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Published in final edited form as: Contemp Clin Trials. 2026 Mar 13;164:108284. doi: 10.1016/j.cct.2026.108284 Search in PMC Search in PubMed View in NLM Catalog Add to search A study within a trial evaluating supplemental, reinforced risk-based training to reduce implementation barriers in a pediatric multicenter randomized controlled trial Danielle J Green Danielle J Green a Department of Pediatrics, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, United States of America Find articles by Danielle J Green a, * , Valeriya Vasenina Valeriya Vasenina b Spencer Fox Eccles School of Medicine, University of Utah, 30 N 1900 E, Salt Lake City, UT 84132, United States of America Find articles by Valeriya Vasenina b , Kelsee Meyerhoffer Kelsee Meyerhoffer a Department of Pediatrics, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, United States of America Find articles by Kelsee Meyerhoffer a , Russell K Banks Russell K Banks a Department of Pediatrics, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, United States of America Find articles by Russell K Banks a , Mark W Hall Mark W Hall c Department of Pediatrics, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, United States of America Find articles by Mark W Hall c , Athena F Zuppa Athena F Zuppa d Department of Anesthesiology and Critical Care, Children’s Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, United States of America Find articles by Athena F Zuppa d , Kevin M Watt Kevin M Watt a Department of Pediatrics, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, United States of America Find articles by Kevin M Watt a , Natalie Dilts Natalie Dilts e Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, 2525 West End Ave, Nashville, TN 37203, United States of America Find articles by Natalie Dilts e , John M VanBuren John M VanBuren a Department of Pediatrics, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, United States of America Find articles by John M VanBuren a , on behalf of the Eunice Kenedy Shriver National Institute for Child Health and Development’s Collaborative Pediatric Critical Care Research Network Author information Article notes Copyright and License information a Department of Pediatrics, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, United States of America b Spencer Fox Eccles School of Medicine, University of Utah, 30 N 1900 E, Salt Lake City, UT 84132, United States of America c Department of Pediatrics, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, United States of America d Department of Anesthesiology and Critical Care, Children’s Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, United States of America e Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, 2525 West End Ave, Nashville, TN 37203, United States of America * Corresponding author at: 295 Chipeta Way, Ste 10, Salt Lake City, UT 84108, United States of America. [email protected] (D.J. Green). Issue date 2026 May. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). PMC Copyright notice PMCID: PMC13075650 NIHMSID: NIHMS2160398 PMID: 41833775 The publisher's version of this article is available at Contemp Clin Trials Abstract Background: High-quality conduct of clinical trials depends on strict adherence to both regulatory protocols and trial-specific procedures to ensure data integrity and participant safety. Standard methods utilized to train research staff have limitations, including lack of specificity and declining impact over time. We developed a Supplemental, Reinforced, Risk-Based Training (SRRBT) program, designed to target study-specific challenges and provide ongoing reinforcement. Our objective was to evaluate whether SRRBT improves protocol adherence. Methods: SRRBT was executed as a cluster-randomized, educational implementation study embedded in a multicenter clinical trial. We compared standard training with and without the addition of SRRBT across 23 clinical sites. SRRBT consisted of five interactive electronic vignettes focusing on trial-specific competencies. The primary outcome was the proportion of eligible participants approached for study participation. Secondary outcomes included consent and enrollment rates, protocol deviations, and completeness of study documentation. Results: Approach rates immediately following training trended higher at SRRBT sites compared to those receiving standard training alone (OR = 3.98, 95% CI [0.87, 18.17], p = 0.074); however, this difference was not statistically significant and attenuated over time, with odds ratios of 2.24 (95% CI [0.78, 6.49], p = 0.14) at six months and 1.38 (95% CI [0.53, 3.59], p = 0.51) at 12 months post-training. Conclusions: SRRBT shows potential in enhancing early site-level protocol adherence but may require ongoing reinforcement to sustain benefits over time. This study highlights the need for continuous, adaptive training approaches in complex clinical trials to maintain high standards of protocol adherence. Keywords: Clinical trials, Study within a trial, Reinforced protocol training, Training metrics, Scenario-based education, Implementation science 1. Introduction Clinical trials are essential for advancing medical therapeutics and require rigorous adherence to both Good Clinical Practice (GCP) and study-specific protocols to ensure the validity of trial results and the safety of participants. General GCP training, mandated by the International Council for Harmonisation (ICH E6 (R3)), provides a foundational training framework [ 1 ]. However, traditional GCP training, typically characterized by a static, “one-size-fits-all” approach, often fails to meet the complex and specific requirements of large-scale clinical studies [ 2 – 6 ]. As a result, protocol-specific training is routinely implemented at the onset of major clinical trials to ensure that all study personnel are informed in the trial-specific procedures and regulations. This tailored training is crucial, as it supplements the broad teachings of GCP with detailed, study-specific information. Despite the comprehensive nature of these initial training sessions, their sustained effectiveness over the duration of a trial has been questioned [ 7 ]. The Clinical Trials Transformation Initiative (CTTI) has specifically acknowledged the limitations in both standard GCP training (e.g. lack of specificity) and protocol-specific training (e.g. insufficient reinforcement over time). Through its Investigator Qualification Project, the CTTI has emphasized the necessity for ongoing, adaptive training methods that extend beyond the initial implementation of the trial [ 7 – 11 ]. Parallel to the evolution in training approaches, the landscape of clinical trial monitoring has also undergone significant changes. In response to the rising cost of trials and the need to prioritize monitoring efforts on critical study elements, clinical trial monitoring has evolved from traditional 100% source data monitoring to more adaptive risk-based monitoring methods [ 12 ]. Risk-based monitoring is more dynamic than traditional monitoring and allows for the continuous adjustment of monitoring priorities based on real-time data and newly recognized risks. This approach not only enhances patient safety and trial integrity but also optimizes resource utilization [ 13 ]. In alignment with the trend toward risk-based monitoring as well as the CTTI’s recommendations for ongoing adaptive training methods, we developed a Supplemental, Reinforced, Risk-Based Training (SRRBT) program. SRRBT was designed to reinforce trial-specific competencies through ongoing, scenario-based educational interventions targeting critical implementation challenges. The primary objective of this study was to evaluate whether SRRBT, when added to standard training, improves protocol adherence, reduces protocol deviations, and enhances participant recruitment in a multicenter clinical trial. This Study Within A Trial (SWAT) was embedded in the PRECISE trial and tested whether targeted, risk-based training could address study-specific vulnerabilities and improve protocol adherence. 2. Methods 2.1. Clinical trial overview This implementation sub-study was embedded in the PeRsonalizEd immunomodulation in pediatriC sepsIS-inducEd MODS (PRECISE; NCT05266001 , NCT05267821 ) trial implementation training. The details of the PRECISE trial design are described elsewhere [ 14 ]. Briefly, PRECISE is a multicenter clinical trial that consists of two independent “nested” randomized, double-blind, placebo-controlled clinical trials. Using real-time immune testing, children with sepsis-induced multiple organ dysfunction syndrome (MODS) are immunophenotyped and randomized to receive a phenotype-specific immunomodulatory therapy or placebo. PRECISE is currently being conducted within the Collaborative Pediatric Critical Care Research Network (CPCCRN) at 26 clinical sites, however, this SWAT was conducted at the 23 sites actively enrolling during the first two years of the trial. 2.2. Study design The SRRBT program was designed as a cluster-randomized, parallel-group, educational implementation SWAT to evaluate the impact of SRRBT on protocol fidelity. The SRRBT sub-study was pre-specified at trial launch as part of an implementation science strategy to evaluate training approaches. Sites were informed that embedded evaluations would be conducted, participation in SRRBT training was voluntary, and responses would not be linked to job performance evaluations or site certification. All 23 sites completed standard training; eleven were randomized to receive SRRBT in addition to standard training. Randomization was conducted using a computer-generated sequence by the Utah Data Coordinating Center. Allocation was not concealed, and blinding was not feasible due to the nature of the intervention. Data were collected at 23 CPCCRN-affiliated pediatric intensive care units across the United States. No changes to study methods were made after trial initiation. 2.3. Standard training Study personnel from all 23 PRECISE sites completed standard training which was didactic-based and conducted via: 1) an in-person, three-day Steering Committee Meeting, 2) role-specific electronic learning modules, and 3) a one-day, on-site, site-initiation visit. The Steering Committee Meeting marked the formal study kickoff and introduction of the standard training curriculum. Training included detailed walkthroughs of eligibility determination, data collection, biospecimen collection and shipping, drug administration, and safety monitoring procedures. To accommodate those unable to attend live, all sessions were recorded and converted into modular eLearning content. Role-specific electronic modules covered REDCap Cloud navigation, workflow logistics, study protocol elements, biospecimen handling, adverse event reporting, and MODS classification. Modules were assigned by job role and did not include quizzes. The site-initiation visit included additional protocol review and hands-on training with specimen processing. Attendance at the Steering Committee Meeting and completion of the electronic modules were required for site activation, though attendance at the Steering Committee Meeting was not mandatory for all staff. All sites retained access to standard protocol-specific training materials for optional, on-demand review. Protocol clarification was also provided through monthly coordinator calls and ad hoc email correspondence. Optional refresher training was offered at the time of site startup, particularly for sites with longer delays between the Steering Committee Meeting and site activation. 2.4. SRRBT development SRRBT was developed in collaboration with the Recruitment Innovation Center (RIC) at Vanderbilt University Medical Center. The RIC is part of the National Center for Advancing Translational Sciences funded Trial Innovation Network. The SRRBT vignettes were created in Research Electronic Data Capture (REDCap) [ 15 , 16 ] using an interactive, “Choose Your Own Adventure” training module template developed by the RIC. The use of REDCap was preferred, as it is a freely available, secure, web-based platform with advanced features including branching logic, customizable question types, photo upload capability, and robust data management features, giving researchers the flexibility to easily create and distribute complex surveys, collect data efficiently, and ensure data integrity across multiple sites. To enhance engagement with the training modules, vignettes included photos of diverse staff interacting with participants, utilized inclusive language representative of different ethnicities and genders, and were written in the first-person. SRRBT consisted of five interactive electronic vignettes, each designed to address a specific study-related challenge identified during the early phases of PRECISE enrollment. The content of each vignette was informed by site-reported uncertainties and common questions raised during the Steering Committee Meeting and/or monthly research coordinator calls. Each vignette took approximately 2 h to develop and was constructed by a multidisciplinary team that included a PRECISE co-investigator (MD) and the trial’s operational leader (RN). Vignettes were designed to take approximately five minutes to complete. Each vignette consisted of five multiple-choice questions and followed a “choose-your-own-adventure” format. All participants received the same five questions, but the sequence in which questions were presented, as well as the accompanying narrative feedback, varied based on their responses. If a respondent answered a question correctly, the next question was delivered along a “correct answer” logic path. If answered incorrectly, the vignette branched to an educational explanation followed by the next question via an “incorrect answer” logic path. Scores for each vignette ranged from 0 to 5. An example screenshot of SRRBT content, including two vignette questions with feedback, is presented in Fig. 1 to illustrate the format, tone, and educational structure of the training modules. Full vignette content is available in Supplementary File 1 ( Supplementary Tables 1 – 5 ). Briefly, the topics addressed in the vignettes are as follows: Fig. 1. Open in a new tab Supplemental, reinforced, risk-based training scenario designed to emphasize study-specific eligibility criteria. Vignette 1: Participant Eligibility, MODS Day Classification, and Consent/Assent Procedures Vignette 2: Blood Sampling and Study Drug Administration Vignette 3: Randomization, Study Drug Dose Adjustment, Protocol Deviations, and Follow-up Timing Vignette 4: Participant Withdrawal and Protocol Amendments Vignette 5: Data Entry Procedures and REDCap Best Practices The vignettes were designed to cover distinct, independent protocol domains and were not delivered in increasing complexity or intended to be completed in a specific sequence. Thus, earlier vignette completion was not a prerequisite for later vignette participation, and scores were not expected to follow a cumulative learning trajectory. These modules were designed not as assessments of individual respondent competency, but as targeted educational interventions focused on reinforcing protocol fidelity in areas identified as high-risk or error-prone during early implementation. 2.5. SRRBT delivery REDCap survey links to the vignettes were distributed via email to site PIs, co-investigators, and study coordinators. All sites randomized to the SRRBT arm received access to all five SRRBT vignettes. Completion was voluntary, asynchronous, and tracked at the site level. Training could be completed individually or collaboratively within a site. Formal retraining on SRRBT content was not conducted, regardless of site engagement with vignettes. 2.6. Timeline The Steering Committee Meeting was held June 7–9, 2022. PRECISE enrollment began on June 8, 2022. All 23 sites were activated between June 8, 2022, and May 2, 2023. SRRBT vignettes were delivered on a fixed schedule at four week intervals between October 31, 2022, and February 15, 2023, irrespective of individual site activation dates. Uptake of training materials occurred pragmatically and was not enforced by protocol. As a result, the interval between site activation and SRRBT exposure varied across sites. Of the 11 SRRBT sites, seven were activated prior to initiation of the vignette series, three were activated during the vignette delivery period, and one site was activated after delivery of all vignettes ( Supplementary Table 6 ). Ten sites received optional refresher training prior to activation. The SRRBT SWAT concluded per protocol in February 2023. 2.7. Outcomes and operational definitions The primary outcome of this SWAT was the proportion of PRECISE-eligible participants who were approached for study participation. Secondary outcomes included consent and enrollment rates, frequency and severity of protocol deviations, completeness of required participant surveys, and completeness of daily study data collection forms. A protocol deviation was defined as any departure from the approved PRECISE protocol recorded in the trial deviation log. Deviations were prospectively classified as reportable or not reportable according to prespecified IRB notification criteria. An incomplete daily study data collection form was defined as any required daily form that was not fully completed at the time of a scheduled data lock. For each enrolled participant, the total number of incomplete daily forms was calculated and stratified by time from enrollment to data lock (0–30 days, 31–60 days, and > 60 days). An incomplete survey was defined as the inability to derive a complete patient-reported outcome due to missing data across any of the four required survey instruments. Survey completion status was assessed at enrollment (baseline) and at the 3-month follow-up. Vignette scores were not considered protocol adherence outcomes and were used solely to characterize engagement with the training intervention. Because SRRBT vignettes targeted distinct protocol domains and were not designed as repeated assessments of the same competency, repeatability was not evaluated. 2.8. Data collection and statistical analysis Data were locked for regularly scheduled Data Safety and Monitoring Board (DSMB) review immediately following the SRRBT training series (February 8, 2023) and approximately six- and 12-months after completion of SRRBT (August 29, 2023 and March 21, 2024). No interim analyses or stopping rules were applied for this SWAT. Because sample size was fixed based on the number of activated PRECISE sites ( n = 23), no formal power calculation was conducted. Participant level dichotomous outcomes were analyzed using logistic regression with arm as the primary predictor. The number of incomplete daily forms was compared using linear regression. Regression models adjusted for training method and included a random effect for site. Analyses were made on an individual site level and did not adjust for multiple comparisons. Within-respondent learning patterns were examined by calculating pairwise Pearson correlation coefficients between vignette scores among the subset of respondents who completed all five vignettes. 3. Results Data from 23 PRECISE sites were included in the final analysis. No sites were excluded after randomization. Table 1 presents primary and secondary protocol adherence outcomes for the standard training and SRRBT arms at approximately 0, 6, and 12 months after SRRBT completion (data lock dates: February 8, 2023; August 29, 2023; and March 21, 2024). Denominators for approach, consent, and enrollment rates included only eligible participants available for PRECISE cohort assignment. Table 1. Site-level protocol adherence outcomes by training arm at three time points. N reflects the number of participants who met PRECISE inclusion criteria. Protocol Adherence Outcome Immediately Post Training ~6 Months Post Training ~12 Months Post Training Standard Training ( N = 116) SRRBT ( N = 80) Standard Training ( N = 583) SRRBT ( N = 254) Standard Training ( N = 1057) SRRBT ( N = 495) Eligible, n (%) 59 (51) 44 (55) 221 (38) 123 (48) 384 (36) 245 (49) Approached, 1 n (%) 29 (49) 30 (68) 118 (53) 88 (72) 237 (62) 169 (69) Consented, 1 n (%) 14 (24) 20 (45) 65 (29) 49 (40) 138 (36) 98 (40) Enrolled, 1 , 2 n (%) 11 (19) 14 (32) 49 (22) 39 (32) 106 (28) 78 (32) Incomplete surveys (baseline), n (%) 1 (9) 2 (14) 5 (10) 7 (18) 7 (7) 12 (15) Incomplete surveys (3-month), n (%) 8 (73) 10 (71) 19 (39) 18 (46) 42 (40) 39 (50) At least one protocol deviation, n (%) 5 (45) 7 (50) 27 (55) 21 (54) 54 (51) 32 (41) Reportable to IRB, n (%) 4 (36) 1 (7) 4 (8) 1 (3) 4 (4) 1 (1) Incomplete daily forms 3 Enrolled 0–30 days n 2 0 0 3 4 3 mean (SD) 8.0 (5.66) - (–) - (–) 12.0 (2.65) 12.5 (8.96) 16.7 (3.21) Enrolled 31–60 days n 1 4 5 2 10 14 mean (SD) 4.0 (–) 7.0 (14.00) 4.2 (9.39) 1.5 (2.12) 6.9 (7.06) 17.9 (10.68) Enrolled >60 days n 8 10 44 34 92 61 mean (SD) 0.5 (1.07) 6.8 (11.19) 0.4 (1.43) 0.9 (4.62) 0.4 (2.11) 1.4 (5.08) Open in a new tab 1 Percentages for Approached, Consented, and Enrolled are calculated among PRECISE eligible participants, excluding: - Those who improved (MODS resolved) or were discharged before approach - Those for whom sepsis was no longer considered the MODS-inciting event - Those meeting a new exclusion criterion prior to approach. - Those in police custody or state custody 2 Enrolled participants underwent immunophenotyping and met final eligibility for cohort assignment. 3 Incomplete daily forms are stratified based on time from enrollment to data lock. Values reflect the number (n) of enrolled participants in each window and the mean (SD) of missing forms. IRB = Institutional Review Board; SRRBT = Supplemental Reinforced Risk-Based Training; SD = Standard Deviation; MODS = Multiple Organ Dysfunction Syndrome; PRECISE = PeRsonalizEd immunomodulation in pediatriC sepsIS-inducEd MODS. The proportion of protocol deviations reportable to the IRB was numerically lower at SRRBT sites across all time points. At the first data lock (February 8, 2023), total number of unit admissions was 26,233 in the standard training arm (116 participants met inclusion criteria; inclusion rate = 0.4%). In the SRRBT arm, total number of unit admissions was 20,838 (80 participants met inclusion criteria; inclusion rate = 0.4%). Table 2 summarizes odds ratios and effect sizes for the primary and secondary protocol adherence outcomes comparing SRRBT with standard training alone. With respect to the primary outcome of site-level protocol adherence, approach rates immediately following training trended higher at SRRBT sites compared to those receiving standard training alone (OR = 3.98, 95% CI [0.87, 18.17], p = 0.074); however, this difference was not statistically significant and attenuated over time, with odds ratios of 2.24 (95% CI [0.78, 6.49], p = 0.14) at six months and 1.38 (95% CI [0.53, 3.59], p = 0.51) at 12 months post-training. Among secondary protocol adherence outcomes, the only statistically significant difference was observed at the 12-month data lock, where SRRBT sites had a higher likelihood of incomplete daily forms for participants enrolled 31–60 days prior (OR = 11.03, 95% CI [2.38, 19.67], p = 0.02). No other secondary outcomes differed significantly between training arms at any timepoint. Table 2. Comparison of protocol adherence outcomes between SRRBT and standard training alone at three time points. Protocol Adherence Outcome Immediately Post Training ~6 Months Post Training ~12 Months Post Training Odds Ratio (95% CI) P -value Odds Ratio (95% CI) P-value Odds Ratio (95% CI) P-value Approached 1 3.98 (0.87, 18.17) 0.074 2.24 (0.78, 6.49) 0.14 1.38 (0.53, 3.59) 0.51 Consented 1 2.14 (0.73, 6.32) 0.16 1.02 (0.59, 1.79) 0.93 0.99 (0.61, 1.61) 0.98 Enrolled 1 , 2 1.35 (0.31, 5.85) 0.68 1.12 (0.64, 1.98) 0.68 1.14 (0.61, 2.12) 0.69 Incomplete surveys (baseline) 1.01 (0.02, 44.19) 1.00 1.84 (0.40, 8.37) 0.43 1.98 (0.53, 7.47) 0.31 Incomplete surveys (3-month) 0.93 (0.05, 18.55) 0.96 1.29 (0.44, 3.81) 0.64 1.34 (0.56, 3.21) 0.50 At least one protocol deviation 1.71 (0.09, 32.52) 0.70 1.04 (0.34, 3.22) 0.95 0.67 (0.37, 1.21) 0.19 Severity of protocol deviations Not reportable to IRB Reference - Reference - Reference - Reportable to IRB 0.18 (0.01, 3.80) 0.25 0.36 (0.03, 4.25) 0.41 0.45 (0.04, 5.43) 0.53 Effect Size (95% CI) P-value Effect Size (95% CI) P-value Effect Size (95% CI) P-value Number of incomplete daily forms 3 Enrolled 0–30 days NE NE NE NE NE NE Enrolled 31–60 days NE NE NE NE 11.03 (2.38, 19.67) 0.02 Enrolled >60 days NE NE 0.50 (−0.98, 1.97) 0.51 0.72 (−0.68, 2.12) 0.31 Open in a new tab 1 Percentages for Approached, Consented, and Enrolled are calculated among PRECISE eligible participants, excluding: - Those who improved (MODS resolved) or were discharged before approach - Those for whom sepsis was no longer considered the MODS-inciting event - Those meeting a new exclusion criterion prior to approach. - Those in police custody or state custody 2 Enrolled participants underwent immunophenotyping and met final eligibility for cohort assignment. 3 Number of incomplete daily forms are stratified based on number of days from enrollment to data lock. NE =Not Estimable; model fit criteria not met. IRB =Institutional Review Board; SRRBT =Supplemental Reinforced Risk-Based Training; CI =Confidence Interval; MODS =Multiple Organ Dysfunction Syndrome; PRECISE =PeRsonalizEd immunomodulation in pediatriC sepsIS-inducEd MODS. Engagement with SRRBT varied across sites. Five of 11 (45%) SRRBT sites completed all five vignettes, while the remaining sites completed between one and four vignettes ( Table 3 ). Research coordinators accounted for the majority of vignette respondents (60–83% per vignette), with principal investigators contributing 13–24% of responses ( Table 4 ). Table 3. Average proportion of correct responses per vignette across SRRBT study sites. Site SRRBT Vignette 1 2 3 4 5 1 0.4 NA NA NA NA 2 1.0 0.9 1.0 1.0 1.0 3 1.0 1.0 1.0 NA NA 4 1.0 NA NA 1.0 NA 5 0.9 1.0 0.8 0.8 0.8 6 1.0 0.9 0.8 1.0 0.7 7 0.9 1.0 0.9 0.8 0.7 8 1.0 0.4 0.8 NA 0.8 9 0.8 NA NA NA NA 10 0.5 0.6 0.8 NA NA 11 0.9 0.9 0.7 0.8 0.4 Open in a new tab Each vignette contained 5 scored questions, for a maximum possible score of 1.0 (proportion correct). NA = Not Available; vignette not completed by any study staff at that site. SRRBT = Supplemental Reinforced Risk-Based Training. Table 4. Distribution of respondent roles by completed SRRBT vignettes. Respondent Role Completed SRRBT Vignettes Vignette 1 ( N = 21) Vignette 2 ( N = 18) Vignette 3 ( N = 16) Vignette 4 ( N = 12) Vignette 5 ( N = 14) Site Principal Investigator, n (%) 5 (24) 3 (17) 2 (13) 2 (17) 3 (21) Site Co-Investigator, n (%) 2 (10) 2 (11) 2 (13) 0 (0) 2 (14) Research Coordinator, n (%) 14 (67) 13 (72) 12 (75) 10 (83) 9 (64) Open in a new tab Percentages reflect the proportion of each respondent role out of the total number (N) of respondents for that vignette. SRRBT = Supplemental Reinforced Risk-Based Training. To assess within-respondent learning patterns, we analyzed scores from 11 respondents who completed all five vignettes. Correlation coefficients between scores ( Table 5 ) showed no strong or consistent relationships across vignettes, supporting the intended design of the modules as independent educational tools rather than a cumulative or progressively complex curriculum. Table 5. Correlation matrix of vignette scores among respondents who completed all five SRRBT training sessions. SRRBT Vignette 1 2 3 4 5 SRRBT Vignette 1 1 −0.194 −0.211 0.289 0.495 2 −0.194 1 −0.228 −0.261 −0.307 3 −0.211 −0.228 1 0.207 −0.013 4 0.289 −0.261 0.207 1 0.772 5 0.495 −0.307 −0.013 0.772 1 Open in a new tab Values represent Pearson correlation coefficients between scores on each SRRBT vignette among the 11 respondents who completed all five modules. Higher values indicate stronger linear relationships in scores across vignettes. SRRBT = Supplemental Reinforced Risk-based Training. 4. Discussion This study evaluated the impact of SRRBT on site-level protocol adherence by embedding a cluster-randomized, educational implementation SWAT within the multicenter PRECISE trial. SRRBT was developed to reinforce trial-specific competencies identified during early implementation using interactive, scenario-based electronic modules. We evaluated whether SRRBT in addition to standard training improves protocol adherence, reduces protocol deviations, and/or improves participant recruitment. Our findings suggest a nuanced impact of SRRBT on protocol adherence, suggesting both potential benefits and areas in need of further investigation. While not statistically significant, approach rates initially trended higher at SRRBT sites compared to those receiving standard training alone, suggesting that SRRBT may have enhanced early staff readiness and attentiveness to protocol-specific details (e.g., eligibility criteria). Over time, approach rates at standard training sites increased, while rates at SRRBT sites remained relatively stable, resulting in convergence between the two groups at later time points. Because site personnel remained constant during the training and evaluation period, the improvement in standard training sites may reflect increased familiarity with the protocol over time or adaptation through routine support mechanisms. These findings suggest that while SRRBT may offer early advantages, its benefits may not persist without reinforcement. We also observed that, counterintuitively, the number of incomplete daily forms was significantly higher at the SRRBT sites compared to their standard training counterparts at the 12-month data lock. One potential explanation for this could be related to the participant enrollment patterns over the course of the study. Specifically, there was a higher number of enrolled participants during each six-month interval between data locks, thus resulting in more daily data forms to manage. This finding suggests that while SRRBT may improve qualitative aspects of trial conduct, quantitative factors such as documentation workload also need to be addressed through appropriate staffing and effective time management practices. Although not the primary focus of this study, seasonal variation in pediatric sepsis incidence may have contributed to the observed enrollment patterns across data locks. Two of the three data locks occurred shortly after winter, when pediatric sepsis may be more prevalent, while one followed the summer. Additionally, the early phase of the trial coincided with the post-COVID period, during which altered viral epidemiology and increased susceptibility among children may have led to changes in PICU admission rates and sepsis presentations. These contextual factors, while not adjusted for statistically, may have confounded some observed outcomes. Vignette scores were generally low across sites and sessions. This may reflect several interrelated factors. First, the vignettes were designed to highlight complex or error-prone protocol areas and therefore may have successfully identified knowledge gaps. Second, the lower scores may also reflect inconsistent engagement with the SRRBT. Survey participation was optional and may have been deprioritized during periods of high clinical demand (e.g., winter viral surges). Third, the variation in roles among respondents (e.g., coordinators, PIs, coinvestigators) may have contributed to score variability. These observations suggest that while SRRBT may effectively identify knowledge gaps, future iterations may benefit from mandatory participation, rolespecific tailoring, and/or strategies to boost engagement. We did not observe consistent improvement in vignette scores over time. This may be due to the vignette structure; each module targeted a unique protocol concept and was not part of a cumulative or scaffolded curriculum. As a result, comprehension of earlier topics may not have translated into higher scores on later vignettes. Indeed, our observation of lower or inconsistent correlation between vignette scores among respondents who completed all five vignettes suggests that differences in topic complexity or vignette timing may have influenced results more than longitudinal knowledge gain. Our use of study-specific risk-based training as a supplement to standard GCP training has not been previously reported and contrasts distinctly with the broader, foundational training approaches previously described in the literature. Loucks et al. describe a comprehensive training program that prepares clinicians to be site investigators through didactic training, mentorship, and practical experience in trial initiation and management. This program emphasizes long-term career development and building a comprehensive trial portfolio, rather than addressing immediate trial-specific challenges [ 17 ]. Similarly, Berkness et al. detail a multidisciplinary training experience that utilizes lectures and workshops to enhance knowledge across various trial roles and to advance the careers of its participants. The training spans broad clinical trial design and management areas and emphasizes diversity and inclusion within the field [ 18 ]. These broader, more holistic training approaches aimed at career development and comprehensive clinical trial management contrast with SRRBT’s focused, risk-based modules designed for quick and direct application within a specific clinical trial. Our study aligns with recent international efforts to harmonize quality improvement metrics across pediatric trial networks. A recent study by Attar et al. identified significant variation in how trial performance is monitored across global networks but emphasized the value of actionable metrics for improving recruitment, feasibility, and efficiency [ 19 ]. SRRBT’s focus on practical, protocol-specific scenarios fits within this emerging framework, supporting both fidelity and continuous improvement. Future work should explore how training interventions like SRRBT can be integrated into unified protocol adherence and trial conduct monitoring systems across multi-site trials. Limitations. This study has several limitations. SRRBT vignettes were delivered on a fixed schedule irrespective of individual site activation dates, and the initiation of training materials was not enforced by protocol; as a result, the timing of SRRBT exposure relative to site activation varied across sites. Given the fixed and limited number of clusters, analyses were not adjusted for refresher training exposure or timing of activation relative to SRRBT delivery. SRRBT vignettes were not repeated or refreshed over time, which may have limited long-term impact. Participation in SRRBT was voluntary and tracked at the site level, limiting our ability to assess individual respondent engagement or role-specific effects. The modest sample size limited statistical power, and analyses did not adjust for multiple comparisons. Unmeasured temporal and sitelevel factors, such as seasonal variation, competing demands, and clinical workload, may have influenced protocol adherence outcomes. The relative rarity of the eligible participant population may have contributed to overall difficulties in maintaining trial staff proficiency. Finally, the asynchronous nature of SRRBT delivery precluded assessment of immediate training effects following site activation. Future Directions. To build on the findings of this study, future research should consider more frequent reinforcement of supplemental, reinforced, risk-based training to assess the sustainability of SRRBT benefits. Incorporating qualitative methods to capture site perspectives and implementing a more adaptive training framework that can be customized in real time may also prove beneficial. SRRBT may be particularly useful in clinical trials that lack robust pre-activation training resources or have limited opportunities for centralized site initiation meetings. Furthermore, expanding this research to include a broader range of clinical trial contexts could help in evaluating the generalizability and scalability of the SRRBT model. 5. Conclusions While SRRBT in addition to standard training may support early sitelevel protocol adherence, its durability over the course of a complex multicenter clinical trial remains unclear. Further research is needed to determine how supplemental, risk-based training can be optimally deployed to sustain protocol adherence and trial quality over time. Supplementary Material Supplement NIHMS2160398-supplement-Supplement.docx (41.1KB, docx) Acknowledgements The authors would like to thank Dr. Shelby Meier and the Vanderbilt Recruitment Innovation Center for their help in developing training materials. We also acknowledge the effort of all study personnel involved in the PRECISE trial. Funding The Collaborative Pediatric Critical Care Research Network (CPCCRN) and the PRECISE study are funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (PL1HD105462). Additional support for this study was provided by the Utah Trial Innovation Center (U24TR001597) and Vanderbilt Recruitment Innovation Center (U24TR004432) which are funded by the National Center for Advancing Translational Sciences. Danielle J. Green receives funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD113189, K23HD115855). Glossary CI Confidence Interval CPCCRN Collaborative Pediatric Critical Care Research Network CTTI Clinical Trials Transformation Initiative DSMB Data Safety Monitoring Board FDA Food and Drug Administration GCP Good Clinical Practice ICH International Council for Harmonisation IRB Institutional Review Board MODS Multiple Organ Dysfunction Syndrome OR Odds Ratio PI Principal Investigator PRECISE PeRsonalizEd immunomodulation in pediatriC sepsIS-inducEd MODS REDCap Research Electronic Data Capture RIC Recruitment Innovation Center RN Registered Nurse SD Standard Deviation SRRBT Supplemental, Reinforced, Risk-Based Training SWAT Study Within A Trial Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.cct.2026.108284 . Footnotes CRediT authorship contribution statement Danielle J. Green: Writing – review & editing, Writing – original draft. Valeriya Vasenina: Writing – review & editing, Writing – original draft. Kelsee Meyerhoffer: Writing – review & editing, Methodology, Data curation, Conceptualization. Russell K. Banks: Writing – review & editing, Methodology, Formal analysis, Data curation, Conceptualization. Mark W. Hall: Writing – review & editing, Methodology, Conceptualization. Athena F. Zuppa: Writing – review & editing, Methodology, Conceptualization. Kevin M. Watt: Writing – review & editing, Methodology, Conceptualization. Natalie Dilts: Writing – review & editing, Methodology, Conceptualization. John M. VanBuren: Writing – review & editing, Methodology, Formal analysis, Data curation, Conceptualization. Ethics approval and consent to participate This study was reviewed and approved as exempt by the University of Utah Institutional Review Board (IRB_00150884). A waiver was granted for informed consent. 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