Pediatric Randomized Controlled Trials Research Articles

Assessment of Usefulness of Randomized Control Trials in Child Health Research Published in 2007 and 2017

ObjectiveTo examine how clinical usefulness in pediatric research with randomized controlled trials (RCTs) has changed over a 10-year period via a research usefulness tool composed of unique clinical usefulness criteria. Study designWe leveraged a pre-existing sample of child health RCTs published in 2007, used by our team in a previous study. Using the same methods, a research librarian executed a literature search in the Cochrane Central Register of Controlled Trials for the 2017 cohort. We included the first 300 eligible citations from the randomly ordered list for each year, creating two cohorts of 300 publications each, one in 2007 and one in 2017. Each publication was analyzed and data regarding primary and secondary outcomes, as well as 11 unique criteria of clinical usefulness, were extracted. Each publication was then graded using a tool created by our research team. After quality review, statistical analysis was then performed. Results600 pediatric RCT publications were included in this review. The mean score increased from 6.07 in 2007 to 9.20 in 2017 (P<0.001). Usefulness factors that saw the largest increase in reporting were context placement, funding statements, and conflict of interest statements, while patient centeredness, value for money, and raw data availability remained infrequently reported. ConclusionOur results demonstrate that clinical usefulness of pediatric research improved over this 10-year period, but there are still areas that need a great deal of improvement in order to maximize clinical usefulness and reduce research waste.

Reasons for parental refusal to provide consent in a pediatric randomized controlled trial: Lessons learned

Abstract BACKGROUND: Results from randomized controlled trials (RCTs) are considered to have the highest level of evidence. Recruiting children for RCT is challenging and greatly influenced by the perception and decision of parents. OBJECTIVES: To find the reasons for refusal to participate in RCT. DESIGNS: Questionnaire-based qualitative study. MATERIALS AND METHODS: Parents who refused to participate in an RCT were asked to fill out the questionnaire, mentioning the reasons for the refusal. RESULTS: A total of 20 (14.8%) participants’ parent out of the 135 participants refused to participate in the trial. The age of participants who refused ranged from 6 weeks to 5 years old. We found that the reasons for refusal were as follows: 60.87% had apprehensions, 21.74% believed that pain pre-prophylaxis was unnecessary or preferred post-vaccination if needed, 8.69% refused because they had not received previous vaccinations, and 8.69% cited time constraints. CONCLUSION: Addressing the apprehension of parents in pediatric RCTs is crucial for reducing refusals. Non-placebo RCTs can be considered wherever feasible to address concerns about no drug administration to children.

Psychopharmacological Treatment Algorithms of Manic/Mixed and Depressed Episodes in Pediatric Bipolar Disorder.

Introduction: Pediatric bipolar disorder (PBD) is a severe psychiatric illness diagnosed before the age of 18, which is associated with extreme shifts in mood characterized by manic and depressive episodes. In 2005, AACAP published algorithms to guide pharmacological treatment of manic/mixed episodes associated with PBD. At that time, lithium was the only Food and Drug Administration (FDA)-approved treatment for pediatric bipolar manic/mixed episodes. The goal of this article is to review evidence that has emerged since the AACAP algorithm in 2005. Methods: Literature searches were conducted through PubMed and limited to studies published between 2005 and 2021, using keywords that focused on randomized controlled trials (RCTs) for available psychopharmacological medications. In addition, the authors conducted in-depth searches for articles providing evidence for agents included in the 2005 AACAP algorithm. Results: Since the publication of the AACAP algorithm in 2005, multiple RCTs have been conducted in PBD, leading to FDA approval of five medications (aripiprazole, asenapine, olanzapine, quetiapine, and risperidone) for the treatment of manic/mixed episodes and two medications (lurasidone and olanzapine-fluoxetine combination) for the treatment of depressed episodes. Divalproex sodium and oxcarbazepine were studied in pediatric RCTs and failed to separate from placebo. Conclusions: We offer an update to the 2005 AACAP algorithms for the treatment of pediatric bipolar mixed/manic episodes and added an evidence-based algorithm for the treatment of depression in PBD. In addition to treatment algorithms, we review current evidence for efficacy of agents proposed in the AACAP algorithm and provide tables summarizing medication side effects and efficacy.

Pragmatism in Pediatric Neurosurgery: More Than a Pipe Dream? A Systematic Literature Review and Analysis

Classic randomized controlled trials (RCTs) form the cornerstone for medical guidelines and protocols. However, in neurosurgery, RCTs are not always applicable to everyday clinical practice. Pragmatic controlled trials aim to incorporate real-life data with the preservation of the methodologic quality. This study is a systematic literature review of all pediatric neurosurgical RCTs published between 2000 and 2020 and an analysis of their pragmatism. An electronic database search was performed in PubMed, EMBASE, and the Cochrane Library to identify all relevant trials. Pragmatism was evaluated retrospectively on 9 domains: eligibility, recruitment, setting, organization, flexibility (delivery and adherence), follow-up, primary outcome, and primary analysis. Of the 1862 studies included, 15 met the inclusion criteria. On average, studies scored between equally pragmatic/explanatory and rather pragmatic (M= 3.59, standard deviation [SD]= 0.56). Lowest ratings were seen for setting (M= 2.80, SD= 1.66) and eligibility (M= 3.20, SD= 1.66). Highest scores of pragmatism were given to analysis (M= 4.67, SD= 0.82) and intervention organization (M= 4.60, SD= 1.06). There was no significant difference between studies based on number of patients included, main subject, or publication year. Pediatric neurosurgical RCTs scored reasonably well on overall pragmatism. In the future, there will be a greater need for pragmatic controlled trials inpediatric neurosurgery to bridge the divide between real-life data and reliable methodological quality. There is an opportunity to develop further applications of pragmatism tailored to surgical interventions.

Disparities in pediatric clinical trials for acne vulgaris: A cross-sectional study

To the Editor: Acne is the most common skin condition, affecting >231 million people globally, with much of the disease burden in pediatric and female populations.1 Treatment often requires medications; however, randomized controlled trials (RCTs) confirming the safety/efficacy of such interventions have not always been demographically equitable.2 Well-designed pediatric RCTs are necessary to judiciously evaluate pharmacologic differences between children/adults, sexes, and ethnicities/races. Clinically, understanding demographic differences can affect the treatment of skin diseases.

Examining Trends in Dermatology Publications: A 10-Year Follow-up.

Examining trends in adult and pediatric dermatology publications by Mimouni et al for 15 years (1993&ndash;2007) showed that there was a higher yearly increase in articles with higher level of evidence such as clinical and randomized controlled trials with a slower rise in articles with a lower level of evidence such as letters and case reports.1 We wanted to see if trends in dermatology research have differed over the following 10 years (2008&ndash;2017). We used the methodology of Mimouni et al to find the total number and categorization of publications in adult and pediatric dermatology from 2008 to 2017. We used MEDLINE to search the terms &lsquo;skin&rsquo; AND &lsquo;disease&rsquo; OR &lsquo;dermatology&rsquo; for adults and pediatrics. A regression analysis (SAS 9.4) was used to understand the change in frequency across the years. By analyzing publications from 2008 to 2017, speculations mentioned in Mimouni et al held true regarding the statistically significant increase in total number of publications in addition to meta-analyses and practice guidelines, which was not shown in the 1993&ndash;2007 analysis. The statistically significant increase previously mentioned in clinical trials, case reports, and pediatric randomized controlled trials was lost in the 2008-2017 data. Trends in pediatric and adult dermatology publications in 2008&ndash;2017 differ from those identified in 1993&ndash;2007. There is a new significant increase in higher level of evidence not reported previously such as meta-analyses and practice guidelines. This is good for dermatology, and we hope the trend continues to further the specialty. J Drugs Dermatol. 2021;20(11)1248-1251. doi:10.36849/JDD.6088.

Large Pediatric Randomized Clinical Trials in ClinicalTrials.gov.

Large, randomized controlled trials (RCTs) are essential in answering pivotal questions in child health. We created a bird's eye view of all large, noncluster, nonvaccine pediatric RCTs with ≥1000 participants registered in ClinicalTrials.gov (last search January 9, 2020). We analyzed the funding sources, countries, outcomes, publication status, and correlation with the pediatric global burden of disease (GBD) for eligible trials. We identified 247 large, nonvaccine, noncluster pediatric RCTs. Only 17 mega-trials with ≥5000 participants existed. Industry funding was involved in only 52 (21%) and exclusively funded 47 (19%) trials. Participants were from high-income countries (HICs) in 100 (40%) trials, from lower-middle-income countries (LMICs) in 122 (49%) trials, and from both HICs and LMICs in 19 (8%) trials; 6 trials did not report participants' country location. Of trials conducted in LMIC, 43% of investigators were from HICs. Of non-LMIC participants trials (HIC or HIC and LMIC), 39% were multicountry trials versus 11% of exclusively LMIC participants trials. Few trials (18%; 44 of 247) targeted mortality as an outcome. 35% (58 of 164) of the trials completed ≥12 months were unpublished at the time of our assessment. The number of trials per disease category correlated well with pediatric GBD overall (ρ = 0.76) and in LMICs (ρ = 0.69), but not in HICs (ρ = 0.29). Incentivization of investigator collaborations across diverse country settings, timely publication of results of large pediatric RCTs, and alignment with the pediatric GBD are of pivotal importance to ultimately improve child health globally.

P value and Bayesian analysis in randomized-controlled trials in child health research published over 10 years, 2007 to 2017: a methodological review protocol

BackgroundThere is an unresolved debate about the reliability of the interpretation of P value. Some investigators have suggested that an alternative Bayesian method is preferred in conducting health research. As randomized-controlled trials (RCTs) are important in generating research evidence, we decided to investigate the extent, if any, the inferential statistical framework in published RCTs in child health research have changed over 10 years. We aim to examine the change in P value and Bayesian analysis in RCTs in child health research papers published from 2007 to 2017.MethodsWe will search the Cochrane Central Register of Controlled Trials (Wiley) to identify relevant citations. We will leverage a pre-existing sample of child health RCTs published in 2007 (n=300) used in our previous study of reporting quality of pediatric RCTs. Using the same strategy and study selection methods, we will identify a comparable random sample of child health RCTs published in 2017 (n=300). Eligible studies will include RCTs in health research among individuals aged 21 years and below. One reviewer will select studies for inclusion and extract the data and another reviewer will verify these. Disagreements will be resolved by a discussion between reviewers or by involving another reviewer. We will perform a descriptive analysis of 2007 and 2017 samples and analyze the results using both the frequentist and Bayesian methods. We will present specific characteristics of the clinical trials from 2007 and 2017 in tabular and graphical forms. We will report the difference in the proportion of P value and Bayesian analysis between 2007 and 2017 to assess the 10-year change. Clustering around P values of significance, if observed, will be reported.DiscussionThis review will present the difference in the proportion of trials that reported on P value and Bayesian analysis between 2007 and 2017 to assess the 10-year change. The implications for future clinical research will be discussed and this research work will be published in a peer-reviewed journal. This review has the potential to help inform the need for a change in the methodological approach from the null hypothesis significance test to Bayesian methods.Systematic review registrationOpen Science Framework https://osf.io/aj2df

Improved quality of reporting safety data of medication in paediatric randomised controlled trials

ObjectiveEvaluating the reporting of safety data of medication in paediatric randomised controlled trials (RCTs) in 2017–2018 compared with our earlier study.DesignLiterature search with a systemic appraisal of adverse drug event...

Publication Trends of Pediatric and Adult Randomized Controlled Trials in General Medical Journals, 2005-2018: A Citation Analysis.

Policy has been developed to promote the conduct of high-quality pediatric randomized controlled trials (RCTs). Whether these strategies have influenced publication trends in high-impact journals is unknown. We aim to evaluate characteristics, citation patterns, and publication trends of pediatric RCTs published in general medical journals (GMJs) compared with adult RCTs over a 13-year period. Studies were identified using Medline, and impact metrics were collected from Web of Science and Scopus. All RCTs published from 2005–2018 in 7 GMJs with the highest impact factors were identified for analysis. A random sample of matched pediatric and adult RCTs were assessed for publication characteristics, academic and non-academic citation. Citations were counted from publication until June 2019. Among 4146 RCTs, 2794 (67.3%) enrolled adults, 591 (14.2%) enrolled children, and 761 RCTs (18.3%) enrolled adult and pediatric patients. Adult RCTs published in GMJs grew by 5.1 publications per year (95% CI: 3.3–6.9), while the number of pediatric RCTs did not show significant change (−0.4 RCTs/year, 95% CI: −1.4–0.6). Adult RCTs were cited more than pediatric RCTs (median(IQR): 29.9 (68.5–462.8) citations/year vs. 13.2 (6.8–24.9) citations/year; p < 0.001); however, social media attention was similar (median(IQR) Altmetric Attention Score: 37 (13.75–133.8) vs. 26 (6.2–107.5); p = 0.25). Despite policies which may facilitate conduct of pediatric RCTs, the publishing gap in high-impact GMJs is widening.

Resective epilepsy surgery: assessment of randomized controlled trials.

Epilepsy is the most common form of chronic neurologic disease. Here, we review the available randomized controlled trials (RCTs) that examined the efficacy of resective epilepsy surgery in select patients suffering from medically intractable epilepsy (defined as persistent epilepsy despite two or more antiepileptic drugs [AEDs]). Three RCTs (two adult RCTs and one pediatric RCT) consistently supported the efficacy of resective surgery as treatment for epilepsy with semiology localized to the mesial temporal lobe. In these studies, 58-100% of the patients who underwent resective surgery achieved seizure freedom, in comparison to 0-13% of medically treated patients. In another RCT, the likelihood of seizure freedom after resective surgery was independent of the surgical approach (transSylvian [64%] versus subtemporal [62%]). Two other RCTs demonstrated that hippocampal resection is essential to optimize seizure control. But, no significant gain in seizure control was achieved beyond removing 2.5cm of the hippocampus. Across RCTs, minor complications (deficit lasting < 3months) and major complications (deficit > 3months) ranged 2-5% and 5-11% respectively. However, nonincapacitating superior subquadrantic visual-field defects (not typically considered a minor or major complication) were noted in up to 55% of the surgical cohort. The available RCTs provide compelling support for resective surgery as a treatment for mesial temporal lobe epilepsy and offer insights toward optimal surgical strategy.

Consent Rates Reported in Published Pediatric Randomized Controlled Trials

To determine the average reported consent rate for published pediatric randomized controlled trials (RCTs) and whether this rate varies by trial characteristics. A review of pediatric RCTs published in Medline in 2009, 2010, or 2015 was performed. Secondary analyses of prior trials, trials including adults, trials not requiring consent, or trials with missing or unclear consent data were excluded. Consent rate was defined as the number of patients enrolled divided by number of eligible patients where families were approached. Random effects meta-regression was conducted to determine the weighted average consent rate. Of 2347 trials identified, 1651 were excluded. An additional 418 of 696 (60%) were excluded because theconsent rate was missing or unclear. The average consent rate for 278 included RCTs was 82.6% (95% CI, 80.3%-84.8%) and was higher for vaccination compared with behavioral trials and for industry-funded compared with National Institutes of Health-funded or other government-funded trials. The average consent rate was <70% for 26% of included trials. Of these trials, US trials (28/77 [36.4%]) had a higher probability of a consent rate of <70% than non-US studies (35/64 [21.3%]) and multinational (9/37 [24.3%]) studies. There was slight variation by funding category. Although the average consent rate for published trials was reasonably high, approximately one-quarter of trials had consent rates of <70%. Consent rates reporting has improved over time, but remains suboptimal. Our findings should assist with the planning of future pediatric RCTs, although consent data from unpublished trials are also needed.

Ethics of randomized trials in pediatric surgery.

To provide the best evidence-based treatment for children, and timely evaluation of innovations, the role of the pediatric surgeon's participation in randomized controlled trials (RCTs) and prospective comparative studies is required. The ethical considerations of pediatric surgical RCTs pose unique practical difficulties in the design and performance of clinical trials in children. There are several ethical issues unique to pediatric surgical RCTs: diseases with low volume, an inability to conduct Phase 1 and 2 trials, parental emotional involvement, difficulty with recruitment in surgical trials, volume, and modified study design, issues with permission vs. assent and investigator bias. This article reviews the ethical aspects unique to pediatric surgical RCTs and prospective comparative studies.Level of evidence: Level 3.

P517 A randomised, placebo-controlled pilot trial of faecal microbiota transplantation for paediatric Crohn’s disease

Abstract Background The role of faecal microbiota transplant (FMT) in Crohn’s disease (CD) remains unclear. Small, open-label case series have shown high rates of clinical remission but protocols have varied across studies, and no randomised controlled trials (RCT) have been performed. We present a protocol for the first pilot RCT of FMT in paediatric CD patients, using a novel colonoscopic + oral capsular intervention that uses fresh-frozen and prepared, lyophilised donor stool. We will measure improvements in clinical disease activity, inflammatory biomarkers, endoscopic markers of mucosal inflammation, as well as, assess key aspects of trial feasibility. Methods Patients 3–17 years with active CD, on stable medication doses for 4 weeks are eligible. Patients will have an initial colonoscopy during which they will receive an infusion into the terminal ileum of normal saline (placebo) or prepared healthy donor stool (RBX2660; Rebiotix, USA) (active). This will be followed by 6-weeks of bi-weekly oral capsular therapy, containing methylcellulose (placebo) or lyophilised healthy adult donor stool (RBX7455; Rebiotix, USA). Randomisation is 2:1 to active and placebo arms (n = 45). Patients will be followed over 24 weeks. (Figure 1) Results Study feasibility will be assessed by: rate of recruitment, completion of sample collections, and frequency and type of adverse events. Clinical outcomes will be measured serially using: Paediatric Crohn’s Disease Activity Index (PCDAI), faecal calprotectin, blood inflammatory markers, and Simple Endoscopic Score for Crohn’s Disease (SES-CD) at baseline and end-of-study. Stool 16s rRNA, metagenomics, and urine metabolomics profiles will be performed on collected stool and urine samples. Patients who complete the placebo arm will be eligible to enter an open-label extension study. Results will be measured through ITT and PP analyses. Proportions and percentages will be reported on feasibility outcomes; odds ratios, mean differences and 95% confidence intervals will be reported on clinical outcomes as preliminary estimates of efficacy. Conclusion This is the first pilot RCT of FMT in the treatment of CD. Recruitment commenced April 2019 and 13 patients have met screening criteria, with 5 enrolled thus far. This study is novel for its focus on paediatric CD patients, and its use of a combined oral + colonoscopic FMT delivery method. The results of this trial will offer preliminary estimates of efficacy for FMT-based therapies in CD, and may support expansion to a future larger multicenter paediatric RCT using our validated study protocol.

Building a Global, Pediatric Vascular Access Registry: A Scoping Review of Trial Outcomes and Quality Indicators to Inform Evidence-Based Practice.

Internationally, there is a lack of comparative vascular access (VA) data for pediatric clinicians and organizations to benchmark outcomes, evaluate quality initiatives, and improve practice. A VA registry is needed to address these knowledge and data capture gaps. To determine the range and heterogeneity of VA outcome measures or quality indicators reported in randomized controlled trials (RCTs) and clinical registries, to inform development of a homogeneous, reliable, minimum dataset for a pediatric VA registry. Scoping review framework. A systematic search for RCTs reporting VA outcomes in pediatrics and neonates was undertaken in the Cochrane library, EMBASE, CINAHL, PubMed, MEDLINE, and EBSCO using a medical subject headings and key words related to VA and pediatrics. We included RCTs of children (0-18years) reporting any VA outcome. We identified clinical registries reporting VA data in children (0-18) through web-based searches using key words related to VA and clinical or quality registries. Additional registries were identified through peer consultation. The frequency and scope of outcome measures and quality indicators were extracted from trials and registries and evaluated. From 93 RCTs included, 214 different VA measures were reported, reflecting 14 outcome domains. The most commonly reported outcome domains were insertion (44 RCTs; 47%), noninfectious complications (33 RCTs; 35%), and infectious complications (30 RCTs; 32%). Of the 22 registries identified, VA-associated infection was the main quality indicator routinely collected (12 registries; 55%). Outcomes such as mechanical complications and patient-reported outcomes were infrequently collected. Vascular access outcomes reported in pediatric and neonatal RCTs are highly heterogeneous. Internationally, clinical registries currently collect minimal VA data with the exception of infection outcomes. A core dataset of reliable, relevant measures to children and clinicians for VA device quality is needed. This will enable a VA registry that facilitates inter-institutional and international benchmarking.

Critical components for designing and implementing randomized controlled trials.

Randomized controlled trials (RCTs) are considered the first level of evidence to assess the efficacy of novel interventions/therapies. Proper design and implementation of an RCT can result in convincing causal inferences. RCTs often represent the gold standard for clinical trials when appropriately designed, conducted and reported. However, there are limitations in implementation of RCTs, including sufficiency of randomized allocation (especial for allocation concealment), implementing standard intervention, maintaining follow‐up and statement of conflicting interests. Therefore, the basic principles of RCTs are outlined here so that pediatric investigators can further understand what is the best evidence based on RCTs. More importantly, the quality of pediatric RCTs may be improved by following challenges in pediatric clinical trials outlined here.

Psychological treatments for people with epilepsy.

Given the significant impact epilepsy can have on the health-related quality of life (HRQoL) of individuals with epilepsy and their families, there is great clinical interest in evidence-based psychological treatments, aimed at enhancing psychological well-being in people with epilepsy. A review of the current evidence was needed to assess the effects of psychological treatments for people with epilepsy on HRQoL outcomes, in order to inform future therapeutic recommendations and research designs. To assess the effects of psychological treatments for people with epilepsy on HRQoL outcomes. We searched the following databases on 20 September 2016, without language restrictions: Cochrane Epilepsy Group Specialized Register, CENTRAL, MEDLINE PsycINFO, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). We screened the references from included studies and relevant reviews, and contacted researchers in the field for unpublished studies. We considered randomized controlled trials (RCTs) and quasi-RCTs for this review. HRQoL was the main outcome measure. For the operational definition of 'psychological treatments', we included a broad range of treatments that used psychological or behavioral techniques designed to improve HRQoL, seizure frequency and severity, and psychiatric comorbidities for adults and children with epilepsy, compared to treatment as usual (TAU) or an active control group. We used standard methodological procedures expected by the Cochrane Collaboration. We included 24 completed RCTs, with a total of 2439 participants. Eleven studies investigated psychological interventions, such as cognitive, behavioral, and mindfulness-based interventions. The remaining studies were classified as educational interventions (N = 7), self-management interventions (N = 3), adherence interventions (N = 1), and mixed interventions (N = 2). Two studies investigated interventions for children and adolescents, and five studies investigated interventions for adolescents and adults. Based on satisfactory clinical and methodological homogeneity, we pooled data from six adult studies, two studies on adolescents and adults, and one on adolescents and young adults (468 participants) for HRQoL, measured with the Quality of Life in Epilepsy-31 (QOLIE-31). We found significant mean changes for the QOLIE-31 total score and six subscales (emotional well-being, energy and fatigue, overall QoL, seizure worry, medication effects, and cognitive functioning). The mean changes of the QOLIE-31 total score (mean improvement of 5.68 points (95% CI 3.11 to 8.24; P < 0.0001), and three subscales, emotional well-being (mean improvement of 7.03 points (95% CI 2.51 to 11.54; P = 0.002); energy and Fatigue (mean improvement of 6.90 points (95% CI 3.49 to 10.31; P < 0.0001); and overall QoL (mean improvement of 6.47 points (95% CI 2.68 to 10.25; P = 0.0008) exceeded the threshold of minimally important change (MIC), indicating a clinically meaningful post-intervention improvement of QoL. We downgraded the quality of the evidence provided by the meta-analysis because of serious risk of bias in some of the included studies. Consequentially, these results provided evidence of moderate quality that psychological treatments for adults with epilepsy may enhance overall QoL in people with epilepsy. Implications for practice: Psychological interventions and self-management interventions improved QoL, and emotional well-being, and reduced fatigue in adults and adolescents with epilepsy. Adjunctive use of psychological treatments for adults and adolescents with epilepsy may provide additional benefits to QoL in those who incorporate patient-centered management. Authors should strictly adhere to the CONSORT guidelines to improve the quality of reporting on their interventions. A thorough description of the intervention protocol is necessary to ensure reproducibility.When researching psychological treatments for people with epilepsy, the use of Quality of Life in Epilepsy Inventories (QOLIE-31, QOLIE-31-P, and QOLIE-89) would increase comparability. There is a critical gap in pediatric RCTs for psychological treatments, particularly those that use an epilepsy-specific measure of HRQoL.Finally, in order to increase the overall quality of study designs, adequate randomization with allocation concealment and blinded outcome assessment should be pursued when conducting RCTs. As attrition is often high in research that requires active participant participation, an intention-to-treat analysis should be carried out.

PP-11 Comparing completion rates of paediatric versus adult randomised controlled trials: a cross-sectional study

Background Clinical trial discontinuation represents a waste in research resources and raises ethical concerns. Conduct of clinical trials is perceived to be more challeng-ing in children than in adults. The aim of this study was to evaluate the impact of the age of participants on comple-tion rates of randomised controlled trials (RCTs). Methods This is a cross-sectional study on RCTs regis-tered in the ClinicalTrials.gov database. All RCTs registered in the database from its inception date (February 29, 2000) to December 31, 2016, were extracted. RCTs with unknown recruitment status or registered more than 60 days after their start date were excluded. Remaining RCTs were classified according to their recruitment status: active, completed, and discontinued trials, and according to the age of participants: children (0–17 years), adults (≥18 years), and mixed age populations. Further RCT charac-teristics were assessed using information registered in the database: study location, funding source, year of reg-istration, study phase, study design, type of intervention evaluated, blinding procedure, study duration, and enroll-ment achieved. A logistic regression model was applied to assess the impact of participant’s age category on trial completion while controlling for other potentially rele-vant trial characteristics. Results A total of 65 095 registered RCTs matched eligi-bility criteria. Paediatric and mixed age trials represented respectively 6.6% (n=4,314) and 8.9% (n=5,806) of regis-tered RCTs, and these proportions remained unchanged over the years. Among paediatric trials, 2151 were com-pleted (49.9%) and 367 were discontinued (8.5%). In adult and mixed age RCTs respectively, 27 338 (49.7%) and 2782 (47.9%) were completed, whereas 5584 (10.2%) and 546 (9.4%) were discontinued. Overall, paediatric and mixed age RCTs were more likely to be registered as com-pleted than adult RCTs (OR: 1.16, CI95%: 1.02–1.30; OR: 1.15, CI95%: 1.04–1.27, respectively). Also, RCTs were more likely to be registered as completed when they evaluat-ed interventions other than drugs/biologicals or devices/procedures, when the primary trial purpose was to eval-uate a non-therapeutical intervention, when they were funded by industry, when they were designed as cross-over trials, and when they included a masking procedure. Conclusion Paediatric or mixed age RCTs are more likely to be registered as completed than RCTs in adults. Con-trary to current perceptions and despite the specific chal-lenges of paediatric research, recruitment of children and adolescents is not a limiting factor to completing a RCT. Other study features, such as funding and design, impact completeness and should be carefully considered before initiating clinical research.

Premature Discontinuation of Pediatric Randomized Controlled Trials: A Retrospective Cohort Study

To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs. A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.

Major discrepancies between what clinical trial registries record and paediatric randomised controlled trials publish.

BackgroundWhether information from clinical trial registries (CTRs) and published randomised controlled trial (RCTs) differs remains unknown. Knowing more about discrepancies should alert those who rely on RCTs for medical decision-making to possible dissemination or reporting bias. To provide help in critically appraising research relevant for clinical practice we sought possible discrepancies between what CTRs record and paediatric RCTs actually publish. For this purpose, after identifying six reporting domains including funding, design, and outcomes, we collected data from 20 consecutive RCTs published in a widely read peer-reviewed paediatric journal and cross-checked reported features with those in the corresponding CTRs.MethodsWe collected data for 20 unselected, consecutive paediatric RCTs published in a widely read peer-reviewed journal from July to November 2013. To assess discrepancies, two reviewers identified and scored six reporting domains: funding and conflict of interests; sample size, inclusion and exclusion criteria or crossover; primary and secondary outcomes, early study completion, and main outcome reporting. After applying the Critical Appraisal Skills Programme (CASP) checklist, five reviewer pairs cross-checked CTRs and matching RCTs, then mapped and coded the reporting domains and scored combined discrepancy as low, medium and high.ResultsThe 20 RCTs were registered in five different CTRs. Even though the 20 RCTs fulfilled the CASP general criteria for assessing internal validity, 19 clinical trials had medium or high combined discrepancy scores for what the 20 RCTs reported and the matched five CTRs stated. All 20 RCTs selectively reported or failed to report main outcomes, 9 had discrepancies in declaring sponsorship, 8 discrepancies in the sample size, 9 failed to respect inclusion or exclusion criteria, 11 downgraded or modified primary outcome or upgraded secondary outcomes, and 13 completed early without justification. The CTRs for seven trials failed to index automatically the URL address or the RCT reference, and for 12 recorded RCT details, but the authors failed to report the results.ConclusionsMajor discrepancies between what CTRs record and paediatric RCTs publish raise concern about what clinical trials conclude. Our findings should make clinicians, who rely on RCT results for medical decision-making, aware of dissemination or reporting bias. Trialists need to bring CTR data and reported protocols into line with published data.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1551-6) contains supplementary material, which is available to authorized users.