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Abstract Background Preterm birth is associated with significant mortality and morbidity for mothers and babies. Women are identified as high risk for preterm birth based on either previous medical/pregnancy history or on ultrasound assessment of the cervix. Women identified as high risk can be offered a cervical cerclage (a purse string stitch) around the cervix (neck of the womb) to reduce the risk of preterm birth. In women who have a cervical cerclage, the procedure can be performed using either a monofilament (single-stranded) or braided (woven) suture material. Both suture materials are routinely used for cervical cerclage and there is uncertainty as to which is superior. Methods A multicentre, open, randomised controlled superiority trial of 2050 women presenting at obstetric units, deemed to be at risk of preterm birth and already scheduled to have a cervical cerclage as part of their standard care. Inclusion criteria include singleton pregnancies and an indication for cervical cerclage for either a history of three or more previous mid-trimester losses or premature births (≤ 28 weeks), insertion of cervical sutures in previous pregnancies, a history of mid trimester loss or premature birth with a (current) shortened (≤ 25 mm) cervix, or women whom clinicians deem to be at risk of preterm birth either by history or the results of an ultrasound scan. Exclusion criteria include women who have taken part in C-STICH previously, are aged less than 18 years old at the time of presentation, require a rescue cerclage, and are unwilling or unable to give informed consent and in whom a cerclage will be placed by any route other than vaginally (e.g. via an abdominal route). Following informed consent, women are randomised on a 1:1 basis to either monofilament or braided suture, by minimisation. The primary outcome is pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life), and secondary outcomes include the core outcome set for preterm birth trials. Discussion Optimising established interventions to prevent preterm birth is important in reducing perinatal mortality rates. Trial registration ISRCTN 15373349 . Registered before recruitment on 03 December 2014 prior to first recruit.

Abstract Background Cervical cerclage is a recognised treatment to prevent late miscarriage and pre-term birth (PTB). Emergency cervical cerclage (ECC) for cervical dilatation with exposed unruptured membranes is less common and the potential benefits of cerclage are less certain. A randomised control trial is needed to accurately assess the effectiveness of ECC in preventing pregnancy loss compared to an expectant approach. Methods C-STICH2 is a multicentre randomised controlled trial in which women presenting with cervical dilatation and unruptured exposed membranes at 16 + 0 to 27 + 6 weeks gestation are randomised to ECC or expectant management. Trial design includes 18 month internal pilot with embedded qualitative process evaluation, minimal data set and a within-trial health economic analysis. Inclusion criteria are ≥16 years, singleton pregnancy, exposed membranes at the external os, gestation 16 + 0–27 + 6 weeks, and informed consent. Exclusion criteria are contraindication to cerclage, cerclage in situ or previous cerclage in this pregnancy. Randomisation occurs via an online service in a 1:1 ratio, using a minimisation algorithm to reduce chance imbalances in key prognostic variables (site, gestation and dilatation). Primary outcome is pregnancy loss; a composite including miscarriage, termination of pregnancy and perinatal mortality defined as stillbirth and neonatal death in the first week of life. Secondary outcomes include all core outcomes for PTB. Two-year development outcomes will be assessed using general health and Parent Report of Children’s Abilities-Revised (PARCA-R) questionnaires. Intended sample size is 260 participants (130 each arm) based on 60% rate of pregnancy loss in the expectant management arm and 40% in the ECC arm, with 90% power and alpha 0.05. Analysis will be by intention-to-treat. Discussion To date there has been one small trial of ECC in 23 participants which included twin and singleton pregnancies. This small trial along with the largest observational study (n = 161) found ECC to prolong pregnancy duration and reduce deliveries before 34 weeks gestation. It is important to generate high quality evidence on the effectiveness of ECC in preventing pregnancy loss, and improve understanding of the prevalence of the condition and frequency of complications associated with ECC. An adequately powered RCT will provide the highest quality evidence regarding optimum care for these women and their babies. Trial registration ISRCTN Registry ISRCTN12981869 . Registered on 13th June 2018.

Abstract Background One of the top three research priorities for the UK clinical trial community is to address the gap in evidence-based approaches to improving participant retention in randomised trials. Despite this, there is little evidence supporting methods to improve retention. This paper reports the PRioRiTy II project, a Priority Setting Partnership (PSP) that identified and prioritised unanswered questions and uncertainties around trial retention in collaboration with key stakeholders. Methods This PSP was conducted in collaboration with the James Lind Alliance, a non-profit making initiative, to support key stakeholders (researchers, patients, and the public) in jointly identifying and agreeing on priority research questions. There were three stages. (1) First an initial online survey was conducted consisting of six open-ended questions about retention in randomised trials. Responses were coded into thematic groups to create a longlist of questions. The longlist of questions was checked against existing evidence to ensure that they had not been answered by existing research. (2) An interim stage involved a further online survey where stakeholders were asked to select questions of key importance from the longlist. (3) A face-to-face consensus meeting was held, where key stakeholder representatives agreed on an ordered list of 21 unanswered research questions for methods of improving retention in randomised trials. Results A total of 456 respondents yielded 2431 answers to six open-ended questions, from which 372 questions specifically about retention were identified. Further analysis included thematically grouping all data items within answers and merging questions in consultation with the Steering Group. This produced 27 questions for further rating during the interim survey. The top 21 questions from the interim online survey were brought to a face-to-face consensus meeting in which key stakeholder representatives prioritised the order. The ‘Top 10’ of these are reported in this paper. The number one ranked question was ’What motivates a participant’s decision to complete a clinical trial?’ The entire list will be available at www.priorityresearch.ie. Conclusion The Top 10 list can inform the direction of future research on trial methods and be used by funders to guide projects aiming to address and improve retention in randomised trials.

Abstract Background Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem complications in the mother. The adverse outcomes of pre-eclampsia include severe hypertension, stroke, renal and hepatic injury, haemorrhage, fetal growth restriction and even death. The optimal time to instigate delivery to prevent morbidity when pre-eclampsia occurs between 34 and 37 weeks’ gestation, without increasing problems related to infant immaturity or complications, remains unclear. Methods/design The PHOENIX trial is a non-masked, randomised controlled trial, comparing planned early delivery (with initiation of delivery within 48 h of randomisation) with usual care (expectant management) in women with pre-eclampsia between 34+ 0 and 36+ 6 weeks’ gestation. The primary objectives of the trial are to determine if planned delivery reduces adverse maternal outcomes, without increasing the short-term harm to infants (composite of perinatal deaths or neonatal unit admissions up to infant hospital discharge) or impacting long-term infant neurodevelopmental status at 2 years corrected age (Parent Report of Cognitive Abilities-Revised). Discussion Current practice in the UK at the time of trial commencement for management of pre-eclampsia varies by gestation. Previous trials have shown that in women with pre-eclampsia after 37 weeks of gestion, delivery is initiated, as maternal complications are reduced without increasing fetal risks. Prior to 34 weeks of gestation, usual management aims to prolong pregnancy for fetal benefit, unless severe complications occur, necessitating preterm delivery. This trial aims to address the uncertainty for women where the balance of benefits and risks of delivery compared to expectant management are uncertain. Previous trials in this area have been undertaken, but have not provided a definitive answer, and the research question remains active. The results of this trial are expected to influence clinical practice internationally, through direct adoption and by incorporation into guidelines in countries with similar settings. Trial registration ISRCTN01879376. Registered on 25 November 2013.

Abstract Background The classification of phase 3 trials as superiority or non-inferiority has become routine, and it is widely accepted that there are important differences between the two types of trial in their design, analysis and interpretation. Main text There is a clear rationale for the superiority/non-inferiority framework in the context of regulatory trials. The focus of our article is non-regulatory trials with a public health objective. First, using two examples from infectious disease research, we show that the classification of superiority or non-inferiority trials is not always straightforward. Second, we show that several arguments for different approaches to the design, analysis and interpretation of superiority and non-inferiority trials are unconvincing when examined in detail. We consider, in particular, the calculation of sample size (and the choice of delta or the non-inferiority margin), intention-to-treat versus per-protocol analyses, and one-sided versus two-sided confidence intervals. We argue that the superiority/non-inferiority framework is not just unnecessary but can have a detrimental effect, being a barrier to clear scientific thought and communication. In particular, it places undue emphasis on tests for significance or non-inferiority at the expense of estimation. We emphasise that these concerns apply to phase 3 non-regulatory trials in general, not just to those where the classification of the trial as superiority or non-inferiority is ambiguous. Conclusions Guidelines and statistical practice should abandon the sharp division between superiority and non-inferiority phase 3 non-regulatory trials and be more closely aligned to the clinical and public health questions that motivate the trial.

Abstract Background Despite the problem of inadequate recruitment to randomised trials, there is little evidence to guide researchers on decisions about how people are effectively recruited to take part in trials. The PRioRiTy study aimed to identify and prioritise important unanswered trial recruitment questions for research. The PRioRiTy study - Priority Setting Partnership (PSP) included members of the public approached to take part in a randomised trial or who have represented participants on randomised trial steering committees, health professionals and research staff with experience of recruiting to randomised trials, people who have designed, conducted, analysed or reported on randomised trials and people with experience of randomised trials methodology. Methods This partnership was aided by the James Lind Alliance and involved eight stages: (i) identifying a unique, relevant prioritisation area within trial methodology; (ii) establishing a steering group (iii) identifying and engaging with partners and stakeholders; (iv) formulating an initial list of uncertainties; (v) collating the uncertainties into research questions; (vi) confirming that the questions for research are a current recruitment challenge; (vii) shortlisting questions and (viii) final prioritisation through a face-to-face workshop. Results A total of 790 survey respondents yielded 1693 open-text answers to 6 questions, from which 1880 potential questions for research were identified. After merging duplicates, the number of questions was reduced to 496. Questions were combined further, and those that were submitted by fewer than 15 people and/or fewer than 6 of the 7 stakeholder groups were excluded from the next round of prioritisation resulting in 31 unique questions for research. All 31 questions were confirmed as being unanswered after checking relevant, up-to-date research evidence. The 10 highest priority questions were ranked at a face-to-face workshop. The number 1 ranked question was “How can randomised trials become part of routine care and best utilise current clinical care pathways?” The top 10 research questions can be viewed at www.priorityresearch.ie. Conclusion The prioritised questions call for a collective focus on normalising trials as part of clinical care, enhancing communication, addressing barriers, enablers and motivators around participation and exploring greater public involvement in the research process.