Reduction of Pericardial Adhesions with polyethylene glycol hydrogel compound, BAX602 in Staged Pediatric Heart Surgery: A Randomized Controlled Trial Protocol

Reduction of Pericardial Adhesions with polyethylene glycol hydrogel compound, BAX602 in Staged Pediatric Heart Surgery: A Randomized Controlled Trial Protocol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Reduction of Pericardial Adhesions with polyethylene glycol hydrogel compound, BAX602 in Staged Pediatric Heart Surgery: A Randomized Controlled Trial Protocol Toshihide Nakano, Shingo Kasahara, Hiroomi Murayama, Keiichi Hirose, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9323924/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Objective: A synthetic hydrogel composed of two polyethylene glycols, BAX602 is an established anti-adhesive agent in adult cardiac surgery; however, clinical data regarding its safety and efficacy in the pediatric population are limited. This study aims to evaluate the efficacy and safety of BAX602 in reducing pericardial adhesions in pediatric patients undergoing staged surgery for congenital heart disease (CHD). Methods: This is a multicenter, randomized, controlled trial in Japan. Thirty pediatric patients (<12 years old) requiring staged cardiac surgery via midline sternotomy will be randomized (1:1) to receive either BAX602 application or no treatment (control) during the initial procedure. Based on Japanese surgical database trends, the interval between surgeries is expected to be 3–12 months. The primary endpoint is the adhesion severity grade at the second surgery, assessed at six anatomical sites: the pericardiotomy edge, right ventricular anterior and diaphragmatic surfaces, right atrial body and appendage, and the ascending aorta. Adhesion severity will be evaluated using a standardized 5-grade scale ranging from 0 (no adhesions) to 4 (dense/cohesive requiring extensive sharp dissection). Results (Expected): This protocol-based study is designed to provide robust clinical evidence to support the potential regulatory approval and clinical utility of BAX602 in pediatric cardiac surgery. Conclusion: This trial will clarify the role of BAX602 in mitigating surgical adhesions, potentially improving safety and outcomes for pediatric patients requiring multiple cardiac interventions. Anti-adhesive Congenital heart disease Pericardial adhesion Reoperation Randomized controlled trial Figures Figure 1 Figure 2 Figure 3 Introduction Surgical treatment for pediatric patients with congenital heart disease (CHD) often requires a staged approach. This necessity arises from factors such as prematurity, low birth weight, chromosomal abnormalities, and the inherent complexity of cardiac lesions [ 1 – 7 ]. Furthermore, long-term repeat interventions are frequently required due to the development of secondary lesions or the degeneration of implanted prosthetic materials [ 8 , 9 ]. A critical challenge in these re-do procedures is the severity of post-surgical pericardial adhesions. Extensive adhesions increase the risk of catastrophic complications during resternotomy, such as injury to the heart or great vessels, and prolong operation time [ 1 , 10 ]. Therefore, effective strategies to prevent or mitigate pericardial adhesions are essential to improve surgical outcomes and patient safety. While the efficacy of natural and synthetic polymer-based anti-adhesives has been established in abdominal and pelvic surgeries [ 11 – 13 ], clinical evidence in the field of cardiac surgery remains limited. BAX602 (COSEAL®; Baxter Healthcare Corp., Deerfield, IL, USA) is a synthetic hydrogel composed of two polyethylene glycols (PEGs). Upon application, these polymers form a protective barrier on the targeted organ surface that undergoes hydrolysis within approximately seven days [ 14 ]. Although BAX602 is CE-marked in Europe for preventing post-surgical adhesions in both adult and pediatric cardiovascular surgery [ 15 , 16 ], its approval in the United Stares is currently limited to vascular hemostasis in adults [ 17 , 18 ]. Regarding the pediatric CHD population, only a single-arm observational study from Europe has suggested its anti-adhesive benefits when applied during sternal closure [ 19 ]. To date, no robust clinical data exist regarding its use in Japan. To address this gap and support regulatory approval, we developed a protocol for a multicenter, randomized controlled trial (RCT) to evaluate the safety and efficacy of BAX602 as an anti-adhesive agent in Japanese pediatric patients undergoing staged cardiac surgery. Methods Ethical Review This clinical trial is conducted in accordance with the ethical principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board (IRB) of Okayama University Hospital (Lead Center; Approval No. D20222001) and the Pediatric Clinical Trial Network (Approval No. NW2022106), which oversees the participating institutions: Shizuoka Children’s Hospital, Aichi Children’s Health and Medical Center, Fukuoka Children’s Hospital, Kobe Children’s Hospital, and Nagano Children’s Hospital. Prior to enrollment, the principal or sub-investigator at each institution will obtain written informed consent from the parents or legal guardians of all participants. When appropriate, informed assent will also be obtained from the pediatric patients, depending on their age and capacity for understanding. Further details regarding the consent process are provided in the Supplementary Methods. Study Design This multicenter RCT in Japan aims to evaluate the safety and efficacy of BAX602 in reducing pericardial adhesions that develop during the interval between staged cardiac procedures via midline sternotomy in pediatric patients with CHD. The study is designed as a prospective, 1:1 randomized, controlled trial comparing two groups: the BAX602 group (application of the agent during the initial surgery) and the Control group (no anti-adhesive application). An overview of the trial flow is illustrated in Fig. 1 . Patient eligibility will be determined by the principal investigator at each participating institution. Eligible patients will be randomly assigned to either the BAX602 or Control group via a centralized web-based registration system. Randomization will be stratified by the use of cardiopulmonary bypass (CPB) during the initial surgery, as CPB is a known factor that may influence the severity of postoperative adhesions. In the BAX602 group, the agent will be applied to the epicardial surface at a dose of 1 mL/10 cm² (up to 4 mL per set) using a dedicated compressed-air injection applicator immediately prior to sternal closure. In the Control group, the chest will be closed without any anti-adhesive treatment. In both groups, the pericardium will be left open to ensure standardized conditions for subsequent adhesion assessment. Following postoperative recovery, all patients will be monitored in an outpatient setting until the scheduled second-stage surgery. Surgical Interval Selection Based on Real-World Data Because the time interval between the initial and subsequent procedures significantly impacts both adhesion severity and trial timelines (e.g., data cut-off after "last-patient-in"), establishing a clinically relevant study window was essential. Due to the lack of published indicators on this interval, we independently determined the optimal period by analyzing real-world data from the Japan Cardiovascular Surgery Database-Congenital Section (JCVSD-Congenital). Between 2016 and 2019, 32,610 patients were registered in the database, of whom 8,604 (26.4%) underwent re-do cardiac surgeries. We focused our analysis on patients who initially received common first-stage palliative procedures: pulmonary artery banding (PAB), bilateral PAB, or systemic-to-pulmonary shunts (e.g., Blalock-Taussig or central shunts). Among these, 1,671 patients underwent a second-stage procedure within a consistent timeframe. The median intervals (days [IQR]) for the most frequent secondary procedures were as follows: bi-directional Glenn procedure (n = 548; 210 [152–320] days), tetralogy of Fallot repair (n = 365; 351 [266–475] days), ventricular septal defect closure (n = 280; 248 [163–338] days), and atrioventricular septal defect repair (n = 186; 271 [196–381] days) ( Fig. 2 ). The Norwood procedure was excluded from this analysis due to its distinctively high perioperative morbidity and mortality [ 2 ]. Based on these findings, the surgical interval for this clinical trial was defined as 3 months (90 days) to 12 months (360 days). Consequently, the data cut-off for the primary analysis was set at 12 months after the enrollment of the last patient. Sample Size and Group Allocation The sample size was determined based on a non-parametric analysis (e.g., Wilcoxon rank-sum test) of adhesion grades, stratified by the type of initial surgery and anatomical evaluation site. To achieve a statistical power of > 90% with a two-sided significance level of 5% (α = 0.05), a minimum of 20 patients is required to detect significant differences between the two groups. To ensure sufficient power for the primary analysis, the target sample size was set at 30 patients. This target accounts for the following factors: (1) a predicted 25.0% dropout rate, assuming that approximately 75.0% of enrolled patients will proceed to the second-stage surgery within the study period, and (2) a 5.0% expected rate of missing or uninterpretable data for adhesion grade assessments. Eligible patients will be randomly assigned in a 1:1 ratio to either the BAX602 or Control group, with stratification based on the use of CPB during the initial procedure. While the Clinical Research Center (CRC) may disclose the group allocation to patients or their legal guardians upon request following the surgery, the allocation will remain undisclosed to the surgical team and the independent evaluation committee to maintain the integrity of the blinded assessment. Study Population (Inclusion and Exclusion Criteria) Detailed inclusion and exclusion criteria are summarized in Table 1 . In brief, the study will enroll pediatric patients aged under 12 years who are scheduled for staged cardiac surgery via midline sternotomy, with an expected re-intervention interval of 3 to 12 months. Key exclusion criteria include patients for whom the scheduled surgery is canceled or postponed beyond the study window, and those with a known hypersensitivity to any component of BAX602. Criteria for trial discontinuation include withdrawal of consent by the patient or legal guardian, the occurrence of serious adverse events that preclude further participation, or other clinical reasons determined by the principal investigator. In the event of discontinuation, appropriate medical follow-up and alternative treatments will be provided to ensure patient safety. Table 1 Study inclusion and exclusion criteria Inclusion criteria a 1. Pediatric patients < 12 years of age 2. Pediatric patients who have undergone the initial scheduled palliative surgery for the following diseases and are scheduled to undergo re-do open heart surgery (anatomical repair surgery): - Ventricular septal defect - Atrioventricular septal defect - Tetralogy of Fallot (spectrum) - Single ventricle disease (the patient should not meet exclusion criteria 1 to 3) 3. Pediatric patients who will undergo systemic pulmonary artery shunting or pulmonary artery banding (including bilateral pulmonary artery banding) for the initial surgery 4. Pediatric patients undergoing repair surgery (anatomical repair surgery) or bi-directional Glenn surgery as the second target procedure 5. Written informed consent has been obtained from the pediatric patient, their parent or guardian Exclusion criteria a,b 1. Pediatric patients with HLHS and its analogues 2. Pediatric patients with asplenia or hypersplenism 3. Pediatric patients undergoing Norwood surgery as re-do surgery 4. Pediatric patients undergoing open heart surgery prior to the initial scheduled palliative surgery 5. Pediatric patients with complications of other organs that affect the indication for cardiac surgery 6. Pediatric patients with chromosomal or genetic abnormalities that may affect the indication for cardiac surgery 7. Pediatric patients with severe infections or multiple organ failure 8. Pediatric patients who require emergency surgery that requires emergency life support 9. Pediatric patients with a body weight < 2,500 g at time of surgery 10. Pediatric patients who are participating in other clinical trials or who are scheduled to participate in other clinical trials during this study period 11. Pediatric patients who are judged by the investigator or sub investigator to be inappropriate to participate in this study for other reasons a The handling of inclusion/exclusion in the analysis set will be determined by the sponsor and the medical expert after discussion before data lock. b Pediatric patients with significant violation of the Good Clinical Practice standards for medical devices will be excluded from all analysis sets. HLHS , hypoplastic left heart syndrome Primary Endpoint The primary endpoint is the severity of intrapericardial adhesions between the surface of the heart or great vessels and the surrounding tissues at the time of the second-stage surgery. Adhesion severity will be assessed at six predefined anatomical sites: (1) the pericardiotomy incision border, (2) the anterior surface of the right ventricle (RV), (3) the diaphragmatic surface of the RV, (4) the right atrial (RA) appendage, (5) the RA body, and (6) the surface of the ascending aorta. Based on a previously validated scoring system [ 19 ], adhesions will be evaluated using a 5-point scale: Grade 0 (no adhesions); Grade 1 (filmy and avascular); Grade 2 (filmy, requiring blunt dissection); Grade 3 (non-cohesive, requiring blunt or sharp dissection); and Grade 4 (dense and cohesive, requiring extensive sharp dissection) ( Fig. 3 , Table 2 ) .To ensure objective and unbiased assessment, surgical procedures from the initial skin incision to the completion of adhesion dissection will be video-recorded. These recordings will be independently reviewed and scored by the Video Adhesion Evaluation Committee, comprising three experienced cardiac surgeons who are strictly blinded to the treatment allocation. The final adhesion grade for each site will be determined based on the consensus or median score of these independent evaluators. Table 2 Adhesion severity scoring Adhesion grade Definition Details 0 • No adhesions • No visible adhesions 1 • Filmy and avascular • Cottony adhesions with low adhesion that can be easily detached with a single blunt manipulation (manual) and do not require further additional dissection 2 • Filmy requiring blunt dissection • Membranous adhesions that do not require sharp dissection using electrocautery or scissors, and can be completely handled by blunt dissection (manual) manipulation 3 • Filmy, noncohesive requiring blunt and sharp dissection • Adherent adhesions which require sharp dissection using electrocautery or scissors • Adhesions must be able to complete dissection without organ damage 4 • Dense and cohesive requiring extensive sharp dissection • Strong adhesions that are difficult to detach with electrocautery or scissors • Adhesions that cannot be detached or have a high risk of organ damage Secondary Endpoints The secondary endpoints are designed to provide a comprehensive assessment of adhesion distribution and clinical impact. These include: (1) the composite total score of adhesion grades across all six evaluation sites; (2) site-specific adhesion grades, stratified by the use of CPB during the initial surgery; (3) the frequency distribution of each adhesion grade across all evaluation sites; (4) the proportion of patients exhibiting specific adhesion grades at any site; and (5) the maximum (worst) adhesion grade recorded for each individual patient. Safety Endpoints Safety will be evaluated based on the incidence and severity of all adverse events (AEs), device malfunctions, and clinically significant changes in laboratory data. These endpoints will be monitored from the time of the initial surgery until 30 days after the second-stage open-heart surgery. Following discharge from the second-stage procedure, all patients will undergo clinical follow-up for up to 30 days to ensure postoperative safety ( Table 3 ) . Detailed definitions of AEs, including those specifically related to the anti-adhesive agent (e.g., localized inflammation or infection), and the reporting procedures for serious adverse events (SAEs) are provided in the Supplementary File . Data Management, Monitoring, and Auditing Data management will be conducted via a validated, web-based electronic data capture (EDC) system. The CRC at each participating institution will be responsible for data entry in accordance with Good Clinical Practice (GCP) standards. The EDC system and data management procedures have been fully validated to comply with Japanese regulatory requirements for clinical trials. To ensure the integrity of the trial data, on-site monitoring, including source document verification (SDV), and periodic auditing will be performed. An independent auditor, unaffiliated with the study sites or the clinical investigators, will conduct audits at both the sponsor's organization and the participating medical institutions. This process will verify that trial conduct, data recording, and reporting strictly adhere to the study protocol and GCP standards for medical devices. A Data Monitoring Committee (DMC) was deemed unnecessary for this trial, in accordance with the Ministry of Health, Labor and Welfare guidelines of Japan. This decision is based on the limited sample size (n = 30) and the absence of planned interim analyses. Furthermore, BAX602 has an established safety profile in adult cardiac surgery, which was also considered in this risk assessment. Statistical Methods Three analysis sets are defined: (1) the Full Analysis Set (FAS), comprising all randomized patients who received the study treatment and provided at least one efficacy endpoint; (2) the Efficacy Analysis Set (EAS), including patients in the FAS who underwent second stage surgery with an interval of ≥ 90 days and provided evaluable primary endpoint data; and (3) the Safety Analysis Set (SAS), including all patients who underwent the initial surgery. Continuous variables will be summarized using descriptive statistics, including mean, standard deviation, median, and range. Categorical data will be presented as frequencies and proportions. No interim analyses are planned. For the primary endpoint, the distribution of adhesion grades at each of the six anatomical sites will be compared between the BAX602 and Control groups. The primary analysis will be performed using a stratified Wilcoxon rank-sum test (van Elteren test) to account for potential confounding factors, specifically the use of CPB during the initial surgery. Subpopulation analyses will further evaluate adhesion grades at each site, stratified by CPB status. Secondary endpoints will be summarized for the EAS, and between-group differences with 90% or 95% confidence intervals will be estimated where appropriate. Safety endpoints, including AEs, will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized for the SAS by system organ class and preferred term. The efficacy of BAX602 will be demonstrated if both of the following criteria are met: (1) the primary analysis yields a two-sided p-value < 0.05, and (2) the incidence of high-grade adhesions (Grade ≥ 3) is lower in the BAX602 group compared to the Control group. Discussion This protocol describes the first multicenter RCT in Japan to evaluate the efficacy and safety of BAX602 in pediatric patients with CHD undergoing staged cardiac surgery. A distinctive strength of this study is the integration of real-world evidence from the JCVSD-Congenital to define the trial's parameters. By analyzing over 32,000 cases, we established a clinically relevant 3-to-12-month interval between staged procedures. This evidence-based approach ensures that the assessment of adhesion severity occurs during the most critical period for surgical re-entry, addressing a gap in previous pediatric literature [ 8 , 19 ]. The study design and protocol were finalized through rigorous consultations with the Japanese Pharmaceuticals and Medical Devices Agency, ensuring high regulatory standards. Furthermore, patient recruitment is strategically supported by the JSPCCS, reflecting the high clinical demand for effective anti-adhesive agents in this field. While BAX602 is already utilized in several regions, robust RCT data in the pediatric CHD population remain scarce. The results of this trial are expected to provide definitive safety and efficacy data, potentially leading to the first regulatory approval of a specialized anti-adhesive for pediatric cardiac surgery in Japan. Reducing pericardial adhesions is not merely a technical convenience; it is a critical factor in mitigating the risks of catastrophic hemorrhage during resternotomy and improving long-term outcomes for children who face a lifetime of multiple cardiac interventions. Conclusions This multicenter RCT will evaluate the impact of BAX602 on reducing pericardial adhesions in pediatric patients undergoing staged heart surgery. By providing high-quality clinical evidence, this study aims to establish a new standard of care for adhesion prevention, ultimately enhancing the safety of subsequent cardiac procedures in this vulnerable population. Declarations Data Access The raw dataset from the Japan Cardiovascular Surgery Database (JCVSD) is not publicly available due to institutional restrictions. Anonymized data used for interval calculations are available from the corresponding author upon reasonable scientific request. Dissemination Policy The findings of this study will be submitted for publication in a peer-reviewed scientific journal and will also be presented at an international conference for dissemination. Acknowledgements The Clinical Trial Promotion Activity Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (JSPCCS; https://jspccs.jp/english/) contributed to the establishment of the clinical trial protocol and patient enrollment. Author Contributions TN: Conceptualization, methodology, project administration, and writing – original draft. SN: Conceptualization, protocol formulation, data analysis, and writing – review & editing. YH: Data curation and statistical analysis. AS: Visualization and data analysis. SK, HM, KH, SM, TK: Data collection and writing – review & editing. All authors have read and approved the final manuscript. Funding and Clinical Trial Cooperation This clinical trial is funded by Baxter Japan K.K. The Japan Cardiovascular Surgery Database (JCVSD-Congenital) provided real-world data for the trial design, supported by funding from Baxter Japan K.K. EPS Co., Ltd. (Osaka, Japan) provides contract research organization (CRO) services, including trial conduct, data management, and statistical analysis. Clinical Trial Information Summaries of the clinical trial information are available at the following trail registries: jRCT2032220540 (https://jrct.niph.go.jp/latest detail/jRCT2032220540) and NCT05647161 (https://clinicaltrials.gov/study/NCT05647161#study-plan). Protocol Version BAX602-PED; May 6, 2025 (Version 4.0). Declarations / Conflicts of Interest Shintaro Nemoto has received consulting fees from Baxter Japan K.K. as a medical expert on this clinical trial. Other Authors have no commercial relationships to be declared. Ethical Approval and Consent to Participate This study was approved by the Institutional Review Board of Okayama University Hospital (D20222001) and the Pediatric Clinical Trial Network (NW2022106). The trial is conducted in accordance with the Declaration of Helsinki. Written informed consent is obtained from the legal guardians of all participants prior to enrollment. References Bhende VV, Sharma TS, Krishnakumar M, Ramaswamy AS, Bilgi K, Pathan SR (2024) The Myths, Perils, and Pitfalls of Redo Pediatric Cardiac Surgery: The New Normal in Developing Countries Such as India. 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Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf/p010022b.pdf (Accessed 10 April) FDA (2003) COSEAL Surgical Sealant. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf3/P030039C.pdf (Accessed 22 May) Napoleone C, Valori A, Crupi G, Ocello S, Santoro F, Vouhé P, Weerasena N, Gargiulo G (2009) An observational study of CoSeal for the prevention of adhesions in pediatric cardiac surgery. Interact Cardiovasc Thorac Surg 9:978–982. https://doi.org/10.1510/icvts.2009.212175 Table 3 Table 3 is available in the Supplementary Files section. Additional Declarations Competing interest reported. Shintaro Nemoto has received consulting fees from Baxter Japan K.K. as a medical expert on this clinical trial. Other Authors have no commercial relationships to be declared. Supplementary Files SupplementaryFileforsubmission.docx Table3.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 22 Apr, 2026 Editor assigned by journal 05 Apr, 2026 Submission checks completed at journal 05 Apr, 2026 First submitted to journal 04 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9323924","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":633431409,"identity":"4ed6718a-e87c-4ce3-a33f-ccf4c2363f69","order_by":0,"name":"Toshihide Nakano","email":"","orcid":"","institution":"Fukuoka Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Toshihide","middleName":"","lastName":"Nakano","suffix":""},{"id":633431417,"identity":"e738af53-bf9c-4dc3-b6ef-25e8183e1ddc","order_by":1,"name":"Shingo Kasahara","email":"","orcid":"","institution":"Okayama University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Kasahara","suffix":""},{"id":633431423,"identity":"3031d906-e39a-4fbd-bd4b-b6dd81fc422e","order_by":2,"name":"Hiroomi Murayama","email":"","orcid":"","institution":"Aichi Children’s Health and Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroomi","middleName":"","lastName":"Murayama","suffix":""},{"id":633431424,"identity":"c7a7ddf9-42b0-4e9b-bf84-fb555c8365f8","order_by":3,"name":"Keiichi Hirose","email":"","orcid":"","institution":"Shizuoka Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Keiichi","middleName":"","lastName":"Hirose","suffix":""},{"id":633431426,"identity":"e28cd749-1f0a-4470-9a45-5dae4f2df627","order_by":4,"name":"Shunsuke Matsushima","email":"","orcid":"","institution":"Kobe Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shunsuke","middleName":"","lastName":"Matsushima","suffix":""},{"id":633431427,"identity":"cd38a150-fc1a-4ec8-b956-cb83dd147ac8","order_by":5,"name":"Takeshi Konuma","email":"","orcid":"","institution":"Nagano Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Konuma","suffix":""},{"id":633431428,"identity":"8d805b5d-26fe-4d19-a150-e4641d3b178d","order_by":6,"name":"Yasutaka Hirata","email":"","orcid":"","institution":"National Center for Child Health and Development","correspondingAuthor":false,"prefix":"","firstName":"Yasutaka","middleName":"","lastName":"Hirata","suffix":""},{"id":633431429,"identity":"7f88438f-39f7-410f-9841-7b6b0a15517b","order_by":7,"name":"Akiyo Suzuki","email":"","orcid":"","institution":"Osaka Medical and Pharmaceutical University","correspondingAuthor":false,"prefix":"","firstName":"Akiyo","middleName":"","lastName":"Suzuki","suffix":""},{"id":633431430,"identity":"05b23934-14d5-407b-8213-43809634dacf","order_by":8,"name":"Shintaro Nemoto","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYBADOTiLsYEoDQkMxqRrSSROIQjIz24+uuHjD5v0frGzxyQYauwYmGcT0G1w51jazRkJabkzZ+elSTAcS2ZgnHOAgBaJHLPbPAmHczfczjGTYGA7wMA4I4GAw2bkfwNpSTcAa/lHhBaGGzlsIC0JYC2MbURoMbiRZnZzRlqaIdAvyRaJfck8BP0iPyP52Y0PNjby/NK5B298+GYnZ0goxJAADyh+GHgMZxCtA6QFbK8E8VpGwSgYBaNgZAAAKnBCrzBQeeAAAAAASUVORK5CYII=","orcid":"","institution":"Osaka Medical and Pharmaceutical University","correspondingAuthor":true,"prefix":"","firstName":"Shintaro","middleName":"","lastName":"Nemoto","suffix":""}],"badges":[],"createdAt":"2026-04-05 04:08:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9323924/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9323924/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108725367,"identity":"4910e92f-54b1-4a41-9d69-867237dd384e","added_by":"auto","created_at":"2026-05-07 16:55:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":223400,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design flow chart. Overview of the multicenter randomized controlled trial comparing BAX602 application and no treatment (NT) during staged pediatric cardiac surgery.\u003c/p\u003e","description":"","filename":"Figure1forsubmission.png","url":"https://assets-eu.researchsquare.com/files/rs-9323924/v1/d1886e5d39d8833a626e85e8.png"},{"id":108725271,"identity":"3c13730e-b66d-43c1-b23e-0c3e0a11a5f1","added_by":"auto","created_at":"2026-05-07 16:55:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":532521,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of intervals between initial and subsequent cardiac procedures. Data derived from the Japan Cardiovascular Surgery Database-Congenital Section (JCVSD-Congenital). Box plots represent the interquartile ranges (IQR) for (A) bi-directional Glenn procedure, (B) tetralogy of Fallot repair, (C) ventricular septal defect closure, and (D) atrioventricular septal defect repair.\u003c/p\u003e","description":"","filename":"Figure2forsubmission.png","url":"https://assets-eu.researchsquare.com/files/rs-9323924/v1/4f09d3952d3db737f6ac42b2.png"},{"id":108725368,"identity":"34776cfa-8d12-4d81-a90a-faf87126bf55","added_by":"auto","created_at":"2026-05-07 16:55:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":216736,"visible":true,"origin":"","legend":"\u003cp\u003eAdhesion severity scoring\u003c/p\u003e","description":"","filename":"Figure3forsubmission.png","url":"https://assets-eu.researchsquare.com/files/rs-9323924/v1/1f956bfc492aea0d78d6d844.png"},{"id":108807598,"identity":"a00b406b-4f20-49bc-838c-5d6c66900118","added_by":"auto","created_at":"2026-05-08 15:30:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1302900,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9323924/v1/cbdd9252-3644-41b9-a73b-9e74245eb851.pdf"},{"id":108725370,"identity":"517c1e98-ce14-45b7-b013-d817227b1a82","added_by":"auto","created_at":"2026-05-07 16:55:33","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15336,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFileforsubmission.docx","url":"https://assets-eu.researchsquare.com/files/rs-9323924/v1/a0986f019e7b1d0d373a348a.docx"},{"id":108725359,"identity":"0146ef5e-bd68-4848-a8eb-f5afe03ffa8a","added_by":"auto","created_at":"2026-05-07 16:55:30","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":54803,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-9323924/v1/370a558f3b862e64e54b4577.docx"}],"financialInterests":"Competing interest reported. Shintaro Nemoto has received consulting fees from Baxter Japan K.K. as a medical expert on this clinical trial. Other Authors have no commercial relationships to be declared.","formattedTitle":"Reduction of Pericardial Adhesions with polyethylene glycol hydrogel compound, BAX602 in Staged Pediatric Heart Surgery: A Randomized Controlled Trial Protocol","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSurgical treatment for pediatric patients with congenital heart disease (CHD) often requires a staged approach. This necessity arises from factors such as prematurity, low birth weight, chromosomal abnormalities, and the inherent complexity of cardiac lesions [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Furthermore, long-term repeat interventions are frequently required due to the development of secondary lesions or the degeneration of implanted prosthetic materials [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A critical challenge in these re-do procedures is the severity of post-surgical pericardial adhesions. Extensive adhesions increase the risk of catastrophic complications during resternotomy, such as injury to the heart or great vessels, and prolong operation time [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, effective strategies to prevent or mitigate pericardial adhesions are essential to improve surgical outcomes and patient safety. While the efficacy of natural and synthetic polymer-based anti-adhesives has been established in abdominal and pelvic surgeries [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], clinical evidence in the field of cardiac surgery remains limited. BAX602 (COSEAL\u0026reg;; Baxter Healthcare Corp., Deerfield, IL, USA) is a synthetic hydrogel composed of two polyethylene glycols (PEGs). Upon application, these polymers form a protective barrier on the targeted organ surface that undergoes hydrolysis within approximately seven days [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Although BAX602 is CE-marked in Europe for preventing post-surgical adhesions in both adult and pediatric cardiovascular surgery [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], its approval in the United Stares is currently limited to vascular hemostasis in adults [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Regarding the pediatric CHD population, only a single-arm observational study from Europe has suggested its anti-adhesive benefits when applied during sternal closure [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. To date, no robust clinical data exist regarding its use in Japan. To address this gap and support regulatory approval, we developed a protocol for a multicenter, randomized controlled trial (RCT) to evaluate the safety and efficacy of BAX602 as an anti-adhesive agent in Japanese pediatric patients undergoing staged cardiac surgery.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthical Review\u003c/h2\u003e \u003cp\u003e This clinical trial is conducted in accordance with the ethical principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board (IRB) of Okayama University Hospital (Lead Center; Approval No. D20222001) and the Pediatric Clinical Trial Network (Approval No. NW2022106), which oversees the participating institutions: Shizuoka Children\u0026rsquo;s Hospital, Aichi Children\u0026rsquo;s Health and Medical Center, Fukuoka Children\u0026rsquo;s Hospital, Kobe Children\u0026rsquo;s Hospital, and Nagano Children\u0026rsquo;s Hospital. Prior to enrollment, the principal or sub-investigator at each institution will obtain written informed consent from the parents or legal guardians of all participants. When appropriate, informed assent will also be obtained from the pediatric patients, depending on their age and capacity for understanding. Further details regarding the consent process are provided in the Supplementary Methods.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Design\u003c/h3\u003e\n\u003cp\u003eThis multicenter RCT in Japan aims to evaluate the safety and efficacy of BAX602 in reducing pericardial adhesions that develop during the interval between staged cardiac procedures via midline sternotomy in pediatric patients with CHD. The study is designed as a prospective, 1:1 randomized, controlled trial comparing two groups: the BAX602 group (application of the agent during the initial surgery) and the Control group (no anti-adhesive application). An overview of the trial flow is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Patient eligibility will be determined by the principal investigator at each participating institution. Eligible patients will be randomly assigned to either the BAX602 or Control group via a centralized web-based registration system. Randomization will be stratified by the use of cardiopulmonary bypass (CPB) during the initial surgery, as CPB is a known factor that may influence the severity of postoperative adhesions. In the BAX602 group, the agent will be applied to the epicardial surface at a dose of 1 mL/10 cm\u0026sup2; (up to 4 mL per set) using a dedicated compressed-air injection applicator immediately prior to sternal closure. In the Control group, the chest will be closed without any anti-adhesive treatment. In both groups, the pericardium will be left open to ensure standardized conditions for subsequent adhesion assessment. Following postoperative recovery, all patients will be monitored in an outpatient setting until the scheduled second-stage surgery.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eSurgical Interval Selection Based on Real-World Data\u003c/h3\u003e\n\u003cp\u003eBecause the time interval between the initial and subsequent procedures significantly impacts both adhesion severity and trial timelines (e.g., data cut-off after \"last-patient-in\"), establishing a clinically relevant study window was essential. Due to the lack of published indicators on this interval, we independently determined the optimal period by analyzing real-world data from the Japan Cardiovascular Surgery Database-Congenital Section (JCVSD-Congenital). Between 2016 and 2019, 32,610 patients were registered in the database, of whom 8,604 (26.4%) underwent re-do cardiac surgeries. We focused our analysis on patients who initially received common first-stage palliative procedures: pulmonary artery banding (PAB), bilateral PAB, or systemic-to-pulmonary shunts (e.g., Blalock-Taussig or central shunts). Among these, 1,671 patients underwent a second-stage procedure within a consistent timeframe. The median intervals (days [IQR]) for the most frequent secondary procedures were as follows: bi-directional Glenn procedure (n\u0026thinsp;=\u0026thinsp;548; 210 [152\u0026ndash;320] days), tetralogy of Fallot repair (n\u0026thinsp;=\u0026thinsp;365; 351 [266\u0026ndash;475] days), ventricular septal defect closure (n\u0026thinsp;=\u0026thinsp;280; 248 [163\u0026ndash;338] days), and atrioventricular septal defect repair (n\u0026thinsp;=\u0026thinsp;186; 271 [196\u0026ndash;381] days) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e The Norwood procedure was excluded from this analysis due to its distinctively high perioperative morbidity and mortality [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Based on these findings, the surgical interval for this clinical trial was defined as 3 months (90 days) to 12 months (360 days). Consequently, the data cut-off for the primary analysis was set at 12 months after the enrollment of the last patient.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eSample Size and Group Allocation\u003c/h3\u003e\n\u003cp\u003eThe sample size was determined based on a non-parametric analysis (e.g., Wilcoxon rank-sum test) of adhesion grades, stratified by the type of initial surgery and anatomical evaluation site. To achieve a statistical power of \u0026gt;\u0026thinsp;90% with a two-sided significance level of 5% (α\u0026thinsp;=\u0026thinsp;0.05), a minimum of 20 patients is required to detect significant differences between the two groups. To ensure sufficient power for the primary analysis, the target sample size was set at 30 patients. This target accounts for the following factors: (1) a predicted 25.0% dropout rate, assuming that approximately 75.0% of enrolled patients will proceed to the second-stage surgery within the study period, and (2) a 5.0% expected rate of missing or uninterpretable data for adhesion grade assessments. Eligible patients will be randomly assigned in a 1:1 ratio to either the BAX602 or Control group, with stratification based on the use of CPB during the initial procedure. While the Clinical Research Center (CRC) may disclose the group allocation to patients or their legal guardians upon request following the surgery, the allocation will remain undisclosed to the surgical team and the independent evaluation committee to maintain the integrity of the blinded assessment.\u003c/p\u003e\n\u003ch3\u003eStudy Population (Inclusion and Exclusion Criteria)\u003c/h3\u003e\n\u003cp\u003eDetailed inclusion and exclusion criteria are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In brief, the study will enroll pediatric patients aged under 12 years who are scheduled for staged cardiac surgery via midline sternotomy, with an expected re-intervention interval of 3 to 12 months. Key exclusion criteria include patients for whom the scheduled surgery is canceled or postponed beyond the study window, and those with a known hypersensitivity to any component of BAX602. Criteria for trial discontinuation include withdrawal of consent by the patient or legal guardian, the occurrence of serious adverse events that preclude further participation, or other clinical reasons determined by the principal investigator. In the event of discontinuation, appropriate medical follow-up and alternative treatments will be provided to ensure patient safety.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudy inclusion and exclusion criteria\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInclusion criteria \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Pediatric patients\u0026thinsp;\u0026lt;\u0026thinsp;12 years of age\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Pediatric patients who have undergone the initial scheduled palliative surgery for the following diseases and are scheduled to undergo re-do open heart surgery (anatomical repair surgery):\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Ventricular septal defect\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Atrioventricular septal defect\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Tetralogy of Fallot (spectrum)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Single ventricle disease (the patient should not meet exclusion criteria 1 to 3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. Pediatric patients who will undergo systemic pulmonary artery shunting or pulmonary artery banding (including bilateral pulmonary artery banding) for the initial surgery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. Pediatric patients undergoing repair surgery (anatomical repair surgery) or bi-directional Glenn surgery as the second target procedure\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5. Written informed consent has been obtained from the pediatric patient, their parent or guardian\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExclusion criteria \u003csup\u003ea,b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1. Pediatric patients with HLHS and its analogues\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2. Pediatric patients with asplenia or hypersplenism\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3. Pediatric patients undergoing Norwood surgery as re-do surgery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4. Pediatric patients undergoing open heart surgery prior to the initial scheduled palliative surgery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5. Pediatric patients with complications of other organs that affect the indication for cardiac surgery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6. Pediatric patients with chromosomal or genetic abnormalities that may affect the indication for cardiac surgery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7. Pediatric patients with severe infections or multiple organ failure\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8. Pediatric patients who require emergency surgery that requires emergency life support\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9. Pediatric patients with a body weight\u0026thinsp;\u0026lt;\u0026thinsp;2,500 g at time of surgery\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10. Pediatric patients who are participating in other clinical trials or who are scheduled to participate in other clinical trials during \u003c/p\u003e \u003cp\u003ethis study period\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11. Pediatric patients who are judged by the investigator or sub investigator to be inappropriate to participate in this study \u003c/p\u003e \u003cp\u003efor other reasons\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"1\"\u003e\u003csup\u003ea\u003c/sup\u003eThe handling of inclusion/exclusion in the analysis set will be determined by the sponsor and the medical expert after discussion before data lock. \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003ePediatric patients with significant violation of the Good Clinical Practice standards for medical devices will be excluded from all analysis sets. \u003cem\u003eHLHS\u003c/em\u003e, hypoplastic left heart syndrome\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Endpoint\u003c/h2\u003e \u003cp\u003eThe primary endpoint is the severity of intrapericardial adhesions between the surface of the heart or great vessels and the surrounding tissues at the time of the second-stage surgery. Adhesion severity will be assessed at six predefined anatomical sites: (1) the pericardiotomy incision border, (2) the anterior surface of the right ventricle (RV), (3) the diaphragmatic surface of the RV, (4) the right atrial (RA) appendage, (5) the RA body, and (6) the surface of the ascending aorta. Based on a previously validated scoring system [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], adhesions will be evaluated using a 5-point scale: Grade 0 (no adhesions); Grade 1 (filmy and avascular); Grade 2 (filmy, requiring blunt dissection); Grade 3 (non-cohesive, requiring blunt or sharp dissection); and Grade 4 (dense and cohesive, requiring extensive sharp dissection) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.To ensure objective and unbiased assessment, surgical procedures from the initial skin incision to the completion of adhesion dissection will be video-recorded. These recordings will be independently reviewed and scored by the Video Adhesion Evaluation Committee, comprising three experienced cardiac surgeons who are strictly blinded to the treatment allocation. The final adhesion grade for each site will be determined based on the consensus or median score of these independent evaluators.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdhesion severity scoring\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdhesion grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDefinition\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDetails\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; No adhesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; No visible adhesions\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Filmy and avascular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; Cottony adhesions with low adhesion that can be easily detached with a single blunt manipulation (manual) and do not require further additional dissection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Filmy requiring blunt dissection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; Membranous adhesions that do not require sharp dissection using electrocautery or scissors, and can be completely handled by blunt dissection (manual) manipulation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Filmy, noncohesive requiring blunt and sharp dissection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; Adherent adhesions which require sharp dissection using electrocautery or scissors\u003c/p\u003e \u003cp\u003e\u0026bull; Adhesions must be able to complete dissection without organ damage\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026bull; Dense and cohesive requiring extensive sharp dissection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026bull; Strong adhesions that are difficult to detach with electrocautery or scissors\u003c/p\u003e \u003cp\u003e\u0026bull; Adhesions that cannot be detached or have a high risk of organ damage\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSecondary Endpoints\u003c/h3\u003e\n\u003cp\u003eThe secondary endpoints are designed to provide a comprehensive assessment of adhesion distribution and clinical impact. These include: (1) the composite total score of adhesion grades across all six evaluation sites; (2) site-specific adhesion grades, stratified by the use of CPB during the initial surgery; (3) the frequency distribution of each adhesion grade across all evaluation sites; (4) the proportion of patients exhibiting specific adhesion grades at any site; and (5) the maximum (worst) adhesion grade recorded for each individual patient.\u003c/p\u003e\n\u003ch3\u003eSafety Endpoints\u003c/h3\u003e\n\u003cp\u003eSafety will be evaluated based on the incidence and severity of all adverse events (AEs), device malfunctions, and clinically significant changes in laboratory data. These endpoints will be monitored from the time of the initial surgery until 30 days after the second-stage open-heart surgery. Following discharge from the second-stage procedure, all patients will undergo clinical follow-up for up to 30 days to ensure postoperative safety \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Detailed definitions of AEs, including those specifically related to the anti-adhesive agent (e.g., localized inflammation or infection), and the reporting procedures for serious adverse events (SAEs) are provided in the \u003cb\u003eSupplementary File\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eData Management, Monitoring, and Auditing\u003c/p\u003e\n\u003cp\u003eData management will be conducted via a validated, web-based electronic data capture (EDC) system. The CRC at each participating institution will be responsible for data entry in accordance with Good Clinical Practice (GCP) standards. The EDC system and data management procedures have been fully validated to comply with Japanese regulatory requirements for clinical trials. To ensure the integrity of the trial data, on-site monitoring, including source document verification (SDV), and periodic auditing will be performed. An independent auditor, unaffiliated with the study sites or the clinical investigators, will conduct audits at both the sponsor\u0026apos;s organization and the participating medical institutions. This process will verify that trial conduct, data recording, and reporting strictly adhere to the study protocol and GCP standards for medical devices. A Data Monitoring Committee (DMC) was deemed unnecessary for this trial, in accordance with the Ministry of Health, Labor and Welfare guidelines of Japan. This decision is based on the limited sample size (n\u0026thinsp;=\u0026thinsp;30) and the absence of planned interim analyses. Furthermore, BAX602 has an established safety profile in adult cardiac surgery, which was also considered in this risk assessment.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Methods\u003c/h2\u003e\n \u003cp\u003eThree analysis sets are defined: (1) the Full Analysis Set (FAS), comprising all randomized patients who received the study treatment and provided at least one efficacy endpoint; (2) the Efficacy Analysis Set (EAS), including patients in the FAS who underwent second stage surgery with an interval of \u0026ge;\u0026thinsp;90 days and provided evaluable primary endpoint data; and (3) the Safety Analysis Set (SAS), including all patients who underwent the initial surgery. Continuous variables will be summarized using descriptive statistics, including mean, standard deviation, median, and range. Categorical data will be presented as frequencies and proportions. No interim analyses are planned. For the primary endpoint, the distribution of adhesion grades at each of the six anatomical sites will be compared between the BAX602 and Control groups. The primary analysis will be performed using a stratified Wilcoxon rank-sum test (van Elteren test) to account for potential confounding factors, specifically the use of CPB during the initial surgery. Subpopulation analyses will further evaluate adhesion grades at each site, stratified by CPB status. Secondary endpoints will be summarized for the EAS, and between-group differences with 90% or 95% confidence intervals will be estimated where appropriate. Safety endpoints, including AEs, will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized for the SAS by system organ class and preferred term. The efficacy of BAX602 will be demonstrated if both of the following criteria are met: (1) the primary analysis yields a two-sided p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05, and (2) the incidence of high-grade adhesions (Grade\u0026thinsp;\u0026ge;\u0026thinsp;3) is lower in the BAX602 group compared to the Control group.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis protocol describes the first multicenter RCT in Japan to evaluate the efficacy and safety of BAX602 in pediatric patients with CHD undergoing staged cardiac surgery. A distinctive strength of this study is the integration of real-world evidence from the JCVSD-Congenital to define the trial's parameters. By analyzing over 32,000 cases, we established a clinically relevant 3-to-12-month interval between staged procedures. This evidence-based approach ensures that the assessment of adhesion severity occurs during the most critical period for surgical re-entry, addressing a gap in previous pediatric literature [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The study design and protocol were finalized through rigorous consultations with the Japanese Pharmaceuticals and Medical Devices Agency, ensuring high regulatory standards. Furthermore, patient recruitment is strategically supported by the JSPCCS, reflecting the high clinical demand for effective anti-adhesive agents in this field. While BAX602 is already utilized in several regions, robust RCT data in the pediatric CHD population remain scarce. The results of this trial are expected to provide definitive safety and efficacy data, potentially leading to the first regulatory approval of a specialized anti-adhesive for pediatric cardiac surgery in Japan. Reducing pericardial adhesions is not merely a technical convenience; it is a critical factor in mitigating the risks of catastrophic hemorrhage during resternotomy and improving long-term outcomes for children who face a lifetime of multiple cardiac interventions.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis multicenter RCT will evaluate the impact of BAX602 on reducing pericardial adhesions in pediatric patients undergoing staged heart surgery. By providing high-quality clinical evidence, this study aims to establish a new standard of care for adhesion prevention, ultimately enhancing the safety of subsequent cardiac procedures in this vulnerable population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Access\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw dataset from the Japan Cardiovascular Surgery Database (JCVSD) is not publicly available due to institutional restrictions. Anonymized data used for interval calculations are available from the corresponding author upon reasonable scientific request.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDissemination Policy \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe findings of this study will be submitted for publication in a peer-reviewed scientific journal and will also be presented at an international conference for dissemination.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Clinical Trial Promotion Activity Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (JSPCCS; https://jspccs.jp/english/) contributed to the establishment of the clinical trial protocol and patient enrollment.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTN: Conceptualization, methodology, project administration, and writing \u0026ndash; original draft. SN: Conceptualization, protocol formulation, data analysis, and writing \u0026ndash; review \u0026amp; editing. YH: Data curation and statistical analysis. AS: Visualization and data analysis. SK, HM, KH, SM, TK: Data collection and writing \u0026ndash; review \u0026amp; editing. All authors have read and approved the final manuscript.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding and Clinical Trial Cooperation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis clinical trial is funded by Baxter Japan K.K. The Japan Cardiovascular Surgery Database (JCVSD-Congenital) provided real-world data for the trial design, supported by funding from Baxter Japan K.K. EPS Co., Ltd. (Osaka, Japan) provides contract research organization (CRO) services, including trial conduct, data management, and statistical analysis.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eClinical Trial Information \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSummaries of the clinical trial information are available at the following trail registries: jRCT2032220540 (https://jrct.niph.go.jp/latest detail/jRCT2032220540) and NCT05647161 (https://clinicaltrials.gov/study/NCT05647161#study-plan).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol Version\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBAX602-PED; May 6, 2025 (Version 4.0).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations / Conflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShintaro Nemoto has received consulting fees from Baxter Japan K.K. as a medical expert on this clinical trial. Other Authors have no commercial relationships to be declared.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of Okayama University Hospital (D20222001) and the Pediatric Clinical Trial Network (NW2022106). The trial is conducted in accordance with the Declaration of Helsinki. Written informed consent is obtained from the legal guardians of all participants prior to enrollment.\u003cbr clear=\"all\"\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBhende VV, Sharma TS, Krishnakumar M, Ramaswamy AS, Bilgi K, Pathan SR (2024) The Myths, Perils, and Pitfalls of Redo Pediatric Cardiac Surgery: The New Normal in Developing Countries Such as India. 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PLoS ONE 17:e0277530. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1371/journal.pone.0277530\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0277530\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWiseman DM, Trout JR, Franklin RR, Diamond MP (1999) Metaanalysis of the safety and efficacy of an adhesion barrier (Interceed TC7) in laparotomy. J Reprod Med 44:325\u0026ndash;331\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu YR, Liu B, Yang BP, Lan Y, Chi YG (2022) Efficacy of hyaluronic acid on the prevention of intrauterine adhesion and the improvement of fertility: A meta-analysis of randomized trials. 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J Hepatobiliary Pancreat Sci 27:648\u0026ndash;654. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/jhbp.786\u003c/span\u003e\u003cspan address=\"10.1002/jhbp.786\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFukushima S, Asakura K, Hamasaki T, Onda K, Watanabe T, Shiose A, Ono M, Fukushima N, Yamamoto H, Fujita T (2020) BAX602 in Preventing Surgical Adhesion after Extracorporeal Ventricular Assist Device Implantation for Refractory Congestive Heart Failure: Study Protocol for a Multicenter Randomized Clinical Trial. Cardiovasc Drugs Ther 34:651\u0026ndash;657. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10557-020-06990-2\u003c/span\u003e\u003cspan address=\"10.1007/s10557-020-06990-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAngiotech Pharmaceuticals (2003) Angiotech receives CE mark approval for new premix CoSeal\u0026reg; surgical sealant. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.sec.gov/Archives/edgar/data/1096481/000117625603000090/form6-kcosealpremix.htm\u003c/span\u003e\u003cspan address=\"https://www.sec.gov/Archives/edgar/data/1096481/000117625603000090/form6-kcosealpremix.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (Accessed 10 April)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDevices FIDM (2024) German Clinical Trials Register. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://drks.de/search/en/trial/DRKS00029296\u003c/span\u003e\u003cspan address=\"https://drks.de/search/en/trial/DRKS00029296\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (Accessed 2025)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFDA (2001) Summary of Safety and Effectiveness Data - CoSeal\u0026trade; Surgical Sealant (P010022). Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.accessdata.fda.gov/cdrh_docs/pdf/p010022b.pdf\u003c/span\u003e\u003cspan address=\"https://www.accessdata.fda.gov/cdrh_docs/pdf/p010022b.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (Accessed 10 April)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFDA (2003) COSEAL Surgical Sealant. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.accessdata.fda.gov/cdrh_docs/pdf3/P030039C.pdf\u003c/span\u003e\u003cspan address=\"https://www.accessdata.fda.gov/cdrh_docs/pdf3/P030039C.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (Accessed 22 May)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNapoleone C, Valori A, Crupi G, Ocello S, Santoro F, Vouh\u0026eacute; P, Weerasena N, Gargiulo G (2009) An observational study of CoSeal for the prevention of adhesions in pediatric cardiac surgery. Interact Cardiovasc Thorac Surg 9:978\u0026ndash;982. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1510/icvts.2009.212175\u003c/span\u003e\u003cspan address=\"10.1510/icvts.2009.212175\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 3","content":"\u003cp\u003eTable 3 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Anti-adhesive, Congenital heart disease, Pericardial adhesion, Reoperation, Randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-9323924/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9323924/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObjective: A synthetic hydrogel composed of two polyethylene glycols, BAX602 is an established anti-adhesive agent in adult cardiac surgery; however, clinical data regarding its safety and efficacy in the pediatric population are limited. This study aims to evaluate the efficacy and safety of BAX602 in reducing pericardial adhesions in pediatric patients undergoing staged surgery for congenital heart disease (CHD).\u003c/p\u003e\n\u003cp\u003eMethods: This is a multicenter, randomized, controlled trial in Japan. Thirty pediatric patients (\u0026lt;12 years old) requiring staged cardiac surgery via midline sternotomy will be randomized (1:1) to receive either BAX602 application or no treatment (control) during the initial procedure. Based on Japanese surgical database trends, the interval between surgeries is expected to be 3–12 months. The primary endpoint is the adhesion severity grade at the second surgery, assessed at six anatomical sites: the pericardiotomy edge, right ventricular anterior and diaphragmatic surfaces, right atrial body and appendage, and the ascending aorta. Adhesion severity will be evaluated using a standardized 5-grade scale ranging from 0 (no adhesions) to 4 (dense/cohesive requiring extensive sharp dissection).\u003c/p\u003e\n\u003cp\u003eResults (Expected): This protocol-based study is designed to provide robust clinical evidence to support the potential regulatory approval and clinical utility of BAX602 in pediatric cardiac surgery.\u003c/p\u003e\n\u003cp\u003eConclusion: This trial will clarify the role of BAX602 in mitigating surgical adhesions, potentially improving safety and outcomes for pediatric patients requiring multiple cardiac interventions.\u003c/p\u003e","manuscriptTitle":"Reduction of Pericardial Adhesions with polyethylene glycol hydrogel compound, BAX602 in Staged Pediatric Heart Surgery: A Randomized Controlled Trial Protocol","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-07 16:54:30","doi":"10.21203/rs.3.rs-9323924/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-04-22T17:38:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-05T11:05:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-05T11:05:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Cardiology","date":"2026-04-05T03:50:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"43622dfe-0d0a-4f8f-8e65-fb9f50e2f88e","owner":[],"postedDate":"May 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-07T16:54:30+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-07 16:54:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9323924","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9323924","identity":"rs-9323924","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}