Title: A randomized, double blind, parallel group, placebo controlled trial of Exenatide once weekly over 2 years as a potential disease modifying treatment for Parkinson's disease.
Funder: Medical Research Council

Abstract: For the first few years after diagnosis, most symptoms of Parkinson’s are partially improved by treatments that replace dopamine in the brain. However, as the disease progresses, symptoms emerge that do not respond well to current treatments, such as falls, difficulty with speech and swallowing and problems with thinking and memory, and these cause major disability. There is therefore an urgent need to find a treatment that can slow down or stop the progression of Parkinson’s._x000D_ _x000D_ There is increasing evidence that exenatide (a licensed drug for the treatment of diabetes) may slow disease progression in Parkinson’s. Furthermore there is evidence that diabetes, or even a slight tendency towards diabetes makes Parkinson's worse. Laboratory results show that exenatide protects nerve cells, while it can also have beneficial effects in a range of animal models of Parkinson's. There are now 2 small randomised controlled trials in which exenatide has been tested in people with Parkinson’s (PwP). Both of these trials showed that PwP that used exenatide for 1 year had lower Parkinson’s severity at the end of the trials than those who did not. In the first of these trials, the advantage of using exenatide was still readily detectable even up to 1 year after the drug had been stopped, indicating that exenatide may have slowed the progression of Parkinson’s._x000D_ _x000D_ In this study we will see if the results of the previous trials can be replicated in a larger group of people. We aim to recruit 200 PwP from 6 centres across the UK. Participants will be randomly allocated to receive exenatide or dummy drug (placebo) which they will be taught to inject themselves under the skin once a week for 2 years. Participants will undergo an assessment at the beginning of the study and then again every 6 months during which the severity of their Parkinson's will be measured first thing in the morning having temporarily withheld their usual PD medication overnight. We will assess whether any beneficial effects of exenatide accumulate in magnitude with prolonged use which would strongly indicate that it does indeed slow Parkinson’s progression. We aim to include as broad a range of PwP as possible into the study so that the results are applicable to most people living with the condition._x000D_ _x000D_ Participants will have blood tests to check the safety of exenatide and give us a range of detailed information about how exenatide might be working. This application has been developed with the full involvement of PwP. The study design has been discussed with a focus group of PwP and their carers. A person with Parkinson’s and a PwP carer will be members of the Trial Steering Committee, who have oversight over the whole study. Our lay committee members will advise on all study documentation and assist with summarising the findings of the study which will be sent to all study participants and other patient groups._x000D_ _x000D_ It is hoped that this study will lead to the first treatment for Parkinson’s that is robustly confirmed to slow progression of the disease, and that this will lead to a major change in the way that Parkinson’s is treated, and spur the development of new, even more effective drugs to slow down the progression of this disease.

Lay abstract: Dopamine replacement therapies can markedly improve the initial motor symptoms of Parkinson’s disease (PD) but these have no effects on the subsequent progression of the disease. Over subsequent years, disabling, treatment refractory symptoms and signs emerge which include falls, swallowing problems and dementia. The most important unmet need in PD is therefore to identify a drug that can slow down or stop the progression of the disease._x000D_ _x000D_ Exenatide is an agonist for the Glucagon-like-peptide 1 (GLP 1) receptor and a licensed treatment for patients with Type 2 diabetes. It has been shown repeatedly to have neuroprotective properties in the laboratory and can rescue motor and non-motor deficits in animal models of PD. Two randomized trials have confirmed beneficial effects in patients with PD exposed to Exenatide for 1 year, that persisted after drug washout, consistent with the possibility that this may be the first agent with disease modifying effects in people with PD._x000D_ _x000D_ In the clinical trials performed to date, the severity of each patient’s PD was assessed after an overnight withdrawal from standard PD dopaminergic medications. This gives a more accurate reflection of PD severity than an assessment performed in the presence of PD medication and enables objective comparison of the rate of progression of PD between groups. The current proposal is to perform a formal efficacy trial to confirm the previous results in a larger sample size using a multi-centre design, and also to clarify whether longer term (2 years) exposure to exenatide confers a cumulative advantage on the motor severity of PD in patients compared to placebo. In other words, do the beneficial effects continue to accumulate in the longer term, detectable as a greater advantage at 2 years than at 1 year, in terms of both the motor and non-motor aspects of PD._x000D_ _x000D_ Eligible patients will be already using conventional dopaminergic treatment for their PD, will be independently mobile, and will have no contraindication to using exenatide. All patients will have optimal conventional PD treatment throughout the trial period. Inclusion criteria will be broad to ensure the results are applicable to the majority of patients with PD._x000D_ _x000D_ The trial will recruit 200 participants with PD from ~6 hospital centres across the UK and will randomize them to self-administer exenatide 2mg subcutaneously once weekly or matched placebo for 2 years. The primary outcome will be the difference in the scores on the Movement Disorders Society Unified PD rating scale (MDS UPDRS PART 3) in the practically defined OFF medication state at the end of the 2 year period, between the 2 groups. MDS UPDRS part 3 is the most well validated outcome measure in PD. The scores will be recorded both in the "practically defined OFF state" to capture the overall motor severity of PD with less masking of severity resulting from dopaminergic treatment, and again while ON dopamine treatment to measure the emergence of "dopa refractory" motor symptoms that evolve as PD progresses. A key secondary outcome will be to compare the effect size between 1 year and 2 year time points to evaluate whether effects are cumulative or static. Additional secondary outcomes will include the Non Motor Symptoms severity scale, the PDQ39 quality of life scale, the Montreal Cognitive assessment, the Beck Depression Inventory and concomitant medication use. Cost effectiveness data will be collected.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL