Trial of Ondansetron as a Parkinson's HAllucinations Treatment

Study Overview
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Brief Summary
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TOPHAT (Trial of Ondansetron as a Parkinson's HAllucinations Treatment) is a double blind, individually randomized, placebo-controlled, parallel group, flexible dose trial of ondansetron (8-24mg/day) as a treatment for Parkinson's hallucinations, with a 12-week primary outcome and follow-up to 24 weeks.

Detailed Description
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This study investigates whether ondansetron, a drug used to treat post-operative sickness, has a meaningful treatment effect on Parkinson's hallucinations, and whether the drug is safe and cost effective for use in the NHS. 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. 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. Based on knowledge of the average hallucinations scores in previous Parkinson's treatment studies, 306 people will be needed for the study to detect a meaningful treatment effect. The study will run for 4 years and involves a series of linked stages: (1) Trial set up across 20-30 UK centres; (2) Recruitment over 2 years; (3) Completion of follow up; and analysis, publication and dissemination of results.

Official Title
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Trial of Ondansetron as a Parkinson's HAllucinations Treatment

Conditions
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Parkinson's Hallucinations, Dementia With Lewy Bodies

Intervention / Treatment
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* Drug: Ondansetron 8mg or matched placebo tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged over 18 years. Meet MDS criteria for Parkinson's disease or revised criteria for DLB. Score of 3 or more on the SAPS-H visual hallucinations item, indicating the presence of visual hallucinations at least weekly in the previous month. Score of 3 or more on SAPS-H global rating, indicating moderate symptom severity. Score of 4 or more on CGI-S, indicating moderate symptom severity. On a stable dose of anti-Parkinson's medication, cholinesterase inhibitor or memantine for at least 28 days. Capacity to give informed consent or, if lacking, legal representative able to give consent. Pre-menopausal women, and men whose partners are of child bearing potential will agree to use effective contraception. 9) If treated with an antipsychotic drug at the time of enrolment, can still participate, provided the drug is stopped the day before trial medication is commenced. - Exclusion Criteria: Bradycardia (<50 bpm) (rescreen if reversible). Congenital long QTc syndrome or presence of clinically significant prolongation of QTc (>460 ms for men or >470 ms for women) on ECG screening. Severe hepatic failure (bilirubin >50 micromole/L) Prescribed apomorphine (if apomorphine is discontinued, rescreen once stable on an alternative anti-Parkinson's treatment). Prescribed tropisetron, granisetron, dolasetron. History of hypersensitivity to ondansetron and its excipients (or those of placebo) or drugs listed in 5). Participation in another Clinical Trial of an Investigational Medicinal Product (IMP) in the previous 28 days. -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: TOPHAT is a double blind, individually randomized, placebo-controlled, parallel group, flexible dose trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Treatment<br>Participants randomised to the active treatment arm will take 8-24mg/day of ondansetron. | Drug: Ondansetron 8mg or matched placebo tablets<br>* Participants will take one tablet daily in weeks 1 and 2, two tablets daily in weeks 3 and 4 and 3 tablets daily in weeks 5 and 6. Dose escalation will be guided by tolerability, through telephone safety monitoring prior to each dose increase<br>* Other names: Tablet, film coated;|
| Placebo Comparator: Matched placebo<br>Participants randomised to the placebo treatment arm will take matched placebo, administered as tablets. | Drug: Ondansetron 8mg or matched placebo tablets<br>* Participants will take one tablet daily in weeks 1 and 2, two tablets daily in weeks 3 and 4 and 3 tablets daily in weeks 5 and 6. Dose escalation will be guided by tolerability, through telephone safety monitoring prior to each dose increase<br>* Other names: Tablet, film coated;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hallucinations | Scale for Assessment of Positive Symptoms-Hallucinations (0-35 points, higher scores indicate greater severity of hallucinations | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delusions | Scale for Assessment of Positive Symptoms-Delusions (0-65 points, higher scores indicate greater symptom severity | 2, 4, 6, 12, 18, 24 weeks | 
| Safety and tolerability | Number of Participants With Treatment-Related Adverse Events | 2, 4, 6, 12, 18, 24 weeks | 
| Health related quality of life | EQ-5D-5L | 6, 12, 18, 24 weeks | 
| Cost effectiveness | Health and social service utilisation | 2, 4, 6, 12, 18, 24 weeks | 
| Pharmacokinetics, plasma concentrations of the study drug | Measured using a validated HPLC/MS assay | 6, 12 weeks | 
| Hallucinations | Scale for Assessment of Positive Symptoms-Hallucinations (0-35 points, higher scores indicate greater severity of hallucinations | 2, 4, 6, 18, 24 weeks | 
| Global illness severity | Clinical Global Impression of Severity Scale (1-7, higher scores indicate greater severity) | 2, 4, 6, 12, 18, 24 weeks | 
| Non-motor symptoms | Non-motor symptoms scale (0-120, higher scores indicate greater severity | 2,4,6,12,18,24 weeks | 
| Cognition | Standardised Mini-Mental State Examination (0-30, higher scores indicate better performance) | 12 weeks | 
| Hallucinations | University of Miami Parkinson's disease Hallucinations Questionnaire (0-15, where higher scores indicate greater symptom severity) | 6, 12 weeks | 
| Feasibility and Acceptability of Video Consultation | The feasibility of video consultation will be measured at baseline, 6 and 12 weeks by the proportion of participants who were able to successfully attend on at least one occasion, the proportion who successfully attended all three assessments, and a Satisfaction questionnaire that allows both quantitative and qualitative information to be collected. | baseline, 6 and 12 weeks |