A clinical trial to explore the potential of ondansetron for treating hallucinations in people with Parkinson’s disease

Plain English summary of protocol

Background and study aims
Visual hallucinations (seeing things that do not exist) occur in 75% of people with Parkinson’s across the illness course, are often highly distressing, have a significant impact on quality of life, and are associated with dementia and earlier care home placement. NHS treatment options are currently limited to medications known as antipsychotics that are associated with significant side-effects, including sedation, falls, worsening of Parkinson’s symptoms (tremor, movement co-ordination) and memory problems. Usual treatment involves quetiapine, as it is safer than other antipsychotic drugs, but of questionable effectiveness, or clozapine, which is effective but not feasible for use outside specialist units due to safety monitoring requirements. Pimavanserin, is a newly developed drug that has shown modest treatment effects, but is highly expensive, and not licensed for use in the UK. Findings treatments that are safe, effective, cost effective and practical for use in NHS clinics is a priority. Ondansetron, a drug used to treat post-operative nausea and vomiting, was identified as a highly promising candidate treatment for Parkinson’s hallucinations in the early 1990s, when 16 people with Parkinson's and persistent severe visual hallucinations improved with ondansetron (12-24mg daily), 14 with complete resolution of symptoms, with no worsening of Parkinson’s symptoms, memory or functional ability. Further studies were not carried out at the time because the drug was then extremely expensive. Costs are now much less (equivalent to usual treatment) and a larger trial in people with Parkinson’s is feasible, timely and highly necessary

Who can participate?
People with Parkinson's, aged over 55 years, who are experiencing hallucinations at least weekly, at a point when other approaches to treatment (altering lighting, reducing Parkinson's medication) have failed

What does the study involve?
Those taking part will be allocated (randomly via a computerized system) to receive drug or placebo and neither the prescribing clinicians or participants will know which treatment they are taking. The dose of the study drug will increase from one (8mg or placebo) tablet, to a maximum of 3 tablets over the first 6 weeks, guided by telephone monitoring of side effects and safety (2 and 4 weeks). Treatment will then continue for a further 6 weeks. Usual treatment (quetiapine) will be available to all participants if required, to ensure that distressing symptoms are not left untreated. Face to face assessments and blood sampling will be carried out after 6 and 12 weeks treatment, and over the telephone after treatment has completed (16 and 24 weeks). Recruitment will take place over 2 years in 15-20 NHS clinics, supported by local Research Networks and Parkinson’s UK. It will also be possible for participants to refer themselves to the study. Agreed recruitment targets are 5 participants per site in the first year, and progress will be assessed 9 months into recruitment by the Trial Management Group, to identify barriers to recruitment or retention to the study and ensure that they are addressed in a timely way. There will be focus group representation on biannual trial committees that will monitor progress towards recruitment targets, safety and data management throughout the study

What are the possible benefits and risks of participating?
Ondansetron is licensed for short term use as an anti-emetic and has undergone extensive safety testing for this indication. Any observed treatment benefits are likely to outweigh the risks. There is no guarantee of any direct benefit to you as a result of participating in this research study but ondansetron may help to treat visual hallucinations and may help reduce delusions associated with Parkinson’s disease. Your participation may provide information useful to the understanding of ondansetron and Parkinson’s disease. Constipation, which is common in people with Parkinson’s, is a known side effect of ondansetron and a dose titration phase will be used to reduce the burden of possible side effects

Where is the study run from?
University College London, UK

When is the study starting and how long is it expected to run for?
April 2020 to July 2026

Who is funding the study?
Parkinson's UK

Who is the main contact?
Dr Olga Zubko
o.zubko@ucl.ac.uk

Contact information

Study information

Eligibility

Locations

Countries of recruitment

• England
• United Kingdom
• Wales

Study participating centres

Sponsor information

Funders

Funder type

Charity

Results and Publications

Study outputs

Editorial Notes

10/04/2024: Following an interim analysis, the TOP HAT Trial is no longer recruiting new participants. Total final enrolment added.
09/01/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/01/2024 to 31/01/2025.
2. The overall end date was changed from 31/07/2025 to 31/07/2026.
3. The intention to publish date was changed from 31/07/2026 to 31/07/2027.
4. The plain English summary was updated to reflect these changes.
04/01/2023: The ethics approval was added.
03/01/2023: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/01/2023 to 31/01/2024.
2. The overall end date was changed from 31/07/2023 to 31/07/2025.
3. The intention to publish date was changed from 01/01/2024 to 31/07/2026.
4. The plain English summary was updated to reflect these changes.
12/07/2021: The following changes have been made:
1. The recruitment end date has been changed from 01/04/2022 to 01/01/2023.
2. The overall trial end date has been changed from 31/10/2022 to 31/07/2023 and the plain English summary has been updated to reflect this change.
04/02/2020: Trial's existence confirmed by the NIHR.