Valerio Balassone

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.

Anastomotic Strictures after Esophageal Atresia Repair: Incidence, Investigations, and Management, Including Treatment of Refractory and Recurrent Strictures

Improved surgical techniques, as well as preoperative and postoperative care, have dramatically changed survival of children with esophageal atresia (EA) over the last decades. Nowadays, we are increasingly seeing EA patients experiencing significant short- and long-term gastrointestinal morbidities. Anastomotic stricture (AS) is the most common complication following operative repair. An esophageal stricture is defined as an intrinsic luminal narrowing in a clinically symptomatic patient, but no symptoms are sensitive or specific enough to diagnose an AS. This review aims to provide a comprehensive view of AS in EA children. Given the lack of evidence-based data, we critically analyzed significant studies on children and adults, including comments on benign strictures with other etiologies. Despite there is no consensus about the goal of the luminal diameter based on the patient’s age, esophageal contrast study, and/or endoscopy are recommended to assess the degree of the narrowing. A high variability in incidence of ASs is reported in literature, depending on different definitions of AS and on a great number of pre-, intra-, and postoperative risk factor influencing the anastomosis outcome. The presence of a long gap between the two esophageal ends, with consequent anastomotic tension, is determinant for stricture formation and its response to treatment. The cornerstone of treatment is endoscopic dilation, whose primary aims are to achieve symptom relief, allow age-appropriate capacity for oral feeding, and reduce the risk of pulmonary aspiration. No clear advantage of either balloon or bougie dilator has been demonstrated; therefore, the choice is based on operator experience and comfort with the equipment. Retrospective evidences suggest that selective dilatations (performed only in symptomatic patients) results in significantly less number of dilatation sessions than routine dilations (performed to prevent symptoms) with equal long-term outcomes. The response to dilation treatment is variable, and some patients may experience recurrent and refractory ASs. Adjunctive treatments have been used, including local injection of steroids, topical application of mitomycin C, and esophageal stenting, but long-term studies are needed to prove their efficacy and safety. Stricture resection or esophageal replacement with an interposition graft remains options for AS refractory to conservative treatments.

Gastroenterology: Intestinal Bleeding

Gastrointestinal (GI) bleeding in infants and children is a fairly common problem, and it could be related to several clinical pathology according to patient age; however, it is usually limited in volume allowing time for diagnosis and treatment. One of the most frequent causes of lower gastrointestinal bleeding in pediatrics is Meckel’s diverticulum.

Gastroenterology: Gastric Emptying – Gastroesophageal Reflux

Gastric emptying is a radionuclide technique with a low effective radiation dose (maximum 0.3 mSv for 37 MBq) that is frequently used for measuring gastric emptying. In addition, other important clinical information achievable by this simple test are identifying repetitive reflux episodes, quantifying reflux level, duration and frequency, and evaluating possible lung aspiration.

An uncommon cause of abdominal pain in a child: Meckel diverticulum

Meckel diverticulum, a common congenital anomaly of the small intestine, can be responsible of several complications due to the presence of ectopic gastric mucosa and represents a challenge for diagnosis. We present the case of a 11-year boy suffering from intestinal pain and bleeding in which radiological examinations unexpectedly raised the suspicion of Meckel diverticulum. The diagnosis was confirmed using 99mTc-pertechnetate scintigraphy. At surgery, a fistulous tract between Meckel diverticulum and an inflamed appendix was found. The authors discuss the role of medical nuclear imaging which, notwithstanding its limitations, is of fundamental importance to achieve a correct and timely diagnosis. This is of particular relevance in unusual cases, as the one presented, in which Meckel diverticulum is found concurrently with other intestinal abnormalities.

How do clinical researchers’ and patients’ preferences influence study hypotheses and reported outcome results for clinical randomised controlled trials? A critical appraisal

ABSTRACT Background Studies designed to promote unbiased research increasingly show that human preferences exert a major influence on randomised controlled trials (RCTs) [ , , ]. More information is needed on how preferences influence clinical trial design and conduction [ , , ]. To fill the information gap between what researchers seek and report and what patients want [ , ], in this study we investigated how researchers’ and patients’ preferences influence study hypotheses and outcome results of published clinical RCTs. Because conventional critical appraisal seemed inappropriate for addressing our research question, in this pilot study we developed a novel assessment method and applied it in an RCT sample. Methods We collected 20 unselected and consecutive RCTs published in a high impact paediatric journal from July to November 2013. Two experienced reviewers identified the following five domains and a grading method to score discrepancy between what authors state in clinical trial registries (CTRs) and report in published RCTs: reported funding (1 point), study hypotheses, information on patients enrolled and study conduction (3 points); primary and secondary outcomes, early study completion, and upgrading or downgrading outcome results (5 points). Higher scores implied marked discrepancy. Two reviewers then independently applied the method on the RCT sample by mapping and coding information for the domains identified and reported discrepancies by comparing CTRs and RCTs (Table). Results Of the 20 RCTs collected and CTRs compared, 14 studies had high total preference discrepancy scores (7 scored 10-12, and 7 scored 16 or more) and 4 had discrepancy in declaring funding. In 12 studies researchers completed the study early and in 8 studies they downgraded or upgraded outcomes. Only 5 CTRs were updated but they neglected to include published RCT results. Only in 5 CTRs, dataset supervisors indicated the RCT URL. None of the 20 RCTs allowed us to assess patients’ preferences (no information reported for non-response and refusal). No difference was found in discrepancy scores among the five CTR databases. Conclusions The high discrepancy scores obtained by comparing what researchers stated in CTRs and published in RCTs suggest possible misconduct. Patients’ preferences during RCT enrolment and conduction remain undetectable owing to the lack of targeted protocols to elicit this issue. These results, if confirmed in further studies, should prompt international regulation developers [2] to encourage researchers to explore patients’ preferences as a strategy to enhance informed decision-making and to improve reporting in RCTs and CTRs.   Table. Reviewers’ estimated discrepancy score between issues reported by authors in clinical trials registries and what they report in published randomised controlled trials National Registries and number of trial registration First author and reference in RCTs published in Pediatrics Total preference discrepancy score High 10-20 Medium 5-9 Low <5 International Standard Randomised Controlled Trial Number Register, BioMed Central, UK ISRCTN 31707342 www.controlled-trials.com McCarthy LK et al. 132, 1, e135-e141 July 2013 0 Low US National Controlled Trials NCT 01822626 https://clinicaltrials.gov Davoli A.M. et al. 132, 5, e1236-e1245 Oct 2013 2 Low International Standard Randomised Controlled Trial Number Register, BioMed Central, UK ISRCTN 59061709 www.controlled-trials.com McCarthy LK et al. 132, 2, e389-e395 Aug 2013 2 Low Australian New Zealand Clinical Trial Registry ACTRN 12608000056392 https://www.anzctr.org.au Daniels LA et al. 132, 1, e109- e118 July 2013 3 Low Netherlands Trial Registry NTR1613 www.trialregister.nl Van der Veek et al. 132, 5, e1163-e1172 Nov 2013 3 Low US National Controlled Trials NCT 00409448 https://clinicaltrials.gov Kurowski et al. 132, 1, e158-e166 Jul 2013 6 Medium US National Controlled Trials NCT00548379 https://clinicaltrials.gov Aluisio A.R. et al. 132,4, e832-e840 Oct 2013 10 High International Standard Randomised Controlled Trial Number Register, BioMed Central, UK ISRCTN 72635512 www.controlled-trials.com Field 132, 5, e1247-e1256 Nov 2013 12 High US National Controlled Trials NCT 01307293 https://clinicaltrials.gov Shaw RJ et al. 132, 4, e886-e894 Oct 2013 12 High International Standard Randomised Controlled Trial Number Register, BioMed Central, UK ISRCTN 03981121 www.controlled-trials.com Wake M et al. 132, 4, e895-e904 Oct 2013 12 High Clinical Trials Registry India CTRI/2010/091/001417 www.ctri.nic.in Malik A et al. 132, 1, e46-e52 July 2013 12 High US National Controlled Trials NCT 01351064 https://clinicaltrials.gov Carroll A.E. 132, 3, e623-e 629 Sept 2013 12 High Netherlands Trial Registry NTR 2061 www.trialregister.nl and Australian New Zealand Clinical Trial Registry ACTRN 12610000230055 https://www.anzctr.org.au Kamlin COF et al. 132, 2, e381-e388 Aug 2013 12 High US National Controlled Trials NCT 01403623 https://clinicaltrials.gov Leadford AE et al. 132, 1, e128-e134 Jul 2103 16 High US National Controlled Trials NCT 01810978 https://clinicaltrials.gov Dilli D. et al. 132, 4, e932-e938 Oct 2013 17 High US National Controlled Trials NCT 00334737 https://clinicaltrials.gov/ Ohls RK et al. 132, 1, e119-e127 Jul 2013 17 High US National Controlled Trials NCT 01065272 https://clinicaltrials.gov Alansari K. et al. 132,4, e810-e816 Sept 2013 17 High Australian New Zealand Clinical Trial Registry ACTRN 12612000976886 https://www.anzctr.org.au McIntosh CG et al. 132, 2, 326-331 Aug 2013 17 High US National Controlled Trials NCT 00551642 https://clinicaltrials.gov Durrmeyer X et al. 132,3, e695-e703 Sept 2013 18 High US National Controlled Trials NCT 01604460 https://clinicaltrials.gov Belsches et al 132, 3, e656-e661 Sept 2013 18 High