Simon Skene is Professor of Medical Statistics at the University of Surrey and Director of Surrey Clinical Trials Unit and Clinical Research Facility.
Simon has over 20 years’ experience as a medical statistician in teaching and research, including the design and analysis of studies investigating medicinal products, advanced therapies, diagnostic accuracy and surgery. His PhD focused on the analysis of very small samples of repeated measurements, addressing small sample issues in longitudinal analysis. He is a Fellow of the Royal Statistical Society and has consultancy experience in the pharmaceutical industry.
As Head of Statistics at the UCL Comprehensive Clinical Trials Unit, he provided leadership and statistical oversight on UK trials coordinated by the unit across phases I-III in multiple therapeutic areas including hepatology and gastroenterology, ophthalmology, neurology and surgery.
Simon's appointment at University of Surrey combines the role of Director of the Clinical Trials Unit (CTU) and Clinical Research Facility (CRF) with leadership in statistics to support decision based practice in medicine. He is additionally Head of Department of Clinical and Experimental Medicine which brings together the CTU, CRF and Surrey Sleep Research Centre (SSRC) with complementary sections comprising Research Design Service - South East (RDS-SE; Surrey), Surrey Health Economics Centre (SHEC), Clinical Medicine and Statistical Multi-Omics. The department is dedicated to academic excellence in education and the delivery of clinical research in health and disease.
Associate Editor (Statistics) for the journal Osteoarthritis and Cartilage
Regional Advisory Panel member for NIHR Research for Patient Benefit (RfPB) South East and Central
Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial.
In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25?75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed.
Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI ?2·6 to 0·7) in the exenatide group and worsened by 2·1 points (?0·6 to 4·8) in the placebo group, an adjusted mean difference of ?3·5 points (?6·7 to ?0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions.
Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials.
Michael J Fox Foundation for Parkinson's Research.
Distributions of measured data are often well modelled by known probability distributions, which provide a useful description of their underlying properties such as location (average), spread (variation) and shape.
Statisticians use probability distributions to interpret and attribute meaning, draw conclusions and answer research questions using the measurements or data that
researchers gather during their studies. Different types of data follow different probability distributions, and these distributions are characterised by certain features
called parameters. Even the most statistically averse of researchers is likely to have heard of the normal distribution, which is often used to approximate the distribution of continuous or measurement data such as intraocular pressure, central retinal thickness and
degree of proptosis. The normal distribution follows a ?bell-shaped curve? (although with a rim stretching to ±infinity) the shape of which is specified by the mean and SD, with different values of each, giving rise to
different bell-shaped curves (see figure 1).
Other distributions such as the binomial and Poisson probability distributions are less commonly reported in ophthalmic research and are characterised by different
parameters. The binomial distribution is used for dichotomous data and is characterised by the probability of success, that is, the number of ?successes? out of a total number of observed events, for example, the proportion of graft transplants that fail within 6 months of transplantation. The Poisson distribution is used for counts data and is characterised by the mean number of
events, for example, endophthalmitis rates.
The assumption that the observed data follow such probability distributions allows a statistician to apply appropriate statistical tests, which are known as parametric tests. The normal distribution is a powerful tool provided the data plausibly arise from that
distribution or can be made to reasonably
approximate this following a suitable transformation
such as by taking natural logarithms to reduce asymmetry. The normal distribution also serves as an approximating
distribution to the Poisson or binomial distribution
under certain circumstances or can be used for large samples to approximate the distribution of the sample mean via the central limit theorem. Tests based on the
normal distribution are therefore extremely useful and form the basis of many analyses, the usual tests being z tests or t tests, which rely on approximate normality or normality, respectively.1 If we can assume a normal distribution, then we expect 95% of values to lie within 1.96 SDs of the mean.
Parametric tests make assumptions about the distribution of the data and sometimes it may be impossible to assess these assumptions, perhaps because the sample size is
small or because that data do not follow any of the more common probability distributions. Alternatively, we may be interested in making inferences about medians rather than means or about ordinal or ranked data. In such circumstances, statisticians may adopt an alternative class of statistical tests, which are known as non-parametric or distribution-free methods. These methods work by ranking the data in numerical order and analysing
these ranks rather than the actual measurements
observed. Two of the most well-known non-parametric methods are the Mann?Whitney test (or U test) and the Wilcoxon matched-pairs signed-rank test, which are
suitable for data from two unpaired samples or two paired samples, respectively.2 3
The Wilcoxon matched-pairs signed-rank test calculates the differences between each matched pair in the two samples and replaces their absolute values with their
ordered ranks (1, 2, 3, etc), ignoring zeros. Under the null hypothesis of no difference between samples, the sum of the positive and negative ranks should be similar. The
test statistic is usually taken to be the smaller of the two sums, and exact p values ca
controlled trial (RCT) comparing total ankle replacement
(TAR) and arthrodesis (fusion) surgery in NHS
patients aged 50-85 with end-stage ankle arthritis. 328
patients will be randomly allocated to TAR or arthrodesis
on an equal basis.
Clinician and patient treatment equipoise is critical to
recruit surgeons and patients successfully.
The TARVA Trial team has developed novel surgeon
and patient engagement techniques involving technology
and multi-media tools to achieve our aims. Examples
include an award-winning video, a white-labelled patient
information brochure, professional newsletters and blogs,
and a particular focus on the use of social networking
tools to engage both investigators and patients.
The impartial trial information video featuring consultant foot and ankle surgeons and patients who have
undergone TAR or fusion surgery can be accessed through the trial website (http://anklearthritis.co.uk).
The pilot phase began with the randomisation of the
first patient in March 2015. An overview of our techniques alongside recruitment data accumulated until
November will be presented at the ICTM conference.
In addition to pain, sickle cell anaemia (HbSS) complications include neurocognitive difficulties in attention and processing speed associated with low daytime and night-time oxygen saturation compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). The aim of this single-blind, randomised, controlled phase II trial is to compare auto-adjusting CPAP (APAP) with standard care to standard care alone in individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life.
Eligibility criteria include: ability to provide informed consent; age > 8 years; diagnosis of HbSS; and mean overnight saturation of
Sixty individuals with HbSS (30 children and 30 adults) will be randomised to standard care + APAP or standard care alone for six months. Minimisation factors are: age group (8?11, 12?15, 16?22 and > 23 years); silent infarction on MRI; minimum overnight oxygen saturation > 90% or
For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist.
The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, blood and urine chemistry, quality of life and daily pain via a smartphone App (GoMedSolutions, Inc) and, where possible MRI heart, echocardiography, and 6-min walk. These outcomes will be assessed at baseline and after six months of treatment by assessors blind to treatment assignment.
Altering oxygen saturation in HbSS may lead to bone marrow suppression. This risk will be reduced by monitoring full blood counts at baseline, two weeks, three months and six months, providing treatment as appropriate and reporting as safety events.
ISRCTN46012373. Registered on 10 July 2015.
Protocol Version: 6.0 Date: 24th December 2015
Sponsor: University Hospital Southampton. Sponsor?s protocol code: RHMCHIOT53
measurements I: An adjusted sandwich
estimator, Statistics in Medicine 29 pp. pp2825-2837 Wiley
Methods and analysis TARVA is a multicentre randomised controlled trial that will randomise 328 patients aged 50?85?years with end-stage ankle arthritis. The 2 arms of the study will be TAR or ankle arthrodesis with 164 patients in each group. Up to 16 UK centres will participate. Patients will have clinical assessments and complete questionnaires before their operation and at 6, 12, 26 and 52?weeks after surgery. The primary clinical outcome of the study is a validated patient-reported outcome measure, the Manchester Oxford foot questionnaire, captured preoperatively and 12?months after surgery. Secondary outcomes include quality-of-life scores, complications, revision, reoperation and a health economic analysis.
Ethics and dissemination The protocol has been approved by the National Research Ethics Service Committee (London, Bloomsbury 14/LO/0807). This manuscript is based on V.5.0 of the protocol. The trial findings will be disseminated through peer-reviewed publications and conference presentations.
Trial registration number NCT02128555.
Introduction Circulating prostaglandin E2 levels are elevated in acutely decompensated cirrhosis and have been shown to contribute to immune suppression. Albumin binds and inactivates this hormone. Human albumin solution could thus be repurposed as an immune restorative drug in these patients.
This feasibility study aims to determine whether it is possible and safe to restore serum albumin to >30?g/L and maintain it at this level in patients admitted with acute decompensated cirrhosis using repeated 20% human albumin infusions according to daily serum albumin levels.
Methods and analysis Albumin To prevenT Infection in chronic liveR failurE (ATTIRE) stage 1 is a multicentre, open label dose feasibility trial. Patients with acutely decompensated cirrhosis admitted to hospital with a serum albumin of
Ethics and dissemination Research ethics approval was given by the London-Brent research ethics committee (ref: 15/LO/0104). The clinical trials authorisation was issued by the medicines and healthcare products regulatory agency (ref: 20363/0350/001-0001).
Results Will be disseminated through peer reviewed journals and international conferences. Recruitment of the first participant occurred on 26/05/2015.
Trial registration number The trial is registered with the European Medicines Agency (EudraCT 2014-002300-24) and has been adopted by the NIHR (ISRCTN 14174793). This manuscript refers to V.4.0 of the protocol; Pre-results.
Patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however, there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E2 (PGE2) and other lipids.
We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS. Immune function was determined by comparison of macrophage function following addition of plasma samples. We also used samples from 12 healthy individuals. We measured binding of plasma proteins to PGE2 and serum levels of endotoxin (lipopolysaccharide) and cytokines; using 10 patients? samples, we investigated the effects of PGE2 inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration.
At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P
Analysis of blood samples from patients with AD/ACLF participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30 g/L reversed plasma-mediated immune dysfunction by binding and inactivating PGE2. We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, which could improve identification of patients most likely to respond to HAS treatment. A randomized controlled trial is needed to determine whether these effects of HAS reduce infections in AD/ACLF. Trial registered with European Medicines Agency (EudraCT 2014-002300-24) and adopted by NIHR (ISRCTN14174793).
Infections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2?mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial.
We performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels.
The patients? mean model for end-stage disease score was 20.9 ± 6.6. The primary end point (albumin e30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded.
In a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014-002300-24 and ISRCTN14174793.
Elevated circulating Prostaglandin E2 (PGE2) levels contribute to immune suppression in acutely decompensated (AD) cirrhosis. PGE2 is more bioavailable because of decreased serum albumin levels in AD patients as albumin binds PGE2. The binding capacity of endogenous albumin is also known to be defective in cirrhosis. Human Albumin Solution (HAS), a safe and common intervention, could thus be repurposed as an immune restorative drug in AD
The primary aim of ATTIRE is to determine if raising serum albumin to >30 g/L in patients with decompensated cirrhosis will decrease rates of infection, extra hepatic organ dysfunction and death.
Flavanols are an important class of food bioactives that can improve vascular function even in healthy subjects. Cocoa flavanols (CFs) are comprised principally of the monomer, (?)-epicatechin (~20%) with a degree of polymerisation of 1 (DP1), and oligomeric procyanidins (~80%, DP2-10).
To investigate the relative contribution of procyanidins and (?)-epicatechin to CF intake-related improvements in vascular function in healthy volunteers.
In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 45 healthy men, (18-35 years), consumed once daily for 1 month (a) a DP1-10 cocoa extract containing 130 mg of (?)-epicatechin and 560 mg of procyanidins (b) a DP2-10 cocoa extract containing 20 mg (?)-epicatechin and 540 mg procyanidins or (c) a Control that was flavanol-free with identical micro- and macronutrient composition. (ClinicalTrials.gov NCT02728466)
Consumption of DP1-10, but neither DP2-10 nor the Control, significantly increased flow-mediated vasodilation (primary endpoint), and the level of structurally-related (?)-epicatechin metabolites (SREMs) in the circulatory system, while decreasing pulse wave velocity and blood pressure. Total cholesterol significantly decreased after daily intake of both DP1-10 and DP2-10 as compared to the Control.
CF-related improvements in vascular function predominantly relate to intake of flavanol monomers and circulating SREMs in healthy humans, but not to the more abundant procyanidins and gut microbiome-derived CF-catabolites. Reduction in total cholesterol was linked to consumption of procyanidins but not necessarily that of (-)-epicatechin.
Previous studies have shown that ultraviolet light can lead to release of nitric oxide (NO) from the skin and decrease blood pressure. In contrast to visible light local application of UV light bears a cancerogenic risk. Here, we investigated whether whole body exposure to visible blue light can also decrease blood pressure and increase endothelial function in healthy subjects.
In a randomized cross-over study, 14 healthy male subjects were exposed on 2 days to monochromatic blue light or blue light with a filter foil (control light) over 30 min. We measured blood pressure (primary endpoint), heart rate, forearm vascular resistance, forearm-blood-flow, endothelial function (flow-mediated dilation), pulse wave velocity, and plasma NO species (NOx), nitrite, and nitroso compounds (RXNO) (secondary endpoints) during and up to 2 hours after exposure.
Blue light exposure significantly decreased systolic blood pressure and increased heart rate as compared to control. In parallel, blue light significantly increased forearm-blood-flow, flow-mediated dilation, circulating NOx and RXNO while it decreased forearm vascular resistance and pulse wave velocity.
Whole body irradiation with visible blue light at real world doses improves blood pressure, endothelial function, and arterial stiffness by NO released from photolabile intracutanous NO metabolites into circulating blood.