Study setting {9}
This study is being started by an academic hospital. The study intends to involve eight centers located in Poland. You may find a current and complete list of these collaborating hospitals on ClinicalTrials.gov.
Eligibility criteria {10}
The study will enroll patients who meet the following criteria:
- Aged ≥18 years
- Diagnosed with paroxysmal, persistent, or permanent AF
- ESC class I indications for preventing ischemic stroke, indicated by a CHA2DS2VASc score of ≥2
- Contraindications to anticoagulant use or a high bleeding risk based on a HAS-BLED score of at least 3 points
Patients meeting any of the following criteria will be excluded from the study:
- History of ischemic stroke
- History of central nervous system infections
- Neurological diseases such as Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, and Pick's disease
- Severe mental disorders, including dementia of any etiology, schizophrenia, bipolar disorder, and depression
- Anatomical obstacles to the LAAC procedure or the insertion of a neuroprotection system
- Presence of mechanical heart prostheses
Who will take informed consent? {26a}
Patients participating in the study must be familiar with the information presented in the informed consent form and give it in writing in the investigator's presence.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
The study does not provide for additional sample collection, which would require additional consent from study participants.
Interventions
Explanation for the choice of comparators {6b}
Patients enrolled in the study will undergo LAAC procedures conducted using the standard approach. However, only the study group will exclusively integrate the CPS Sentinel neuroprotection system during this procedure. The selection of this specific neuroprotection system stems from its approval for clinical use and its capability to safeguard approximately 95% of brain tissue from potential embolisms during intracardiac interventions.
Furthermore, the favorable outcomes observed when implementing the CPS Sentinel in patients undergoing TAVI procedures are compelling evidence of its high effectiveness. As a result, the researchers have chosen this system for investigation in the context of LAAC procedures to assess its potential benefits in reducing embolic events and enhancing patient outcomes.
Intervention description {11a}
The LAAC procedure in the study group will involve the utilization of Amplatzer Amulet occluders along with the Sentinel CPS for cerebral circulation protection. Transcatheter LAAC interventions will be carried out under deep sedation or general anesthesia, using right femoral vein access.
The procedure encompasses several key steps to ensure accurate and safe placement of the Amplatzer Amulet occluder. Initially, a guide is positioned in the superior vena cava via the right femoral vein to establish a pathway for accessing the left atrium. Subsequently, a transeptal catheter is introduced and gradually withdrawn through the first and second slopes (foramen ovale) until access to the left atrium is achieved. This puncture process is meticulously monitored using fluoroscopy and transesophageal examination to ensure precise needle positioning and safety during atrial septum puncture.
Once left atrium access is established, a catheter is guided to the left atrial appendage (LAA) for angiography, providing a detailed assessment of LAA anatomy. Following this, the catheter is advanced to the left upper pulmonary vein and replaced with a specialized catheter designed for LAAC. The catheter is carefully positioned within the LAA at the appropriate depth, and a self-expanding Amplatzer Amulet occluder is inserted to close the LAA effectively. After successful occluder deployment, it is carefully pulled to verify proper positioning and assess the efficacy of LAA elimination. Finally, the guide catheter is removed, and a hemostatic suture is applied to the groin to ensure proper closure and minimize bleeding risk.
In the study group, before the LAAC procedure, a Sentinel CPS will be inserted to provide neuroprotection. Several steps are undertaken during the insertion of the Sentinel CPS. Firstly, arterial access is obtained through a radial artery puncture, and a pigtail catheter is inserted into the ascending aorta to perform aortography, assessing the aortic arch and cerebral arteries' anatomy. The proximal filter of the Sentinel CPS is expanded in the brachiocephalic trunk, and the device is carefully rotated in the ascending aorta to position its tip in the left common carotid artery accurately. Subsequently, the distal filter of the Sentinel CPS is expanded, and fluoroscopy is used to ensure the correct positioning of both filters, thereby providing neuroprotection during the LAAC procedure.
After the successful implantation of the occluder in the LAA, the Sentinel CPS will be removed. The activated clotting time (ACT) must be maintained above 250 seconds during the procedure. Therefore, heparin will be administered. In the control group, heparin will be administered after the transeptal puncture. In the control group, the LAAC procedure will be performed in the same manner as in the study group but without installing the Sentinel CPS.
Criteria for discontinuing or modifying allocated interventions {11b}
Analyses within the study will be carried out in accordance with the principle of intent-to-treat. Consequently, should a participant assigned to the study group not receive the Sentinel CPS intervention, they will still be retained within the study group. There will be no reassignment of participants between the study and control groups.
Strategies to improve adherence to interventions {11c}
Given the interventional nature of this study, strategies for monitoring adherence pertain to the execution of follow-up visits and the associated procedures delineated for such instances. During follow-up visits, patients will be scheduled for subsequent appointments and receive timely telephonic reminders ahead of their impending appointments.
Relevant concomitant care permitted or prohibited during the trial {11d}
Participation in the study does not influence the treatment of alternative medical conditions. Concerning prior therapeutic approaches, the patient enrolled in the study will not use oral anticoagulants after the procedure. Instead, they are advised to undergo dual antiplatelet therapy for three months post-LAAC intervention.
Provisions for post-trial care {30}
The study incorporates an insurance policy designed to address any potential harm experienced by participants. After completing participation in the study, patients will no longer be obligated to undergo oral anticoagulant treatment as a component of stroke prevention in cases of atrial fibrillation. Instead, they will solely be recommended to take acetylsalicylic acid.
Outcomes {12}
The study's primary endpoint is the number of new SBIs or stroke foci in the DW MRI. In addition, the following secondary endpoints were defined:
• Volume of SBI and stroke foci in DW MRI
• Deterioration of cognitive functions assessment using standardized tests: The Montreal Cognitive Assessment (MoCA) test versions 8.1 and 8.3, Trail Making Test (TMT) parts A and B, Controlled Oral Word Association Test (COWAT)
• Development of dementia syndrome
• Occurrence of depressive disorders using Hospital Anxiety and Depression Scale (HADS)
• Presence of embolic material in the filters of the neuroprotection device
• Complications related to the use of the neuroprotection system during LAAC
Participant timeline {13}
Sample size {14}
Based on the assumptions that cerebral protection during LAAC would result in a favorable response in 85% of patients and that the absence of new SBI on DW MRI in the control group would affect 70% of patients, the minimum group size was estimated to be 118 individuals per group. This estimation ensured 80% power to detect the anticipated difference at a significance level of 5%. Considering a withdrawal or invalidation ratio of 2%, a total of 120 individuals will be enrolled in each group, resulting in a sample size of 240 patients for the study. This sample size is necessary to provide sufficient statistical power and enable meaningful comparisons between the study and control groups.
Recruitment {15}
Medical centers known to conduct a substantial volume of LAAC procedures were invited to participate in the study. Among individuals referred to these centers, patients eligible to participate in the study will be selected based on the inclusion and exclusion criteria.
Assignment of interventions: allocation
Sequence generation {16a}
Block randomization will be employed to uphold the proportional allocation of subjects across the two groups. The blocks will consist of four subjects each. Randomization will be centrally executed to mitigate the foreseeability of the forthcoming treatment modality for successive patients. This will be accomplished by utilizing existing computer algorithms facilitated by the Interactive Web Response System.
Concealment mechanism {16b}
To eliminate subjectivity during the assessment of patients during follow-up visits, individuals within the control group will similarly undergo arterial puncture and aortography. Furthermore, the neurologist conducting the neurological examination, utilizing the NIHSS score and cognitive functionality assessments, will be kept unaware of the patient's allocation to either study arm. This approach, known as "investigator blinding," aims to ensure impartial evaluation.
Implementation {16c}
Researchers will enroll patients at each participating medical center based on predetermined inclusion and exclusion criteria. Additionally, these researchers will carry out patient randomization utilizing a central computer system. External monitors to the study sponsor will oversee the accuracy of patient inclusion and adherence to the randomized assignments. These monitors are affiliated with the BioStat Sp. z o.o., a Clinical Research Organization (CRO) specializing in comprehensive research services. The study Sponsor has established a contractual agreement with this CRO for these monitoring purposes.
Assignment of interventions: Blinding
Who will be blinded {17a}
Both the patient undergoing assessment and the neurologist conducting the physical examination and cognitive tests will be kept uninformed regarding the utilization of neuroprotection with the Sentinel CPS during the LAAC procedure. Furthermore, DWI MRI images will be evaluated at a central laboratory separate from the centers participating in the study. The radiologist responsible for analyzing the DWI MRI images will also remain unaware whether the patient was assigned to the study or control groups. This approach ensures an unbiased and impartial assessment of outcomes
Procedure for unblinding if needed {17b}
Given that the Sentinel CPS is employed to prevent perioperative stroke, details concerning its utilization remain independent of managing potential perioperative complications or the emergence of new medical conditions during the follow-up period. Consequently, it is anticipated that no unblinding procedures will be implemented throughout the study.
Data collection and management
Plans for assessment and collection of outcomes {18a}
For the study, researchers must possess a valid Good Clinical Practice certificate. To acquire robust data regarding the efficacy of neuroprotection during LAAC procedures and to evaluate the clinical advantages of employing the Sentinel CPS, both imaging data—specifically brain DWI MRI—and assessments of cognitive functions and mood disorders will be collected. To ensure the accuracy of DWI MRI data, these images will undergo analysis at a central laboratory. Additionally, detailed instructions regarding the DWI MRI protocol will be furnished to participating centers.
Conversely, the evaluation of cognitive functions and mood disorders will involve the utilization of validated questionnaires. The use of these questionnaires is authorized by entities holding the respective copyrights. Researchers tasked with administering the Montreal Cognitive Assessment (MoCA) test must hold certification for conducting and interpreting the test. This certification is granted after completing appropriate training, available at mocacognition.com.
Plans to promote participant retention and complete follow-up {18b}
To ensure participants' continued engagement in the study, a telephone reminder will be implemented before the upcoming follow-up visit. If a participant becomes unable to attend follow-up visits due to health-related or other reasons (excluding withdrawal of informed consent), the researcher will make diligent attempts to document the observation comprehensively. This will involve initiating telephone correspondence with the participant, contacting their family, or liaising with their healthcare provider or relevant institution/authority. These measures are intended to facilitate remote interviews and accurately assess the participant's condition.
Data management {19}
A data management plan version 1.0 has been prepared, the purpose of which is to present the procedures and control mechanisms necessary to ensure the protection, authenticity, confidentiality, completeness and integrity of data collected from study participants, as well as the mechanisms necessary to ensure that the clinical database created as part of the study will be complete, cleaned and usable for the Sponsor and statisticians to analyze the collected data and prepare the clinical trial report. This document has been prepared in accordance with the guidelines of "Good Clinical Data Management Practices" and the regulations of 21 CFR Part 11. This document will be updated throughout the study to reflect changes to the electronic Case Report Form (eCRF) and comments from Monitors, Sponsor, Investigators, and Coordinators. Clinical data for the LAAC-SBI study is collected through the eCRF.bizTM system, an Electronic Data Capture platform developed by BioStat. This system is fully validated and serves as the repository for study-related information. The eCRF.bizTM system operates on a server running the GNU/Linux Debian 11 operating system. It utilizes PHP version 7.2.34, MySQL database version 8.0.29-2, and Apache web server version 2.4.54. Certain functionalities linked to reporting and encoding medical data involve using the R statistical software (version 3.3 or later) and the Python programming language (version 3.5). To ensure security, the system has been situated on a secure server hosted at the data centre of OVH, a prominent European service provider known for its reliable infrastructure.
Confidentiality {27}
All patient data entered into the eCRF are anonymous and identifiable by a unique patient number generated when creating the patient card. The research team is responsible for keeping information about the patient's assigned number in the records kept at the site.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
The current study does not plan to obtain biological material for genetic and molecular research.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
The primary analysis of all endpoints will be conducted using an intention-to-treat approach, wherein participants will be analyzed according to their initial randomization assignment, irrespective of the actual treatment received. Quantitative variables will be presented as either mean or median values, while qualitative variables will be reported as counts (with percentages). To assess the distribution of quantitative variables, the skewness index will be employed. Between-group comparisons will be carried out using independent t-tests and ANCOVA for quantitative variables. A chi-square test will be used to compare distributions between the two groups for qualitative variables.
Interim analyses {21b}
The monitoring committee will act in an advisory role to ensure safety by reviewing the cumulative data from the clinical trial at specified intervals. Its tasks also include monitoring the clinical trial's current validity and scientific value. The monitoring committee may recommend modifying or terminating a clinical trial based on any perceived safety concerns, regardless of statistical significance. The sponsor is authorized to stop the study at any time if the safety of the participants is compromised. The test may end prematurely, especially if:
• serious adverse events outweigh the previously positive balance of benefits and risks,
• adverse events occur with such intensity and/or frequency that the proposed treatment regimen can no longer be continued.
The sponsor is responsible for reporting the discontinuation of the trial to the Bioethics Committee, giving the reason for discontinuing the trial, and informing in writing about the potential risk to the health of clinical trial participants or other persons.
Methods for additional analyses (e.g. subgroup analyses) {20b}
No subgroup analysis is planned.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Instances where the procedure is not conducted per protocol, must be documented along with the underlying reasons. The analysis will still include data regarding the study participants who did not undergo the procedure aligned with their randomized group. The CRO and the Sponsor will regularly review the Protocol Deviation Reports. Should repeated deviations from the study protocol occur, the Sponsor reserves the authority to suspend recruitment at a particular center based on their judgment and decision-making.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The protocol may be made available by the principal investigator upon reasonable request.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The study's sponsor is the Silesian Centre for Diseases in Zabrze, which also serves as the coordinating center for the study. Managing the Clinical Research Organization tasks has been delegated to an external organization named BioStat sp z o.o. The Silesian Centre for Heart Diseases in Zabrze is responsible for establishing contracts with other participating centers and providing the necessary equipment and materials for conducting the study.
Furthermore, a Steering Committee has been instituted to oversee the clinical trial's scientific and operational aspects. This committee convenes regularly to supervise participant recruitment, overall data collection, and any instances of site-specific non-compliance with the study protocol. It also evaluates and follows up on recommendations by the monitoring committee, addresses operational concerns that might arise warranting modifications to the study protocol or corrective actions, and establishes a policy for publishing findings from the clinical trial's collected data.
Composition of the data monitoring committee, its role and reporting structure {21a}
Team of Data Managers BioStat Sp. z o. o. is responsible for data management and monitoring. The eCRF.bizTM system has many tools to monitor the progress and status of the study in real-time. In addition, the clinical database of the LAAC-SBI study has been equipped with validators and transition rules. To ensure adequate data quality control, the Data Managers team of BioStat Sp. z o. o. will apply additional data verification procedures on the database snapshot exported from eCRF.bizTM to personal computers. To increase the accuracy and repeatability of verification, Data Managers will develop a series of scripts in the R statistical program and use MS Excel. The quality control of the clinical database dumps will take place at the beginning of the study after the inclusion of each subsequent ten patients (however, at intervals not longer than one month). Once all patients are included, the verification frequency will increase to at least one check per week.
Adverse event reporting and harms {22}
Any Adverse Events (AEs) or Adverse Device Events (ADEs) that meet the criteria for severity must be promptly reported to the Sponsor within 24 hours of their occurrence or as soon as awareness of their occurrence is established. The same procedure applies to instances of Product Defects that could potentially lead to Serious Adverse Events (SAEs) if appropriate action had not been taken, interventions were not carried out, or circumstances were less favorable.
On an annual basis throughout the study duration, the Principal Investigator will furnish the Ethics Committee that issued the study's approval with a comprehensive list encompassing all suspected serious adverse events that transpired within that specific year. Furthermore, an annual report about patient safety will also be submitted. Information related to all SAEs will be incorporated into the finalized Clinical Study Report.
Frequency and plans for auditing trial conduct {23}
The Clinical Research Associate (CRA) employed by BioStat Sp. z o. o. is tasked with overseeing the following study-related visits:
- Initiation Visit: This visit occurs prior to center activation to verify its readiness to initiate the study. The monitor assesses facility equipment, explains relevant regulations and protocol requirements, and conducts any necessary staff training.
- Monitoring visits: These visits are conducted to protect study participants' rights, adherence to the protocol and applicable regulations (including Good Clinical Practice), accurate collection and reporting of safety data, and study endpoints.
- Closing Visit: The closing visit is conducted to ascertain the completeness of study data and documentation, confirming that all required audit-related procedures have been executed.
The frequency of monitoring visits to each center is contingent on the pace of patient recruitment and the quality of work. The study accommodates up to 64 monitoring visits. Around 60 patients will be included in the Source Data Verification pool, enabling the verification of approximately 25% of the data. Following each monitoring visit, the CRA will compile a visit report and send a summary letter detailing the visit's outcomes to the center.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
To ensure the flow of all relevant and up-to-date information regarding the audit on an ongoing basis, the implementation of updated documents describing the procedures, compliance with deadlines, and conducting training, detailed requirements regarding the method and frequency of communication were set out in the Project Management Plan. The first contact person for the Sponsor is the Project Manager (PM) at Biostat Sp Z o.o. The PM also acts as the initial point of contact for the monitoring team. In turn, the PM provides the Sponsor and the monitoring team with all information requiring their attention on an ongoing basis. In urgent situations, especially those concerning safety in the study, the monitoring team/Sponsor will also send their notification by e-mail to the PM and the entire team.
The first point of contact for the center is the CRA. The CRA should contact the center to conduct necessary training and discuss current topics such as available study updates, deadlines, recruitment, eCRF completion and response to data input queries, center supplies, and other open issues. Any protocol amendments will be reported to the Ethics Committee and registered to ClinicalTrials.gov.
Dissemination plans {31a}
The study results will be announced through peer-reviewed publications and conference reports.