Pediatric Clinical Trials Research Articles

Brief Report: Dolutegravir Plasma Protein Binding and Unbound Concentrations During Pregnancy and Postpartum.

Clinical interpretation of the reduced dolutegravir (DTG) plasma concentrations reported during pregnancy is complicated by its high plasma protein binding. Plasma proteins significantly decrease during pregnancy, and understanding changes in DTG protein binding and its therapeutically active unbound concentrations are necessary to evaluate the impact of pregnancy changes on DTG pharmacokinetics. Retrospective assessment of plasma samples from pregnant women living with HIV enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s study receiving 50 mg DTG film-coated tablets once daily as part of clinical care. Unbound and total DTG concentrations were determined predose (C0) and at maximum (Cmax) concentrations during the second trimester (2T), third trimester (3T), and postpartum (PP). Percentage unbound was calculated as the ratio of ultrafiltrate unbound DTG concentration to total DTG concentration. Twenty-nine mothers were included for protein binding evaluations; 15, 27, and 23 from the 2T, 3T, and PP, respectively. DTG % unbound for C0 and Cmax were significantly different by stage of pregnancy, with 3T significantly higher compared with PP; 1.02% vs. 0.69% (P = 0.0067) for C0 and 0.76% vs. 0.46% for Cmax (P = 0.0056). Median (IQR) unbound concentrations for C0 were 6.3 (4.7-18.4) for the 2T, 8.0 (5.6-16.9) for the 3T, and 13.3 (8.4-22.7) ng/mL PP, significantly different between 2T and PP (P = 0.0039), but not different between 3T and PP (P = 0.46). Lower total DTG plasma concentrations during pregnancy coincide with temporal decreases in DTG protein binding, resulting in comparable unbound DTG concentrations during the 3T and PP.

Plastic Surgery Clinical Trials: A Systematic Review of Characteristics, Research Themes, and Predictors of Publication and Discontinuation

Summary: Clinical trials (CTs) are crucial for evidence-based surgical care. Despite growing interest in plastic and reconstructive surgery (PRS) research, the status of PRS CTs remains unknown. We obtained PRS CTs from ClinicalTrials.gov and WHO’s International Clinical Trials Registry Platform (November 2022). Topic modeling identified research themes and machine learning models generated CT-publication pairs. Kaplan-Meier curves visualized CT discontinuation and nonpublication. Of the 4685 PRS CTs identified, 79% were interventional and 81% recruited adults. Most were single-center-led (67%) and academic-funded (77%). Male investigators led 77% of CTs. Female-only patient CTs outnumbered male-only (31% versus 1%). The United States led with 41% of CTs, followed by France, Canada, and China. Industry-funded CTs were higher in the USA, Germany, and Belgium, and academic-funded in France, Canada, and China. PRS CTs clustered into aesthetics (43%), reconstructive (20%), wound healing (8%), peripheral nerve (6%), tumor excision (5%), craniofacial (5%), perioperative pain (5%), and burns (4%). Industry preferred funding aesthetics, whereas academia and industry co-funded wound healing. Publication rates of completed (24%) and terminated (10%) CTs varied by cluster, with perioperative pain CTs exhibiting higher rates. Industry-funded CTs had lower publication rates (hazard ratio: 0.64, 95% confidence interval: 0.5–0.81) and higher discontinuation (hazard ratio: 1.34, confidence interval: 1.06–1.68) driven by sponsors’ decision to terminate prematurely. Global growth in PRS trialome reflects rising interest in evidence-based plastic surgery. Yet, imbalances in participant age, geography, funding source, and trial design influence likelihood of CT discontinuation and publication. Key research gaps include pediatric CTs, accountability in industry-funded research, and multicenter collaborations with underrepresented regions.

Survival Disparities By Frontline Clinical Trial Enrollment Status for Treatment of Pediatric Acute Myeloid Leukemia

Introduction: Studies have suggested superior outcomes for patients enrolled on clinical trials for their cancer treatment. While sociodemographic disparities in trial enrollment are well established in adults, the literature in children is mixed and limited. A deeper understanding of disparities in pediatric clinical trial enrollment and potential survival differences is critical to ensure the generalizability of trial results and equitable outcomes. In a cohort of children with AML, we sought to examine (1) differences in sociodemographic and clinical characteristics by trial enrollment status, (2) the impact of trial enrollment on survival, and (3) the potential drivers of survival differences. Methods: A retrospective cohort including all pediatric (age <19 years) patients with AML treated at 10 institutions in the United States from 2011-2018 was established and is being actively expanded to include diagnoses through 2023. Chart abstraction by trained study personnel collected detailed demographic and clinical information. Resource utilization data from the Pediatric Health Information System was merged to ascertain patient acuity. Higher acuity was defined as requiring ICU-level resources for 2 or more organ systems within 72 hours of diagnosis. Only patients who had a frontline therapeutic trial option available at their treating institution were included. This was operationalized as a center-level restriction to patients initiating therapy while any frontline trial was enrolling at the center. We additionally included only patients with complete data for all covariates in this analysis. Statistical Analysis: Demographic and clinical characteristics by trial enrollment status were compared using t-test or Fisher's exact test as appropriate. Cox proportional hazards regression estimated hazard ratios (HR) with a doubly robust estimator (adjusted models only) of 4-year OS and EFS by trial enrollment status. A stepwise propensity score (PS) approach assessed the impact of potential drivers of the associations between trial enrollment and overall survival (OS) and event-free survival (EFS). PS were computed by logistic regression and generated stabilized inverse probability weights used for adjustment. First, a Base PS model including a predefined set of potential confounders (age, sex, weight category, preferred language, risk classification, mean annual hospital AML volume) was created. Additional variables of interest were then sequentially added to the PS. The change in adjusted HR relative to the unadjusted comparison was used to quantify the proportion of the association explained at each step. Results: 342 pediatric patients diagnosed with AML with representation from three distinct frontline clinical trials (AAML1031, AML08, and AML16) were included. Patients who were Black (11% vs. 24%), Hispanic (24% vs. 28%), publicly insured (44% vs. 55%), higher acuity (3% vs. 8%), and high-risk classification (29% vs. 34%) were underrepresented in the trial enrollment group compared to non-trial enrolled (Table 1). In unadjusted analyses, trial enrollment was significantly associated with superior OS (HR=0.69, 95% CI 0.47-0.99, p=0.04); there was no significant difference in EFS (HR=0.95, 95% CI 0.69-1.31, p=0.75). Adjustment for the Base PS accounted for 23% of the observed association between trial enrollment and OS (Figure 1). Acuity explained an additional 7% of the association. Inclusion of race/ethnicity and insurance did not result in further adjustment. In fully adjusted analysis, the association was substantially attenuated (HR=0.93, 95% CI 0.59-1.46, p=0.76). Conclusions: Significant sociodemographic and clinical differences exist in frontline trial enrollment for pediatric AML, which may contribute to worse overall survival outcomes for patients not enrolled on trials. Acuity at diagnosis may be a potential modifiable driver of survival differences. These findings support the need to evaluate enrollment patterns across pediatric clinical trials, including how enrollment disparities impact generalizability of clinical trial results, as well as a critical need for interventions designed to improve equity in healthcare access.

Longitudinal Differences By Treatment Arm in Health-Related Quality of Life Among High Risk Pediatric Hodgkin's Lymphoma Patients Treated on the Children's Oncology Group Ahod 1331 Study

Introduction: Brentuximab vendotin (BV) with AVE-PC demonstrated superior efficacy to ABVE-PC for pediatric patients with high-risk HL in the AHOD 1331 trial. However, there are no data regarding the impact on health-related quality of life (HRQoL) with the addition of BV into the treatment of pediatric HL. Methods: Eligibility for AHOD 1331 (NCT 02166463) included previously untreated HL with high risk disease, defined as stage IIB +bulk, IIIB, IVA, or IVB classic HL. Participants were randomized to either BV-AVE-PC (“BV” arm) or ABVE-PC (standard arm). Among the first 309 participants enrolled in a prespecified longitudinal patient-reported outcomes sub study, 280 were age 11+ years and eligible to self-report HRQoL using the seven-item Child Health Ratings Inventories (CHRIs)-Global scale. HRQoL was assessed prior to treatment (T1), at cycle 2 (T2), at cycle 5 (T3), and at the end of treatment (T4). A clinically meaningful increase in HRQoL was considered a change of 7 points in the CHRIs-Global score (CHRIs), translating to a 1/3 standard deviation. Multivariable linear regression estimated the association between demographic/clinical variables and HRQoL at T1. Linear mixed models estimated the change in HRQoL relative to T1 with a time*treatment arm interaction to estimate differences in the change in HRQoL across treatment arm. This model was adjusted for age, sex, race/ethnicity, stage, large mediastinal adenopathy (LMA), B-symptoms at diagnosis, and a time-varying covariate for involved site radiation prior to T4. Results: Participant and disease characteristics were balanced by treatment arm; mean age at enrollment was 15.6 years (SD= 1.9), 52% were female, 60.4% had LMA, and 58% were stage IV. 93% of participants completed the CHRIs at T1, 92% at T2, 89% at T3, and 74% at T4. At T1, female sex (mean (SD) 64.1 (20.2) vs 71.3 (23.3) p=0.004) and fever (60.8 (23.0) vs. 71.9 (20.4) p=0.024) were associated with worse HRQoL. At each time point after pre-treatment (T1), HRQoL was higher, on average, in the BV arm compared to the standard arm (Figure 1). By T2, participants in the BV arm experienced a statistically and clinically significant increase in HRQoL compared to pre-treatment (T1) (Table 1; β=7.3 95%CI 3.2, 11.4; p≤0.001), which was greater than the change experienced in the standard arm (difference in change β=5.1 95%CI -0.2, 10.3; p=0.057). At T3 and T4 the BV arm continued to experience statistically significant improvements in HRQoL relative to T1 (T3 β=5.3 95%CI 0.8, 9.9; p=0.022; T4 β=14.6 95%CI 10.3, 18.9; p≤0.001). The standard arm did not experience a statistically or clinically significant increase in HRQoL from T1 until T4 (β=9.3 95%CI 4.7, 11.5; p<0.001). Conclusion: Patients with high-risk pediatric HL treated with BV-AVE-PC experienced more rapid and sustained improvement in HRQoL compared to patients treated with ABVE-PC. These data also demonstrate the feasibility and importance of incorporating HRQoL assessments into pediatric clinical trials.

Effect of Hydroxyurea Treatment on Body Composition in Children with Sickle Cell Anemia in Uganda Using Bioelectrical Impedance Analysis (BIA)

Introduction Children with sickle cell anemia (SCA) experience severe illness and risk of malnutrition in sub-Saharan Africa. Treatment with hydroxyurea (HU) decreases SCA complications. In high-income regions, hydroxyurea also improves pediatric growth and overall quality of life. We assessed the effects of hydroxyurea on growth and body composition of children with SCA in Uganda. Methods This study was nested in an open-label, single-arm pediatric clinical trial of hydroxyurea 20-30mg/kg/day for prevention of neurological and cognitive impairment. In all, 267 study participants with SCA, ages 3-9 years, initiated hydroxyurea treatment at the Mulago Hospital SCA Clinic in Kampala, Uganda. Anthropometric measurements (weight, height) were obtained at enrollment and at month 18 of therapy; age- and sex-specific z-scores were assigned, per World Health Organization (WHO) international standards. Non-invasive bioelectric impedance analysis (BIA), was used to estimate total body fat mass (FM) and fat-free mass (FFM) at both timepoints. A control sample of110 siblings/family members without SCA, aged 3-12 years, established local z-scores for BIA assessments. Results Among SCA participants and controls, 50.6% and 57.3% were female, respectively. Mean age was younger foror the SCA sample: 5.1±0.1 and 7.1±0.3 years ( p<.001). At trial month 18, mean hydroxyurea dose 25.4mg/kg, SCA hemoglobin rose from 7.8±1.2 to 8.9±1.5 g/dL( p<.001), remaining lower than mean hemoglobin level of non-SCA controls 12.5±1.1 ( p<.001). Using the World Health Organization definition of “wasting,” SCA participants at enrollment had a higher proportion of low weight-for-height than controls: 9.8% vs 3.8%, p=.009). By body composition, the SCA sample also had lower FFM (-0.67±0.56 vs. 0.00 ±1.00, p < .001) and FM (-0.68±0.60 vs. 0.00 ±1.00, p<.001) than controls. At month 18, for the 254 active SCA participants (95.1%), the proportion with wasting was unchanged. In contrast, z-scores for FFM (-0.65±0.57 to -0.16±0.57, p < .001) and FM (-0.66±0.61 to -0.18±0.61, p<.001) significantly increased (Figure) to near control levels. Conclusion Hydroxyurea therapy in children with SCA increased hemoglobin yet did not reduce the proportion with wasting after 18 months. Nonetheless, treatment led to significantly improved FM and FFM to near normal levels. These results suggest that hydroxyurea therapy may play a crucial role in enhancing body composition of children with SCA in the region. The ongoing hydroxyurea trial will enable assessment of longer-term impact on health-related growth and body composition in children with SCA in Uganda.

“Direct and indirect impacts of the COVID-19 pandemic on operational conduct of pediatric vaccine clinical trials”

ABSTRACT The coronavirus 2019 (COVID-19) pandemic, as well as the resulting public health measures, impacted many aspects of society. The conduct of important pediatric vaccine trials was among these. Analyzing data from six ongoing non-COVID-19 pediatric vaccine trials we aimed to assess the operational impact of the COVID-19 pandemic using descriptive analyses. We identified multiple operational disruptions in trial conduct. Additionally, we identified higher percentages of missed routine vaccinations than investigational vaccines throughout the observation period. Overall, the impact of the COVID-19 pandemic was most apparent early in the pandemic period while adaptations to the pandemic were developed; however, some disruptions persisted throughout the observation period. Pediatric vaccine clinical trials are critical to developing new and/or improved vaccines for the pediatric population. Continued evaluation of the impacts of COVID-19 on pediatric vaccine clinical trials is warranted.

Emicizumab Use in Infancy: A Survey of United States Pediatric Hemophilia Treatment Center Medical Directors

Introduction: Emicizumab, a bispecific antibody directed against activated factor IX and factor X, is a subcutaneous non-factor prophylactic option for individuals with hemophilia A (HA). The safety and efficacy of emicizumab has been demonstrated in both adult and pediatric patients. It was approved by the United States (U.S.) Food and Drug Administration for routine prophylaxis to prevent or reduce bleeding episodes in individuals with HA, ages newborn and older, both with (2017) and without (2018) factor VIII (FVIII) inhibitors. Despite this approval, data on emicizumab in infants are limited. The HAVEN 2 pediatric clinical trial had only two infants under 24 months of age, though interim analysis of the HAVEN 7 trial demonstrated emicizumab efficacy and safety in infants. Thus, the optimal use of emicizumab in infants under 12 months of age remains unclear. The objective of this study was to understand the rationale and treatment decisions regarding initiation of emicizumab prophylaxis in children under 12 months of age among pediatric Hemophilia Treatment Center (HTC) Medical Directors in the U.S. Methods: An electronic survey was conducted from April to May 2023 of U.S. HTC Medical Directors via REDCap. Invitations were sent to all individuals listed as HTC Directors at pediatric medical centers on the Center for Disease Control and Prevention database. The survey included two hemophilia patient case scenarios associated with 15 multiple-choice questions and additional free-text options. The first case was of a 9-month-old male with severe HA, without prior bleeding history or exposure to FVIII, who presented for his initial visit to an HTC. The second case was a 3-month-old male with severe HA receiving FVIII replacement therapy for an intracranial hemorrhage. This study was approved by the Baylor College of Medicine Institutional Review Board. Results: Overall, 33 of 97 (34%) pediatric HTC Medical Directors participated in the survey. One survey was minimally completed and excluded for a total of 32 surveys included in the final analysis. The majority of participants had over 15 years of experience caring for patients with HA (n=21, 65.6%) and represented HTCs with over 250 patients (n=22, 68.8%; Table 1). For previously untreated or minimally treated infants (Case 1), 96.9% of responses (n=31) stated they would consider starting emicizumab prophylaxis; 45.2% (n=14) would consider initiating it as young as 1 week of age. The most common reason cited for starting emicizumab in an infant was to prevent an intracranial hemorrhage (n=17, 53.1%) followed by the desire to avoid central line placement (n=7, 21.9%). The majority of respondents did not wait for a minimum number of factor exposure days prior to starting emicizumab (n=31, 96.9%) nor did they report regularly exposing infants to FVIII concentrate until 50 EDs are reached (n=29, 90.6%). After the initial loading phase, the majority of respondents selected an emicizumab dosing regimen of every 2 weeks (n=19, 59.4%). There was a varied approach to monitoring for inhibitor development after starting emicizumab; 40.6% (n=13) reported monitoring at regular intervals between every 6 to 24 months, whereas 46.8% (n=15) did not report following a set schedule and instead obtain FVIII inhibitor testing only after FVIII exposure (Table 2). For infants receiving FVIII replacement for treatment of an intracranial hemorrhage (Case 2), 96.9% (n=31) of participants stated they would transition to emicizumab as a prophylactic agent. Over half (n=16, 51.6%) stated they would initiate emicizumab during the treatment period for the hemorrhage rather than waiting until therapy completion. For providers that use emicizumab in moderate hemophilia, emicizumab was reported to be used routinely by 27.3% (n=6) and on a case-by-case basis in 40.9% (n=9, Table 2) in infants with moderate HA. Conclusion: Pediatric HTC Medical Directors in the U.S. report commonly utilizing emicizumab in infants under 12 months of age despite the lack of robust data in this age group. This practice is consistent with recommendations by the National Hemophilia Foundation's Medical and Scientific Advisory Council. With the completion of clinical trials focused on infants with HA, along with additional long-term outcomes data, more specific guidance around initiation, follow-up and monitoring may be available to inform the optimal management for these patients.

A Real-World, Single Institution, Post-Market Comparison of Pegaspargase and Calasparagase Pegol-Mknl Therapeutic Drug Monitoring and Toxicity

Introduction: Calaspargase pegol-mknl (CalPEG) was FDA-approved in December 2018 as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia/lymphoma (ALL/LLy) in pediatric patients and adolescent and young adults (AYA). It has recently been incorporated into national pediatric ALL consortia clinical trials. The pharmacokinetics and toxicity profiles were reported in two clinical trials (AALL07P4; Angiolillo et al, J Clin Oncol, 2014 and DFCI 11-001; Vrooman et al, J Clin Oncol, 2021), with similar safety profiles to historical pegaspargase (PEGasp). There is a paucity of published data regarding serum asparaginase activity (SAA) level variation or toxicity between CalPEG and PEGasp since FDA-approval. This is timely given the recent transition in asparaginase product availability, which may impact resource utilization, comprehensive drug safety monitoring, and clinical practice guidelines. Methods: We conducted a single institution retrospective review of children and AYA with ALL/LLy who received an asparaginase product during upfront or relapse therapy between January 2022 to June 2023 as part of our chemotherapy quality and safety monitoring (Table). Patients received either PEGasp, CalPEG, and/or asparaginase Erwinia chrysanthemi recombinant (Rylaze) and had correlative SAA documented by a validated assay (NEXT Molecular Analytics; Chester, VA). The Common Terminology Criteria for Adverse Events version 5.0 was used to retrospectively grade asparaginase-related toxicities, including pancreatitis (≥ grade 3), venous thromboembolism (VTE; ≥ grade 2), hyperbilirubinemia (total bilirubin ≥ 5 mg/dL), allergy (≥ grade 3), and silent inactivation (SI, SAA < 0.025 IU/mL within 7 days post-treatment without allergic symptoms). Fisher's exact and Wilcoxon rank-sum tests were used to compare patient characteristics and toxicity incidence with pairwise post-hoc comparisons. P values were two-sided and considered significant if < 0.05. Generalized linear modeling (GLM) was used to model SAA over time and interactions among asparaginase product, toxicity, and immunophenotype. Results: One hundred twenty-five patients received either PEGasp, CalPEG, and/or Rylaze. (Table). Frequency of total asparaginase-related toxicity was comparable between CalPEG (27.7%) and PEGasp (27.4%). However, the incidence of pancreatitis was significantly higher in patients who received CalPEG (12.8%) compared to PEGasp (2.4%), P=0.025, with an Odds Ratio (OR) 5.91. T-ALL/LLy patients who received CalPEG had an increased incidence of both pancreatitis and VTE (33.3% each), with statistically significant pairwise interactions to PEGasp and/or B-ALL cohorts. Conversely, allergy was significantly higher in PEGasp (17.9%) compared to CalPEG (4.3%), P=0.03, with an OR 4.46. SI was found in 5.8% of PEGasp with none yet identified in CalPEG patients. The median peak SAA level over the first 10 days was not different among patients with adverse events; nor were median SAA levels higher in CalPEG patients, despite increased incidence in treatment-related toxicity (Figure). GLM fit slopes were predictably less negative in CalPEG compared to those of PEGasp; patients with toxicity had a larger modeled area under the curve. In 6 patients who were dose-capped to 3750 IU for body mass index (BMI) ≥ 40, all exhibited therapeutic SAA without any asparaginase-related toxicity. Conclusions: To our knowledge this is the first single-institution post-market retrospective quality and safety analysis comparing CalPEG and PEGasp therapeutic drug monitoring and toxicity. Interestingly, the incidence of pancreatitis and VTE is significantly higher in patients receiving CalPEG and disproportionately higher in T-lineage. Median peak SAA levels were not predictive of toxicity, though GLM may help provide a predictive model. The rate of SI emphasizes the need for continued resource utilization of SAA monitoring. Our observed differences in CalPEG and PEGasp toxicity are discordant with two previously published clinical trials used for FDA approval of CALPEG (AALL07P4 and DFCI 11-001). Larger analyses of CalPEG SAA and toxicities are necessary to determine if these trends are reproducible. This information will help establish optimal utilization of SAA safety monitoring with the broader goal of identifying necessary practice changes in CalPEG clinical management.

Future of Treatment of Adolescents and Young Adults With ALL: A Vision for Collaboration and Equity.

Over the past several decades, survival of children with ALL has improved dramatically with treatment regimens refined through cooperative group trials. Despite aggressive treatment and iterative therapy changes for adolescents and young adults (AYAs), improvement has not been as promising. Comparisons between pediatric and adult clinical trials have consistently demonstrated superior outcomes for AYAs treated on pediatric ALL protocols, leading to the implementation of pediatric-inspired ALL protocols by several groups worldwide and/or expansion of the age limit of pediatric trials to include the full spectrum of the AYA population. Despite these efforts, AYAs in both pediatric and adult settings continue to have inferior survival compared with younger children with ALL. Real-world data suggest that uptake of pediatric-style treatment is variable, and even with identical pediatric-style treatment, AYAs still fare worse than younger children. As we enter an era of immunotherapy and precision medicine for newly diagnosed ALL, now is an opportune time to consider how best to approach future therapy for AYA patients. Comparisons of pediatric and adult treatment approaches and subanalyses of AYA patients will help guide harmonization of treatment. The focus of the next stage of ALL therapy for AYA should not only involve novel treatment approaches but also standardization and optimization of supportive care measures, psychosocial support, adherence interventions, oncofertility treatment, and survivorship care. All these efforts should simultaneously work to address health disparities to ensure that a future of improved outcomes is experienced equitably for all AYA patients.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Assessing asthma symptoms in children: qualitative research supporting the development of the Pediatric Asthma Diary—Child (PAD-C) and Pediatric Asthma Diary—Observer (PAD-O)

BackgroundPediatric asthma has been identified by regulators, clinicians, clinical trial sponsors, and caregivers as an area in need of novel fit-for-purpose clinical outcome assessments (COAs) developed in accordance with the U.S. Food and Drug Administration’s (FDA’s) regulatory guidance for evaluating clinical benefit in treatment trials. To address this gap, the Patient-Reported Outcome (PRO) Consortium’s Pediatric Asthma Working Group has continued development of 2 COAs to assess asthma signs and symptoms in pediatric asthma clinical trials to support efficacy endpoints: a PRO measure, the Pediatric Asthma Diary—Child (PAD-C) for children 8–11 years old (y.o.) and an observer-reported outcome measure, the Pediatric Asthma Diary-Observer (PAD—O) for caregivers of children 4–11 y.o. This qualitative research aimed to generate evidence regarding the content validity of the PAD-C and PAD-O.MethodsSemi-structured combined concept elicitation and cognitive interviews were conducted with a diverse sample of U.S. participants (15 children 8–11 y.o. and 30 caregivers of children 4–11 y.o.). All children had clinician-diagnosed mild to severe asthma. Interviews explored the experience of pediatric asthma and assessed the understanding and relevance of both measures. Interviews were conducted across 3 iterative rounds to allow for modifications.ResultsConcept elicitation findings demonstrated that the core sign/symptom and impact concepts assessed in the PAD-C (cough, hard to breathe, out of breath, wheezing, chest tightness, and nighttime awakenings/symptoms) and PAD-O (cough, difficulty breathing, short of breath, wheezing, and nighttime awakenings/signs) correspond to those most frequently reported by participants; concept saturation was achieved. All PAD-C and PAD-O instructions and core items were well understood and considered relevant by most participants. Feedback from participants, the Pediatric Asthma Working Group, advisory panel, and FDA supported modifications to the measures, including addition of 1 new item to both measures and removal of 1 caregiver item.ConclusionsFindings provide strong support for the content validity of both measures. The cross-sectional measurement properties of both measures and their user experience and feasibility in electronic format will be assessed in a future quantitative pilot study with qualitative exit interviews, intended to support the reliability, construct validity, final content, and, ultimately, FDA qualification of the measures.

Exploring Barriers to Pediatric Cancer Clinical Trials: The Role of a Networked, Just-in-Time Study Program

The Research to Accelerate Cures and Equity (RACE) for Children Act mandates that newly developed targeted oncology drugs be tested in children when molecular targets are relevant to pediatric cancers. In its first year, the RACE for Children Act was effective in creating novel drug development opportunities for children with cancer; however, significant barriers to clinical trial enrollment persist. Pediatric cancer clinical trials are impacted by challenges surrounding logistics, complexity, and access. As such, there is potential for a networked and centralized study approach to address these barriers. Here we discuss adapting a just-in-time clinical trial approach for adults to serve the pediatric oncology population. Through innovative patient matching solutions leveraging large, real-world datasets with high computational power, the Tempus Integrated Molecular Evaluation (TIME) for Kids Program aims to address barriers in the development of new therapies. This commentary explores the potential for reducing challenges in developing novel pediatric therapeutics, advancing equity in genomic biomarker testing for precision tailored treatment, and improving outcomes for pediatric oncology patients.

75 Factors that Influence Parental Decision-making Regarding Analgesia for their Children with Musculoskeletal Injury-related Pain: A Qualitative Study

Abstract Background Parents/caregivers are often the gatekeepers for the pharmacologic management of their children’s pain. Parents’ unique expertise in assessing their children’s pain reactions, alongside a deep emotional drive to protect their children, make them invaluable advocates and partners. Parents are highly invested in optimizing pain management outcomes for children. Concerns and preferences regarding medications, including opioids, influence their choices. An improved understanding of caregiver decision-making should encourage a family-centred approach to communication with parents when deciding analgesic plans for children with acute pain, facilitate shared clinical decision-making, and optimize paediatric pain management outcomes in the clinical setting. Objectives Our primary objective was to explore and understand caregiver decision-making as it relates to acute pain management for children presenting to the emergency department, with particular focus on opioids. Design/Methods This qualitative study was embedded within an ongoing paediatric clinical trial (‘The No OUCH Trials’, NCT03767933), which aims to evaluate the clinical efficacy of a combination of oral opioid (hydromorphone) and non-opioid (ibuprofen and acetaminophen) analgesics to manage paediatric musculoskeletal injury-related pain. This study employed one-on-one semi-structured interviews. Parents of children with acute musculoskeletal injuries were recruited from three Canadian paediatric emergency departments (Stollery Children’s Hospital [Edmonton, Alta.], CHU Sainte-Justine [Montreal, Qué.], and Winnipeg Children’s Hospital [Winnipeg, Man.]). Interviews were conducted via telephone from June 2019 to March 2021. Verbatim transcription and thematic analyses occurred concurrently with data collection, supporting data saturation and theory development considerations. Results Twenty-seven interviews were completed. Five major themes regarding pain assessment and treatment emerged: a) My child’s comfort is a priority; b) Every situation is unique; c) Opioids only if necessary; d) Considerations when choosing opioids; and e) Pain research is important. Overall, parents were highly comfortable with their assessment of their child’s pain. Participants’ willingness to use opioid analgesia for their children was primarily dependent on perceptions of injury and pain severity. Although considerations for opioid use were similar between opioid-averse and opioid-willing families, the trade-offs between maximizing pain relief and minimizing risks were weighed differently. Conclusion Our study revealed that parents assess their child’s pain and distress as a global entity, with great confidence in their own assessment and decision-making. For most parents, the desire to relieve their children’s pain outweighed concerns of addiction, misuse, and adverse events when making decisions about opioid analgesia for short-term use. These results can inform evidence-based family-centred approaches to co-decision-making of analgesic plans for children with acute pain.

Application of behavioral economic strategies to enhance recruitment into a pediatric randomized clinical trial for postoperative pain relief: A randomized clinical trial.

A major challenge in conducting clinical trials is recruitment. Trial under-enrollment leads to underpowered studies. Behavioral economics offers strategies that may enhance trial recruitment. This study assessed the impact of behavioral economic strategies versus a standard biological approach to recruit children into a randomized clinical trial assessing a biofeedback-based virtual reality intervention for postoperative pain management. We hypothesized the behavioral economics-informed approach would increase enrollment into the future trial, intention to adhere to therapy, acceptability of the intervention, and perceived efficacy while decreasing perception of treatment burden and risk. This single-center, prospective, randomized trial recruited patients 12-18 years old undergoing surgery requiring postoperative admission and narcotic administration. Patient-parent dyads were randomized to watch a behavioral economics-informed (n = 64) or standard biological (n = 66) recruitment video about a study designed to assess impact of a virtual reality pain management intervention. There was no difference in rates of intention to enroll in the study between groups (behavioral economics: 75%, control: 79%, p = 0.744) or in median response scores to questions regarding intention to adhere to therapy (4.0 [3.0, 4.0] vs. 4.0 [3.0, 4.0], p=0.084), acceptability of therapy (4.0 [3.0, 4.0] vs. 4.0 [3.0, 4.0], p = 0.376), perceptions of treatment burden (3.0 [3.0, 4.0] vs. 4.0 [3.0, 4.0], p=0.251), and efficacy (3.0 [3.0, 4.0] vs. 3.0 [3.0, 4.0], p = 0.914). Patients in the behavioral economics group were less likely to perceive risk associated with virtual reality versus the control group (behavioral economics: 2.0 [1.0, 2.0], control: 2.0 [2.0, 3.0], p = 0.023). A behavioral economics-informed video did not increase patients' intentions to enroll into a clinical trial assessing the impact of virtual reality intervention for postoperative pain management. Either approach would be sufficient for patient recruitment for this type of clinical trial since the overall intention to enroll rate was 77%.

Pathophysiology of primary hypertension in children and adolescents.

The progress in research on the physiology of the cardiovascular system made in the last 100years allowed for the development of the pathogenesis not only of secondary forms of hypertension but also of primary hypertension. The main determinants of blood pressure are described by the relationship between stroke volume, heart rate, peripheral resistance, and arterial stiffness. The theories developed by Guyton and Folkow describe the importance of the volume factor and total peripheral resistance. However, none of them fully presents the pathogenesis of essential hypertension. The multifactorial model of primary hypertension pathogenesis developed by Irving Page in the 1940s, called Page's mosaic, covers most of the pathophysiological phenomena observed in essential hypertension. The most important pathophysiological phenomena included in Page's mosaic form a network of interconnected "nodes". New discoveries both from experimental and clinical studies made in recent decades have allowed the original Page mosaic to be modified and the addition of new pathophysiological nodes. Most of the clinical studies confirming the validity of the multifactorial pathogenesis of primary hypertension concern adults. However, hypertension develops in childhood and is even perinatally programmed. Therefore, the next nodes in Page's mosaic should be age and perinatal factors. This article presents data from pediatric clinical trials describing the most important pathophysiological processes associated with the development of essential hypertension in children and adolescents.

The Role of Therapeutic Drug Monitoring in Children.

The use of biologic therapies has changed the treatment landscape for children with inflammatory bowel disease. While the novel biologics have improved clinical outcomes, there remains a significant gap in achieving endoscopic remission, prolonged steroid-free remission, and drug durability. Contributing to this gap is the paucity of real-world pharmacokinetic studies in children and a failure to dose optimize therapy during induction. Emerging data from a pediatric clinical trial and several observational studies have shown that the combination of proactive therapeutic drug monitoring and achievement of early therapeutic concentrations is effective in achieving improved outcomes. The next steps will be to leverage these past studies to develop more innovative clinical trials to properly assess the safety and effectiveness of proactive therapeutic drug monitoring in children.

Clinical Nurses' Identification of a Wearable Universal Serial Bus Used for Pediatric Oncology Clinical Trial Participant Safety Management.

The expanded access to clinical trials has provided more patients the opportunity to participate in novel therapeutics research. There is an increased likelihood of a patient, as a pediatric oncology clinical trial participant, to present for clinical care outside the research site, such as at an emergency room or urgent care center. A novel wearable universal serial bus device is a proposed technology to bridge potential communication gaps, pertaining to critical information such as side effects and permitted therapies, between research teams and clinical teams where investigational agents may be contraindicated to standard treatments. Fifty-five emergency and urgent care nurses across the United States were presented, via online survey without priming to the context of clinical trials or the device, a picture of a pediatric patient wearing the novel wearable device prompted to identify significant, environmental cues important for patient care. Of the 40 nurses observing the patient photo, three identified the wearable device within Situational Awareness Global Assessment Tool formatted narrative response fields. Analysis of the narrative nurse-participant responses of significant clinical findings upon initial assessment of the pediatric patient photo is described, as well as the implications for subsequent prototyping of the novel universal serial bus prototype.

Reporting and Representation of Participant Race and Ethnicity in National Institutes of Health–Funded Pediatric Clinical Trials

Enrolling racially and ethnically diverse pediatric research participants is critical to ensuring equitable access to health advances and generalizability of research findings. To examine the reporting of race and ethnicity for National Institutes of Health (NIH)-funded pediatric clinical trials and to assess the representation of pediatric participants from different racial and ethnic groups compared with distributions in the US population. This cross-sectional study included NIH-funded pediatric (ages 0-17 years) trials with grant funding completed between January 1, 2017, and December 31, 2019, and trial results reported as of June 30, 2022. National Institutes of Health policies and guidance statements on the reporting of race and ethnicity of participants in NIH-funded clinical trials. The main outcome was reporting of participant race and ethnicity for NIH-funded pediatric clinical trials in publications and ClinicalTrials.gov. There were 363 NIH-funded pediatric trials included in the analysis. Reporting of race and ethnicity data was similar in publications and ClinicalTrials.gov, with 90.3% (167 of 185) of publications and 93.9% (77 of 82) of ClinicalTrial.gov reports providing data on race and/or ethnicity. Among the 160 publications reporting race, there were 43 different race classifications, with only 3 publications (1.9%) using the NIH-required categories. By contrast, in ClinicalTrials.gov, 61 reports (79.2%) provided participant race and ethnicity using the NIH-specified categories (P < .001). There was racially and ethnically diverse enrollment of pediatric participants, with overrepresentation of racial and ethnic minority groups compared with the US population. This cross-sectional study of NIH-funded pediatric clinical trials found high rates of reporting of participant race and ethnicity, with diverse representation of trial participants. These findings suggest that the NIH is meeting its directive of ensuring diverse participant enrollment in the research it supports.

Assessing attitudes towards pediatric research participation across diverse populations: Psychometric properties of a novel tool

BackgroundClinical trials play a crucial role in advancing medical knowledge and improving health outcomes. However, there is a recognized need for greater representation of marginalized groups to ensure that research findings can be generalized and effectively applied to all individuals. While the Pediatric Research Participation Questionnaire (PRPQ) was developed to assist pediatric clinical trials research by identifying benefits and barriers to research participation among children with chronic medical conditions, there is still limited insight into the structure of the PRPQ when administered in diverse samples, including the general pediatric population. Therefore, the current study examined the factor structure of the PRPQ in a general pediatric population to investigate whether rural-urban differences exist in the PRPQ factor structure. MethodsCaregivers (N = 600) of children under age 18 completed the PRPQ in a population-based survey in Mississippi. Sampling was stratified to ensure equal representation in rural (n = 300) and urban areas (n = 300). Exploratory and confirmatory factor analyses were conducted to determine the factor structure of the PRPQ. ResultsA five-factor structure was identified, compromising: social pressure, direct benefit, reasons for participation, mistrust in research/researchers, reasons against participation. While results were similar among urban participants, a three-factor structure emerged for rural participants. ConclusionsThis study contributes to the broader understanding of research participation among underrepresented groups. The findings suggest that clinical researchers should consider tailoring recruitment strategies to increase clinical trial participation among children in rural areas. Understanding factors that influence pediatric research participation, particularly among marginalized communities, is crucial for developing effective recruitment and retention strategies.

Effects of Teduglutide on Diarrhea in Pediatric Patients with Short Bowel Syndrome-Associated Intestinal Failure.

This post-hoc analysis evaluated the effect of teduglutide treatment on diarrhea in patients with short bowel syndrome-associated intestinal failure (SBS-IF). Data from 2 open-label, multicenter, phase 3 pediatric SBS-IF clinical trials of teduglutide (NCT01952080 and NCT02682381) were pooled where possible. The primary objective was to evaluate the change in stool consistency, frequency, and volume from baseline to weeks 12 and 24 of treatment in patients who received any teduglutide dose from both studies ("total teduglutide"). Safety assessments included gastrointestinal adverse event reporting. Overall, 101 patients were analyzed. Among the total teduglutide group (n = 87), there were significant changes from baseline to weeks 12 and 24 in mean (standard error) Bristol Stool Form Scale (BSFS) score [-1.8 (0.26; P < 0.0001) and -2.2 (0.27; P < 0.0001), respectively], parenteral nutrition and/or intravenous fluid (PN/IV) volume [-16.9 (1.7; P < 0.0001) and -20.1 (2.3; P < 0.0001) mL/kg/day, respectively], and enteral nutrition volume [9.2 (1.7; P < 0.0001) and 9.6 (2.3; P = 0.0002) mL/kg/day, respectively]. Among patients in the standard of care group (n = 14) there were numerical changes in BSFS score, and enteral nutrition volume at weeks 12 and 24; significant changes in PN/IV volume [-6.9 (1.5) mL/kg/day; P = 0.0041] were observed at 24 weeks, but not at 12 weeks. In this post-hoc analysis, short-term treatment with teduglutide was associated with improved stool consistency, as well as trends towards reductions in PN/IV requirements and advancements in enteral nutrition volume in children with SBS-IF. Further research assessing the impact of patient-level factors on stool characteristics when using teduglutide is warranted.