Recommendations for clinical research in children presenting to primary care out-of-hours services: a randomised controlled trial with parallel cohort study

Abstract

Background: Research in primary care is essential, but recruiting children in this setting can be complex and may cause selection bias. Challenges surrounding informed consent, particularly in an acute clinical setting, can undermine feasibility. The off-protocol use of an intervention nearing implementation has become common in pragmatic randomized controlled trials (RCTs) set in primary care. Aim: To describe how the informed consent procedure affects study inclusion and to assess how off-protocol medication prescribing affects participant selection in a paediatric RCT. Design: A pragmatic RCT evaluating the cost-effectiveness of oral ondansetron in children diagnosed with acute gastroenteritis in primary care out-of-hours services and a parallel cohort study. Method: Consecutive children aged 6 months to 6 years attending primary care out-of-hours services with acute gastroenteritis were evaluated to assess the feasibility of obtaining informed consent, the off-protocol use of ondansetron, and other inclusion/exclusion criteria. Results: The RCTs feasibility was reduced by the informed consent procedure because 39.0% (325/834) of children were accompanied by only one parent. General practitioners prescribed ondansetron off-protocol to 34 children (4.1%), whereof 19 children were eligible for the RCT. RCT-eligible children included in the parallel cohort had fewer risk factors for dehydration than children in the RCT despite similar dehydration assessments by general practitioners. Conclusion: The informed consent procedure and off-protocol use of study medication affect the inclusion rate but had little effect on selection. A parallel cohort study alongside the RCT can help evaluate selection bias, and a pilot study can reveal potential barriers to inclusion.

Cost-effectiveness of oral ondansetron for children with acute gastroenteritis in primary care: a randomised controlled trial

“…The design, recruitment strategy, outcomes, and informed-consent procedure of the RCT are reported elsewhere. 17 In agreement with the Medical Ethics Review Committee of the University Medical Center Groningen, the primary outcome changed from referral to vomiting to guarantee an outcome that was more relevant to patients. The researchers were allowed to include children from the pilot study in the final trial (NL5830) ( https://www.trialregister.nl/trial/5830 ).…”

Oral ondansetron for paediatric gastroenteritis in primary care: a randomised controlled trial

“…We enrolled participants from December 2015 until January 2018 at three OOH-PC in the north of the Netherlands, located in Groningen, Zwolle, and Assen. A detailed description of the study design, recruitment strategy, outcomes, and discussion of the informed consent procedure are described elsewhere (14). This study started with a pilot (NL4700) from December 2015 until October 2016 but because of the low inclusion rate the primary outcome was changed from 'referrals' to 'vomiting'.…”

“…A detailed description of the study design, recruitment strategy, outcomes, and discussion of the informed consent procedure are described elsewhere. 14 This study started with a pilot (Dutch Trial Register reference number: NL4700) undertaken from December 2015 until October 2016 but, as a result of the low inclusion rate, the primary outcome was changed from ‘referrals’ to ‘vomiting’. In agreement with the Medical Ethics Review Committee of the University Medical Center Groningen, children included from the pilot were also included in the new trial and the RCT was approved.…”

Managing paediatric gastroenteritis in primary care: is there a role for ondansetron?

“…Third, the authors conducted a parallel controlled cohort study to look at those children who were not enrolled, and highlighted the ethical and logistical challenges in conducting a trial in children in primary care. 6 However, there are important methodological limitations. First, unlike the original trial by Freedman et al, there was no placebo arm.…”

“…However, only 39% of visits had both parents, which would have made the trial not feasible, which was later modified to immediate written consent by one parent plus immediate verbal consent from the other, followed by written consent by the second parent at a later stage. 6 Such an onerous ethical burden on families is an unreasonable impediment to including children in trials. 9 The trial clearly shows the benefit of conducting a pilot study prior to full study enrolment, and importance of tracking patients who do not consent.…”