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.

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. 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. 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. 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. 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.