Elizabeth Jane Conroy

Kidney transplantation is the preferred treatment for end-stage renal disease and is limited by donor organ availability. Normothermic Machine Perfusion (NMP) might facilitate safe transplantation of marginal organs. NKP1 is a single centre, phase 1, 36-patient, three-stage cohort study investigating the safety and feasibility of up to 24 hours of renal NMP prior to transplantation. 30-day graft survival (primary endpoint) was 100%. Secondary objectives were assessment of the effect of NMP on post-transplant clinical outcomes and ischaemia-reperfusion injury, identification of predictive biomarkers, and characterisation of the performance of the preservation system. Clinical outcomes were comparable to a matched control cohort with 12-month estimated glomerular filtration rate (eGFR) 46.3 vs 49.5 mL/min/1.73m² (p = 0.44) despite much longer total preservation times (15.7 vs 8.9 hours controls, p < 0.0001). We saw strong correlations between biomarkers measured ex-situ and post-transplant outcomes, including graft function at one year (correlation between GST-Pi delta and 12-month eGFR, R = 0.54, p = 0.001). Renal NMP is useful for optimising logistics and as an organ assessment technique, and has potential to expand the donor pool. Trial registration number: ISRCTN13292277.

Background/aims: When conducting a randomised controlled trial in surgery, it is important to consider surgical learning, where surgeons’ familiarity with one, or both, of the interventions increases during the trial. If present, learning may compromise trial validity. We demonstrate a statistical investigation into surgical learning within a trial of cleft palate repair. Methods: The Timing of Primary Surgery compared primary surgery, using the Sommerlad technique, for cleft palate repair delivered at 6 or 12 months of age. Participating surgeons had varying levels of experience with the intervention and in repair across the age groups. Trial design aimed to reduce the surgical learning via pre-trial surgical technique training and balancing the randomisation process by surgeon. We explore residual learning effects by applying visual methods and statistical models to a surgical outcome (fistula formation) and a process indicator (operation time). Results: Notably, 26 surgeons operated on 521 infants. As the trial progressed, operation time reduced for surgeons with no pre-trial Sommerlad experience (n = 2), before plateauing at 30 operations, whereas it remained stable for those with prior experience. Fistula rates remained stable regardless of technique experience. Pre-trial age for primary surgery experience had no impact on either measures. Conclusion: Managing learning effects through design was not fully achieved but balanced between trial arms, and residual effects were minimal. This investigation explores the presence of learning, within a randomised controlled trial that may be valuable for future trials. We recommend such investigations are undertaken to aid trial interpretation and generalisability, and determine success of trial design measures.

Background: The complexities associated with delivering randomised surgical trials, such as clustering effects, by centre or surgeon, and surgical learning, are well known. Despite this, approaches used to manage these complexities, and opinions on these, vary. Guidance documents have been developed to support clinical trial design and reporting. This work aimed to identify and examine existing guidance and consider its relevance to clustering effects and learning curves within surgical trials. Methods: A review of existing guidelines, developed to inform the design and analysis of randomised controlled trials, is undertaken. Guidelines were identified using an electronic search, within the Equator Network, and by a targeted search of those endorsed by leading UK funding bodies, regulators, and medical journals. Eligible documents were compared against pre-specified key criteria to identify gaps or inconsistencies in recommendations. Results: Twenty-eight documents were eligible (12 Equator Network; 16 targeted search). Twice the number of guidance documents targeted design (n/N=20/28, 71%) than analysis (n/N=10/28, 36%). Managing clustering by centre through design was well documented. Clustering by surgeon had less coverage and contained some inconsistencies. Managing the surgical learning curve, or changes in delivery over time, through design was contained within several documents (n/N=8/28, 29%), of which one provided guidance on reporting this and restricted to early phase studies only. Methods to analyse clustering effects and learning were provided in five and four documents respectively (N=28). Conclusions: To our knowledge, this is the first review as to the extent to which existing guidance for designing and analysing randomised surgical trials covers the management of clustering, by centre or surgeon, and the surgical learning curve. Twice the number of identified documents targeted design aspects than analysis. Most notably, no single document exists for use when designing these studies, which may lead to inconsistencies in practice. The development of a single document, with agreed principles to guide trial design and analysis across a range of realistic clinical scenarios, is needed.

BackgroundThe complexities associated with delivering randomised surgical trials, such as clustering effects, by centre or surgeon, and surgical learning, is well known. Despite this, approaches used to manage these complexities, and opinions on these, vary. Guidance documents have been developed to support clinical trial design and reporting. This work aimed to identify and examine existing guidance and consider their relevance to clustering effects and learning curves within surgical trials.MethodsA review of existing guidelines, developed to inform the design and analysis of randomised controlled trials, is undertaken. Guidelines were identified using an electronic search, within the Equator Network, and by a targeted search those endorsed by leading UK funding bodies, regulators, and medical journals. Eligible documents were compared against pre-specified key criteria to identify gaps or inconsistencies in recommendations. ResultsTwenty-eight documents were eligible (12: Equator Network; 16 targeted search). Twice the number of guidance documents targeted design (n/N=20/28, 71%) than analysis (n/N=10/28, 36%). Managing clustering by centre through design was well documented. Clustering by surgeon had less coverage and contained some inconsistencies. Managing the surgical learning curve, or changes in delivery over time, through design was contained within several documents (n/N=8/28, 29%), of which one provided guidance on reporting this and restricted to early phase studies only. Methods to analyse clustering effects and learning were provided in five and four documents respectively. (N=28)ConclusionsTo our knowledge this is the first review as to the extent to which existing guidance for designing and analysing randomised surgical trials covers the management of clustering, by centre or surgeon, and the surgical learning curve. Twice the number of identified documents targeted design aspects than analysis. Most notably, no single document exists for use when designing these studies, which may lead to inconsistencies in practice. The development of a single document, with agreed principles to guide trial design and analysis across a range of realistic clinical scenarios, is needed.RegistrationNot applicable.

The prevalence of idiopathic intracranial hypertension (IIH), a complex disorder, is increasing globally in association with obesity. The IIH syndrome occurs as the result of elevated intracranial pressure, which can cause permanent visual impairment and loss if not adequately managed. CSF diversion via ventriculoperitoneal and lumboperitoneal shunts is a well-established strategy to protect vision in medically refractory cases. Success of CSF diversion is compromised by high rates of complication; including over-drainage, obstruction, and infection. This review outlines currently used techniques and technologies in the management of IIH. Neurosurgical CSF diversion is a vital component of the multidisciplinary management of IIH.

Background: Cleft palate is among the most common birth abnormalities. The success of primary surgery in the early months of life is crucial for successful feeding, hearing, dental development, and facial growth. Over recent decades, age at palatal surgery in infancy has reduced. The Timing Of Primary Surgery for cleft palate (TOPS) trial aims to determine whether, in infants with cleft palate, it is better to perform primary surgery at age 6 or 12 months (corrected for gestational age). Methods/design: The TOPS trial is an international, two-arm, parallel group, randomised controlled trial. The primary outcome is insufficient velopharyngeal function at 5 years of age. Secondary outcomes, measured at 12 months, 3 years, and 5 years of age, include measures of speech development, safety of the procedure, hearing level, middle ear function, dentofacial development, and growth. The analysis approaches for primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The TOPS protocol has been published previously. Discussion: This paper provides details of the planned statistical analyses for the TOPS trial and will reduce the risk of outcome reporting bias and data-driven results. Trial registration: ClinicalTrials.gov NCT00993551. Registered on 9 October 2009.

Background: Patient outcomes can depend on the treating centre, or health professional, delivering the intervention. A health professional’s skill in delivery improves with experience, meaning that outcomes may be associated with learning. Considering differences in intervention delivery at trial design will ensure that any appropriate adjustments can be made during analysis. This work aimed to establish practice for the allowance of clustering and learning effects in the design and analysis of randomised multicentre trials. Methods: A survey that drew upon quotes from existing guidelines, references to relevant publications and example trial scenarios was delivered. Registered UK Clinical Research Collaboration Registered Clinical Trials Units were invited to participate. Results: Forty-four Units participated (N = 50). Clustering was managed through design by stratification, more commonly by centre than by treatment provider. Managing learning by design through defining a minimum expertise level for treatment provider was common (89%). One-third reported experience in expertise-based designs. The majority of Units had adjusted for clustering during analysis, although approaches varied. Analysis of learning was rarely performed for the main analysis (n = 1), although it was explored by other means. The insight behind the approaches used within and reasons for, or against, alternative approaches were provided. Conclusions: Widespread awareness of challenges in designing and analysing multicentre trials is identified. Approaches used, and opinions on these, vary both across and within Units, indicating that approaches are dependent on the type of trial. Agreeing principles to guide trial design and analysis across a range of realistic clinical scenarios should be considered.

Background: Insertion of a ventriculoperitoneal shunt to treat hydrocephalus is one of the most common neurosurgical procedures worldwide. Shunt infection affects up to 15% of patients, resulting in long hospital stays, multiple surgeries and reduced cognition and quality of life. Objectives: The aim of this trial was to determine whether or not antibiotic-impregnated ventriculoperitoneal shunts (hereafter referred to as antibiotic shunts) (e.g. impregnated with rifampicin and clindamycin) or silver-impregnated ventriculoperitoneal shunts (hereafter referred to as silver shunts) reduce infection compared with standard ventriculoperitoneal shunts (hereafter referred to as standard shunts). Design: This was a three-arm, superiority, multicentre, parallel-group randomised controlled trial. Patients and a central primary outcome review panel, but not surgeons or operating staff, were blinded to the type of ventriculoperitoneal shunt inserted. Setting: The trial was set in 21 neurosurgical wards across the UK and the Republic of Ireland. Participants: Participants were patients with hydrocephalus of any aetiology who were undergoing insertion of their first ventriculoperitoneal shunt. Interventions: Participants were allocated 1 : 1 : 1 by pressure-sealed envelope to receive a standard non-impregnated, silver-impregnated or antibiotic-impregnated ventriculoperitoneal shunt at the time of insertion. Ventriculoperitoneal shunts are medical devices, and were used in accordance with the manufacturer’s instructions for their intended purpose. Main outcome measures: The primary outcome was time to ventriculoperitoneal shunt failure due to infection. Secondary outcomes were time to failure for any cause, reason for failure (infection, mechanical), types of ventriculoperitoneal shunt infection, rate of infection after first clean (non-infected) revision and health economics. Outcomes were analysed by intention to treat. Results: Between 26 June 2013 and 9 October 2017, 1605 patients from neonate to 91 years of age were randomised to the trial: n = 36 to the standard shunt, n = 538 to the antibiotic shunt and n = 531 to the silver shunt. Patients who did not receive a ventriculoperitoneal shunt (n = 4) or who had an infection at the time of insertion (n = 7) were not assessed for the primary outcome. Infection occurred in 6.0% (n = 32/533) of those who received the standard shunt, in 2.2% (n = 12/535) of those who received the antibiotic shunt and in 5.9% (n = 31/526) of those who received the silver shunt. Compared with the standard shunt, antibiotic shunts were associated with a lower rate of infection (cause-specific hazard ratio 0.38, 97.5% confidence interval 0.18 to 0.80) and a decreased probability of infection (subdistribution hazard ratio 0.38, 97.5% confidence interval 0.18 to 0.80). Silver shunts were not associated with a lower rate of infection than standard shunts (cause-specific hazard ratio 0.99, 97.5% confidence interval 0.56 to 1.74). The ventriculoperitoneal shunt failure rate attributable to any cause was 25.0% overall and did not differ between arms. Antibiotic shunts save £135,753 per infection avoided. There were no serious adverse events. Limitations: It was not possible to blind treating neurosurgeons to the ventriculoperitoneal shunt type. The return rate for patient-reported outcomes was low. Limitations to the economic evaluation included failure to obtain Hospital Episode Statistics data from NHS Digital, as per protocol. Reliance on patient-level information and costing systems data mitigated these limitations. Conclusions: Antibiotic shunts have a reduced infection rate compared with standard shunts, whereas silver shunts do not. Antibiotic shunts are cost-saving. Future work: A sample collection has been established that will enable the study of surrogate markers of ventriculoperitoneal shunt infection in cerebrospinal fluid or blood using molecular techniques. A post hoc analysis to study factors related to shunt failure will be performed as part of a future study. An impact analysis to assess change in practice is planned. Trial registration: Current Controlled Trials ISRCTN49474281. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 17. See the NIHR Journals Library website for further project information.