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Design
TOPHAT is a double-blind, individually randomized, placebo-controlled flexible-dose trial of ondansetron as a treatment for Parkinson’s hallucinations, with a 12-week primary outcome and follow-up to 24 week. Consort Flowchart.
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.
We will compare ondansetron to placebo (a tablet that looks identical but contains no drug) over 12 weeks treatment, with follow up (once treatment ends) for a further 12 weeks. We will also investigate whether treatment effects against hallucinations are related to improved processing of visual information.
- Specific aims
In particular, the study will answer the following questions:
- Can flexibly dosed ondansetron effectively treat visual hallucinations in people with Parkinson’s, evidenced by clinically meaningful superiority over placebo at 12 weeks?
- Will ondansetron reduce delusions?
- Is ondansetron safe and well-tolerated in people with Parkinson’s, in terms of side-effects, and whether it has any impact on motor, cognitive, and other non-motor symptoms?
- Can ondansetron improve quality of life in people with Parkinson’s?
- Will ondansetron be cost effective in the NHS?
Pharmacokinetic data will also be collected at steady state and used to understand variability in dose-concentration and concentration-response relationships, with the aim of optimizing dosage strategies for clinical use.
Assessments
Assessments of symptoms will be carried out during treatment (after 6 and 12 weeks), and once treatment ends (18, 24 weeks), to measure hallucinations, delusions (false beliefs), Parkinson's symptoms (tremor, anxiety, sleep disturbance), memory, quality of life, possible side-effects such as constipation and headache, and the proportion of people who drop out due to side effects, or require additional treatment for their hallucinations. Blood drug concentration (measured after 6 and 12 weeks) will provide information on how quickly the drug is cleared from the body, and how this relates to treatment effects and side-effects, to guide future prescribing in people with Parkinson's.
- Outcome measures
The primary and secondary outcome measures are summarised in the table below:
Primary Objective
Primary Outcome Measure or End Point
Visual Hallucinations
SAPS-H (12 weeks +-7days post baseline)
Secondary Objective(s)
Secondary Outcome Measure(s) or End Point(s)
Visual Hallucinations
SAPS-H (2, 4, 6, 12, 18, 24 weeks)
Delusions
SAPS-D (2, 4, 6, 12, 18, 24 weeks)
Global Severity (Impact) of symptoms
CGI-S (2, 4, 6, 12, 18, 24 weeks)
Hallucinations
UM-PDHQ (6, 12 weeks)
Non-motor symptoms
NMSS (6, 12, 18, 24 weeks)
Proportion receiving quetiapine rescue medication
End of treatment (12 weeks) and follow-up (24 weeks) periods
Health related quality of life
EQ-5D-5L (6, 12, 18, 24 weeks)
Health and social care service utilisation
Concomitant medication log (2, 4, 6, 12, 18, 24 weeks and unscheduled); Use of quetiapine rescue medication (2, 4, 6, 12, 18, 24 weeks and unscheduled); Estimated resource use from adverse event checklist information (2, 4, 6, 12, 18, 24 weeks and unscheduled)
Parkinson’s symptoms (tremor, rigidity)
UPDRS III (6, 12 weeks)
Cognition
sMMSE (12 weeks)
ECG changes
QTc interval (6 weeks)
Tolerability
Adverse event checklist (2, 4, 6, 12, 18, 24 weeks)
Pharmacokinetics
Venous blood drug concentration (6, 12 weeks)
Exploratory Objective(s)
Exploratory Outcome Measure(s) or End Point(s)
Recruitment target and timelines
Map of Top Hat recruitment sites
- We will also recruit 90 people with Lewy Body dementia, whose data will be analysed separately, to provide proof of principle that the drug might be effective in treating hallucinations in people with this condition.
- Recruitment will end Jan 2025, and follow up will end July 2025.
- We currently have 42 recruiting sites, with a further three in the process of setting up.
More information on inclusion and exclusion criteria.
Safety and tolerability
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. Constipation, which is common in people with Parkinson’s, is a known side effect of ondansetron and a potential dose-limiting toxicity. A dose escalation phase, guided by telephone safety monitoring is thus necessary, to reduce the side effect burden.
Tolerability will be measured using an adverse events checklist that will include known side effects of ondansetron such as constipation and by comparing the proportion of people in drug and placebo treated patients who drop-out or reduce the drug dose due to side effects.
- Dose escalation schedule
The dose of the study drug will increase from a single 8mg tablet (AM or PM) (weeks 1 and 2), to 8mg twice daily (weeks 3 and 4), with a further increase to 8mg AM, 16mg PM (weeks 5 and 6), see table below for more details. Dose escalation will be guided via telephone safety monitoring prior to each dose increase, and a face to face assessment at the end of week 6.
Investigational Medicinal Product (IMP)
Generic name
Ondansetron
Formulation or device and strength
8mg film-coated tablets
Route or mode of administration
Oral
Dose and frequency of dosing
Flexible dose regimen, guided by safety and tolerability (described 8.3)
Weeks 1-2; 8mg AM
- Safety monitoring - decision to increase or hold at the current dose
Weeks 3-4; 16mg (8mg AM, 8mg PM)
- Safety monitoring – decision to increase, hold or decrease
Weeks 5-6: 24mg (8mg AM, 16mg PM)
- Safety monitoring will take place in clinic as part of a 6 week assessment, and a decision made to hold or decrease
Weeks 7-12: 24mg (8mg AM, 16mg PM) unless a decision is made to reduce dose (see section 13.4)
Comparator
Placebo
Matched to 8mg tablet (prescribed as above)