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Design

TOPHAT is aÌýdouble-blind, individually randomized, placebo-controlled flexible-dose trialÌýof 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.ÌýÌý

Specific aims

In particular, the study will answer the following questions:

1. Can flexibly dosed ondansetron effectively treat visual hallucinations in people with Parkinson’s, evidenced by clinically meaningful superiority over placebo at 12 weeks?
2. Will ondansetron reduce delusions?
3. 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?
4. Can ondansetron improve quality of life in people with Parkinson’s?
5. 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.Ìý

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)
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Exploratory Objective(s)	Exploratory Outcome Measure(s) or End Point(s)

Recruitment target and timelines

-ÌýÌý ÌýWe 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.Ìý

-ÌýÌý ÌýRecruitment will end Jan 2025, and follow up will end July 2025.Ìý

-ÌýÌý ÌýWe currently have 42Ìýrecruiting sites, with a further threeÌýin the process of setting up.

Ìý

More information onÌýinclusion 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) Ìý	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)

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