Simon S. Skene

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

BACKGROUND Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinsons disease. We investigated whether these effects would be apparent in a clinical trial. METHODS In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinsons 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 Parkinsons 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 Parkinsons 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. FINDINGS 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. INTERPRETATION Exenatide had positive effects on practically defined off-medication motor scores in Parkinsons 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 Parkinsons disease, and effects on everyday symptoms should be examined in longer-term trials. FUNDING Michael J Fox Foundation for Parkinsons Research.

The analysis of very small samples of repeated measurements I: An adjusted sandwich estimator

The statistical analysis of repeated measures or longitudinal data always requires the accommodation of the covariance structure of the repeated measurements at some stage in the analysis. The general linear mixed model is often used for such analyses, and allows for the specification of both a mean model and a covariance structure. Often the covariance structure itself is not of direct interest, but only a means to producing valid inferences about the response. Existing methods of analysis are often inadequate where the sample size is small. More precisely, statistical measures of goodness of fit are not necessarily the right measure of the appropriateness of a covariance structure and inferences based on conventional Wald-type procedures do not approximate sufficiently well their nominal properties when data are unbalanced or incomplete. This is shown to be the case when adopting the Kenward-Roger adjustment where the sample size is very small. A generalization of an approach to Wald tests using a bias-adjusted empirical sandwich estimator for the covariance matrix of the fixed effects parameters from generalized estimating equations is developed for Gaussian repeated measurements. This is shown to attain the correct test size but has very low power. Copyright

The analysis of very small samples of repeated measurements II: a modified Box correction

There is a need for appropriate methods for the analysis of very small samples of continuous repeated measurements. A key feature of such analyses is the role played by the covariance matrix of the repeated observations. When subjects are few it can be difficult to assess the fit of parsimonious structures for this matrix, while the use of an unstructured form may lead to a serious lack of power. The Kenward-Roger adjustment is now widely adopted as a means of providing an appropriate inferences in small samples, but does not perform adequately in very small samples. Adjusted tests based on the empirical sandwich estimator can be constructed that have good nominal properties, but are seriously underpowered. Further, when such data are incomplete, or unbalanced, or non-saturated mean models are used, exact distributional results do not exist that justify analyses with any sample size. In this paper, a modification of Boxs correction applied to a linear model-based F-statistic is developed for such small sample settings and is shown to have both the required nominal properties and acceptable power across a range of settings for repeated measurements.

Albumin Counteracts Immune-Suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease

Background & Aims: 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. Methods: 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. Results: At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P <.0001). Plasma from patients after HAS infusion induced significantly higher levels of tumor necrosis factor production by macrophages (19.5 ± 4.8 ng/mL) compared with plasma collected before treatment (17.7 ± 4.5 ng/mL; P =.0013). There was a significantly lower proportion of plasma protein (albumin) binding to PGE2 from patients with AD/ACLF plasma (mean, 61.9%) compared with plasma from control subjects (77.1%; P =.0012). AD/ACLF plasma protein binding to PGE2 increased following HAS treatment compared with baseline (mean increase, 8.7%; P <.0001). Circulating levels of PGE2, lipopolysaccharide, and inflammatory or anti‐inflammatory cytokines were higher in patients with AD/ACLF than healthy volunteers. Unexpectedly, HAS infusion had no effect on mediator levels. Principal component analysis of baseline levels of lipids that induce or resolve inflammation identified 2 distinct groups of patients that differed according to baseline plasma level of lipopolysaccharide. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group. Conclusions: 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).

Total ankle replacement versus arthrodesis (TARVA): protocol for a multicentre randomised controlled trial

Introduction Total ankle replacement (TAR) or ankle arthrodesis (fusion) is the main surgical treatments for end-stage ankle osteoarthritis (OA). The popularity of ankle replacement is increasing while ankle fusion rates remain static. Both treatments have efficacy but to date all studies comparing the 2 have been observational without randomisation, and there are no published guidelines as to the most appropriate management. The TAR versus arthrodesis (TARVA) trial aims to compare the clinical and cost-effectiveness of TAR against ankle arthrodesis in the treatment of end-stage ankle OA in patients aged 50–85 years. 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.

ATTIRE: Albumin To prevenT Infection in chronic liveR failurE: study protocol for a single-arm feasibility trial.

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 <30 g/L are eligible, subject to exclusion criteria. Daily intravenous human albumin solution will be infused, according to serum albumin levels, for up to 14 days or discharge in all patients. The primary end point is daily serum albumin levels for the duration of the treatment period and the secondary end point is plasma-induced macrophage dysfunction. The trial will recruit 80 patients. Outcomes will be used to assist with study design for an 866 patient randomised controlled trial at more than 30 sites across the UK. 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.

Post hoc analysis of the Exenatide-PD trial-Factors that predict response

Exenatide, a glucagon‐like peptide‐1 agonist and a licensed treatment for Type 2 diabetes significantly reduced deterioration in motor symptoms in patients with Parkinsons disease in a randomized, placebo‐controlled trial. In addition, there were trends favouring the exenatide group in assessments of nonmotor symptoms, cognition, and quality of life. The aim of this exploratory post hoc analysis was to generate new hypotheses regarding (a) whether candidate baseline factors might predict the magnitude of response to exenatide; and (b) whether the beneficial effects of exenatide reported for the overall population are consistent in various subgroups of patients. Univariate and multivariate analyses were conducted to determine possible predictors of motor response to exenatide in this cohort. Potential treatment by subgroup interactions for changes in; motor severity, nonmotor symptoms, cognition, and quality of life after 48‐weeks treatment with exenatide were evaluated among post hoc subgroups defined by age, motor phenotype, disease duration, disease severity, body mass index (BMI), and insulin resistance. In the subgroup analyses, exenatide once‐weekly was associated with broadly improved outcome measures assessing motor severity, nonmotor symptoms, cognition, and quality of life across all subgroups, however, tremor‐dominant phenotype and lower Movement Disorder Society‐Sponsored Revision of the Unified Parkinsons Disease Rating Scale (MDS‐UPDRS) Part‐2 scores predicted greatest motor response to exenatide and there was an indication that patients with older age of onset and disease duration over 10 years responded less well. While patients with a range of demographic and clinical factors can potentially benefit from exenatide once‐weekly, these data support an emphasis towards recruiting patients at earlier disease in future planned clinical trials of gluacagon‐like peptide‐1 (GLP‐1) receptor agonists in Parkinsons disease (PD).

Administration of Albumin Solution Increases Serum Levels of Albumin in Patients With Chronic Liver Failure in a Single-Arm Feasibility Trial

Background & Aims: 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. Methods: 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. Results: The patients’ mean model for end‐stage disease score was 20.9 ± 6.6. The primary end point (albumin ≥30 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. Conclusions: 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.

Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: Randomized-controlled, double-masked intervention trial

ABSTRACT Background Flavanols are an important class of food bioactives that can improve vascular function even in healthy subjects. Cocoa flavanols (CFs) are composed principally of the monomer (−)-epicatechin (∼20%), with a degree of polymerisation (DP) of 1 (DP1), and oligomeric procyanidins (∼80%, DP2–10). Objective Our objective was to investigate the relative contribution of procyanidins and (−)-epicatechin to CF intake–related improvements in vascular function in healthy volunteers. Design In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 45 healthy men (aged 18–35 y) consumed the following once daily for 1 mo: 1) a DP1–10 cocoa extract containing 130 mg (−)-epicatechin and 560 mg procyanidins, 2) a DP2–10 cocoa extract containing 20 mg (−)-epicatechin and 540 mg procyanidins, or 3) a control capsule, which was flavanol-free but had identical micro- and macronutrient composition. Results Consumption of DP1–10, but not of either DP2–10 or the control capsule, significantly increased flow-mediated vasodilation (primary endpoint) and the concentration 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 with the control. Conclusions CF-related improvements in vascular function are predominantly related to the 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 to that of (−)-epicatechin. This trial was registered at clinicaltrials.gov as NCT02728466.

Blue light exposure decreases systolic blood pressure, arterial stiffness, and improves endothelial function in humans

Aims Previous studies have shown that ultraviolet light can lead to the release of nitric oxide from the skin and decrease blood pressure. In contrast to visible light the local application of ultraviolet 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. Methods In a randomised crossover 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 minutes. We measured blood pressure (primary endpoint), heart rate, forearm vascular resistance, forearm blood flow, endothelial function (flow-mediated dilation), pulse wave velocity and plasma nitric oxide species, nitrite and nitroso compounds (secondary endpoints) during and up to 2 hours after exposure. Results 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 nitric oxide species and nitroso compounds while it decreased forearm vascular resistance and pulse wave velocity. Conclusion Whole body irradiation with visible blue light at real world doses improves blood pressure, endothelial function and arterial stiffness by nitric oxide released from photolabile intracutanous nitric oxide metabolites into circulating blood.