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Duchenne muscular dystrophy (DMD), a rare pediatric disease, presents numerous challenges when designing clinical trials, mainly due to the scarcity of available trial participants and the heterogeneity of disease progression. A quantitative clinical trial simulator (CTS) has been developed based on previously published five disease progression models describing each of the longitudinal changes in the velocity at which individuals can complete specified timed functional tests, frequently used as clinical trial efficacy endpoints (supine-stand, 4-stair climb, and 10 m walk/run test or 30-foot walk/run test), as well as each of the longitudinal changes in forced vital capacity and North Star Ambulatory Assessment total score. The model-based CTS allows researchers to optimize the selection of numerous trial parameters for designing trials for the five functional measures commonly used as endpoints in DMD clinical trials. This case report serves as a demonstration of the tool's functionality while providing an easy-to-follow guide for users to reference when preparing simulations of their own design. Two case studies, using input selection based on previous DMD clinical trials, provide realistic examples of how the tool can help optimize clinical trial design without the risk of decreasing statistical significance. This optimization allows researchers to mitigate the risk of designing trials that may be longer, larger, or more inclusive/exclusive than necessary., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The importance of patient engagement in product development and clinical research is widely acknowledged. In pediatrics, parents and guardians are often vocal advocates for their children in the process, but investigators and sponsors rarely directly solicit children's or adolescents' perspectives in clinical research planning or as patient partners during the conduct of research. Here, we provide compelling reasons and recommendations for investigators and sponsors to systematically engage young people in the design, conduct, and review of research, and the premise that input will be incorporated as a routine expectation. We consider the theoretical, ethical, and practical implications of this approach., Competing Interests: SJ is a paid member of a data monitoring committee for CSL Behring. SH was formerly the Global Head of Scientific Patient Engagement and stockholder of Novartis AG. CB-R is a full time employee and stockholder of Novartis AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Bierer, Koppelman, Croker, Hosseinzadeh, Hovinga, Joffe, McMillan, Nelson and Bucci-Rechtweg.)

Background/aims: Due to a lack of standard pediatric prescribing information, medicines are often used in a dosage form or for an indication that has not been investigated in children. Pediatric clinical trial research networks aim to facilitate the timely availability of innovative drugs for children by developing standardized trial facilitation and conduct processes. This paper aims to assess the (pre)feasibility duration and characteristics of a US-sponsored clinical trial, in collaboration with I-ACT for Children, for distribution across European sites via European clinical research facilitation networks., Method: A transatlantic partnership between the Belgian Pediatric Clinical Research Network (BPCRN,) and I-ACT for Children conducted feasibilities in Europe for industry-sponsored early-stage pharmacological clinical trials between 2019 and 2022. The collaboration recorded time to event for key elements of feasibility, influences on successful feasibility, and benefits of collaboration., Results: Trials were conducted across 17 European countries with 202 participating hospital sites. The initial phase, the pre-feasibility questionnaire had a 70% response rate from 142 sites, and sites took a median 38 days (IQR 20 days) to complete the questionnaire for five trials. All responses underwent a quality control, addressing inaccuracies in site capabilities and recruitment. The first trial's CDA and feasibility questionnaire were completed in roughly 2 months for 7 countries. Time to completion was affected by precontracted sites, limited scope of studies, changes in timelines, COVID-related disruptions, and a learning curve for collaboration., Conclusion: Collaboration between European collaborative national networks and US-network I-ACT for Children has supported site identification of global pediatric clinical trials. This illustrates one method for the importance of early engagement with sponsors and implementation of effective communication systems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Degraeuwe, Hovinga, De Maré, Fernandes, Heaton, Nuytinck, Persijn, Raes, Vande Walle and Turner.)

Background: Despite global efforts to improve paediatric clinical trials, significant delays continue in paediatric drug approvals. Collaboration between research networks is needed to address these delays. This paper is a first step to promote interoperability between paediatric networks from different jurisdictions by comparing drivers for, and content of, metrics about clinical trial conduct., Methods: Three paediatric networks, Institute for Advanced Clinical Trials for Children, the Maternal Infant Child and Youth Research Network and conect4children, have each developed metrics to address delays and create efficiencies. We identified the methodology by which each network identified metrics, described the metrics of each network, and mapped consistency to come to consensus about core metrics that networks could share., Results: Metric selection was driven by site quality improvement in one network (11 metrics), by network performance in one network (13 metrics), and by both in one network (five metrics). The domains of metrics were research capacity/capability, site identification/feasibility, trial start-up, and recruitment/enrolment. The network driven by site quality improvement did not have indicators for capacity/capability or identification/feasibility. Fifteen metrics for trial start up and conduct were identified. Metrics related to site approvals were found in all three networks. The themes for metrics can inform the development of 'shared' metrics., Conclusion: We found disparity in drivers, methodology and metrics. Tackling this disparity will result in a unified approach to addressing delays in paediatric drug approvals. Collaborative work to define inter-operable metrics globally is outlined., (© 2024. The Author(s).)

Background: Recent decades have seen many advances in policy and legislation that support the development of drugs used by neonates, infants, children, and young people. This review summarizes the characteristics and performance of networks capable of conducting studies needed to meet regulatory requirements and make advances in pediatric drug development., Methods: Description of network goals and capabilities by network leaders., Results: In the United States, Europe, Japan, and Canada, clinical research networks have been organized to meet the needs of biopharmaceutical and academic sponsors for timely access to high-quality sites, as well as to provide advice about drug development with regard to strategic and operational feasibility. Each network addresses the specificities of its context while working toward shared principles including standards and timelines; alignment of goals and processes, while not disturbing arrangements for conducting trials that work well; wide geographic coverage; all age groups and pediatric conditions; sources of funding; sites that compete on performance; performance monitoring for benchmarking, and opportunities to optimize the allocation of resources; and education and training for network members. Facilitation in interactions among these networks is based on a single point-of-contact for each; similar approaches to strategic and operational feasibility assessment, and site selection; and collaborative approaches to education and training., Conclusion: Within five years, clinical research networks will support the needs of biopharmaceutical and publicly funded pediatric drug development through locally appropriate and globally interoperable approaches., (© 2022. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Including adolescents in adult clinical trials can play an important role in making innovative new medicines available to children in a timelier fashion. Stakeholders involved in the processes leading to regulatory approval and labeling of new drugs recognize that challenges exist in involving adolescents and older children in clinical trials before the safety and efficacy of these drugs are established for adults. However, it has been possible to design and execute phase 3 trials that combine adults with adolescents which are medically and scientifically sound and ethically justified. Based on this experience and considerations of the medical and scientific, ethical, and operation-related matters, the 2019 Pediatric Innovation Research Forum advocated for the position that adolescents routinely be considered for enrollment in phase 3 clinical trials. The Forum also concluded that exclusion of adolescents in adult pivotal trials occur only when a thorough evaluation of the target disease and the potential benefit and risks of the study intervention supports a delay in their involvement until after completion of clinical trials in adults.

Objectives: Antiepileptic drug (AED) monotherapy is usually effective in 60% of the patients with epilepsy while the remaining patients have refractory epilepsy. This study compared treatment patterns (adherence, persistence, addition, and switching) associated with refractory and nonrefractory epilepsy., Methods: Texas Medicaid claims from 09/01/07-12/31/13 were analyzed, and patients eligible for the study 1) were between 18 and 62 years of age, 2) had a prescription claim for an AED during the identification period (03/01/08-12/31/11) with no prior baseline AED use (6-month), and 3) had evidence of epilepsy diagnosis within 6 months of AED use. Based on AED use in the identification period, patients were categorized into "refractory" (≥3AEDs) and "nonrefractory" (<3AEDs) cohorts. The index date was the date of the first AED claim. Patients in both cohorts were matched 1:1 using propensity scoring and compared for adherence (proportion of days covered (PDC) ≥80% vs. <80%), persistence, addition (yes/no), and switching (yes/no) using multivariate conditional regression models. Conditional logistic regression and Cox proportional hazard models were used to address the study objectives., Results: Of the 10,599 eligible patients, 2798 (26.5%) patients in the refractory cohort were matched to patients in the nonrefractory cohort. Patients in the refractory cohort had significantly higher (p < 0.005) mean (±Standard deviation (SD)) adherence (88.6% (±19.1%) vs. 77.0% ± (25.8%)) and persistence (328.0 (±87.3) days vs. 294.9 ± (113.4) days) as compared with patients in the nonrefractory cohort. Compared with patients with nonrefractory epilepsy, patients with refractory epilepsy were 3.6 times (odds ratio (OR) = 3.553; 95% confidence interval (CI) = 3.060-4.125; p < 0.0001) more likely to adhere to AEDs and had a 34.7% (hazard ratio (HR) = 0.653; 95% CI = 0.608-0.702; p < 0.0001) lower hazard rate of discontinuation of AEDs. Also, patients with refractory epilepsy were 3.7 times (OR = 3.723; 95% CI = 2.902-4.776; p < 0.0001) more likely to add an alternative AED and 3.6 times (OR = 3.591; 95% CI = 3.010-4.284; p < 0.0001) more likely to switch to an alternative AED., Conclusion: Patients with refractory epilepsy were significantly more likely to adhere and persist to AED regimen and were significantly more likely to add and switch to an alternative AED than patients with nonrefractory epilepsy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to determine if a rapid albuterol delivery pathway with a breath-enhanced nebulizer can reduce emergency department (ED) length of stay (LOS), while maintaining admission rates and side effects, when compared to a traditional asthma pathway with a standard jet nebulizer., Methods: Children aged 3-18 presenting to a large urban pediatric ED for asthma were enrolled if they were determined by pediatric asthma score to have a moderate to severe exacerbation. Subjects were randomized to either a standard treatment arm where they received up to 2 continuous albuterol nebulizations, or a rapid albuterol arm where they received up to 4 rapid albuterol treatments with a breath-enhanced nebulizer, depending on severity scoring. The primary endpoint was ED LOS from enrollment until disposition decision. Asthma scores, albuterol dose, side effects, and return visits were also recorded., Results: A total of 50 subjects were enrolled (25 in each arm). The study LOS was shorter in the rapid albuterol group (118 vs. 163 minutes, p = 0.0002). When total ED LOS was analyzed, the difference was no longer statistically significant (192 vs. 203 minutes, p = 0.65). There were no statistically significant differences with respect to admission rates, asthma score changes, side effects, or return visits., Conclusion: A rapid albuterol treatment pathway that utilizes a breath-enhanced nebulizer is an effective alternative to traditional pathways that utilize continuous nebulizations for children with moderate to severe asthma exacerbations in the ED.

Background and Objectives: Family-centered rounds (FCR) are an important and recommended component of pediatric hospital care. This study compares direct observations versus perceptions and ideals of who talks during FCR., Methods: A silent investigator observed FCR and noted who spoke, time in patient rooms, nurse and family presences, and patient information. After the observation period, the medical team was offered an anonymous survey regarding typical and ideal usage of time on FCR. Data analysis included general linear models and analysis of variance tests., Results: Thirty rounding sessions involving 234 encounters of FCR over a 12-week period were analyzed. On average, teams spent 7 minutes in each patient room and approximately the same amount of time outside of the room. Attending physicians were the dominant medical speakers during rounds (30.8%), and nurses spoke the least (2%). When inside a patient room, there was no significant difference between the percentage of time that attending physicians spoke (25.6%) and that of families and patients (23.0%). The surveys revealed that the medical team consistently underestimated the percentage of time attending physicians talked and desired attending physicians to talk less. They also overestimated the time spent in the patient rooms, the time families talked, and nurse presence during rounds and desired an increase in each of these areas., Conclusions: The medical teams' perceptions of FCR do not reflect clinical observations. Medical teams believe and desire that attending physicians talk less and families and nurses talk more than observations reveal., (Copyright © 2016 by the American Academy of Pediatrics.)

Background: The safety and efficacy of thrombolysis after acute stroke in children have not been established. Our aim was to describe current practices and results of the use of alteplase for acute arterial ischaemic stroke in children enrolled in an international pediatric stroke registry and to compare current practices with those published in case reports and with guidelines for the use of alteplase for adult stroke., Methods: In this multicentre observational cohort study, we analysed the clinical features, the dosing and timing of treatment, and the short-term outcome in children treated with alteplase for acute arterial ischaemic stroke who were enrolled in the International Pediatric Stroke Study (IPSS) between January, 2003, and July, 2007. The findings from the IPSS were compared with published case reports for clinical features, adherence to adult guidelines for alteplase, and outcomes., Findings: Of 687 children with acute arterial ischaemic stroke enrolled in the IPSS, 15 (2%) received alteplase: nine received intravenous alteplase and six received intra-arterial alteplase. The median time to treatment from stroke onset was 3.3 h (range 2.0-52.0 h) for intravenous alteplase and 4.5 h (3.8-24.0 h) for intra-arterial alteplase. Two patients died (one owing to massive infarction and brain herniation, and one owing to brainstem infarction). At discharge from hospital, one patient was healthy and 12 patients had neurological deficits. Intracranial haemorrhage after alteplase occurred in four of 15 patients, although none of the bleeding events was judged to be acutely symptomatic. When compared with ten patients reported in published articles who were given intravenous alteplase, the nine patients in the IPSS cohort were mostly younger, waited longer for treatment, and had worse outcomes, which suggests there is a publication bias towards short treatment intervals from symptom onset and favourable outcomes., Interpretation: Children with acute stroke received alteplase infrequently and at time intervals that often deviated from adult guidelines. Although no alteplase-related deaths or symptomatic intracranial haemorrhage was reported, poor neurological outcome was common. Clinical trials to evaluate the dose and the safety and efficacy of alteplase are needed in childhood stroke.

Unlabelled: A proportion of patients undergoing epilepsy surgery, and receiving carbamazepine (CBZ), experience significant elevations in CBZ plasma concentrations, some with associated CBZ toxicity. The objective of this study was to identify significant risk factors for elevations (>12 microg/ml) in CBZ concentrations and CBZ-induced toxicity following epilepsy surgery., Methods: We retrospectively examined charts of 74 inpatients (31 children and 43 adults) chronically receiving CBZ and undergoing epilepsy surgery between January 1996 and June 2000. Patient demographics, medications, type of surgery, seizure history, adverse events, CBZ doses and concentrations were evaluated., Results: 51.2% of adults and 51.6% of pediatric patients had drug elevations. In the pediatric group, 12.9% had symptoms of toxicity compared to 9.3% in the adult group. Five risk factors-pre-operative CBZ dose, fentanyl dose, surgery day CBZ concentration, body weight, and blood loss-were related to post-operative CBZ concentrations. Three risk factors: age <18 years, pre-operative CBZ dose, and the surgery day CBZ (immediate pre-operative) concentration, were significantly related to the outcome measure of abnormal CBZ concentration (>12 microg/ml). Two variables significantly related to toxicity were average post-operative CBZ dose and the surgery day CBZ concentration. Increases in concentrations occurred at a mean 33+/-13.7 h (range: 11-74 h) after surgery., Discussion: Based upon our results in patients with one or more risk factors, we suggest that reduction of post-operative CBZ doses be considered.

Levetiracetam is a new antiepileptic drug, structurally and mechanistically dissimilar to other marketed antiepileptic drugs. It is effective in reducing partial seizures in patients with epilepsy, both as adjunctive treatment and as monotherapy. Levetiracetam has many therapeutic advantages for patients with epilepsy. It has favorable pharmacokinetic characteristics (good bioavailability, linear pharmacokinetics, insignificant protein binding, lack of hepatic metabolism, and rapid achievement of steady-state concentrations) and a low potential for drug interactions. Recommended starting dosages are considered to be clinically effective; therefore, patients can have some protection from seizures soon after they begin levetiracetam. The most common adverse effects observed with levetiracetam are mild and include somnolence, asthenia, and dizziness. Clinical experience and data from meta-analyses indicate that levetiracetam is well tolerated, with efficacy comparable or slightly better than that observed with other new antiepileptic drugs. Levetiracetam may be particularly useful in patients who are unresponsive to other antiepileptic drugs, patients receiving drugs with increased potential for drug interactions, or those with hepatic impairment.

Objective: To report the pharmacokinetics of intravenous valproate (VPA) in children with generalized convulsive status epilepticus (GCSE) or nonconvulsive status epilepticus (NCSE). To provide loading and maintenance dosing for patients with hepatic induction secondary to concurrent anticonvulsants., Case Summary: Two patients (10 y, 34 mo) with GCSE refractory to benzodiazepines, phenobarbital, phenytoin, and pentobarbital received intravenous VPA. Apparent volume of distribution (Vd) following a 20 mg/kg loading dose was 0.29 L/kg. Maintenance infusions of 4-6 mg/kg/h produced steady-state total concentrations of 66 mg/L and 92.4 mg/L (unbound concentration 44.6 mg/L). Clearance ranged from 63-66 mL/h/kg. An eight-year-old with NCSE received intravenous VPA (13.4 mg/kg load followed by 9 mg/kg every 8 h). Total and unbound steady-state VPA concentrations were 32.9 mg/L and 21.2 mg/L, respectively. Elimination half-life was eight hours., Discussion: We constructed a pharmacokinetic simulation using VPA parameters from children receiving mono- or polyanticonvulsants. Our Vd and elimination half-life rates were comparable with published pediatric values. Patients on hepatic inducers had clearance rates 2.5 times those of children receiving oral anticonvulsant polytherapy. Unbound fractions (48.3% and 66%) were significantly higher than normal., Conclusions: A 20 mg/kg loading dose should produce a concentration after the bolus dose of approximately 75 mg/L. Initial infusion should consider hepatic induction (noninduced = 1 mg/kg/h, polyanticonvulsant therapy = 2 mg/kg/h, and high-dose pentobarbital = 4 mg/kg/h). Adjustments should be based on response and serum concentrations.