Changing Agendas on Sleep, Treatment and Learning in Epilepsy (CASTLE) Sleep-E: a protocol for a randomised controlled trial comparing an online behavioural sleep intervention with standard care in children with Rolandic epilepsy.

INTRODUCTION: Sleep and epilepsy have an established bidirectional relationship yet only one randomised controlled clinical trial has assessed the effectiveness of behavioural sleep interventions for children with epilepsy. The intervention was successful, but was delivered via face-to-face educational sessions with parents, which are costly and non-scalable to population level. The Changing Agendas on Sleep, Treatment and Learning in Epilepsy (CASTLE) Sleep-E trial addresses this problem by comparing clinical and cost-effectiveness in children with Rolandic epilepsy between standard care (SC) and SC augmented with a novel, tailored parent-led CASTLE Online Sleep Intervention (COSI) that incorporates evidence-based behavioural components. METHODS AND ANALYSES: CASTLE Sleep-E is a UK-based, multicentre, open-label, active concurrent control, randomised, parallel-group, pragmatic superiority trial. A total of 110 children with Rolandic epilepsy will be recruited in outpatient clinics and allocated 1:1 to SC or SC augmented with COSI (SC+COSI). Primary clinical outcome is parent-reported sleep problem score (Children's Sleep Habits Questionnaire). Primary health economic outcome is the incremental cost-effectiveness ratio (National Health Service and Personal Social Services perspective, Child Health Utility 9D Instrument). Parents and children (≥7 years) can opt into qualitative interviews and activities to share their experiences and perceptions of trial participation and managing sleep with Rolandic epilepsy. ETHICS AND DISSEMINATION: The CASTLE Sleep-E protocol was approved by the Health Research Authority East Midlands (HRA)-Nottingham 1 Research Ethics Committee (reference: 21/EM/0205). Trial results will be disseminated to scientific audiences, families, professional groups, managers, commissioners and policymakers. Pseudo-anonymised individual patient data will be made available after dissemination on reasonable request. TRIAL REGISTRATION NUMBER: ISRCTN13202325.

The Clinical and Cost Effectiveness of Inotuzumab Ozogamicin for the Treatment of Adult Relapsed or Refractory B-Cell Acute Lymphoblastic Leukaemia: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Pfizer, the manufacturer of inotuzumab ozogamicin (henceforth inotuzumab), to submit clinical- and cost-effectiveness evidence for inotuzumab as part of NICE's single technology appraisal process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned as the independent evidence review group (ERG). The clinical-effectiveness data were from a multicentre randomised controlled trial that compared inotuzumab with standard of care (SoC), where SoC was the investigator's choice of chemotherapy. Inotuzumab demonstrated statistically significant improvements in response rates or in the proportion of patients progressing to haematopoietic stem cell transplant (HSCT) but failed to meet the second primary objective of longer overall survival. Treatment-emergent adverse events were more frequent in the SoC arm, except veno-occlusive disease, which was more frequent in the inotuzumab arm. The company's economic model split patients into three post-hoc subgroups and used a partitioned survival approach within each group, with a cure assumption 3 years after receiving HSCT. In contrast with the trial results, the economic model estimated substantial improvement in survival with inotuzumab compared with SoC, providing an additional 5.2 life-years and 2.2 quality-adjusted life-years (QALYs) using a discount rate of 1.5% per annum. The ERG's critique highlighted a number of concerns, including the use of a post-hoc post-randomisation patient subset for extrapolation, the choice of a 1.5% discount rate, the complexity of the parametric modelling, the assumption of further treatment benefit post-HSCT, the nature of the cure assumption, and the length of inpatient stay while receiving treatment. The combination of the ERG's adjustments resulted in an incremental cost-effectiveness ratio (ICER) of £122,174 per QALY gained using Kaplan-Meier survival estimates and £114,078 per QALY gained with parametric survival models fit to the trial data. The final determination of the appraisal followed four NICE Appraisal Committee meetings, an appeal by the company and other stakeholders, two patient access schemes, and a company response to each appraisal consultation. The final ICER post-consultation was between £33,749 and £37,497 per QALY gained compared with SoC (excluding the confidential discount for blinatumomab received as subsequent therapy). The Appraisal Committee concluded that the ICER for inotuzumab was within the range usually considered cost effective for end-of-life care and recommended inotuzumab within its licensed indication.

The use of clinical study reports to enhance the quality of systematic reviews: a survey of systematic review authors.

BACKGROUND: Clinical study reports (CSRs) are produced for marketing authorisation applications. They often contain considerably more information about, and data from, clinical trials than corresponding journal publications. Use of data from CSRs might help circumvent reporting bias, but many researchers appear to be unaware of their existence or potential value. Our survey aimed to gain insight into the level of familiarity, understanding and use of CSRs, and to raise awareness of their potential within the systematic review community. We also aimed to explore the potential barriers faced when obtaining and using CSRs in systematic reviews. METHODS: Online survey of systematic reviewers who (i) had requested or used CSRs, (ii) had considered but not used CSRs and (iii) had not considered using CSRs was conducted. Cochrane reviewers were contacted twice via the Cochrane monthly digest. Non-Cochrane reviewers were reached via journal and other website postings. RESULTS: One hundred sixty respondents answered an open invitation and completed the questionnaire; 20/160 (13%) had previously requested or used CSRs and other regulatory documents, 7/160 (4%) had considered but not used CSRs and 133/160 (83%) had never considered this data source. Survey respondents mainly sought data from the European Medicines Agency (EMA) and/or the Food and Drug Administration (FDA). Motivation for using CSRs stemmed mainly from concerns about reporting bias 11/20 (55%), specifically outcome reporting bias 11/20 (55%) and publication bias 5/20 (25%). The barriers to using CSRs noted by all types of respondents included current limited access to these documents (43 respondents), the time and resources needed to obtain and include these data in evidence syntheses (n = 25) and lack of guidance about how to use these sources in systematic reviews (n = 26). CONCLUSIONS: Most respondents (irrespective of whether they had previously used them) agreed that access to CSRs is important, and suggest that further guidance on how to use and include these data would help to promote their use in future systematic reviews. Most respondents who received CSRs considered them to be valuable in their systematic review and/or meta-analysis.

Evaluating progestogens for prevention of preterm birth international collaborative (EPPPIC) individual participant data (IPD) meta-analysis: protocol.

BACKGROUND: Preterm birth is the most common cause of death and harm to newborn babies. Babies that are born early may have difficulties at birth and experience health problems during early childhood. Despite extensive study, there is still uncertainty about the effectiveness of progestogen (medications that are similar to the natural hormone progesterone) in preventing or delaying preterm birth, and in improving birth outcomes. The Evaluating Progestogen for Prevention of Preterm birth International Collaborative (EPPPIC) project aims to reduce uncertainty about the specific conditions in which progestogen may (or may not) be effective in preventing or delaying preterm birth and improving birth outcomes. METHODS: The design of the study involves international collaborative individual participant data meta-analysis comprising systematic review, re-analysis, and synthesis of trial datasets. Inclusion criteria are as follows: randomized controlled trials comparing progestogen versus placebo or non-intervention, or comparing different types of progestogen, in asymptomatic women at risk of preterm birth. Main outcomes are as follows; fetal/infant death, preterm birth or fetal death (<=37 weeks, <=34 weeks, <= 28 weeks), serious neonatal complications or fetal/infant death, neurosensory disability (measured at 18 months or later) or infant/child death, important maternal morbidity, or maternal death. In statistical methods, IPD will be synthesized across trials using meta-analysis. Both 'two-stage' models (where effect estimates are calculated for each trial and subsequently pooled in a meta-analysis) and 'one-stage' models (where all IPD from all trials are analyzed in one step, while accounting for the clustering of participants within trials) will be used. If sufficient suitable data are available, a network meta-analysis will compare all types of progesterone and routes of administration extending the one-stage models to include multiple treatment arms. DISCUSSION: EPPPIC is an international collaborative project being conducted by the forming EPPPIC group, which includes trial investigators, an international secretariat, and the research project team. Results, which are intended to contribute to improvements in maternal and child health, are expected to be publicly available in mid 2018. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017068299.

Pilot Testing of a Sampling Methodology for Assessing Seed Attachment Propensity and Transport Rate in a Soil Matrix Carried on Boot Soles and Bike Tires.

Land managers of natural areas are under pressure to balance demands for increased recreation access with protection of the natural resource. Unintended dispersal of seeds by visitors to natural areas has high potential for weedy plant invasions, with initial seed attachment an important step in the dispersal process. Although walking and mountain biking are popular nature-based recreation activities, there are few studies quantifying propensity for seed attachment and transport rate on boot soles and none for bike tires. Attachment and transport rate can potentially be affected by a wide range of factors for which field testing can be time-consuming and expensive. We pilot tested a sampling methodology for measuring seed attachment and transport rate in a soil matrix carried on boot soles and bike tires traversing a known quantity and density of a seed analog (beads) over different distances and soil conditions. We found % attachment rate on boot soles was much lower overall than previously reported, but that boot soles had a higher propensity for seed attachment than bike tires in almost all conditions. We believe our methodology offers a cost-effective option for researchers seeking to manipulate and test effects of different influencing factors on these two dispersal vectors.