Patient Monitoring in a Pragmatic, Multicenter Trial of Incremental Hemodialysis: Early Experience from the TwoPlus Randomized Controlled Trial

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Gautam, Alaa S Awad, Vandana Dua Niyyar, Jennifer E Flythe, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7706387/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Dec, 2025 Read the published version in BMC Nephrology → Version 1 posted 20 You are reading this latest preprint version Abstract Background Pragmatic randomized controlled trials (RCTs) must be embedded within routine clinical workflows, which requires monitoring strategies that are feasible in everyday practice. Incremental hemodialysis—initiating treatment twice weekly in patients with preserved residual kidney function and escalating frequency as needed—differs from conventional thrice-weekly initiation. Implementing this approach in a pragmatic trial among providers and dialysis staff unfamiliar with incremental dialysis necessitated additional preparation and oversight. The TwoPlus trial is a multicenter pragmatic RCT evaluating incremental versus conventional initiation of chronic hemodialysis. We describe the patient monitoring framework developed for TwoPlus, which integrates digital infrastructure, human touchpoints, and provider engagement to ensure participant safety. Methods/Design TwoPlus is an ongoing multicenter RCT enrolling adults initiating chronic hemodialysis with residual kidney function (urine urea clearance ≥2.0 mL/min and urine output ≥500 mL/24 hours). Participants are randomized to incremental hemodialysis—twice-weekly treatment supported by diuretics and sodium bicarbonate, with transition to thrice-weekly as clinically indicated—or conventional thrice-weekly initiation. The primary outcome is a composite of all-cause death, hospitalization, or emergency department visits. Secondary outcomes include preservation of residual kidney function and treatment adherence. The monitoring framework combines automated dialysis data downloads, manual data abstraction, assessments conducted by investigators or clinical research coordinators and reviewed at the site level, structured team reviews, and regular communication with treating providers. Discussion This layered monitoring model balances feasibility, safety, and fidelity in a pragmatic trial where provider engagement and site-specific adaptation were essential. The monitoring approach adopted in TwoPlus will inform the design of monitoring frameworks for future pragmatic nephrology trials. Trial registration: NCT05828823 hemodialysis incremental monitoring pragmatic randomized controlled trial Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Pragmatic randomized controlled trials (RCTs) are designed to evaluate interventions under real-world conditions and must operate within routine clinical workflows[1]. This design increases the involvedness of trial operations—particularly patient monitoring—because oversight must be integrated into standard care processes rather than layered on top of them[2]. Traditional safety monitoring, which often relies on retrospective reporting of serious adverse events to Institutional Review Boards or Data and Safety Monitoring Committees, may be insufficient in this setting[3]. Beyond traditional oversight, proactive, real-time strategies are required—especially when the intervention alters foundational aspects of care delivery[4]. In many RCTs, interventions remain fixed after randomization, and safety oversight is narrowly focused on predefined outcomes. By contrast, trials involving emerging interventions that employ existing tools and knowledge and that need to be embedded in routine care require more flexible and layered monitoring frameworks[2]. This adaptability not only enhances participant safety but also supports continuous learning across diverse clinical sites. Here, we describe the operationalization of the monitoring strategy in the TwoPlus trial—a multicenter pragmatic RCT comparing incremental versus conventional initiation of chronic hemodialysis[5]. The rationale for evaluating incremental hemodialysis versus conventional thrice-weekly initiation has been detailed elsewhere[5]. Briefly, incremental hemodialysis leverages residual kidney function and adjuvant therapies, allowing a gradual transition to full-dose therapy. Tailored to clinical manifestations and residual kidney function, incremental hemodialysis is supported by growing evidence for its potential to improve quality of life, reduce treatment burden, and preserve residual function[6], without compromising clinical safety[7]. However, most prior studies were conducted at institutions where clinicians were already familiar and comfortable with prescribing and monitoring patients on incremental hemodialysis. In routine practice, this approach challenges entrenched norms and relies heavily on the experience and engagement of treating nephrologists and dialysis staff, many of whom are unaccustomed to deviating from the thrice-weekly standard[8]. The current manuscript focuses on the patient monitoring framework of the TwoPlus trial, which has not previously been described in detail, and aims to provide a model for safety oversight in pragmatic nephrology research. Participants, Interventions, Outcomes The TwoPlus trial is an ongoing multicenter RCT comparing incremental versus conventional initiation of chronic hemodialysis in patients with kidney dysfunction requiring dialysis[5]. Eligibility criteria, recruitment settings, interventions, and outcomes are fully described in the published TwoPlus protocol[5]. In brief, adults initiating chronic hemodialysis who have residual kidney function based on timed urine collection of kidney urea clearance ≥2.0 mL/min and urine output ≥500 mL/24 hours, and who meet other clinical eligibility criteria, are randomized across multiple academic and community dialysis units to either incremental hemodialysis or conventional thrice-weekly initiation ( Figure 1 ). Participants randomized to the intervention group of incremental hemodialysis are treated with twice-weekly hemodialysis supported by adjuvant oral medications (diuretics, potassium binders and sodium bicarbonate if needed) and progress to thrice-weekly treatment when clinically indicated. The primary outcome is a composite of all-cause death, hospitalization, or emergency department visits, with secondary outcomes including residual kidney function and treatment adherence. Sample Size and Statistical Considerations The planned sample size is 350 patient participants. The primary analysis will follow the intention-to-treat principle. The primary outcome—a composite of all-cause death, hospitalization, or emergency department visits—will be compared between study arms using time-to-event methods. Recurrent event models will be used for secondary analyses. Additional outcomes, including preservation of residual kidney function and treatment adherence, will be analyzed using mixed-effects and survival models, as appropriate. Data Collection, Management, and Analysis Clinical data in TwoPlus are collected through a hybrid model that combines automated downloads from dialysis electronic medical records (EMRs) with complementary manual data entry. Electronic dialysis data downloads (DDDs) are generated at participating dialysis organizations and transmitted on a standardized format and schedule to the Data Coordinating Center (DCC) ( Figure 2 ). When direct electronic extraction from dialysis EMR is not feasible, equivalent data are abstracted through structured dialysis EMR review and entered manually into the centralized TwoPlus database. Both electronic and manual streams capture treatment-level information from each dialysis session, including prescription details, vital signs, interdialytic weights, ultrafiltration volume, and delivered Kt/V. To supplement treatment-level metrics, clinical research coordinators abstract data from non-dialysis healthcare institutions’ EMR, including emergency department visits, hospitalizations, and other adverse events. Patient-reported outcomes are also obtained through structured in-person or virtual assessments at regular study visits. This dual approach ensures that the monitoring framework incorporates both objective clinical parameters and contextual patient information. All data streams feed into a secure, web-based system managed by the DCC ( Figure 2 ). The DCC reconciles incoming DDDs and manual entries against expected participant lists, generates automated alerts for discrepancies, and ingests validated datasets into the central repository. Logic and range checks are applied at the point of entry to enhance data quality. Curated participant-level summaries—including residual kidney function, dialysis stdKt/V, kidney stdKt/V, total stdKt/V, and routine laboratory values—are produced quarterly and returned to sites to support ongoing monitoring and intervention fidelity. Access is role-restricted, and all transmissions are encrypted. Patient Monitoring in the TwoPlus Trial Drawing on best practices from prior pragmatic trials[2], the TwoPlus monitoring framework integrates electronic health records, human-centered follow-up, and team-based decision-making to support safe implementation of an emerging intervention across varied practice settings. Monitoring in TwoPlus extends beyond detecting adverse events. It is designed to: Identify early signs of clinical instability. Support adjustments to the dialysis prescription. Assess adherence to treatment assignment. Provide guidance and reassurance to treating providers. Safeguard trial equipoise across diverse practice settings. These goals require that providers remain well-informed and supported, and that study teams maintain close, ongoing collaboration with treating nephrologists and dialysis unit staff. As illustrated in Figure 3 , patient monitoring in TwoPlus spans five interconnected domains: a) Provider engagement — active involvement of treating nephrologists to confirm eligibility, approve randomization, and maintain ongoing communication about clinical status. b) Human touchpoints — monthly participant check-ins, informal communication with dialysis staff, and structured tracking logs that provide context beyond electronic data. c) Team-based review — structured meetings at the site and investigator level where clinical research coordinators and investigators assess longitudinal data, discuss cases, and recommend adjustments in treatment or monitoring. d) Digital surveillance — near real-time monitoring through dialysis EMR downloads, Admission-Discharge-Transfer (ADT) alerts, and interoperability with regional health information exchanges, integrated with quarterly reports from the Data Coordinating Center. e) Site-level adaptation — tailoring implementation to local infrastructures, workflows, and patient populations, including cultural and language considerations, to ensure feasibility and fidelity across diverse care environments. The following sections describe how these principles have been operationalized across participating TwoPlus sites. Provider Engagement In pragmatic trials, provider engagement functions as both a safety mechanism and a key determinant of adherence to the trial protocol[9]. In TwoPlus, the treating nephrologist is often not a study investigator. Successful implementation of the intervention—and protection of participant safety—therefore depends heavily on the engagement and support of non-research clinicians. Positioning providers as partners, rather than passive recipients of study protocols, was critical to enhancing both intervention safety and fidelity—an approach previously advocated for pragmatic trials[10]. To address the limited prior experience with incremental hemodialysis among many treating nephrologists and dialysis staff, structured training sessions were conducted at each site before recruitment began ( Figure 4 ). All patients initiating chronic hemodialysis at participating centers are prescreened for eligibility with input and approval from the treating nephrologist to confirm appropriateness for incremental therapy—for example, adequate volume status and the ability to follow dynamic medical instructions. At randomization, treating providers are notified of the assigned study arm, and for participants randomized to the incremental arm, this communication emphasizes the need for closer monitoring and offers an opportunity to raise safety concerns. To sustain engagement, study teams maintain regular communication with providers throughout follow-up. Some sites use recurring email updates or designate liaisons to ensure timely information flow, while others involve study-affiliated nephrologists as consultants when dialysis staff express discomfort with non-standard schedules. These arrangements provide peer-to-peer support and reinforce decision-making while respecting provider autonomy. In some cases, coverage providers unfamiliar with the trial temporarily overruled randomization assignments or delayed intervention implementation. Such episodes underscored the importance of continuous communication and rapid clarification. Ultimately, consistent provider engagement has improved protocol adherence, facilitated timely treatment adjustments, and supported the safe delivery of incremental hemodialysis across diverse dialysis settings. Human Touchpoints Digital systems alone cannot ensure participant safety in a pragmatic trial.. Human touchpoints—structured, intentional interactions between study staff, participants, and dialysis teams—are essential to gather insights into participant experiences and clinical changes that are not consistently documented in electronic records. At all sites, trained clinical research coordinators conduct monthly in-person with patient participants. These checkpoints use a conversational approach, asking open-ended questions such as “How are you feeling?” or “Have you been to the hospital since we last spoke?” These touchpoints uncover issues that may not be evident in the medical record—such as fluid imbalance, missed treatments, or medication changes—and foster rapport, which supports retention and adherence. Individual sites also maintain internal tracking logs for participants in the incremental arm. These typically include treatment dates, prescribed and achieved weights, blood pressures, and medication adjustments. Study teams review these logs regularly—often weekly or biweekly—during structured meetings involving the site investigator and clinical research coordinator. This facilitates early recognition of clinical drift, such as rising interdialytic weight gains or unexplained weight adjustments. Informal communication with dialysis staff further enhances monitoring. Nurse managers and front-line dialysis staff frequently notify the study team about missed treatments, evolving symptoms, or social barriers. In some cases, treating nephrologists initiate discussions about patient eligibility or reassess suitability for continued participation in the incremental arm. Team-Based Decision-Making Decisions to maintain or escalate dialysis frequency in TwoPlus are informed by structured, collaborative reviews that integrate both clinical context and laboratory data. At each site, assessments are conducted by clinical research coordinators or investigators and reported to the site principal investigator. These reviews occur weekly or biweekly and focus on key indicators such as interdialytic weight gain, dry weight changes, blood pressure patterns, diuretic use, hospitalizations, and relevant laboratory results. Many sites employ pre-populated tracking templates to visualize longitudinal trends, enabling early recognition of clinical drift or emerging safety concerns. In some instances, treating providers identified clinical instability and adjusted dialysis prescriptions before the study team’s scheduled review. In these cases, the study team documented the rationale, confirmed alignment with trial protocol, and incorporated the adjustment into ongoing monitoring. In other instances, findings from site-level reviews were communicated to treating providers along with recommendations to maintain the current regimen or to adjust diuretics, potassium binders, sodium bicarbonate dosing, target weight, or dialysis frequency. Final prescribing decisions always rested with the treating providers, ensuring that adjustments reflected both clinical judgment and trial objectives. Cross-site learning was promoted through biweekly investigator meetings, where teams presented cases, shared challenges, and exchanged solutions. These peer discussions fostered consistency in protocol implementation while allowing flexibility to adapt to local clinical environments. Collectively, this multi-level review process supported treatment decisions that were patient-centered, evidence-informed, and faithful to the intent of the trial. Digital Infrastructure and Surveillance EMR systems form the backbone of safety monitoring in the TwoPlus trial. Participating sites implemented automated tools to capture dialysis session data and clinical events in near real-time, ensuring close alignment between study monitoring and routine clinical care. A key element is the deployment of research-specific ADT alerts within institutional EMRs. These alerts notify study teams of hospitalizations or emergency department visits involving enrolled participants and prompt chart review and documentation of adverse events. Several sites enhanced surveillance further by leveraging interoperability with regional EMR networks—such as CRISP and EPIC’s CareEverywhere—to capture events occurring outside their home health systems. This cross-institutional visibility strengthened monitoring in regions with fragmented care networks. When safety events were identified, responses could be initiated either by treating providers—who sometimes adjusted dialysis prescriptions immediately—or by the study team following review of alert data. In both cases, the study team documented the event, verified consistency with trial protocol, and integrated the information into ongoing monitoring. At the coordinating level, the DCC supports oversight by generating quarterly participant-level reports. These reports summarize key metrics including residual kidney function, dialysis stdKt/V, kidney stdKt/V, total stdKt/V, volume management parameters, and routine laboratory values. Investigators use these reports to obtain a high-level overview of each participant’s trajectory, allowing for early recognition of concerning trends and for timely discussions with treating providers. Site-Specific Adaptations Although all sites follow a unified TwoPlus protocol, implementation required local adaptations to maintain safety, support provider engagement, and ensure fidelity in diverse clinical environments. These differences reflected variability in institutional infrastructure, dialysis organization, geography, and patient populations. While most participating sites are embedded within academic medical centers, several involve collaborations with private nephrology practices which will enhance the relevance and generalizability of TwoPlus findings across real-world settings. At many sites, study activities follow highly structured workflows. Digital tools, physician-led consent, and weekly team reviews are coordinated through centralized tracking systems. One or more clinical research coordinators visit dialysis units in person, and physician investigators are actively engaged across all phases—from prescreening and consent to ongoing patient monitoring. Some sites faced distinct challenges, including caring for largely underserved populations, high proportions of patients with limited English proficiency, and many participants with undocumented status. In these settings, frequent communication with treating providers, close collaboration with social work and pharmacy teams, and flexible approaches to medication access and transportation were critical to increase recruitment and sustain intervention adherence. Operational challenges also influenced study conduct. At some sites, dialysis centers experienced temporary holds on onboarding new patients due to staffing shortages. In other instances, the addition of new dialysis centers was required—and is anticipated to remain a recurring need—depending on local operational workflows and recruitment rates. Across all sites, strong rapport with dialysis staff has proved critical. Dialysis nurses frequently act as informal liaisons, alerting the study team to clinical instability or emerging concerns. At certain sites, medical directors have served as study champions, reinforcing awareness and engagement across dialysis unit personnel. In others, close coordination between investigators and treating nephrologists on sharing kidney clearance results—including dialysis and kidney stdKt/V calculations—to inform hemodialysis prescriptions in the incremental arm. Discussion The TwoPlus trial offers a unique opportunity to evaluate incremental hemodialysis in a pragmatic, multicenter setting, and the monitoring framework described here is central to its safe implementation. Unlike conventional efficacy trials, pragmatic designs require oversight systems that are embedded within routine workflows and adaptable to diverse care environments. Our experience highlights several principles that may be relevant to future pragmatic nephrology trials. First, provider engagement emerged as both a safeguard and a determinant of protocol fidelity. Active communication with treating nephrologists and dialysis staff supported adherence and facilitated timely adjustments, whereas lapses in engagement led to delays or protocol drift. Embedding provider engagement as a core element of monitoring may therefore improve both safety and intervention delivery. Second, the integration of digital and human monitoring touchpoints provided complementary strengths. Automated dialysis data downloads allowed for near real-time tracking of treatment-level variables, while manual data entry and structured patient check-ins collects adverse events and patient concerns not always captured in the dialysis EMRs. Third, team-based decision-making and site-specific adaptations proved essential in translating the protocol into varied practice settings. Structured case reviews, cross-site investigator meetings, and informal communication channels created a learning network that promoted consistency while allowing flexibility to accommodate local contexts. This adaptability may be particularly important for emerging interventions that challenge established norms of dialysis delivery. Despite these strengths, several challenges warrant consideration. The monitoring framework depends on the quality and completeness of electronic health record data, which may vary across institutions. Manual data entry, while critical for capturing contextual information, increases workload and may introduce variability in documentation. Finally, the TwoPlus trial is conducted within academic and partnered community settings, and further work will be needed to assess the scalability of this monitoring approach in other dialysis environments. In summary, the TwoPlus monitoring strategy balances safety, feasibility, and fidelity through a layered approach that combines digital infrastructure with human-centered oversight. By embedding provider engagement and site-specific adaptations, this model may guide the design of future pragmatic nephrology trials testing real-world implementation of emerging interventions. Trial Status Recruitment for the TwoPlus trial began in January 2024 and was initiated in a staggered fashion across participating sites over the subsequent months. As of September 2025, enrollment and randomization remain ongoing at academic and community dialysis units throughout the United States. Declarations Ethics and Dissemination Ethics approval and consent to participate The TwoPlus trial and this monitoring protocol have been approved by the Institutional Review Boards (IRBs) of all participating institutions. Written informed consent is obtained from all participants prior to enrollment. Confidentiality All data are handled in accordance with institutional and federal regulations. Identifiable information is stored only at the enrolling site. De-identified data are transferred to the Data Coordinating Center for analysis. Dissemination policy Study results will be disseminated through peer-reviewed publications, conference presentations, and engagement with stakeholders including dialysis providers, professional societies, and patient advocacy groups. Authorship will follow International Committee of Medical Journal Editors (ICMJE) guidelines. A lay summary will be prepared for participants and made publicly available. Acknowledgements We gratefully acknowledge the nephrologists and advanced practice providers at the recruitment centers for their engagement, support, and ongoing clinical monitoring of study participants. We also extend our sincere thanks to the dialysis personnel who collaborate with the TwoPlus research team and provide care to patients on hemodialysis enrolled in the study. Additionally, we thank the clinical research coordinators and project managers at each recruitment site for their invaluable contributions to the TwoPlus trial. Author contributions SCG, ASA, and MM conceptualized the manuscript. SCG and MM wrote the first draft of the manuscript. All authors contributed to manuscript drafting or critical revision for intellectual content and approved the final version for submission. Funding The TwoPlus trial is funded by the Patient-Centered Outcomes Research Institute (PCORI), award number CER-2022C1-26300. It has been registered in clinical trials.gov. Clinical trial no: NCT05828823. Registration date: 2023-04-25 Data availability Not applicable. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Ford I, Norrie J: Pragmatic Trials. New England Journal of Medicine 2016, 375(5):454-463. Simon GE, Shortreed SM, Rossom RC, Penfold RB, Sperl-Hillen JAM, O’Connor P: Principles and procedures for data and safety monitoring in pragmatic clinical trials. Trials 2019, 20(1):690. Evans SR: Independent Oversight of Clinical Trials through Data and Safety Monitoring Boards. NEJM Evidence 2022, 1(1):EVIDctw2100005. Curtis LH, Morain S, O'Rourke PP, Staman K, Jarvik JG, Cheville A, Dailey DL, Sluka KA, Heagerty P, Melnick ER et al : Monitoring in pragmatic trials lessons from the NIH pragmatic trials collaboratory. Contemporary Clinical Trials 2025, 152:107866. Murea M, Raimann JG, Divers J, Maute H, Kovach C, Abdel-Rahman EM, Awad AS, Flythe JE, Gautam SC, Niyyar VD et al : Comparative effectiveness of an individualized model of hemodialysis vs conventional hemodialysis: a study protocol for a multicenter randomized controlled trial (the TwoPlus trial). Trials 2024, 25(1):424. Casino DFG, Murea M, Floege MJ, Zoccali C: Incremental dialysis: two complementary views. Clinical Kidney Journal 2024, 17(2). Caton E, Sharma S, Vilar E, Farrington K: Impact of incremental initiation of haemodialysis on mortality: a systematic review and meta-analysis. Nephrology Dialysis Transplantation 2022, 38(2):435-446. Murea M, Torreggiani M, Deira J, Sirich TL, Viecelli AK, Vilar E, Suárez-Santisteban M, Daugirdas JT, Farrington K, Kalantar-Zadeh K et al : From Niche to Norm: A Multi-Action Plan to Close Gaps and Mainstream Incremental Hemodialysis. Kidney Int 2025. Propes C, O’Rourke PP, Morain SR: Recurring and Emerging Ethical Issues in Pragmatic Clinical Trials. Circulation: Cardiovascular Quality and Outcomes 2024, 17(7):e010847. Faden RR, Kass NE, Goodman SN, Pronovost P, Tunis S, Beauchamp TL: An Ethics Framework for a Learning Health Care System: A Departure from Traditional Research Ethics and Clinical Ethics. Hastings Center Report 2013, 43(s1):S16-S27. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 09 Dec, 2025 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 16 Oct, 2025 Reviews received at journal 14 Oct, 2025 Reviews received at journal 13 Oct, 2025 Reviews received at journal 12 Oct, 2025 Reviews received at journal 11 Oct, 2025 Reviewers agreed at journal 07 Oct, 2025 Reviewers agreed at journal 06 Oct, 2025 Reviews received at journal 05 Oct, 2025 Reviewers agreed at journal 04 Oct, 2025 Reviewers agreed at journal 04 Oct, 2025 Reviewers agreed at journal 03 Oct, 2025 Reviews received at journal 03 Oct, 2025 Reviewers agreed at journal 02 Oct, 2025 Reviewers agreed at journal 02 Oct, 2025 Reviewers agreed at journal 01 Oct, 2025 Reviewers agreed at journal 01 Oct, 2025 Reviewers invited by journal 01 Oct, 2025 Editor assigned by journal 26 Sep, 2025 Submission checks completed at journal 26 Sep, 2025 First submitted to journal 24 Sep, 2025 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-7706387","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":529044712,"identity":"141f7006-ab70-4afa-a32c-ee95b035f58b","order_by":0,"name":"Samir C. 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10:33:46","extension":"xml","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":61845,"visible":true,"origin":"","legend":"","description":"","filename":"eddc4bdfca624789b7265f37b91dabdd1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7706387/v1/ed50e57f9ee3563fe532a9da.xml"},{"id":93580898,"identity":"679609eb-33e8-4a5e-bc77-759e31904fd1","added_by":"auto","created_at":"2025-10-15 10:25:46","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":72902,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7706387/v1/c05f3c19bbad67bc3ee59d64.html"},{"id":93580888,"identity":"d37fec1f-a7bb-4041-9061-5ab50c07efed","added_by":"auto","created_at":"2025-10-15 10:25:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58929,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTwoPlus trial schema.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants with new-onset chronic hemodialysis undergo prescreening, informed consent, screening, and randomization to either incremental hemodialysis (n=175) or conventional hemodialysis (n=175). Data collection and patient monitoring include timed urine collections, study-specific blood tests, and adjustments to dialysis prescriptions and medications as clinically indicated by the study team or treating providers.\u003c/p\u003e","description":"","filename":"Figure1TwoPlustrialschema1.png","url":"https://assets-eu.researchsquare.com/files/rs-7706387/v1/38a85bb3a66d3c381be0b6ec.png"},{"id":93581468,"identity":"c027cc69-504a-4a67-a252-fa66adf69b17","added_by":"auto","created_at":"2025-10-15 10:33:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":157293,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eData flow and monitoring in the TwoPlus trial.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical data are collected through a hybrid model combining automated Dialysis Data Downloads (DDD) from dialysis electronic medical records (EMRs), manual abstraction from dialysis and healthcare system EMRs, and centralized data integration at the Data Coordinating Center (DCC). The DCC reconciles data streams, applies quality checks, and generates quarterly computations and summaries—including kidney stdKt/V, dialysis stdKt/V, total stdKt/V, biochemistry, weight management, and intervention adherence—which are then returned to sites in the form of monitoring reports.\u003c/p\u003e","description":"","filename":"Figure2Dataflowandmonitoring1.png","url":"https://assets-eu.researchsquare.com/files/rs-7706387/v1/f8494480ef5bbefff90cec81.png"},{"id":93580907,"identity":"c4ce70d6-dbb3-42b3-8973-2f3c3f5469a4","added_by":"auto","created_at":"2025-10-15 10:25:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":269288,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLayered patient monitoring framework in the TwoPlus trial.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe TwoPlus monitoring framework spans five interconnected domains: provider engagement, human touchpoints, team-based review, digital surveillance, and site-level adaptation. Each domain incorporates specific activities to ensure participant safety, intervention fidelity, and trial feasibility. Examples include treating nephrologist approval and communication with providers (provider engagement); monthly participant check-ins and dialysis staff input (human touchpoints); standardized tracking logs and case discussions at investigators’ meetings (team-based review); EMR-integrated admission–discharge–transfer (ADT) alerts and monitoring of dialysis, volume management, and laboratory metrics (digital surveillance); and tailoring for underserved populations, variable infrastructures, and workflow integration across academic and community practices (site-level adaptation).\u003c/p\u003e","description":"","filename":"Figure3Layeredpatientmonitoringframework1.png","url":"https://assets-eu.researchsquare.com/files/rs-7706387/v1/067ae5f605183c16571cceb2.png"},{"id":93580891,"identity":"703dcc57-5859-4e5c-88c0-f9fe6a4a2814","added_by":"auto","created_at":"2025-10-15 10:25:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":78293,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTraining structure for implementation of the TwoPlus trial.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTraining for TwoPlus was delivered through a stepwise inter- and intra-institutional structure that cascaded across stakeholders. Multi–principal investigators (MPIs) trained local study teams, including site investigators and clinical research coordinators. Local study teams, in turn, trained local treating teams such as faculty attendings, nephrology fellows, and advanced practice practitioners (e.g., nurse practitioners, physician assistants). Finally, local study teams and treating providers provided training and orientation to dialysis staff, including nurses, dietitians, and social workers at participating dialysis centers.\u003c/p\u003e","description":"","filename":"Figure4Trainingstructure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7706387/v1/08e6f20a8fb4661acd77628f.png"},{"id":98245965,"identity":"3c88a6ed-f344-4357-ac11-4a86cd5d486c","added_by":"auto","created_at":"2025-12-15 16:18:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1166676,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7706387/v1/fc8f9181-3026-4974-a3d3-a371c47e37eb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Patient Monitoring in a Pragmatic, Multicenter Trial of Incremental Hemodialysis: Early Experience from the TwoPlus Randomized Controlled Trial","fulltext":[{"header":"Background","content":"\u003cp\u003ePragmatic randomized controlled trials (RCTs) are designed to evaluate interventions under real-world conditions and must operate within routine clinical workflows[1]. This design increases the involvedness of trial operations\u0026mdash;particularly patient monitoring\u0026mdash;because oversight must be integrated into standard care processes rather than layered on top of them[2]. Traditional safety monitoring, which often relies on retrospective reporting of serious adverse events to Institutional Review Boards or Data and Safety Monitoring Committees, may be insufficient in this setting[3]. Beyond traditional oversight, proactive, real-time strategies are required\u0026mdash;especially when the intervention alters foundational aspects of care delivery[4].\u003c/p\u003e\n\u003cp\u003eIn many RCTs, interventions remain fixed after randomization, and safety oversight is narrowly focused on predefined outcomes. By contrast, trials involving emerging interventions that employ existing tools and knowledge and that need to be embedded in routine care require more flexible and layered monitoring frameworks[2]. This adaptability not only enhances participant safety but also supports continuous learning across diverse clinical sites.\u003c/p\u003e\n\u003cp\u003eHere, we describe the operationalization of the monitoring strategy in the TwoPlus trial\u0026mdash;a multicenter pragmatic RCT comparing incremental versus conventional initiation of chronic hemodialysis[5]. \u0026nbsp;The rationale for evaluating incremental hemodialysis versus conventional thrice-weekly initiation has been detailed elsewhere[5]. Briefly, incremental hemodialysis leverages residual kidney function and adjuvant therapies, allowing a gradual transition to full-dose therapy. Tailored to clinical manifestations and residual kidney function, incremental hemodialysis is supported by growing evidence for its potential to improve quality of life, reduce treatment burden, and preserve residual function[6], without compromising clinical safety[7]. However, most prior studies were conducted at institutions where clinicians were already familiar and comfortable with prescribing and monitoring patients on incremental hemodialysis. In routine practice, this approach challenges entrenched norms and relies heavily on the experience and engagement of treating nephrologists and dialysis staff, many of whom are unaccustomed to deviating from the thrice-weekly standard[8]. The current manuscript focuses on the patient monitoring framework of the TwoPlus trial, which has not previously been described in detail, and aims to provide a model for safety oversight in pragmatic nephrology research.\u0026nbsp;\u003c/p\u003e"},{"header":"Participants, Interventions, Outcomes","content":"\u003cp\u003eThe TwoPlus trial is an ongoing multicenter RCT comparing incremental versus conventional initiation of chronic hemodialysis in patients with kidney dysfunction requiring dialysis[5]. Eligibility criteria, recruitment settings, interventions, and outcomes are fully described in the published TwoPlus protocol[5]. In brief, adults initiating chronic hemodialysis who have residual kidney function based on timed urine collection of kidney urea clearance \u0026ge;2.0 mL/min and urine output \u0026ge;500 mL/24 hours, and who meet other clinical eligibility criteria, are randomized across multiple academic and community dialysis units to either incremental hemodialysis or conventional thrice-weekly initiation (\u003cstrong\u003eFigure 1\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants randomized to the intervention group of incremental hemodialysis are treated with twice-weekly hemodialysis supported by adjuvant oral medications (diuretics, potassium binders and sodium bicarbonate if needed) and progress to thrice-weekly treatment when clinically indicated. The primary outcome is a composite of all-cause death, hospitalization, or emergency department visits, with secondary outcomes including residual kidney function and treatment adherence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Size and Statistical Considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe planned sample size is 350 patient participants. The primary analysis will follow the intention-to-treat principle. The primary outcome\u0026mdash;a composite of all-cause death, hospitalization, or emergency department visits\u0026mdash;will be compared between study arms using time-to-event methods. Recurrent event models will be used for secondary analyses. Additional outcomes, including preservation of residual kidney function and treatment adherence, will be analyzed using mixed-effects and survival models, as appropriate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Collection, Management, and Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical data in TwoPlus are collected through a hybrid model that combines automated downloads from dialysis electronic medical records (EMRs) with complementary manual data entry. Electronic dialysis data downloads (DDDs) are generated at participating dialysis organizations and transmitted on a standardized format and schedule to the Data Coordinating Center (DCC) (\u003cstrong\u003eFigure 2\u003c/strong\u003e). When direct electronic extraction from dialysis EMR is not feasible, equivalent data are abstracted through structured dialysis EMR review and entered manually into the centralized TwoPlus database. Both electronic and manual streams capture treatment-level information from each dialysis session, including prescription details, vital signs, interdialytic weights, ultrafiltration volume, and delivered Kt/V.\u003c/p\u003e\n\u003cp\u003eTo supplement treatment-level metrics, clinical research coordinators abstract data from non-dialysis healthcare institutions\u0026rsquo; EMR, including emergency department visits, hospitalizations, and other adverse events. Patient-reported outcomes are also obtained through structured in-person or virtual assessments at regular study visits. This dual approach ensures that the monitoring framework incorporates both objective clinical parameters and contextual patient information.\u003c/p\u003e\n\u003cp\u003eAll data streams feed into a secure, web-based system managed by the DCC (\u003cstrong\u003eFigure 2\u003c/strong\u003e). The DCC reconciles incoming DDDs and manual entries against expected participant lists, generates automated alerts for discrepancies, and ingests validated datasets into the central repository. Logic and range checks are applied at the point of entry to enhance data quality. Curated participant-level summaries\u0026mdash;including residual kidney function, dialysis stdKt/V, kidney stdKt/V, total stdKt/V, and routine laboratory values\u0026mdash;are produced quarterly and returned to sites to support ongoing monitoring and intervention fidelity. Access is role-restricted, and all transmissions are encrypted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient Monitoring in the TwoPlus Trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDrawing on best practices from prior pragmatic trials[2], the TwoPlus monitoring framework integrates electronic health records, human-centered follow-up, and team-based decision-making to support safe implementation of an emerging intervention across varied practice settings. Monitoring in TwoPlus extends beyond detecting adverse events. It is designed to:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eIdentify early signs of clinical instability.\u003c/li\u003e\n \u003cli\u003eSupport adjustments to the dialysis prescription.\u003c/li\u003e\n \u003cli\u003eAssess adherence to treatment assignment.\u003c/li\u003e\n \u003cli\u003eProvide guidance and reassurance to treating providers.\u003c/li\u003e\n \u003cli\u003eSafeguard trial equipoise across diverse practice settings.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThese goals require that providers remain well-informed and supported, and that study teams maintain close, ongoing collaboration with treating nephrologists and dialysis unit staff. As illustrated in \u003cstrong\u003eFigure 3\u003c/strong\u003e, patient monitoring in TwoPlus spans five interconnected domains:\u003c/p\u003e\n\u003cp\u003ea) Provider engagement \u0026mdash; active involvement of treating nephrologists to confirm eligibility, approve randomization, and maintain ongoing communication about clinical status.\u003c/p\u003e\n\u003cp\u003eb) Human touchpoints \u0026mdash; monthly participant check-ins, informal communication with dialysis staff, and structured tracking logs that provide context beyond electronic data.\u003c/p\u003e\n\u003cp\u003ec) Team-based review \u0026mdash; structured meetings at the site and investigator level where clinical research coordinators and investigators assess longitudinal data, discuss cases, and recommend adjustments in treatment or monitoring.\u003c/p\u003e\n\u003cp\u003ed) Digital surveillance \u0026mdash; near real-time monitoring through dialysis EMR downloads, Admission-Discharge-Transfer (ADT) alerts, and interoperability with regional health information exchanges, integrated with quarterly reports from the Data Coordinating Center.\u003c/p\u003e\n\u003cp\u003ee) Site-level adaptation \u0026mdash; tailoring implementation to local infrastructures, workflows, and patient populations, including cultural and language considerations, to ensure feasibility and fidelity across diverse care environments.\u003c/p\u003e\n\u003cp\u003eThe following sections describe how these principles have been operationalized across participating TwoPlus sites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eProvider Engagement\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn pragmatic trials, provider engagement functions as both a safety mechanism and a key determinant of adherence to the trial protocol[9]. In TwoPlus, the treating nephrologist is often not a study investigator. Successful implementation of the intervention\u0026mdash;and protection of participant safety\u0026mdash;therefore depends heavily on the engagement and support of non-research clinicians. Positioning providers as partners, rather than passive recipients of study protocols, was critical to enhancing both intervention safety and fidelity\u0026mdash;an approach previously advocated for pragmatic trials[10]. To address the limited prior experience with incremental hemodialysis among many treating nephrologists and dialysis staff, structured training sessions were conducted at each site before recruitment began (\u003cstrong\u003eFigure 4\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAll patients initiating chronic hemodialysis at participating centers are prescreened for eligibility with input and approval from the treating nephrologist to confirm appropriateness for incremental therapy\u0026mdash;for example, adequate volume status and the ability to follow dynamic medical instructions. At randomization, treating providers are notified of the assigned study arm, and for participants randomized to the incremental arm, this communication emphasizes the need for closer monitoring and offers an opportunity to raise safety concerns.\u003c/p\u003e\n\u003cp\u003eTo sustain engagement, study teams maintain regular communication with providers throughout follow-up. Some sites use recurring email updates or designate liaisons to ensure timely information flow, while others involve study-affiliated nephrologists as consultants when dialysis staff express discomfort with non-standard schedules. These arrangements provide peer-to-peer support and reinforce decision-making while respecting provider autonomy.\u003c/p\u003e\n\u003cp\u003eIn some cases, coverage providers unfamiliar with the trial temporarily overruled randomization assignments or delayed intervention implementation. Such episodes underscored the importance of continuous communication and rapid clarification. Ultimately, consistent provider engagement has improved protocol adherence, facilitated timely treatment adjustments, and supported the safe delivery of incremental hemodialysis across diverse dialysis settings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHuman Touchpoints\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDigital systems alone cannot ensure participant safety in a pragmatic trial.. Human touchpoints\u0026mdash;structured, intentional interactions between study staff, participants, and dialysis teams\u0026mdash;are essential to gather insights into participant experiences and clinical changes that are not consistently documented in electronic records.\u003c/p\u003e\n\u003cp\u003eAt all sites, trained clinical research coordinators conduct monthly in-person with patient participants. These checkpoints use a conversational approach, asking open-ended questions such as \u0026ldquo;How are you feeling?\u0026rdquo; or \u0026ldquo;Have you been to the hospital since we last spoke?\u0026rdquo; These touchpoints uncover issues that may not be evident in the medical record\u0026mdash;such as fluid imbalance, missed treatments, or medication changes\u0026mdash;and foster rapport, which supports retention and adherence.\u003c/p\u003e\n\u003cp\u003eIndividual sites also maintain internal tracking logs for participants in the incremental arm. These typically include treatment dates, prescribed and achieved weights, blood pressures, and medication adjustments. Study teams review these logs regularly\u0026mdash;often weekly or biweekly\u0026mdash;during structured meetings involving the site investigator and clinical research coordinator. This facilitates early recognition of clinical drift, such as rising interdialytic weight gains or unexplained weight adjustments.\u003c/p\u003e\n\u003cp\u003eInformal communication with dialysis staff further enhances monitoring. Nurse managers and front-line dialysis staff frequently notify the study team about missed treatments, evolving symptoms, or social barriers. In some cases, treating nephrologists initiate discussions about patient eligibility or reassess suitability for continued participation in the incremental arm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTeam-Based Decision-Making\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDecisions to maintain or escalate dialysis frequency in TwoPlus are informed by structured, collaborative reviews that integrate both clinical context and laboratory data.\u003c/p\u003e\n\u003cp\u003eAt each site, assessments are conducted by clinical research coordinators or investigators and reported to the site principal investigator. These reviews occur weekly or biweekly and focus on key indicators such as interdialytic weight gain, dry weight changes, blood pressure patterns, diuretic use, hospitalizations, and relevant laboratory results. Many sites employ pre-populated tracking templates to visualize longitudinal trends, enabling early recognition of clinical drift or emerging safety concerns.\u003c/p\u003e\n\u003cp\u003eIn some instances, treating providers identified clinical instability and adjusted dialysis prescriptions before the study team\u0026rsquo;s scheduled review. In these cases, the study team documented the rationale, confirmed alignment with trial protocol, and incorporated the adjustment into ongoing monitoring. In other instances, findings from site-level reviews were communicated to treating providers along with recommendations to maintain the current regimen or to adjust diuretics, potassium binders, sodium bicarbonate dosing, target weight, or dialysis frequency. Final prescribing decisions always rested with the treating providers, ensuring that adjustments reflected both clinical judgment and trial objectives.\u003c/p\u003e\n\u003cp\u003eCross-site learning was promoted through biweekly investigator meetings, where teams presented cases, shared challenges, and exchanged solutions. These peer discussions fostered consistency in protocol implementation while allowing flexibility to adapt to local clinical environments. Collectively, this multi-level review process supported treatment decisions that were patient-centered, evidence-informed, and faithful to the intent of the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDigital Infrastructure and Surveillance\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEMR systems form the backbone of safety monitoring in the TwoPlus trial. Participating sites implemented automated tools to capture dialysis session data and clinical events in near real-time, ensuring close alignment between study monitoring and routine clinical care.\u003c/p\u003e\n\u003cp\u003eA key element is the deployment of research-specific ADT alerts within institutional EMRs. These alerts notify study teams of hospitalizations or emergency department visits involving enrolled participants and prompt chart review and documentation of adverse events. Several sites enhanced surveillance further by leveraging interoperability with regional EMR networks\u0026mdash;such as CRISP and EPIC\u0026rsquo;s CareEverywhere\u0026mdash;to capture events occurring outside their home health systems. This cross-institutional visibility strengthened monitoring in regions with fragmented care networks.\u003c/p\u003e\n\u003cp\u003eWhen safety events were identified, responses could be initiated either by treating providers\u0026mdash;who sometimes adjusted dialysis prescriptions immediately\u0026mdash;or by the study team following review of alert data. In both cases, the study team documented the event, verified consistency with trial protocol, and integrated the information into ongoing monitoring.\u003c/p\u003e\n\u003cp\u003eAt the coordinating level, the DCC supports oversight by generating quarterly participant-level reports. These reports summarize key metrics including residual kidney function, dialysis stdKt/V, kidney stdKt/V, total stdKt/V, volume management parameters, and routine laboratory values. Investigators use these reports to obtain a high-level overview of each participant\u0026rsquo;s trajectory, allowing for early recognition of concerning trends and for timely discussions with treating providers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSite-Specific Adaptations\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough all sites follow a unified TwoPlus protocol, implementation required local adaptations to maintain safety, support provider engagement, and ensure fidelity in diverse clinical environments. These differences reflected variability in institutional infrastructure, dialysis organization, geography, and patient populations. While most participating sites are embedded within academic medical centers, several involve collaborations with private nephrology practices which will enhance the relevance and generalizability of TwoPlus findings across real-world settings.\u003c/p\u003e\n\u003cp\u003eAt many sites, study activities follow highly structured workflows. Digital tools, physician-led consent, and weekly team reviews are coordinated through centralized tracking systems. One or more clinical research coordinators visit dialysis units in person, and physician investigators are actively engaged across all phases\u0026mdash;from prescreening and consent to ongoing patient monitoring.\u003c/p\u003e\n\u003cp\u003eSome sites faced distinct challenges, including caring for largely underserved populations, high proportions of patients with limited English proficiency, and many participants with undocumented status. In these settings, frequent communication with treating providers, close collaboration with social work and pharmacy teams, and flexible approaches to medication access and transportation were critical to increase recruitment and sustain intervention adherence.\u003c/p\u003e\n\u003cp\u003eOperational challenges also influenced study conduct. At some sites, dialysis centers experienced temporary holds on onboarding new patients due to staffing shortages. In other instances, the addition of new dialysis centers was required\u0026mdash;and is anticipated to remain a recurring need\u0026mdash;depending on local operational workflows and recruitment rates.\u003c/p\u003e\n\u003cp\u003eAcross all sites, strong rapport with dialysis staff has proved critical. Dialysis nurses frequently act as informal liaisons, alerting the study team to clinical instability or emerging concerns. At certain sites, medical directors have served as study champions, reinforcing awareness and engagement across dialysis unit personnel. In others, close coordination between investigators and treating nephrologists on sharing kidney clearance results\u0026mdash;including dialysis and kidney stdKt/V calculations\u0026mdash;to inform hemodialysis prescriptions in the incremental arm.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe TwoPlus trial offers a unique opportunity to evaluate incremental hemodialysis in a pragmatic, multicenter setting, and the monitoring framework described here is central to its safe implementation. Unlike conventional efficacy trials, pragmatic designs require oversight systems that are embedded within routine workflows and adaptable to diverse care environments. Our experience highlights several principles that may be relevant to future pragmatic nephrology trials.\u003c/p\u003e\n\u003cp\u003eFirst, provider engagement emerged as both a safeguard and a determinant of protocol fidelity. Active communication with treating nephrologists and dialysis staff supported adherence and facilitated timely adjustments, whereas lapses in engagement led to delays or protocol drift. Embedding provider engagement as a core element of monitoring may therefore improve both safety and intervention delivery.\u003c/p\u003e\n\u003cp\u003eSecond, the integration of digital and human monitoring touchpoints provided complementary strengths. Automated dialysis data downloads allowed for near real-time tracking of treatment-level variables, while manual data entry and structured patient check-ins collects adverse events and patient concerns not always captured in the dialysis EMRs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThird, team-based decision-making and site-specific adaptations proved essential in translating the protocol into varied practice settings. Structured case reviews, cross-site investigator meetings, and informal communication channels created a learning network that promoted consistency while allowing flexibility to accommodate local contexts. This adaptability may be particularly important for emerging interventions that challenge established norms of dialysis delivery.\u003c/p\u003e\n\u003cp\u003eDespite these strengths, several challenges warrant consideration. The monitoring framework depends on the quality and completeness of electronic health record data, which may vary across institutions. Manual data entry, while critical for capturing contextual information, increases workload and may introduce variability in documentation. Finally, the TwoPlus trial is conducted within academic and partnered community settings, and further work will be needed to assess the scalability of this monitoring approach in other dialysis environments.\u003c/p\u003e\n\u003cp\u003eIn summary, the TwoPlus monitoring strategy balances safety, feasibility, and fidelity through a layered approach that combines digital infrastructure with human-centered oversight. By embedding provider engagement and site-specific adaptations, this model may guide the design of future pragmatic nephrology trials testing real-world implementation of emerging interventions.\u003c/p\u003e"},{"header":"Trial Status","content":"\u003cp\u003eRecruitment for the TwoPlus trial began in January 2024 and was initiated in a staggered fashion across participating sites over the subsequent months. As of September 2025, enrollment and randomization remain ongoing at academic and community dialysis units throughout the United States.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics and Dissemination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The TwoPlus trial and this monitoring protocol have been approved by the Institutional Review Boards (IRBs) of all participating institutions. Written informed consent is obtained from all participants prior to enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;All data are handled in accordance with institutional and federal regulations. Identifiable information is stored only at the enrolling site. De-identified data are transferred to the Data Coordinating Center for analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination policy\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Study results will be disseminated through peer-reviewed publications, conference presentations, and engagement with stakeholders including dialysis providers, professional societies, and patient advocacy groups. Authorship will follow International Committee of Medical Journal Editors (ICMJE) guidelines. A lay summary will be prepared for participants and made publicly available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe gratefully acknowledge the nephrologists and advanced practice providers at the recruitment centers for their engagement, support, and ongoing clinical monitoring of study participants. We also extend our sincere thanks to the dialysis personnel who collaborate with the TwoPlus research team and provide care to patients on hemodialysis enrolled in the study. Additionally, we thank the clinical research coordinators and project managers at each recruitment site for their invaluable contributions to the TwoPlus trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSCG, ASA, and MM conceptualized the manuscript. SCG and MM wrote the first draft of the manuscript. All authors contributed to manuscript drafting or critical revision for intellectual content and approved the final version for submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe TwoPlus trial is funded by the Patient-Centered Outcomes Research Institute (PCORI), award number CER-2022C1-26300.\u003c/p\u003e\n\u003cp\u003eIt has been registered in clinical trials.gov. Clinical trial no:\u0026nbsp;NCT05828823. Registration date: 2023-04-25\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFord I, Norrie J: Pragmatic Trials. \u003cem\u003eNew England Journal of Medicine \u003c/em\u003e2016, 375(5):454-463.\u003c/li\u003e\n\u003cli\u003eSimon GE, Shortreed SM, Rossom RC, Penfold RB, Sperl-Hillen JAM, O\u0026rsquo;Connor P: Principles and procedures for data and safety monitoring in pragmatic clinical trials. \u003cem\u003eTrials \u003c/em\u003e2019, 20(1):690.\u003c/li\u003e\n\u003cli\u003eEvans SR: Independent Oversight of Clinical Trials through Data and Safety Monitoring Boards. \u003cem\u003eNEJM Evidence \u003c/em\u003e2022, 1(1):EVIDctw2100005.\u003c/li\u003e\n\u003cli\u003eCurtis LH, Morain S, O\u0026apos;Rourke PP, Staman K, Jarvik JG, Cheville A, Dailey DL, Sluka KA, Heagerty P, Melnick ER\u003cem\u003e et al\u003c/em\u003e: Monitoring in pragmatic trials lessons from the NIH pragmatic trials collaboratory. \u003cem\u003eContemporary Clinical Trials \u003c/em\u003e2025, 152:107866.\u003c/li\u003e\n\u003cli\u003eMurea M, Raimann JG, Divers J, Maute H, Kovach C, Abdel-Rahman EM, Awad AS, Flythe JE, Gautam SC, Niyyar VD\u003cem\u003e et al\u003c/em\u003e: Comparative effectiveness of an individualized model of hemodialysis vs conventional hemodialysis: a study protocol for a multicenter randomized controlled trial (the TwoPlus trial). \u003cem\u003eTrials \u003c/em\u003e2024, 25(1):424.\u003c/li\u003e\n\u003cli\u003eCasino DFG, Murea M, Floege MJ, Zoccali C: Incremental dialysis: two complementary views. \u003cem\u003eClinical Kidney Journal \u003c/em\u003e2024, 17(2).\u003c/li\u003e\n\u003cli\u003eCaton E, Sharma S, Vilar E, Farrington K: Impact of incremental initiation of haemodialysis on mortality: a systematic review and meta-analysis. \u003cem\u003eNephrology Dialysis Transplantation \u003c/em\u003e2022, 38(2):435-446.\u003c/li\u003e\n\u003cli\u003eMurea M, Torreggiani M, Deira J, Sirich TL, Viecelli AK, Vilar E, Su\u0026aacute;rez-Santisteban M, Daugirdas JT, Farrington K, Kalantar-Zadeh K\u003cem\u003e et al\u003c/em\u003e: From Niche to Norm: A Multi-Action Plan to Close Gaps and Mainstream Incremental Hemodialysis. \u003cem\u003eKidney Int \u003c/em\u003e2025.\u003c/li\u003e\n\u003cli\u003ePropes C, O\u0026rsquo;Rourke PP, Morain SR: Recurring and Emerging Ethical Issues in Pragmatic Clinical Trials. \u003cem\u003eCirculation: Cardiovascular Quality and Outcomes \u003c/em\u003e2024, 17(7):e010847.\u003c/li\u003e\n\u003cli\u003eFaden RR, Kass NE, Goodman SN, Pronovost P, Tunis S, Beauchamp TL: An Ethics Framework for a Learning Health Care System: A Departure from Traditional Research Ethics and Clinical Ethics. \u003cem\u003eHastings Center Report \u003c/em\u003e2013, 43(s1):S16-S27.\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"hemodialysis, incremental, monitoring, pragmatic, randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-7706387/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7706387/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePragmatic randomized controlled trials (RCTs) must be embedded within routine clinical workflows, which requires monitoring strategies that are feasible in everyday practice. Incremental hemodialysis—initiating treatment twice weekly in patients with preserved residual kidney function and escalating frequency as needed—differs from conventional thrice-weekly initiation. Implementing this approach in a pragmatic trial among providers and dialysis staff unfamiliar with incremental dialysis necessitated additional preparation and oversight. The TwoPlus trial is a multicenter pragmatic RCT evaluating incremental versus conventional initiation of chronic hemodialysis. We describe the patient monitoring framework developed for TwoPlus, which integrates digital infrastructure, human touchpoints, and provider engagement to ensure participant safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods/Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwoPlus is an ongoing multicenter RCT enrolling adults initiating chronic hemodialysis with residual kidney function (urine urea clearance ≥2.0 mL/min and urine output ≥500 mL/24 hours). Participants are randomized to incremental hemodialysis—twice-weekly treatment supported by diuretics and sodium bicarbonate, with transition to thrice-weekly as clinically indicated—or conventional thrice-weekly initiation. The primary outcome is a composite of all-cause death, hospitalization, or emergency department visits. Secondary outcomes include preservation of residual kidney function and treatment adherence. The monitoring framework combines automated dialysis data downloads, manual data abstraction, assessments conducted by investigators or clinical research coordinators and reviewed at the site level, structured team reviews, and regular communication with treating providers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis layered monitoring model balances feasibility, safety, and fidelity in a pragmatic trial where provider engagement and site-specific adaptation were essential. The monitoring approach adopted in TwoPlus will inform the design of monitoring frameworks for future pragmatic nephrology trials.\u003c/p\u003e\n\u003cp\u003eTrial registration: NCT05828823\u003c/p\u003e","manuscriptTitle":"Patient Monitoring in a Pragmatic, Multicenter Trial of Incremental Hemodialysis: Early Experience from the TwoPlus Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-15 10:25:41","doi":"10.21203/rs.3.rs-7706387/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-16T14:01:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-14T19:00:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-13T19:40:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-12T20:05:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-11T22:16:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37768678998587456560474498738871747013","date":"2025-10-07T08:16:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"293299954929543445436692679192491858501","date":"2025-10-06T18:29:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-05T04:16:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"124818529643067836743847484905994852602","date":"2025-10-04T15:12:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"49306071617457402035944488468905605826","date":"2025-10-04T13:56:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"59343075018180133178899275580686250097","date":"2025-10-03T19:04:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-03T09:01:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"48437290366401477066858771204373017188","date":"2025-10-02T07:13:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3731704248027039935099344258984958950","date":"2025-10-02T07:06:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"81024747269549749018063429302205298929","date":"2025-10-01T19:53:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"254994258846347164652304543659616145813","date":"2025-10-01T18:25:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-01T18:20:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-26T12:43:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-26T12:42:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-09-24T18:30:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"585ae4a1-c0ce-45e2-ad81-1b5d2bfd8297","owner":[],"postedDate":"October 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-15T16:17:11+00:00","versionOfRecord":{"articleIdentity":"rs-7706387","link":"https://doi.org/10.1186/s12882-025-04659-2","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2025-12-09 15:59:18","publishedOnDateReadable":"December 9th, 2025"},"versionCreatedAt":"2025-10-15 10:25:41","video":"","vorDoi":"10.1186/s12882-025-04659-2","vorDoiUrl":"https://doi.org/10.1186/s12882-025-04659-2","workflowStages":[]},"version":"v1","identity":"rs-7706387","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7706387","identity":"rs-7706387","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}