Condition category
Nervous System Diseases
Date applied
10/10/2019
Date assigned
05/02/2020
Last edited
04/02/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

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 June 2023

Who is funding the study?
Parkinson's UK

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

Trial website

Contact information

Type

Public

Primary contact

Dr Olga Zubko

ORCID ID

Contact details

Wing A
6th Floor Maple House
149 Tottenham Court Rd
London
W1T 7NF
United Kingdom
+44 (0)20 3545 9073
o.zubko@ucl.ac.uk

Additional identifiers

EudraCT number

2019-003962-41

ClinicalTrials.gov number

NCT04167813

Protocol/serial number

17/0909, IRAS 266504

Study information

Scientific title

Trial of Ondansetron as a Parkinson’s HAllucinations Treatment

Acronym

TOP HAT

Study hypothesis

The study will test the hypothesis that flexibly dosed ondansetron (8-24mg/day) will have a clinically meaningful treatment effect on visual hallucinations in people with Parkinson’s, without worsening motor or cognitive symptoms.

Ethics approval

Not provided at time of registration

Study design

Double-blind individually randomized placebo-controlled parallel-group flexible-dose trial

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Parkinson's hallucinations

Intervention

The intervention will consist of flexible dosing of ondansetron/placebo (8-24mg/day) as a treatment for Parkinson’s hallucinations, with a 12-week primary outcome and follow-up to 24 weeks. The treatment dose will increase from a single daily 8 mg tablet (AM) (weeks 1 and 2), to 16 mg/day (8 mg twice daily) (weeks 3 and 4), with a further increase to 24 mg/day (8 mg AM, 16 mg PM) (weeks 5 and 6).

The study will recruit 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. 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 (8 mg 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.

Intervention type

Drug

Phase

Phase II

Drug names

Ondansetron

Primary outcome measure

Visual Hallucinations measured using SAPS-H (12 weeks)

Secondary outcome measures

1. Visual Hallucinations measured using SAPS-H (2, 4, 6, 12, 18, 24 weeks)
2. Delusions measured using SAPS-D (2, 4, 6, 12, 18, 24 weeks)
3. Global Severity (Impact) of symptoms measured using CGI-S (2, 4, 6, 12, 18, 24 weeks)
4. Hallucinations measured using UM-PDHQ (12 weeks)
5. Non-motor symptoms measured using NMSS (6, 12, 18, 24 weeks)
6. Proportion receiving quetiapine rescue medication at end of treatment (12 weeks) and follow-up (24 weeks) periods
7. Health-related quality of life measured using Euro-QoL, EQ-5D (6, 12, 18, 24 weeks) Parkinson’s symptoms (tremor, rigidity) UPDRS III (6, 12 weeks)
8. Cognition measured using sMMSE (12 weeks)
9. ECG changes measured using QTc interval (6 weeks)
10. Tolerability measured using Adverse event checklist (2, 4, 6, 12, 18, 24 weeks)
11. Pharmacokinetics measured using Venous blood drug concentration (6, 12 weeks)
12. Visual information processing measured using HVOT (12 weeks)

Overall trial start date

14/06/2019

Overall trial end date

31/10/2022

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Aged over 55 years
2. Meet Brain Bank criteria for Parkinson’s disease
3. Visual hallucinations have been present at least weekly in the month before screening and are moderately severe
4. On a stable dose of anti-Parkinson’s medication, cholinesterase inhibitor or memantine for at least 28 days
5. Capacity to give informed consent or (if lacking) caregiver or other legal representative able to give consent
6. Pre-menopausal women, and men whose partners are of child bearing potential who agree to use effective contraception during the trial treatment period

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

216

Participant exclusion criteria

1. Bradycardia (<50 bpm) (rescreen if reversible)
2. Congenital long QTc syndrome or presence of clinically significant prolongation of QTc (>460 ms for men or >470 ms for women) on ECG screening.
3. Severe hepatic failure (bilirubin >50 micromole/L)
4. Prescribed any antipsychotic medication in the past 2 weeks
5. Prescribed apomorphine
6. Prescribed tropisetron, granisetron, dolasetron
7. History of hypersensitivity to ondansetron and its excipients (or those of placebo) or drugs listed in 6
8. Participation in another Clinical Trial of an Investigational Medicinal Product (IMP) in the previous 28 days

Recruitment start date

01/04/2020

Recruitment end date

01/04/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Leonard Wolfson Experimental Neurology Centre
Gower St Bloomsbury
Epsom
WC1N 3BG
United Kingdom

Trial participating centre

Salford Royal NHS Foundation Trust
Stott Lane
Manchester
M6 8HD
United Kingdom

Trial participating centre

Pennine Acute Hospitals NHS Trust
Fairfield General Hospital Rochdale Old Road
Bury
BL9 7TD
United Kingdom

Trial participating centre

Cambridge University Hospitals NHS Foundation Trust
Hills Road
Cambridge
CBQ 0QQ
United Kingdom

Trial participating centre

Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
Castle Ln E
Bournemouth
BH7 7DW
United Kingdom

Trial participating centre

Northumbria Healthcare NHS Foundation Trust
Unit 7-8 Silver Fox Way Cobalt Business Park
Newcastle upon Tyne
NE12 8EW
United Kingdom

Trial participating centre

Royal Devon and Exeter NHS Trust
Barrack Rd
Exeter
EX2 5DW
United Kingdom

Trial participating centre

Royal United Hospitals Bath
Combe Park
Bath
BA1 3NG
United Kingdom

Trial participating centre

Wrexham Maelor Hospital
Croesnewydd Road
Wrexham
LL137TD
United Kingdom

Trial participating centre

Ysbyty Gwynedd
Bangor
LL57 2PW
United Kingdom

Trial participating centre

LLandudno Hospital
Hospital Rd
Llandudno
LL30 1LB
United Kingdom

Trial participating centre

Holyhead Hospital
Penrhos Beach Rd Anglesey
Holyhead
LL65 2QA
United Kingdom

Sponsor information

Organisation

PRIMENT CTU

Sponsor details

UCL Medical School
Upper 3rd Floor
Royal Free Campus
Rowland Hill Street
London
NW3 2PF
United Kingdom
+44 (0)20 7794 0500 ext 36724
priment@ucl.ac.uk

Sponsor type

University/education

Website

https://www.ucl.ac.uk/priment/

Funders

Funder type

Charity

Funder name

Parkinson's UK

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

Associations and societies (private and public)

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Progress of the study will be shared with people with Parkinson's through newsletters, individual letters, and quarterly updates that will be available on Parkinson's UK and linked websites. Information will also be shared locally by Parkinson's UK and by clinicians who are leading recruitment across the UK. The research findings will be submitted for publication to high quality peer reviewed journals and shared at national and international conferences. There will also be talks, training and seminars delivered via existing platforms for NHS service improvement and education. This includes the Parkinson’s Excellence Network, which is supported by Parkinson's UK, and educational meetings led by the British Geriatric Society and the Association of British Neurologists.

IPD sharing statement:
The current data sharing plans for this study are unknown and will be available at a later date

Intention to publish date

01/01/2024

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

04/02/2020: Trial's existence confirmed by the NIHR.