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Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study).

ABSTRACT: BACKGROUND:Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12?months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. METHODS/DESIGN:ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12?months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study-Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. DISCUSSION:Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01843075 . Registration 30 April 2013.

SUBMITTER: Femminella GD

PROVIDER: S-EPMC6448216 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study).

Femminella Grazia Daniela GD Frangou Eleni E Love Sharon B SB Busza Gail G Holmes Clive C Ritchie Craig C Lawrence Robert R McFarlane Brady B Tadros George G Ridha Basil H BH Bannister Carol C Walker Zuzana Z Archer Hilary H Coulthard Elizabeth E Underwood Ben R BR Prasanna Aparna A Koranteng Paul P Karim Salman S Junaid Kehinde K McGuinness Bernadette B Nilforooshan Ramin R Macharouthu Ajay A Donaldson Andrew A Thacker Simon S Russell Gregor G Malik Naghma N Mate Vandana V Knight Lucy L Kshemendran Sajeev S Harrison John J Hölscher Christian C Brooks David J DJ Passmore Anthony Peter AP Ballard Clive C Edison Paul P

Trials 20190403 1

<h4>Background</h4>Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rat ...[more]

PMID: 30944040

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Project description:BackgroundWhile existing psychological treatments for depression are effective for many, a significant proportion of depressed individuals do not respond to current approaches and few remain well over the long-term. Anhedonia (a loss of interest or pleasure) is a core symptom of depression which predicts a poor prognosis but has been neglected by existing treatments. Augmented Depression Therapy (ADepT) has been co-designed with service users to better target anhedonia alongside other features of depression. This mixed methods pilot trial aims to establish proof of concept for ADepT and to examine the feasibility and acceptability of a future definitive trial evaluating the clinical and cost-effectiveness of ADepT, compared to an evidence-based mainstream therapy (Cognitive Behavioural Therapy; CBT) in the acute treatment of depression, the prevention of subsequent depressive relapse, and the enhancement of wellbeing.MethodsWe aim to recruit 80 depressed participants and randomise them 1:1 to receive ADepT (15 weekly acute and 5 booster sessions in following year) or CBT (20 weekly acute sessions). Clinical and health economic assessments will take place at intake and at 6-, 12-, and 18-month follow-up. Reductions in PHQ-9 depression severity and increases in WEMWBS wellbeing at 6-month assessment (when acute treatment should be completed) are the co-primary outcomes. Quantitative and qualitative process evaluation will assess mechanism of action, implementation issues, and contextual moderating factors. To evaluate proof of concept, intake-post effect sizes and the proportion of individuals showing reliable and clinically significant change on outcome measures in each arm at each follow-up will be reported. To evaluate feasibility and acceptability, we will examine recruitment, retention, treatment completion, and data completeness rates and feedback from patients and therapists about their experience of study participation and therapy. Additionally, we will establish the cost of delivery of ADepT.DiscussionWe will proceed to definitive trial if any concerns about the safety, acceptability, feasibility, and proof of concept of ADepT and trial procedures can be rectified, and we recruit, retain, and collect follow-up data on at least 60% of the target sample.Trial registrationISCRTN85278228, registered 27/03/2017.

Project description:BackgroundDiabetes mellitus (DM) is associated with poor outcome after surgery. The prevalence of DM in hospitalised patients is up to 40%, meaning that the anaesthesiologist will encounter a patient with DM in the operating room on a daily basis. Despite an abundance of published glucose lowering protocols and the known negative outcomes associated with perioperative hyperglycaemia in DM, there is no evidence regarding the optimal intraoperative glucose lowering treatment. In addition, protocol adherence is usually low and protocol targets are not simply met. Recently, incretins have been introduced to lower blood glucose. The main hormone of the incretin system is glucagon-like peptide-1 (GLP-1). GLP-1 increases insulin and decreases glucagon secretion in a glucose-dependent manner, resulting in glucose lowering action with a low incidence of hypoglycaemia. We set out to determine the optimal intraoperative treatment algorithm to lower glucose in patients with DM type 2 undergoing non-cardiac surgery, comparing intraoperative glucose-insulin-potassium infusion (GIK), insulin bolus regimen (BR) and GPL-1 (liragludite, LG) treatment.Methods/designThis is a multicentre randomised open label trial in patients with DM type 2 undergoing non-cardiac surgery. Patients are randomly assigned to one of three study arms; intraoperative glucose-insulin-potassium infusion (GIK), intraoperative sliding-scale insulin boluses (BR) or GPL-1 pre-treatment with liraglutide (LG). Capillary glucose will be measured every hour. If necessary, in all study arms glucose will be adjusted with an intravenous bolus of insulin. Researchers, care givers and patients will not be blinded for the assigned treatment. The main outcome measure is the difference in median glucose between the three study arms at 1 hour postoperatively. We will include 315 patients, which gives us a 90% power to detect a 1 mmol l(-1) difference in glucose between the study arms.DiscussionThe PILGRIM trial started in January 2014 and will provide relevant information on the perioperative use of GLP-1 agonists and the optimal intraoperative treatment algorithm in patients with diabetes mellitus type 2.Trial registrationClinicalTrials.gov, NCT02036372.

Project description:IntroductionPeople living with and beyond cancer are vulnerable to a number of physical, functional and psychological issues. Undertaking a holistic needs assessment (HNA) is one way to support a structured discussion of patients' needs within a clinical consultation. However, there is little evidence on how HNA impacts on the dynamics of the clinical consultation. This study aims to establish (1) how HNA affects the type of conversation that goes on during a clinical consultation and (2) how these putative changes impact on shared decision-making and self-efficacy.Methods and analysisThe study is hosted by 10 outpatient oncology clinics in the West of Scotland and South West England. Participants are patients with a diagnosis of head and neck, breast, urological, gynaecological and colorectal cancer who have received treatment for their cancer. Patients are randomised to an intervention or control group. The control group entails standard care--routine consultation between the patient and clinician. In the intervention group, the patient completes a holistic needs assessment prior to consultation. The completed assessment is then given to the clinician where it informs a discussion based on the patient's needs and concerns as identified by them. The primary outcome measure is patient participation, as determined by dialogue ratio (DR) and preponderance of initiative (PI) within the consultation. The secondary outcome measures are shared decision-making and self-efficacy. It is hypothesised that HNA will be associated with greater patient participation within the consultation, and that shared decision-making and feelings of self-efficacy will increase as a function of the intervention.Ethics and disseminationThis study has been given a favourable opinion by the West of Scotland Research Ethics Committee and NHS Research & Development. Study findings will be disseminated through peer-reviewed publications and conference attendance.Trail registration numberClinical Trials.gov NCT02274701.

Project description:Aims/hypothesisLiraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome).MethodsIn 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center.ResultsImmunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation.Conclusions/interpretationFor the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity.Trial registrationClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Project description:BACKGROUND:Despite evidence from clinical trials that intravenous (IV) thrombolysis is a cost-effective treatment for selected acute ischaemic stroke patients, there remain large variations in the rate of IV thrombolysis delivery between stroke services. This study is evaluating whether an enhanced care pathway delivered by paramedics (the Paramedic Acute Stroke Treatment Assessment (PASTA)) could increase the number of patients who receive IV thrombolysis treatment. METHODS:Study design: Cluster randomised trial with economic analysis and parallel process evaluation. SETTING:National Health Service ambulance services, emergency departments and hyper-acute stroke units within three geographical regions of England and Wales. Randomisation: Ambulance stations within each region are the units of randomisation. According to station allocation, paramedics based at a station deliver the PASTA pathway (intervention) or continue with standard stroke care (control). Study intervention: The PASTA pathway includes structured pre-hospital information collection, prompted pre-notification, structured handover of information in hospital and assistance with simple tasks during the initial hospital assessment. Study-trained intervention group paramedics deliver this pathway to adults within 4 h of suspected stroke onset. Study control: Standard stroke care according to national and local guidelines for the pre-hospital and hospital assessment of suspected stroke. PARTICIPANTS:Participants enrolled in the study are adults with confirmed stroke who were assessed by a study paramedic within 4 h of symptom onset. PRIMARY OUTCOME:Proportion of participants receiving IV thrombolysis. SAMPLE SIZE:1297 participants provide 90% power to detect a 10% difference in the proportion of patients receiving IV thrombolysis. DISCUSSION:The results from this trial will determine whether an enhanced care pathway delivered by paramedics can increase thrombolysis delivery rates. TRIAL REGISTRATION:ISRCTN registry, ISRCTN12418919 . Registered on 5 November 2015.

Project description:Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH.Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ?25 kg/m(2)) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis.The protocol was approved by the National Research Ethics Service (East Midlands-Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is currently ongoing and is due to finish in July 2014. The findings of this trial will be disseminated through peer-reviewed publications and international presentations.clinicaltrials.gov NCT01237119.

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Dataset Information

Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study).

Publications

Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study).

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