dilation pressure, dilation and re-dilation (if performed) duration of balloons.
Plans to promote participant retention and complete follow-up {18b}
Participants will be informed comprehensively of the study purposes and trial requirements during recruitment. Follow-up will be conducted through clinic visit or phone call. Researchers will monitor the process and remind participants to complete follow-up when necessary.
Data management {19}
The electronic data capture (EDC) system enables investigators to collect data accurately and completely without filling in paper case report forms. After the data entry is completed and submitted, the system enters a soft lock and the statistician will generate a data review report. If the data needs no modification, the study sponsor, the data manager, and the statistician will sign a database lock form and any modification will not be allowed after the data manager lock the database. If there indeed exists error that affects the primary endpoint, the unlocking, modification and re-locking should still be completed by the above personnel.
Confidentiality {27}
Medical information of each subject is confidential and prohibited from disclosure to the third parties without subjects’ consent.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Collected biological specimens are used for biochemistry evaluation as shown in Table 3. Participants will be informed of the purposes of collecting biological specimens in the informed consent form.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The statistical analysis for this study will be based on the following populations: full analysis set (FAS), per protocol set (PPS) and safety analysis set (SS). Baseline demographic data will be analyzed based on the FAS, which is identified according to the Intention to Treat (ITT) principle. Primary endpoint analysis will be performed based on the FAS and the PPS. For subjects who drop out of the study, their data will still be included in the final statistical analysis and detailed reasons for withdrawal should be described in the statistical report.
Count data will be described by frequency and composition ratios, and quantitative data be described by mean, standard deviation, maximum and minimum values, median, 25th and 75th quartiles. The c2 test or Fisher’s exact probability method is used for the intergroup comparison of count data; the t-test is used for the intergroup comparison of normally distributed quantitative data; the Wilcoxon Rank Sum test is used for the comparison between groups of non-normally distributed quantitative data. The first primary endpoint will first be tested, and if noninferiority of DCB is valid, the superiority of DCB regarding the second primary endpoint will be further tested.
All statistical analysis will be performed with SAS 9.4 software and refer to the requirements of ICH (The International Conference on Harmonization) E9 and the “Biostatistical Guidelines for Clinical Trials” issued by the National Medical Products Administration (NMPA). The statistical analysis plan (SAP) should be finalized prior to data lock. In principle, the analysis sets and main analytical methods will not be substantially modified, and all changes will be documented.
Interim analyses {21b}
There are no planned interim analyses.
Methods for additional analyses (e.g. subgroup analyses) {20b}
There are no planned subgroup analyses.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
For missing data, imputation will routinely be performed only for missing primary endpoints. Wrong or unreasonable data will be addressed during the data cleaning process before statistical analysis.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Participant-level dataset and the statistical data of this trial can be obtained from the corresponding author upon reasonable request.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The study team meets biweekly and the following provide day-to-day support for the research: (1) principle investigator: trial supervision and medical responsibility of the participants; (2) data manager: data capture and quality safeguards; (3) study coordinator: trial registration, study visit coordination, safety reports; (4) study physician: participant recruitment, informed consent collection, follow-up; (5) experts in cardiovascular interventions and methodology: judging adverse events.
Composition of the data monitoring committee, its role and reporting structure {21a}
Direct access to source data and documents will be made available by the investigators and institutions for study-related monitoring.
Adverse event reporting and harms {22}
AE refers to an undesired medical event that occurs during or after a subject is treated with a medical device. AE that threatens health, causes death or harms fetuses is SAE. When an AE happens, it should be recorded on the adverse event form and targeted treatments and follow-up should be provided by investigators until symptoms are resolved and stabilized. If SAE occurs, investigators should immediately treat the subject and report it in writing to EC, the relevant administration and the other study centers and investigators. The causal relationship between AEs or SAEs and the trial should be carefully considered.
Frequency and plans for auditing trial conduct {23}
Trial auditing process takes place twice per year and is independent form investigators and the sponsor. The investigators and institutions will allow direct access to source data and documents for study-related audits.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Protocol deviation must be promptly reported to the medical device clinical study administration, the study sponsor and EC. Participants will be informed of the amendments and additional consent may be requested.
Dissemination plans {31a}
Without the written consent of the study sponsor, investigators are not permitted to use study data for any purpose other than to complete the clinical study or prepare materials for publication. The study sponsor gives consent to the principal investigator to release study results of multiple centers, before which individual research centers are not permitted to publish or report their results. The research results will be communicated by the principal investigator with all parties, including publications, the trial register, sponsor and participants, in the form of statistical analysis reports, research summary reports, and research papers.