Title: A phase 3 trial of Rivastigmine to prevent falls in Parkinson's Disease
Funder: Department of Health and Social Care

Abstract: DESIGN: A multicentre, phase 3, double-blind, RCT of rivastigmine versus placebo to prevent falls in PD. SETTING: Secondary care movement disorder services. POPULATION: For inclusion, participants must be over 18, have a diagnosis of idiopathic PD, Hoehn and Yahr stage 1-4, not be taking a ChEi, have fallen in the previous year and be able to walk >10m without aids or assistance. Participants will be excluded if there is any absolute contraindication or they have been previously treated with a ChEi, have dementia or are falling >4x per day. HEALTH TECHNOLOGY: Intervention is rivastigmine patches. 4.6mg (4 weeks); 9.5mg (26 weeks); 13.3mg (22 weeks). Control is matched placebo patches. MEASUREMENT OF COSTS AND OUTCOMES: Falls (primary outcome) will be assessed prospectively using gold standard methods with diaries and phone calls. The primary analysis will be based on the rate of falls for each participant as the unit of analysis and will follow the intention to treat principle. A linear regression model of log transformed fall rates, adjusted for participants' age, cognition and fall history at baseline, will estimate the treatment effect as a percentage difference in average fall rate. Secondary outcome measures are validated in PD. NHS, social service, and informal care costs will be collected using monthly diaries with hospital episode statistics recording hospitalisations. Quality of life will be assessed using EQ5D-5L to calculate QALYs. We will use a well-being measure ICECAP-O, to capture the broader impact of PD-falls on patients and the Carer Experience Scale for carers. In primary economic analysis, we will estimate the cost per QALY gained of rivastigmine from as NHS and social services perspective. Uncertainty will be summarised using cost effectiveness acceptability curves and by calculating incremental net benefit statistics. If the intervention is potentially, cost-effective at 12 months, we will develop a simple extrapolation model to assess cost-effectiveness over a lifetime horizon. SAMPLE SIZE: We will recruit 600 people and assuming a 20% drop out (n=120), we will have 480, 240 per arm, to detect a 25% difference in mean fall rate between groups with 90% power and a two-sided 5% significance level. This clinically important difference equates to preventing on average 5 falls/ patient/ year. TIMETABLE and RECRUITMENT: Total trial duration will be 4 yrs, 3 months comprising 9 months set up, 3 years recruitment and follow-up and 6 months analysis and dissemination. Accrual is based on staggered adoption of 26 sites recruiting 1.25 patients site/ month or 9.25 patients/ site/ year. An internal pilot of recruitment for 9 months with prespecified stop/ amend/ go criteria will be undertaken. EXPERTISE: EH is a PD Consultant Clinician who successfully delivered the phase 2 trial and is supported by a Senior clinician (AW), Senior Trials Methodologists (CM, WH, YBS) and Senior Clinical Epidemiologist (YBS), Senior Statistician (CM) and Senior Health Economist (WH). The TSC will comprise Prof C Clarke (Chair) who has expertise in running large PD trials (Birmingham), YBS and EH, Prof J Close, Prof S Lord (Neuroscience Research Australia) and F Lindop (Derby) as gait and falls experts, a person with PD and a statistician. Collaborations with experts in cognition, (Dr Yarnall, Newcastle), and quality of life measures (Prof Coast, Bristol) strengthens the team.

Lay abstract: AIM: Reducing falls was identified as the top research priority by people living with Parkinson’s disease. This study aims to determine whether a drug, known as a cholinesterase inhibitor (ChEi), can prevent falls in Parkinson’s. BACKGROUND: Parkinson’s disease is a common condition particularly affecting older people. Falls are a very frequent complication of the disease affecting 60% of people with Parkinson's every year. Having a fall can be devastating, resulting in broken bones, injuries and hospital admission. In addition, people lose confidence in their walking and ability to get out and about so can become more isolated and anxious. As the population ages, the number of people living with Parkinson’s disease and the occurrence of complications will increase. The loss of the chemical dopamine in the brain causes walking in Parkinson's to become slower, unsteady and irregular. People with the condition are therefore at a very high risk of falling. To some extent, people can compensate for these changes by paying more attention to their walking. However, Parkinson's also diminishes memory and thinking ability. This decreases people’s ability to pay attention to their walking, especially when doing something at the same time. ChEis are drugs that are currently used to treat people with memory problems in Parkinson’s and other conditions like Alzheimer’s disease. The effect of these drugs on falls in Parkinson’s has been tested in 3 small trials showing that treatment has the potential to almost halve the number of falls. DESIGN and METHODS: A larger, phase 3 trial is now required to provide a more certain answer as to whether people with Parkinson’s who fall should be treated with these drugs. This will involve enrolling people at hospitals throughout the UK and randomly assigning people to receive the drug (ChEi) via a patch or a placebo (dummy) treatment. Neither the researchers nor the participants will know which group they are in. Participants will take the medication for 12 months and record any falls that they experience in diaries, which they post back each month for a year. Side effects can occur with the drug, the most common being stomach upsets and rashes. However, these are mostly mild and either settle after a short period of time or with discontinuation of the medication. People with Parkinson's have been helped design this trial and will advise on how it is carried out. We are committed to working with key stakeholders including our patient public involvement (PPI) group, Parkinson's-UK, the National Institute for Health and Care Excellence (NICE) and commissioning groups to ensure that our findings change clinical practice. Findings from the trial will be made accessible and disseminated to the trial participants and the public as well as being written up in research journals. CONCLUSION: There is an urgent need to identify treatments that reduce falls in Parkinson’s disease. This trial will provide better evidence as to the role of ChEi for falls. If successful, this treatment has the potential to be tested in other groups of patients who are at high risk of falls. In Parkinson’s disease, it would tackle one of the most disabling complications of the disease.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL