Polyacrylic acid-polyvinylpyrrolidone complex for achieving hemostasis after hemodialysis: study protocol for an open-label crossover randomized controlled trial (PAA-PVP study)

Polyacrylic acid-polyvinylpyrrolidone complex for achieving hemostasis after hemodialysis: study protocol for an open-label crossover randomized controlled trial (PAA-PVP study) | 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 Polyacrylic acid-polyvinylpyrrolidone complex for achieving hemostasis after hemodialysis: study protocol for an open-label crossover randomized controlled trial (PAA-PVP study) Ryohei Terashima, Mototsugu Tanaka, Atsushi Hashimoto, Daiki Omori, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3917166/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 May, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background Achieving rapid and secure hemostasis of the vascular access point is important for patients undergoing maintenance hemodialysis (HD). We developed a polyacrylic acid-polyvinylpyrrolidone (PAA-PVP) complex that absorbs moisture such as blood or sterilizing solution, forms a hydrogel, and adheres to the body’s surface, thereby exerting a powerful hemostatic effect. This study aims to compare the effect of PAA-PVP complex versus a conventional non-woven fabric pad on hemostasis at the needle puncture vascular access site in patients on HD. Methods This open-label crossover randomized controlled trial will include 50 participants who undergo thrice-weekly HD. Participants in whom hemostasis requires more than 10 min by compression using a conventional pad or who have a severe skin problem at the needle puncture vascular access site will be excluded from the study. Participants will be randomized in a 1:1 ratio to receive either the PAA-PVP complex or conventional pads. Three consecutive weekly hemostatic tests will be performed at 11, 9, 7, 5, 3, and 1 min. The study will employ an individual 3 + 3 design in which participants in whom hemostasis is achieved in all three sessions in a week will be challenged to a shorter time in the three sessions of the next week. Those in whom hemostasis is achieved in two of three sessions will be tested at the same time point in the three sessions of the next week. The study treatment will be terminated if hemostasis is achieved in only one or none of the sessions, and the minimum time with three consecutive successes will be recorded as the hemostasis time. The primary endpoint, the hemostasis time on the arterial side of the vascular access, will be analyzed using mixed-effect models for repeated measures and include the hemostatic technique and group, period, and individual effects as covariates. Discussion The study will provide evidence on whether the PAA-PVP complex reduces hemostasis time of the vascular access compared to conventional pad in patients on HD. Trial registration jRCTs032220597 (Japan Registry of Clinical Trials; registered on January 30, 2023, https://jrct.niph.go.jp/latest-detail/jRCTs032220597 ) arteriovenous fistula arteriovenous graft bleeding time clotting time end-stage kidney disease end-stage renal disease vascular access Figures Figure 1 Figure 2 Figure 3 Background Hemodialysis (HD), a standard renal replacement therapy for patients with end-stage kidney disease, requires repetitive needle puncture of the vascular access point for extracorporeal blood purification. At the end of HD, the needle is removed from the vascular access, and the puncture site is compressed to stop the bleeding. This usually takes 5–15 min using a conventional non-woven fabric pad to achieve hemostasis. A shorter hemostasis time reduces the burden on patients and medical staff because patients must stay in HD facilities until the completion of hemostasis. Furthermore, medical staff must apply compression hemostasis to patients with low activities of daily living who have a difficulty in achieving hemostasis themselves. Although hemostasis time may be associated with many factors, including comorbidities, skin conditions at the needle puncture site, platelet count, anticoagulant or antiplatelet agent use, and blood flow rate of the vascular access point, a new medical device that can quickly achieve hemostasis of the vascular access point is needed for patients on HD. The bioadhesive polyacrylic acid-polyvinylpyrrolidone (PAA-PVP) complex is a novel material that was developed to achieve hemostasis. PAA-PVP forms a soft hydrogel when absorbing moisture, such as blood or antiseptic solutions, adheres to the body’s surface, and exhibits a solid hemostatic effect[ 1 , 2 ]. In a previous study, immediate hemostasis was achieved at the tooth extraction site using PAA-PVP[ 3 ]. PAA-PVP was also reportedly effective for achieving hemostasis of a vascular access point in a patient on HD[ 3 ]. No serious adverse events were reported after its use. This study aimed to investigate whether PAA-PVP reduces hemostasis time at the needle puncture vascular access site compared with conventional pads in patients on HD with an open-label crossover randomized controlled trial. Methods/Design Study design and setting This multicenter open-label crossover randomized controlled trial will use a 1:1 allocation to PAA-PVP (Aron Cure®; Toagosei, Tokyo, Japan) or a conventional non-woven fabric pad (Injection Pad Mild®; Nichiban, Tokyo, Japan) (Fig. 1 ). This study will be performed at Itoigawa General Hospital and Niigata University Medical and Dental Hospital in Japan. The anticipated participant timelines and study assessments at specific time points are shown in Fig. 2 . Study population Inclusion criteria Patients who meet all of the following criteria will be considered eligible: 1) Age ≥ 18 years; 2) Undergoing HD (including hemodiafiltration) three times a week for the treatment of end-stage kidney disease; 3) Use of a vascular access, including arteriovenous fistula or graft; 4) Use of heparin or low molecular weight heparin as an anticoagulant during HD; and 5) Hemostasis achieved using a conventional pad with a tourniquet within 10 min after needle removal. Exclusion criteria Patients with any of the following conditions will be excluded: 1) Currently participating in other clinical studies; 2) Currently pregnant or planning to become pregnant; 3) Requirement for compression hemostasis with fingers after needle removal; 4) Severe skin disease at the needle puncture vascular access site; 5) Scheduled to start anticoagulant or antiplatelet agents for daily use; and 6) Considered inappropriate to participate in the study by the investigators. Recruitment and consent Outpatients undergoing HD who meet the study eligibility criteria will be recruited. The investigators will provide potential study participants with sufficient information. Written informed consent will be obtained from all the participants before randomization. Study procedure The individual 3 + 3 design will be employed in this study (Fig. 3 ). The procedure to achieve hemostasis will be performed by medical staff. The PAA-PVP or conventional pad will be placed on the needle puncture site, the needle is then removed, and a tourniquet is quickly and tightly wrapped around the area. These procedures will initially be performed on the arterial side, followed by the venous side. Once the prespecified time has passed, the tourniquet will be removed, and the bleeding is checked. No bleeding for 10 s will be considered successful. Success or failure to achieve hemostasis will be examined at 11, 9, 7, 5, 3, and 1 min in at least three sessions. If hemostasis is achieved in all three sessions at those time points, a shorter time will be attempted in the subsequent three sessions. However, if two of three are completed successfully, another three tests at the same time point will be performed in the next week. If two or more fail, the study treatment will be terminated, and the patient will be moved on to another treatment. These decisions depend on the outcome of the arterial side of vascular access. The total study period will be a maximum of 15 weeks per participant, including 7 and 1 weeks for each study treatment and washout period, respectively. Minimum hemostasis time is defined as the minimum time required for three consecutive successful hemostatic procedures in a week. If hemostasis is not achieved, a conventional pad will be applied until the bleeding stops. Participant withdrawal Participants will be allowed to withdraw from the study at any time and for any reason. Participants who do not meet the eligibility criteria, do not undergo dialysis, are lost to follow-up, or are judged inappropriate to continue participating by the principal investigator will also be regarded as withdrawn. The principal investigator will record the reason for immature termination in the case report form and medical records. Data obtained before withdrawal will be analyzed after participant consent is provided. Participants who withdraw from the study will receive standard dialysis therapy. Outcome measures Primary outcome The primary outcome will be the minimum hemostatic time on the arterial side of vascular access. Secondary outcomes The secondary outcomes will be minimum hemostatic time in the venous side of vascular access and success or failure to achieve hemostasis during the initial hemostatic period (11 min). Safety outcomes The study safety outcomes will include: skin disorders (e.g., rash/redness, blistering, peeling skin, itching), number of re-bleeding episodes after hemostasis is achieved; influence of hemostasis on the needle puncture site in the next dialysis session; and device failure. Adverse events and device failure reporting The principal investigator will immediately determine the causal relationship between the adverse event/device failure and study and report the “disease or the like,” including any disease, disability, death, or infection associated with the study participation, to the Niigata University Central Review Board of Clinical Research, according to the Clinical Trials Act in Japan. The case report forms and medical records will also be used to collect data on adverse events and device failures. Sample size calculation The sample size was calculated for the primary outcome using SAS® ver. 9.4 (SAS Institute Inc., Cary, NC, USA). A previous study demonstrated that the mean hemostasis times (standard deviation) achieved using WoundClot®, a cellulose-based gauze, on the arterial and venous sides were 6.64 (4.53) and 6.55 (5.35) min, respectively 4) . The mean hemostasis times using a conventional pad were 13.06 (7.24) min for the arterial side and 10.54 (5.03) min for the venous side. In the crossover study, when the intraindividual correlation and significance level were 0 and 5%, respectively, on both sides, the minimum number of cases with power > 90% was 21 for arteries and 38 for veins. The sample size for this study was determined based on the hemostasis time for the venous side in previous studies and by considering the use of different hemostatic materials and variations in methods for measuring hemostatic time. A target enrollment of 50 cases was set with an anticipated dropout rate of approximately 20%. Data management and monitoring Registration, randomization, and data collection will be performed using UHCT ACReSS, a web-based electronic data capture system designed by data managers at the Clinical and Translational Research Center of Niigata University Medical and Dental Hospital. The randomization will be performed centrally using a web-based system with a minimization procedure. The principal investigator will designate monitors independent of the study investigators, and the monitors will verify the source data and raise queries with the trial site staff. Missing data and discrepancies will be reviewed and queried by the data managers to ensure data quality. Statistical analysis Analysis sets The full analysis set (FAS) includes all randomized participants with at least one efficacy data point after enrollment. The per-protocol set includes all participants from the FAS who complete the study treatment and show no valid findings that may have affected the efficacy. The safety analysis set will include all randomized participants who receive at least one study treatment. Statistical methods for primary and secondary outcomes The minimum hemostasis time in the arteries, the primary outcome measure, will be analyzed using a mixed-effects model for repeated measures. The objective variable will be hemostasis time, whereas the explanatory variables will include the individual effect as a random effect and the hemostasis method and group and period effects as fixed effects. Hemostasis time will be a continuous variable, whereas the hemostasis method and group, period, and individual effects will be discrete variables. We will calculate the minimum least-squares mean value of the treatment effect (difference in hemostasis time between PAA-PVP and the conventional pad) along with p-values and 95% confidence intervals (CI). When testing the statistical hypothesis, the p-values will have a two-sided significance level of 5%. We will also determine the simple mean and standard deviation of the hemostasis time for each hemostasis material. The minimum hemostasis time for the venous side of the vascular access, the secondary outcome measure, will be analyzed similarly; however, the p-value will not be calculated. Failure or success to achieve hemostasis during the initial hemostatic period (11 min) will be examined, and the percentages of successful hemostasis achieved using PAA-PVP versus the conventional pad will be calculated along with the corresponding 95% CI. All analyses will be performed using the statistical package SAS® ver. 9.4 (SAS Institute Inc.). Subgroup analysis A subgroup analysis will be conducted based on the presence or absence of antiplatelet or anticoagulant medication use. Interim analysis No interim analysis is planned. Missing data This study will not use an imputation approach for missing values. The handling of lost, rejected, or abnormal data will be determined through discussions in a review meeting of the research personnel. Storage of samples and information All data collected in this study will be stored for 5 years from the study completion date and disposed of in an unrecoverable manner thereafter. Discussion This study will compare the efficacy and safety of PAA-PVP versus a conventional pad for hemostasis in patients undergoing HD. Accurate measurement of hemostasis time is crucial for evaluating the hemostatic effect of a novel material. We will employ an individual 3 + 3 design to ensure a more precise measurement of hemostatic time and patient safety. This study will provide high-level evidence on the benefits and risks of PAA-PVP use in patients on HD. The study is designed as an open-label crossover randomized controlled trial. The study treatment cannot be effectively blinded because PAA-PVP (Aron Cure®) has a distinctive form compared with the conventional pad (Injection Pad Mild®). The study treatment will have no carry-over effect because these materials will be used on the skin for only a few minutes. The crossover study design reduces the number of participants and increases the feasibility of the study implementation. These factors are suitable for this study design. The individual 3 + 3 design in this study will be adapted from the 3 + 3 design commonly used in dose-finding studies of anticancer agents. Although the 3 + 3 design in such studies is designed to address interindividual variations in outcomes, the individual 3 + 3 design in our study is intended to address intraindividual variations. Employing this method will allow us to minimize random errors and obtain more precise measurements of hemostasis time, which have substantial intraindividual differences and are challenging to measure at an exact point, thereby enhancing the validity of our findings. Several studies on hemostatic materials for patients on HD have been reported (Table 1 ). However, these studies have some limitations, including a lack of detailed information on the hemostasis time measurement procedure[ 4 , 5 ], lack of a control group[ 6 , 7 ], or inconsistent test/materials use 5) . Moreover, accurately measuring the hemostasis time was difficult owing to repeated compression hemostasis[ 6 , 7 ]. We will overcome these limitations and allow for more precise and intensive measurements that are essential for securing participant safety in such a study, in which a reduction in hemostasis time will be examined. Table 1 Previous studies on hemostasis of vascular access point among patients undergoing HD Author Study design Hemostatic techniques Issues in study design Choi et al. 3) Single-center open-label parallel-group RCT Plastic cannulae vs. metal needles Primary endpoint: initial cannulation failure Secondary endpoints: time for hemostasis at the end of HD; patients’ pain degrees; cannulation difficulty degree reported by nursing staff; and HD adequacy No information No information Bassat et al. 4) Single-center open-label parallel-group RCT WoundClot vs. regular cotton gauze Primary endpoint: reducing bleeding time Secondary endpoint: vascular access preservation Bleeding time with conventional gauze in arterial and venous sides of vascular access is measured at the end of three HD sessions, and the minimum bleeding time is recorded. In the WoundClot group, patients are treated with WoundClot for at least half the time required to achieve hemostasis with conventional gauze (or a minimum of 2 min). In subsequent HD sessions, the compression time is reduced by 1 min, and bleeding time with WoundClot is measured in three consecutive HD sessions. The rationale for hemostasis with the WoundClot to be initiated in half the time of conventional gauze hemostasis is unclear. The technique for measuring the hemostasis time of conventional gauze is not specified. Bizari et al. 5) Single-center single-arm before-after study HemoFoam vs. conventional gauze Primary endpoint: hemostasis time Secondary endpoint: recurrence of hematoma and bleeding Hemostasis is assessed 2 min after initiating compression hemostasis. The assessment is repeated if bleeding persists. No parallel control group is present. Evaluating the actual hemostatic effect is difficult because repeated bleedings and compressions may have altered hemostatic time. Misgav et al. 6) A single-center, single-arm, before-after study Chitosan pad vs. conventional gauze Primary endpoint: hemostasis time Secondary endpoint: post-discharge bleeding and local skin reactions Hemostasis is assessed 2 min after initiating compression hemostasis using a chitosan pad. If the bleeding persists, the second/third hemostasis is attempted using a new chitosan pad for 4 min. If hemostasis is not achieved after the third attempt, conventional gauze used until the bleeding stops. No parallel control group exists. The protocol for hemostasis using conventional gauze is inconsistent with that of the chitosan pad. Evaluate the actual hemostatic effect is difficult because repeated bleedings and compressions may have altered hemostatic time. HD, hemodialysis; RCT, randomized controlled study The limitations of this study are that the crossover trial design necessitates a more extended study period than a parallel-group study. Furthermore, success or failure to achieve hemostasis is determined at only a preset time, and testing at the same time point is allowed only for a maximum of six times. Additionally, no statistical evidence supports the notion that failure is favorable if it occurs less than 16.67% of the time. In addition, the safety of PAA-PVP remains unclear, although no serious adverse events have been reported to date. In conclusion, this study design may contribute to the development of new effective hemostatic materials that facilitates more rapid hemostasis than conventional treatment in patients on HD. It may also provide evidence for the efficacy and safety of PAA-PVP in patients undergoing HD. Prompt hemostasis after HD is important to reduce the burden on patients and medical staff. Trial status This manuscript is based on the protocol (version 1.2, last updated on April 24, 2023). The first participant was recruited on June 20, 2023. Recruitment is expected to be completed in March 2025. Abbreviations CI, confidence interval; FAS, full analysis set; HD, hemodialysis; PAA-PVP, polyacrylic acid-polyvinylpyrrolidone Declarations Ethics approval and consent to participate This study will be conducted in compliance with the latest Declaration of Helsinki, the Clinical Trials Act, and the Act on the Protection of Personal Information in Japan. The study protocol was approved by the Niigata University Central Review Board of Clinical Research and registered in the Japan Registry of Clinical Trials (jRCT) on January 30, 2023 (jRCTs032220597). Written informed consent to participate will be obtained from all participants. Plans for communicating important protocol modifications The principal investigator is responsible for the distribution of protocol amendments to site investigators. Site investigators are responsible for the distribution of amendments to all staff involved in this study. Dissemination policy The results of this study will be published in a peer-reviewed journal and presented at national and international medical congresses. Requests for the anonymized dataset presented in the final paper should be submitted via email to the corresponding authors. Availability of data and materials The corresponding authors will have access to the final trial dataset. There are no contractual agreements that limit such access for investigators and will be available on reasonable request. Competing interests The authors declare that they have no competing interests. Funding Toagosei Co., Ltd. is sponsoring this study. The funder will play no role in collecting, analyzing, and interpreting the study data or drafting the manuscript for publication. Authors’ contributions All authors contributed to the study protocol. RT: methodology, statistical analysis, and draft writing; MT: methodology, project administration, and draft writing; AH, TT, HM, and MI: methodology and project administration; DO: data management; SG: monitoring; YT and IN: supervision; KS: implementation; SY: principal investigator, conceptualization, and implementation. All authors have read and approved the final manuscript. Acknowledgments Not applicable. References Ito T, Otani N, Fujii K, Mori K, Eriguchi M, Koyama Y. Bioadhesive and biodissolvable hydrogels consisting of water-swellable poly(acrylic acid)/poly(vinylpyrrolidone) complexes. J Biomed Mater Res B Appl Biomater. 2020;108(2):503-12. Ito T, Yamaguchi S, Soga D, Yoshimoto T, Koyama Y. Bioabsorbable bioadhesive hydrogel comprising poly (acrylic acid) and poly (vinylpyrrolidone) for adhesion barrier and hemostatic device. MRS Communications. 2015;5:291-5. Ito T, Yamaguchi S, Soga D, Ueda K, Yoshimoto T, Koyama Y. Water-Absorbing Bioadhesive Poly(Acrylic Acid)/Polyvinylpyrrolidone Complex Sponge for Hemostatic Agents. Bioengineering (Basel). 2022;9(12):755-66. Kliuk-Ben Bassat O, Schwartz D, Zubkov A, Gal-Oz A, Gorevoy A, Romach I, et al. WoundClot(R) Hemostatic Gauze Reduces Bleeding Time after Arterial Venous Fistula Decannulation. Blood purification. 2021;50(6):952-8. Choi YS, Lee HS, Joo N, Park P, Cho SN, Youn IJ, et al. Efficacy and Safety of Plastic Cannulae Compared with Metal Needles in the Initial Use of an Arteriovenous Fistulae in Incident Hemodialysis Patients: A Randomized Controlled Study. American journal of nephrology. 2021;52(6):479-86. Misgav M, Lubetszki A, Brutman-Barazani T, Martinowitz U, Kenet G. The hemostatic efficacy of chitosan-pads in hemodialysis patients with significant bleeding tendency. J Vasc Access. 2017;18(3):220-4. Bizari D, Khoshmohabat H, Salahshour Kordestani S, Zarepur R. Comparison of HemoFoam(R) and Conventional Gauze Dressing on Hemostasis of Vascular Access Site in Hemodialysis Patients. Galen Med J. 2019;8:e1395. Cite Share Download PDF Status: Published Journal Publication published 24 May, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Major revision 03 Mar, 2025 Reviewers agreed at journal 24 Apr, 2024 Reviewers invited by journal 23 Apr, 2024 Editor assigned by journal 17 Apr, 2024 First submitted to journal 31 Mar, 2024 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-3917166","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":294546519,"identity":"f4bcd9a4-42c2-4d04-b053-71048c1255f9","order_by":0,"name":"Ryohei Terashima","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital: Niigata Daigaku Ishigaku Sogo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Ryohei","middleName":"","lastName":"Terashima","suffix":""},{"id":294546520,"identity":"d2e2643c-cb2f-4fee-b718-7428d4e4bb85","order_by":1,"name":"Mototsugu Tanaka","email":"","orcid":"https://orcid.org/0000-0002-8082-8945","institution":"Niigata University Medical and Dental Hospital: Niigata Daigaku Ishigaku Sogo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Mototsugu","middleName":"","lastName":"Tanaka","suffix":""},{"id":294546522,"identity":"e4f6e8c3-579d-4563-9e41-3f2fa5d4bac2","order_by":2,"name":"Atsushi Hashimoto","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital: Niigata Daigaku Ishigaku Sogo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Hashimoto","suffix":""},{"id":294546523,"identity":"b99c7973-adab-4a65-95ef-78f4102c86b0","order_by":3,"name":"Daiki Omori","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital: Niigata Daigaku Ishigaku Sogo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Daiki","middleName":"","lastName":"Omori","suffix":""},{"id":294546524,"identity":"746e834b-e31f-498a-86c3-11ab58db0c37","order_by":4,"name":"Takahiro Tanaka","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital: Niigata Daigaku Ishigaku Sogo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Tanaka","suffix":""},{"id":294546525,"identity":"c9c50183-b089-4666-b852-087a63c4134a","order_by":5,"name":"Haruna Miyazawa","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital: Niigata Daigaku Ishigaku Sogo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Haruna","middleName":"","lastName":"Miyazawa","suffix":""},{"id":294546526,"identity":"f4671e07-3a4d-494e-97db-69035b7457a7","order_by":6,"name":"Masahiro Ishizawa","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital: Niigata Daigaku Ishigaku Sogo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Ishizawa","suffix":""},{"id":294546527,"identity":"6d37cedf-0f99-4488-951c-64fd17686e00","order_by":7,"name":"Yoshihiko Tomita","email":"","orcid":"","institution":"Niigata University Medical and Dental Hospital: Niigata Daigaku Ishigaku Sogo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yoshihiko","middleName":"","lastName":"Tomita","suffix":""},{"id":294546528,"identity":"3a2b89e8-2ff8-43ba-b254-3dc9074466b4","order_by":8,"name":"Tomoko Ito","email":"","orcid":"","institution":"Obara Hospital Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Ito","suffix":""},{"id":294546529,"identity":"b7e0681c-6373-44bf-88f2-d9e23a1246c0","order_by":9,"name":"Yoshiyuki Koyama","email":"","orcid":"","institution":"Obara Hospital Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Yoshiyuki","middleName":"","lastName":"Koyama","suffix":""},{"id":294546530,"identity":"c67b30fb-db89-4803-9672-e3a029a5fa31","order_by":10,"name":"Kokichi Saito","email":"","orcid":"","institution":"Itoigawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kokichi","middleName":"","lastName":"Saito","suffix":""},{"id":294546531,"identity":"91b8424b-87dd-4808-9ed5-d3b1120d392f","order_by":11,"name":"Suguru Yamamoto","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-8279-2966","institution":"Niigata University Graduate School of Meidical and Dental Sciences","correspondingAuthor":true,"prefix":"","firstName":"Suguru","middleName":"","lastName":"Yamamoto","suffix":""},{"id":294546532,"identity":"1c479a42-029a-42d7-a95b-ede48cefc394","order_by":12,"name":"Shin Goto","email":"","orcid":"","institution":"Niigata University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Shin","middleName":"","lastName":"Goto","suffix":""},{"id":294546533,"identity":"e6692ee7-2509-4cad-80b1-50349f8c6af5","order_by":13,"name":"Ichiei Narita","email":"","orcid":"","institution":"Niigata University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ichiei","middleName":"","lastName":"Narita","suffix":""}],"badges":[],"createdAt":"2024-02-01 11:27:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3917166/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3917166/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-08877-9","type":"published","date":"2025-05-24T15:58:37+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55632871,"identity":"a63aa8d6-1081-4092-a69b-a668e4e947ee","added_by":"auto","created_at":"2024-04-30 20:00:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":165269,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe crossover study design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients will be randomly allocated at a 1:1 ratio to a group treated with polyacrylic acid/polyvinylpyrrolidone (PAA-PVP; Aron Cure\u003csup\u003e®\u003c/sup\u003e; Toagosei, Tokyo, Japan) or that treated with conventional non‐woven fabric pad (Injection Pad Mild\u003csup\u003e®\u003c/sup\u003e; Nichiban, Tokyo, Japan).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3917166/v1/4d77cfc22932741d882e90a0.png"},{"id":55632872,"identity":"f4a3f7c0-4015-433d-b004-ecd2c6344a54","added_by":"auto","created_at":"2024-04-30 20:00:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":262641,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSchedule of study enrollment process, interventions, and assessments\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3917166/v1/d04c5cbe98bc398319e20f2e.png"},{"id":55632870,"identity":"d2308b2a-8649-420e-a5df-2c2863b10a8d","added_by":"auto","created_at":"2024-04-30 20:00:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":403380,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe individual 3+3 design for determining hemostasis time\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe individual 3+3 design enables determination of the accurate hemostasis time of vascular access while ensuring patient safety and considering intraindividual variation. The white circles indicate successful hemostasis, whereas the black circles indicate failed hemostasis. The “x” indicates the end of the study for each participant.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-3917166/v1/fd8c24d36eb411628d13a352.png"},{"id":83460596,"identity":"1558b1ef-3633-42e2-8874-06b2f73a844a","added_by":"auto","created_at":"2025-05-26 16:12:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1739835,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3917166/v1/a472b937-df8b-4b0f-be6b-d493498a492a.pdf"}],"financialInterests":"","formattedTitle":"Polyacrylic acid-polyvinylpyrrolidone complex for achieving hemostasis after hemodialysis: study protocol for an open-label crossover randomized controlled trial (PAA-PVP study)","fulltext":[{"header":"Background","content":"\u003cp\u003eHemodialysis (HD), a standard renal replacement therapy for patients with end-stage kidney disease, requires repetitive needle puncture of the vascular access point for extracorporeal blood purification. At the end of HD, the needle is removed from the vascular access, and the puncture site is compressed to stop the bleeding. This usually takes 5\u0026ndash;15 min using a conventional non-woven fabric pad to achieve hemostasis.\u003c/p\u003e \u003cp\u003eA shorter hemostasis time reduces the burden on patients and medical staff because patients must stay in HD facilities until the completion of hemostasis. Furthermore, medical staff must apply compression hemostasis to patients with low activities of daily living who have a difficulty in achieving hemostasis themselves. Although hemostasis time may be associated with many factors, including comorbidities, skin conditions at the needle puncture site, platelet count, anticoagulant or antiplatelet agent use, and blood flow rate of the vascular access point, a new medical device that can quickly achieve hemostasis of the vascular access point is needed for patients on HD.\u003c/p\u003e \u003cp\u003eThe bioadhesive polyacrylic acid-polyvinylpyrrolidone (PAA-PVP) complex is a novel material that was developed to achieve hemostasis. PAA-PVP forms a soft hydrogel when absorbing moisture, such as blood or antiseptic solutions, adheres to the body\u0026rsquo;s surface, and exhibits a solid hemostatic effect[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In a previous study, immediate hemostasis was achieved at the tooth extraction site using PAA-PVP[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. PAA-PVP was also reportedly effective for achieving hemostasis of a vascular access point in a patient on HD[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. No serious adverse events were reported after its use.\u003c/p\u003e \u003cp\u003eThis study aimed to investigate whether PAA-PVP reduces hemostasis time at the needle puncture vascular access site compared with conventional pads in patients on HD with an open-label crossover randomized controlled trial.\u003c/p\u003e"},{"header":"Methods/Design","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and setting\u003c/h2\u003e \u003cp\u003eThis multicenter open-label crossover randomized controlled trial will use a 1:1 allocation to PAA-PVP (Aron Cure\u0026reg;; Toagosei, Tokyo, Japan) or a conventional non-woven fabric pad (Injection Pad Mild\u0026reg;; Nichiban, Tokyo, Japan) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This study will be performed at Itoigawa General Hospital and Niigata University Medical and Dental Hospital in Japan. The anticipated participant timelines and study assessments at specific time points are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eInclusion criteria\u003c/h2\u003e \u003cp\u003ePatients who meet all of the following criteria will be considered eligible:\u003c/p\u003e \u003cp\u003e1) Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years;\u003c/p\u003e \u003cp\u003e2) Undergoing HD (including hemodiafiltration) three times a week for the treatment of end-stage kidney disease;\u003c/p\u003e \u003cp\u003e3) Use of a vascular access, including arteriovenous fistula or graft;\u003c/p\u003e \u003cp\u003e4) Use of heparin or low molecular weight heparin as an anticoagulant during HD; and\u003c/p\u003e \u003cp\u003e5) Hemostasis achieved using a conventional pad with a tourniquet within 10 min after needle removal.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eExclusion criteria\u003c/h2\u003e \u003cp\u003ePatients with any of the following conditions will be excluded:\u003c/p\u003e \u003cp\u003e1) Currently participating in other clinical studies;\u003c/p\u003e \u003cp\u003e2) Currently pregnant or planning to become pregnant;\u003c/p\u003e \u003cp\u003e3) Requirement for compression hemostasis with fingers after needle removal;\u003c/p\u003e \u003cp\u003e4) Severe skin disease at the needle puncture vascular access site;\u003c/p\u003e \u003cp\u003e5) Scheduled to start anticoagulant or antiplatelet agents for daily use; and\u003c/p\u003e \u003cp\u003e6) Considered inappropriate to participate in the study by the investigators.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eRecruitment and consent\u003c/h2\u003e \u003cp\u003eOutpatients undergoing HD who meet the study eligibility criteria will be recruited. The investigators will provide potential study participants with sufficient information. Written informed consent will be obtained from all the participants before randomization.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy procedure\u003c/h2\u003e \u003cp\u003eThe individual 3\u0026thinsp;+\u0026thinsp;3 design will be employed in this study (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The procedure to achieve hemostasis will be performed by medical staff. The PAA-PVP or conventional pad will be placed on the needle puncture site, the needle is then removed, and a tourniquet is quickly and tightly wrapped around the area. These procedures will initially be performed on the arterial side, followed by the venous side. Once the prespecified time has passed, the tourniquet will be removed, and the bleeding is checked. No bleeding for 10 s will be considered successful. Success or failure to achieve hemostasis will be examined at 11, 9, 7, 5, 3, and 1 min in at least three sessions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIf hemostasis is achieved in all three sessions at those time points, a shorter time will be attempted in the subsequent three sessions. However, if two of three are completed successfully, another three tests at the same time point will be performed in the next week. If two or more fail, the study treatment will be terminated, and the patient will be moved on to another treatment. These decisions depend on the outcome of the arterial side of vascular access. The total study period will be a maximum of 15 weeks per participant, including 7 and 1 weeks for each study treatment and washout period, respectively. Minimum hemostasis time is defined as the minimum time required for three consecutive successful hemostatic procedures in a week. If hemostasis is not achieved, a conventional pad will be applied until the bleeding stops.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eParticipant withdrawal\u003c/h2\u003e \u003cp\u003eParticipants will be allowed to withdraw from the study at any time and for any reason. Participants who do not meet the eligibility criteria, do not undergo dialysis, are lost to follow-up, or are judged inappropriate to continue participating by the principal investigator will also be regarded as withdrawn. The principal investigator will record the reason for immature termination in the case report form and medical records. Data obtained before withdrawal will be analyzed after participant consent is provided. Participants who withdraw from the study will receive standard dialysis therapy.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measures\u003c/h2\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003ePrimary outcome\u003c/h2\u003e \u003cp\u003eThe primary outcome will be the minimum hemostatic time on the arterial side of vascular access.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003eThe secondary outcomes will be minimum hemostatic time in the venous side of vascular access and success or failure to achieve hemostasis during the initial hemostatic period (11 min).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSafety outcomes\u003c/h2\u003e \u003cp\u003eThe study safety outcomes will include: skin disorders (e.g., rash/redness, blistering, peeling skin, itching), number of re-bleeding episodes after hemostasis is achieved; influence of hemostasis on the needle puncture site in the next dialysis session; and device failure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events and device failure reporting\u003c/h2\u003e \u003cp\u003eThe principal investigator will immediately determine the causal relationship between the adverse event/device failure and study and report the \u0026ldquo;disease or the like,\u0026rdquo; including any disease, disability, death, or infection associated with the study participation, to the Niigata University Central Review Board of Clinical Research, according to the Clinical Trials Act in Japan. The case report forms and medical records will also be used to collect data on adverse events and device failures.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSample size calculation\u003c/h2\u003e \u003cp\u003eThe sample size was calculated for the primary outcome using SAS\u0026reg; ver. 9.4 (SAS Institute Inc., Cary, NC, USA). A previous study demonstrated that the mean hemostasis times (standard deviation) achieved using WoundClot\u0026reg;, a cellulose-based gauze, on the arterial and venous sides were 6.64 (4.53) and 6.55 (5.35) min, respectively\u003csup\u003e4)\u003c/sup\u003e. The mean hemostasis times using a conventional pad were 13.06 (7.24) min for the arterial side and 10.54 (5.03) min for the venous side. In the crossover study, when the intraindividual correlation and significance level were 0 and 5%, respectively, on both sides, the minimum number of cases with power\u0026thinsp;\u0026gt;\u0026thinsp;90% was 21 for arteries and 38 for veins. The sample size for this study was determined based on the hemostasis time for the venous side in previous studies and by considering the use of different hemostatic materials and variations in methods for measuring hemostatic time. A target enrollment of 50 cases was set with an anticipated dropout rate of approximately 20%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eData management and monitoring\u003c/h2\u003e \u003cp\u003eRegistration, randomization, and data collection will be performed using UHCT ACReSS, a web-based electronic data capture system designed by data managers at the Clinical and Translational Research Center of Niigata University Medical and Dental Hospital. The randomization will be performed centrally using a web-based system with a minimization procedure. The principal investigator will designate monitors independent of the study investigators, and the monitors will verify the source data and raise queries with the trial site staff. Missing data and discrepancies will be reviewed and queried by the data managers to ensure data quality.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003eAnalysis sets\u003c/h2\u003e \u003cp\u003eThe full analysis set (FAS) includes all randomized participants with at least one efficacy data point after enrollment. The per-protocol set includes all participants from the FAS who complete the study treatment and show no valid findings that may have affected the efficacy. The safety analysis set will include all randomized participants who receive at least one study treatment.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods for primary and secondary outcomes\u003c/h2\u003e \u003cp\u003eThe minimum hemostasis time in the arteries, the primary outcome measure, will be analyzed using a mixed-effects model for repeated measures. The objective variable will be hemostasis time, whereas the explanatory variables will include the individual effect as a random effect and the hemostasis method and group and period effects as fixed effects. Hemostasis time will be a continuous variable, whereas the hemostasis method and group, period, and individual effects will be discrete variables. We will calculate the minimum least-squares mean value of the treatment effect (difference in hemostasis time between PAA-PVP and the conventional pad) along with p-values and 95% confidence intervals (CI). When testing the statistical hypothesis, the p-values will have a two-sided significance level of 5%. We will also determine the simple mean and standard deviation of the hemostasis time for each hemostasis material.\u003c/p\u003e \u003cp\u003eThe minimum hemostasis time for the venous side of the vascular access, the secondary outcome measure, will be analyzed similarly; however, the p-value will not be calculated. Failure or success to achieve hemostasis during the initial hemostatic period (11 min) will be examined, and the percentages of successful hemostasis achieved using PAA-PVP versus the conventional pad will be calculated along with the corresponding 95% CI.\u003c/p\u003e \u003cp\u003eAll analyses will be performed using the statistical package SAS\u0026reg; ver. 9.4 (SAS Institute Inc.).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analysis\u003c/h2\u003e \u003cp\u003eA subgroup analysis will be conducted based on the presence or absence of antiplatelet or anticoagulant medication use.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eInterim analysis\u003c/h2\u003e \u003cp\u003eNo interim analysis is planned.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eMissing data\u003c/h2\u003e \u003cp\u003eThis study will not use an imputation approach for missing values. The handling of lost, rejected, or abnormal data will be determined through discussions in a review meeting of the research personnel.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eStorage of samples and information\u003c/h2\u003e \u003cp\u003eAll data collected in this study will be stored for 5 years from the study completion date and disposed of in an unrecoverable manner thereafter.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study will compare the efficacy and safety of PAA-PVP versus a conventional pad for hemostasis in patients undergoing HD. Accurate measurement of hemostasis time is crucial for evaluating the hemostatic effect of a novel material. We will employ an individual 3\u0026thinsp;+\u0026thinsp;3 design to ensure a more precise measurement of hemostatic time and patient safety. This study will provide high-level evidence on the benefits and risks of PAA-PVP use in patients on HD.\u003c/p\u003e \u003cp\u003eThe study is designed as an open-label crossover randomized controlled trial. The study treatment cannot be effectively blinded because PAA-PVP (Aron Cure\u0026reg;) has a distinctive form compared with the conventional pad (Injection Pad Mild\u0026reg;). The study treatment will have no carry-over effect because these materials will be used on the skin for only a few minutes. The crossover study design reduces the number of participants and increases the feasibility of the study implementation. These factors are suitable for this study design.\u003c/p\u003e \u003cp\u003eThe individual 3\u0026thinsp;+\u0026thinsp;3 design in this study will be adapted from the 3\u0026thinsp;+\u0026thinsp;3 design commonly used in dose-finding studies of anticancer agents. Although the 3\u0026thinsp;+\u0026thinsp;3 design in such studies is designed to address interindividual variations in outcomes, the individual 3\u0026thinsp;+\u0026thinsp;3 design in our study is intended to address intraindividual variations. Employing this method will allow us to minimize random errors and obtain more precise measurements of hemostasis time, which have substantial intraindividual differences and are challenging to measure at an exact point, thereby enhancing the validity of our findings.\u003c/p\u003e \u003cp\u003eSeveral studies on hemostatic materials for patients on HD have been reported (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). However, these studies have some limitations, including a lack of detailed information on the hemostasis time measurement procedure[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], lack of a control group[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], or inconsistent test/materials use\u003csup\u003e5)\u003c/sup\u003e. Moreover, accurately measuring the hemostasis time was difficult owing to repeated compression hemostasis[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. We will overcome these limitations and allow for more precise and intensive measurements that are essential for securing participant safety in such a study, in which a reduction in hemostasis time will be examined.\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\u003ePrevious studies on hemostasis of vascular access point among patients undergoing HD\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHemostatic techniques\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIssues in study design\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChoi et al.\u003csup\u003e3)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-center open-label parallel-group RCT\u003c/p\u003e \u003cp\u003ePlastic cannulae vs. metal needles\u003c/p\u003e \u003cp\u003ePrimary endpoint: initial cannulation failure\u003c/p\u003e \u003cp\u003eSecondary endpoints: time for hemostasis at the end of HD; patients\u0026rsquo; pain degrees; cannulation difficulty degree reported by nursing staff; and HD adequacy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo information\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo information\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBassat et al.\u003csup\u003e4)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-center open-label parallel-group RCT\u003c/p\u003e \u003cp\u003eWoundClot vs. regular cotton gauze\u003c/p\u003e \u003cp\u003ePrimary endpoint: reducing bleeding time\u003c/p\u003e \u003cp\u003eSecondary endpoint: vascular access preservation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBleeding time with conventional gauze in arterial and venous sides of vascular access is measured at the end of three HD sessions, and the minimum bleeding time is recorded. In the WoundClot group, patients are treated with WoundClot for at least half the time required to achieve hemostasis with conventional gauze (or a minimum of 2 min). In subsequent HD sessions, the compression time is reduced by 1 min, and bleeding time with WoundClot is measured in three consecutive HD sessions.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThe rationale for hemostasis with the WoundClot to be initiated in half the time of conventional gauze hemostasis is unclear. The technique for measuring the hemostasis time of conventional gauze is not specified.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBizari et al.\u003csup\u003e5)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-center single-arm before-after study\u003c/p\u003e \u003cp\u003eHemoFoam vs. conventional gauze\u003c/p\u003e \u003cp\u003ePrimary endpoint: hemostasis time\u003c/p\u003e \u003cp\u003eSecondary endpoint: recurrence of hematoma and bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHemostasis is assessed 2 min after initiating compression hemostasis. The assessment is repeated if bleeding persists.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo parallel control group is present. Evaluating the actual hemostatic effect is difficult because repeated bleedings and compressions may have altered hemostatic time.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMisgav et al.\u003csup\u003e6)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eA single-center, single-arm, before-after study\u003c/p\u003e \u003cp\u003eChitosan pad vs. conventional gauze\u003c/p\u003e \u003cp\u003ePrimary endpoint: hemostasis time\u003c/p\u003e \u003cp\u003eSecondary endpoint: post-discharge bleeding and local skin reactions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHemostasis is assessed 2 min after initiating compression hemostasis using a chitosan pad. If the bleeding persists, the second/third hemostasis is attempted using a new chitosan pad for 4 min. If hemostasis is not achieved after the third attempt, conventional gauze used until the bleeding stops.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo parallel control group exists.\u003c/p\u003e \u003cp\u003eThe protocol for hemostasis using conventional gauze is inconsistent with that of the chitosan pad. Evaluate the actual hemostatic effect is difficult because repeated bleedings and compressions may have altered hemostatic time.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eHD, hemodialysis; RCT, randomized controlled study\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe limitations of this study are that the crossover trial design necessitates a more extended study period than a parallel-group study. Furthermore, success or failure to achieve hemostasis is determined at only a preset time, and testing at the same time point is allowed only for a maximum of six times. Additionally, no statistical evidence supports the notion that failure is favorable if it occurs less than 16.67% of the time. In addition, the safety of PAA-PVP remains unclear, although no serious adverse events have been reported to date.\u003c/p\u003e \u003cp\u003eIn conclusion, this study design may contribute to the development of new effective hemostatic materials that facilitates more rapid hemostasis than conventional treatment in patients on HD. It may also provide evidence for the efficacy and safety of PAA-PVP in patients undergoing HD. Prompt hemostasis after HD is important to reduce the burden on patients and medical staff.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003eThis manuscript is based on the protocol (version 1.2, last updated on April 24, 2023). The first participant was recruited on June 20, 2023. Recruitment is expected to be completed in March 2025.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI, confidence interval; FAS, full analysis set; HD, hemodialysis; PAA-PVP, polyacrylic acid-polyvinylpyrrolidone\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will be conducted in compliance with the latest Declaration of Helsinki, the Clinical Trials Act, and the Act on the Protection of Personal Information in Japan. The study protocol was approved by the Niigata University Central Review Board of Clinical Research and registered in the Japan Registry of Clinical Trials (jRCT) on January 30, 2023 (jRCTs032220597). Written informed consent to participate will be obtained from all participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003ePlans for communicating important protocol modifications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe principal investigator is responsible for the distribution of protocol amendments to site investigators. Site investigators are responsible for the distribution of amendments to all staff involved in this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eDissemination policy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of this study will be published in a peer-reviewed journal and presented at national and international medical congresses. Requests for the anonymized dataset presented in the final paper should be submitted via email to the corresponding authors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe corresponding authors will have access to the final trial dataset. There are no contractual agreements that limit such access for investigators and will be available on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eToagosei Co., Ltd. is sponsoring this study. The funder will play no role in collecting, analyzing, and interpreting the study data or drafting the manuscript for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study protocol. RT: methodology, statistical analysis, and draft writing; MT: methodology, project administration, and draft writing; AH, TT, HM, and MI: methodology and project administration; DO: data management; SG: monitoring; YT and IN: supervision; KS: implementation; SY: principal investigator, conceptualization, and implementation. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIto T, Otani N, Fujii K, Mori K, Eriguchi M, Koyama Y. Bioadhesive and biodissolvable hydrogels consisting of water-swellable poly(acrylic acid)/poly(vinylpyrrolidone) complexes. J Biomed Mater Res B Appl Biomater. 2020;108(2):503-12.\u003c/li\u003e\n\u003cli\u003eIto T, Yamaguchi S, Soga D, Yoshimoto T, Koyama Y. Bioabsorbable bioadhesive hydrogel comprising poly (acrylic acid) and poly (vinylpyrrolidone) for adhesion barrier and hemostatic device. MRS Communications. 2015;5:291-5.\u003c/li\u003e\n\u003cli\u003eIto T, Yamaguchi S, Soga D, Ueda K, Yoshimoto T, Koyama Y. Water-Absorbing Bioadhesive Poly(Acrylic Acid)/Polyvinylpyrrolidone Complex Sponge for Hemostatic Agents. Bioengineering (Basel). 2022;9(12):755-66.\u003c/li\u003e\n\u003cli\u003eKliuk-Ben Bassat O, Schwartz D, Zubkov A, Gal-Oz A, Gorevoy A, Romach I, et al. WoundClot(R) Hemostatic Gauze Reduces Bleeding Time after Arterial Venous Fistula Decannulation. Blood purification. 2021;50(6):952-8.\u003c/li\u003e\n\u003cli\u003eChoi YS, Lee HS, Joo N, Park P, Cho SN, Youn IJ, et al. Efficacy and Safety of Plastic Cannulae Compared with Metal Needles in the Initial Use of an Arteriovenous Fistulae in Incident Hemodialysis Patients: A Randomized Controlled Study. American journal of nephrology. 2021;52(6):479-86.\u003c/li\u003e\n\u003cli\u003eMisgav M, Lubetszki A, Brutman-Barazani T, Martinowitz U, Kenet G. The hemostatic efficacy of chitosan-pads in hemodialysis patients with significant bleeding tendency. J Vasc Access. 2017;18(3):220-4.\u003c/li\u003e\n\u003cli\u003eBizari D, Khoshmohabat H, Salahshour Kordestani S, Zarepur R. Comparison of HemoFoam(R) and Conventional Gauze Dressing on Hemostasis of Vascular Access Site in Hemodialysis Patients. Galen Med J. 2019;8:e1395.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"arteriovenous fistula, arteriovenous graft, bleeding time, clotting time, end-stage kidney disease, end-stage renal disease, vascular access","lastPublishedDoi":"10.21203/rs.3.rs-3917166/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3917166/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAchieving rapid and secure hemostasis of the vascular access point is important for patients undergoing maintenance hemodialysis (HD). We developed a polyacrylic acid-polyvinylpyrrolidone (PAA-PVP) complex that absorbs moisture such as blood or sterilizing solution, forms a hydrogel, and adheres to the body\u0026rsquo;s surface, thereby exerting a powerful hemostatic effect. This study aims to compare the effect of PAA-PVP complex versus a conventional non-woven fabric pad on hemostasis at the needle puncture vascular access site in patients on HD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis open-label crossover randomized controlled trial will include 50 participants who undergo thrice-weekly HD. Participants in whom hemostasis requires more than 10 min by compression using a conventional pad or who have a severe skin problem at the needle puncture vascular access site will be excluded from the study. Participants will be randomized in a 1:1 ratio to receive either the PAA-PVP complex or conventional pads. Three consecutive weekly hemostatic tests will be performed at 11, 9, 7, 5, 3, and 1 min. The study will employ an individual 3\u0026thinsp;+\u0026thinsp;3 design in which participants in whom hemostasis is achieved in all three sessions in a week will be challenged to a shorter time in the three sessions of the next week. Those in whom hemostasis is achieved in two of three sessions will be tested at the same time point in the three sessions of the next week. The study treatment will be terminated if hemostasis is achieved in only one or none of the sessions, and the minimum time with three consecutive successes will be recorded as the hemostasis time. The primary endpoint, the hemostasis time on the arterial side of the vascular access, will be analyzed using mixed-effect models for repeated measures and include the hemostatic technique and group, period, and individual effects as covariates.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThe study will provide evidence on whether the PAA-PVP complex reduces hemostasis time of the vascular access compared to conventional pad in patients on HD.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003ejRCTs032220597 (Japan Registry of Clinical Trials; registered on January 30, 2023, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://jrct.niph.go.jp/latest-detail/jRCTs032220597\u003c/span\u003e\u003cspan address=\"https://jrct.niph.go.jp/latest-detail/jRCTs032220597\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)\u003c/p\u003e","manuscriptTitle":"Polyacrylic acid-polyvinylpyrrolidone complex for achieving hemostasis after hemodialysis: study protocol for an open-label crossover randomized controlled trial (PAA-PVP study)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-30 20:00:35","doi":"10.21203/rs.3.rs-3917166/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-03-03T05:35:55+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-04-24T11:30:41+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-23T12:36:46+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-17T09:10:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2024-03-31T08:53:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e4eae286-1a47-469c-8c19-05e2ad3361b0","owner":[],"postedDate":"April 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-26T16:08:27+00:00","versionOfRecord":{"articleIdentity":"rs-3917166","link":"https://doi.org/10.1186/s13063-025-08877-9","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-05-24 15:58:37","publishedOnDateReadable":"May 24th, 2025"},"versionCreatedAt":"2024-04-30 20:00:35","video":"","vorDoi":"10.1186/s13063-025-08877-9","vorDoiUrl":"https://doi.org/10.1186/s13063-025-08877-9","workflowStages":[]},"version":"v1","identity":"rs-3917166","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3917166","identity":"rs-3917166","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}