Laura Flight

Background: Limited public understanding of randomized controlled trials (RCTs) hinders recruitment, retention, and confidence in research. Early exposure to trial concepts may strengthen health literacy and research engagement. The Kid’s Trial was a global, decentralized, child-led study that cocreated and conducted an RCT to help children understand trials and their importance and to improve critical thinking. Objective: This paper evaluated the feasibility and methodological implications of engaging children in the cocreation and conduct of a fully online RCT. Methods: The Kid’s Trial ed a dedicated website guiding children through each step of designing and conducting an RCT. Materials were codeveloped with 2 patient and public involvement groups of children and parents. Any child aged 7-12 years could take part in as many steps as desired. Recruitment combined online and offline strategies, and engagement and self-reported learning were descriptively analyzed. The cocreated Randomized Evaluation of Sleeping With a Toy or Comfort Item (REST) trial was a 2-arm, pragmatic RCT comparing one week of sleeping with a comfort item versus without a comfort item. The primary outcome was sleep-related impairment, and the secondary outcome was overall sleep quality. Analyses followed an intention-to-treat (ITT) approach using mixed effects models adjusted for baseline measures. Results: Overall, 224 children participated in at least one step of The Kid’s Trial. Participation varied: 37% (n=82) completed one step, and 21% (n=48) completed 6 surveys. The REST trial randomized 139 children, with 73% (n=101) completing outcome surveys. Adjusted mean differences (intervention – control) were −0.53 (95% CI −3.40 to 2.34) for sleep-related impairment ( P =.71) and 0.28 (95% CI 0.01-0.55) for sleep quality ( P =.04). The difference was small and was not supported by sensitivity analyses. Poststudy responses (n=20) suggested improved self-reported trial understanding among respondents but were limited by low response rate and potential selection bias. Conclusions: The Kid’s Trial demonstrates the feasibility of a decentralized, child-led RCT cocreated through participatory citizen-science methods. Children can meaningfully contribute to trial design and conduct, and experiential participation may support engagement with trial concepts. Future studies should enhance engagement through community partnerships, shorter intervals between steps, and embedded learning assessments to improve inclusivity and retention.

Objectives: The use of surrogate endpoints poses challenges to health technology assessment (HTA) agencies and payers when informing the clinical and cost-effectiveness of health technologies. Decision makers often need to make recommendations in the absence of well-established evidence on their validation, particularly when the surrogate endpoint is novel without clear links to the longer-term outcome. This study explored the guidance needs of HTA agencies and identified how they have considered and dealt with surrogate endpoints in cost-effectiveness analysis. Methods: A qualitative study was used to explore the professional experiences of international HTA staff and their collaborators. Data were collected using three focus groups with 29 participants representing 20 HTA agencies or associated organizations. Framework analysis was used to identify themes from the transcripts. Results: HTA agencies frequently see submissions featuring surrogate endpoints. Issues they face include definitional concerns, absent or weak evidentiary links, and resource-intensive validation methods. Versatile guidance that is mindful of these challenges, such as those faced with rare diseases, is required. This would help to clarify expectations and help ascertain the required information from industry for economic modeling, on how to present the uncertainty arising from surrogate endpoints, and how to appropriately report the findings. Conclusions: Decision making using surrogate endpoints is a frequent and challenging problem faced by HTA agencies. These results provide the first-hand experiences and reflect the needs of HTA agencies globally. The resulting recommendations and considerations for the use of surrogate endpoints in economic modeling should benefit HTA agencies moving forward.

Background: Ovarian hyperstimulation syndrome is a potentially serious complication of fertility treatments. Standard care often involves monitoring, then hospitalisation for severe cases. Some evidence suggests early outpatient paracentesis may prevent hospitalisation, but adequately powered randomised trials are lacking. Objectives: To establish the clinical and cost-effectiveness, safety and acceptability of early active outpatient management for moderate or severe ovarian hyperstimulation syndrome. Design and methods: A pragmatic, parallel, open-label, multicentre, superiority, adaptive, group sequential randomised controlled trial with an internal pilot was planned. The study included preliminary qualitative work and a post-trial survey. The main trial recruited participants with moderate or severe, early or late ovarian hyperstimulation syndrome from UK fertility clinics. Participants were randomised 1 : 1 to receive either outpatient paracentesis or usual care (conservative management). The primary outcome was ovarian hyperstimulation syndrome-related hospital admission within 28 days. Results: The trial was terminated early due to poor recruitment. Only 8 participants were randomised (5 to conservative management, 3 to outpatient paracentesis) across 3 of 9 opened sites, compared to the planned 224 participants. All eight had moderate ovarian hyperstimulation syndrome at baseline. Two participants were hospitalised for ovarian hyperstimulation syndrome-related reasons (one from each group). Six participants’ symptoms resolved during follow-up, while two had unknown outcomes. There were no reported serious adverse events caused by the intervention. The post-trial survey of 16 fertility centres found increased use of preventive measures like freeze-all cycles, antagonist protocols and gonadotropin-releasing hormone trigger, during and after the SARS-CoV-2 (COVID-19) pandemic. Limitations: The small sample size precludes drawing any definitive conclusions about effectiveness, safety or cost-effectiveness. The study was severely impacted by the COVID-19 pandemic, affecting site set-up and recruitment, and changes in clinical practice during the pandemic may have reduced ovarian hyperstimulation syndrome cases. Conclusions: No definitive clinical conclusions can be drawn from this study about the effectiveness of outpatient management compared to conservative management. The pandemic prompted lasting modifications in ovarian hyperstimulation syndrome prevention strategies at many fertility clinics. Future work: Given the observed low incidence rates of ovarian hyperstimulation syndrome and challenges in recruitment, future research may need to consider alternative study designs in observational settings rather than randomised trials that reflect the changing reality of clinical management and prevention of ovarian hyperstimulation syndrome, particularly following the recent COVID pandemic. Additionally, the research community should reflect on strategies to improve trial resilience and adaptability in the face of major disruptions like pandemics. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128137.

BACKGROUND Limited public understanding of randomized controlled trials (RCTs) hinders recruitment, retention, and confidence in research. Early exposure to trial concepts may strengthen health literacy and research engagement. The Kid’s Trial was a global, decentralized, child-led study that co-created and conducted an RCT to help children understand trials, their importance, and improve critical thinking. OBJECTIVE This paper presents its design, outcomes, and methodological reflections. METHODS The Kid’s Trial employed a dedicated website with study materials guiding children through each step of designing and conducting an RCT. Each step was linked to an online survey. Materials were co-developed with two patient and public involvement groups of children and parents. Any child, aged 7 to 12 years, could take part in as many or as few steps as desired. Recruitment combined online and offline strategies, and engagement and self-reported learning were descriptively analyzed. The co-created REST (Randomized Evaluation of Sleeping with a Toy or Comfort Item) trial was a two-arm, pragmatic RCT comparing one week of sleeping with versus without a comfort item. The primary outcome was sleep-related impairment, and the secondary outcome was overall sleep quality. Analyses followed an intention-to-treat approach using mixed-effects models adjusted for baseline measures. RESULTS Overall, 224 children from 15 countries participated in at least one step. Participation varied: 37% (n = 82) completed one step and 21% (n = 48) completed six. The REST trial randomized 139 children, with 73% (n = 101) completing outcome surveys. Adjusted mean differences (intervention–control) were −0.53 for sleep-related impairment (95% CI −3.40 to 2.34; P=.71) and 0.28 for sleep quality (95% CI 0.01 to 0.55; P=.04), a small, uncertain difference not supported with sensitivity analyses. Post-study responses (n = 20) indicated improved understanding of RCT concepts. CONCLUSIONS The Kid’s Trial demonstrates the feasibility of a decentralized, child-led RCT co-created through participatory citizen-science methods. Children can meaningfully contribute to trial design and conduct, and experiential participation may foster early trial literacy and critical thinking. Future studies should enhance engagement through community partnerships, shorter intervals between steps, and embedded learning assessments to improve inclusivity and retention.

Background: Anxiety in children prior to general anaesthesia is common, with up to half displaying distress. Anxiety and distress may lead to unsuccessful anaesthesia, together with greater postoperative pain, agitation and behavioural changes after surgery including sleep disturbances. Midazolam is the current standard premedication; however, it has adverse effects such as the potential for respiratory suppression and unpredictable effects which may result in agitation rather than anxiolysis. Melatonin is an alternative preoperative anxiolytic; however, previous trials have delivered conflicting results. The aim of this non-inferiority trial was to evaluate the effectiveness of melatonin compared to midazolam in reducing anxiety in children undergoing general anaesthesia. Methods: We undertook a randomised-controlled, parallel-group, double-blind, non-inferiority trial in 20 United Kingdom National Health Service trusts, with an embedded qualitative study and health economic evaluation. Anxious children having day case elective surgery under general anaesthesia were randomly assigned to either control (standard of care) group: midazolam; or intervention group: melatonin. The primary outcome was preoperative distress (non-inferiority hypothesis) as assessed by modified Yale Preoperative Anxiety Scale Short Form. Secondary outcomes included safety and efficacy objectives. Analyses were by intention to treat, with an additional per-protocol analysis. The sample size of the trial was 624 children. Results: The trial was stopped early due to recruitment futility. Between 30 July 2019 and 9 November 2022, 110 children were recruited; 55 allocated to midazolam and 55 allocated to melatonin. Pre-planned analyses showed an adjusted mean difference of 13.1 (95% confidence interval 3.7 to 22.4) for the intention-to-treat population and 12.9 (95% confidence interval 3.1 to 22.6) for the per-protocol population, in favour of midazolam. In both analyses, the upper limit of the 95% confidence interval exceeds the predefined margin of 4.3; therefore, melatonin is not non-inferior to midazolam. The lower limit of the 95% confidence intervals excludes zero and thus melatonin is inferior to midazolam; the difference found is considered to be clinically meaningful. Adverse events in the midazolam arm (26%) were slightly higher than melatonin (18%); there were no serious adverse events in either arm. Challenges to recruitment included study-related factors (eligibility criteria and trial design), participant factors (caregiver stress on the day of treatment) and practitioner factors (valuing predictability). In terms of acceptability, preferences of the anaesthetist, patient and caregiver factors and medication side effects profile were influential and suggest the choice of preoperative anxiolytic is more complex than previously described. On average, costs over the 14 days post surgery were lower for those who received melatonin (−£46.20, 95% confidence interval −£166.14 to £66.74) with a mean incremental difference in procedure success of −0.02 (95% confidence interval −0.08 to 0.004), although there was uncertainty around the results. Conclusion: In children with preoperative anxiety, midazolam is more effective than melatonin at reducing preoperative anxiety prior to general anaesthesia, although the early termination of the trial increases the likelihood of bias. Limitations: The trial was prematurely terminated due to recruitment futility. Despite this, a clinically meaningful and statistically significant finding was observed about the primary outcome. Future work: There remains a need to develop or repurpose another drug with a more favourable side effects profile to midazolam. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/80/08.

Background: Value-adaptive designs for clinical trials are a novel set of emerging methods for delivering greater value for clinical research. There is increasing interest in using them within publicly funded health systems. A value-adaptive design permits ‘in progress’ changes to be made to the trial according to criteria which reflect its overall value to the healthcare system, including the cost-effectiveness of the technologies under investigation, the cost of running the trial and the total health benefit delivered to patients. These trial designs offer the potential to explicitly balance the costs and benefits of adaptive clinical trials with the health economic benefits expected for populations that are affected by any subsequent health technology adoption decisions. They may also improve the expected value of learning from the budget that is spent within a trial. Main body: This paper introduces value-adaptive designs for publicly funded clinical trials. It discusses the idea of delivering ‘value for money’ in health technology assessment, what is meant by being ‘value-adaptive’ and the key features that characterise these designs. The methodology behind one kind of value-adaptive design – the value-based sequential model of a two-armed clinical trial proposed by Chick et al. (2017) – is described and illustrated using three retrospective case studies from the United Kingdom. The paper concludes by reviewing a range of perspectives provided by stakeholders, together with our own thoughts, on the practical opportunities and changes required for implementing a value-adaptive approach. Conclusions: Value-adaptive clinical trial designs offer the potential to align health research funding allocations with population health economic goals. Many of the systems required to deploy value-adaptive designs within a publicly funded health system already exist and, with increased application, experience, and refinement they have the potential to deliver improved value for money.

Background: Paediatric trials must contend with many challenges that adult trials face but often bring additional obstacles. Decentralised trials, where some or all trial methods occur away from a centralised location, are a promising strategy to help meet these challenges. This scoping review aims to (a) identify what methods and tools have been used to create and conduct entirely online-decentralised trials with children and (b) determine the gaps in the knowledge in this field. This review will describe the methods used in these trials to identify their facilitators and the gaps in the knowledge. Methods: The methods were informed by guidance from the Joanna Briggs Institute and the PRISMA extension for scoping reviews. We systematically searched MEDLINE, CENTRAL, CINAHL, and Embase databases, trial registries, pre-print servers, and the internet. We included randomised and quasi-randomised trials conducted entirely online with participants under 18 published in English. A risk of bias assessment was completed for all included studies. Results: Twenty-one trials met our inclusion criteria. The average age of participants was 14.6 years. Social media was the most common method of online recruitment. Most trials employed an external host website to store and protect their data. Duration of trials ranged from single-session interventions up to ten weeks. Fourteen trials compensated participants. Eight trials involved children in their trial design process; none reported compensation for this. Most trials had a low risk of bias in “random sequence generation”, “selective reporting”, and “other”. Most trials had a high risk of bias in “blinding participants and personnel”, “blinding of outcome assessment”, and “incomplete outcome data”. “Allocation concealment” was unclear in most studies. Conclusions: There was a lack of transparent reporting of the recruitment, randomisation, and retention methods used in many of the trials included in this review. Patient and public involvement (PPI) was not common, and the compensation of PPI partners was not reported in any study. Consent methods and protection against fraudulent entries to trials were creative and thoroughly discussed by some trials and not addressed by others. More work and thorough reporting of how these trials are conducted is needed to increase their reproducibility and quality. Ethics and dissemination: Ethical approval was not necessary since all data sources used are publicly available.

Background Paediatric trials must contend with many challenges that adult trials face but often bring additional obstacles. Decentralised trials, where some or all trial methods occur away from a centralised location, are a promising strategy to help meet these challenges. This scoping review aims to (a) identify what methods and tools have been used to create and conduct entirely online-decentralised trials with children and (b) determine the gaps in the knowledge in this field. This review will describe the methods used in these trials to identify their facilitators and the gaps in the knowledge. Methods The methods were informed by guidance from the Joanna Briggs Institute and the PRISMA extension for scoping reviews. We systematically searched MEDLINE, CENTRAL, CINAHL, and Embase databases, trial registries, pre-print servers, and the internet. We included randomised and quasi-randomised trials conducted entirely online with participants under 18 published in English. A risk of bias assessment was completed for all included studies. Results Twenty-one trials met our inclusion criteria. The average age of participants was 14.6 years. Social media was the most common method of online recruitment. Most trials employed an external host website to store and protect their data. Duration of trials ranged from single-session interventions up to ten weeks. Fourteen trials compensated participants. Eight trials involved children in their trial design process; none reported compensation for this. Most trials had a low risk of bias in “random sequence generation”, “selective reporting”, and “other”. Most trials had a high risk of bias in “blinding participants and personnel”, “blinding of outcome assessment”, and “incomplete outcome data”. “Allocation concealment” was unclear in most studies. Conclusions There was a lack of transparent reporting of the recruitment, randomisation, and retention methods used in many of the trials included in this review. Patient and public involvement (PPI) was not common, and the compensation of PPI partners was not reported in any study. Consent methods and protection against fraudulent entries to trials were creative and thoroughly discussed by some trials and not addressed by others. More work and thorough reporting of how these trials are conducted is needed to increase their reproducibility and quality. Ethics and Dissemination Ethical approval was not necessary since all data sources used are publicly available.

In adaptive clinical trials, the conventional end-of-trial point estimate of a treatment effect is prone to bias, that is, a systematic tendency to deviate from its true value. As stated in recent FDA guidance on adaptive designs, it is desirable to report estimates of treatment effects that reduce or remove this bias. However, it may be unclear which of the available estimators are preferable, and their use remains rare in practice. This paper is the second in a two-part series that studies the issue of bias in point estimation for adaptive trials. Part I provided a methodological review of approaches to remove or reduce the potential bias in point estimation for adaptive designs. In part II, we discuss how bias can affect standard estimators and assess the negative impact this can have. We review current practice for reporting point estimates and illustrate the computation of different estimators using a real adaptive trial example (including code), which we use as a basis for a simulation study. We show that while on average the values of these estimators can be similar, for a particular trial realisation they can give noticeably different values for the estimated treatment effect. Finally, we propose guidelines for researchers around the choice of estimators and the reporting of estimates following an adaptive design. The issue of bias should be considered throughout the whole lifecycle of an adaptive design, with the estimation strategy pre-specified in the statistical analysis plan. When available, unbiased or bias-reduced estimates are to be preferred.

Adaptive designs are a class of methods for improving efficiency and patient benefit of clinical trials. Although their use has increased in recent years, research suggests they are not used in many situations where they have potential to bring benefit. One barrier to their more widespread use is a lack of understanding about how the choice to use an adaptive design, rather than a traditional design, affects resources (staff and non-staff) required to set-up, conduct and report a trial. The Costing Adaptive Trials project investigated this issue using quantitative and qualitative research amongst UK Clinical Trials Units. Here, we present guidance that is informed by our research, on considering the appropriate resourcing of adaptive trials. We outline a five-step process to estimate the resources required and provide an accompanying costing tool. The process involves understanding the tasks required to undertake a trial, and how the adaptive design affects them. We identify barriers in the publicly funded landscape and provide recommendations to trial funders that would address them. Although our guidance and recommendations are most relevant to UK non-commercial trials, many aspects are relevant more widely.