Fenfluramine and Cognition

Study Overview
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Brief Summary
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In this study, the investigators will investigate the cognitive effects of fenfluramine, a drug that directly stimulates the release of serotonin in the brain and positively modulates σ1 function. The investigators will use fenfluramine to assess the cognitive effects of modulating serotonin and σ1 function in healthy volunteers using a battery of cognitive tasks that measure learning and memory, executive functioning, reward processing, and emotional processing. The study design is double-blind, and participants will be randomised to either seven days of fenfluramine or placebo administration. All participants will attend two screening visits to assess eligibility. There are two main study visits; during the first, participants will undertake cognitive tasks and questionnaires before taking the initial study dose. One the second study visit, participants will once again complete these tasks and questionnaires after a week of fenfluramine/placebo administration.

Official Title
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The Effect of Seven Day Fenfluramine Administration on Cognition in Healthy Volunteers

Conditions
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Cognitive Function

Intervention / Treatment
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* Drug: Fenfluramine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is willing and able to give informed consent for participation in the research Not currently taking any medications (except the contraceptive pill) Aged 18-22 years Male or female Sufficiently fluent English to understand and complete the task Body Mass Index above 18-30 Weight of 40-75kg Exclusion Criteria: Current pregnancy (as determined by urine pregnancy test taken during Screening and First Dose Visit) or breast feeding Any past or current Axis 1 DSM-V psychiatric disorder Clinically significant abnormal values for liver function tests, clinical chemistry, urine drug screen, blood pressure measurement and ECG. A participant with a clinical abnormality or parameters outside the reference range for the population being studied may be included only if the Investigator considers that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures History of, or current medical conditions which, in the opinion of the investigator, may interfere with the safety of the participant or the scientific integrity of the study, including epilepsy/seizures, brain injury, hepatic or renal disease, severe gastro-intestinal problems, Central Nervous System (CNS) tumours, neurological conditions Current or past history of drug or alcohol dependency Current or past use of 3,4-Methylenedioxymethamphetamine (MDMA) Use of recreational drugs (e.g. cannabis, cocaine, amphetamines) within past 3 months Participation in a study which uses the same computer tasks as those in the present study (determined by asking participants about previous studies participated in during screening) Participation in a study that involves the use of a medication within the last three months Smoking > 5 cigarettes per day Typically drinks > 6 caffeinated drinks per day (e.g. tea, coffee, coca cola, Red Bull) Participant is unlikely to comply with the clinical study protocol or is unsuitable for any other reason, in the opinion of the Investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomly allocated to one of two groups (fenfluramine or placebo), stratified on group allocation, gender and cognitive task version administered. Participants in the fenfluramine group will receive oral solution of fenfluramine 15mg twice daily (BID) for seven days. Participants in the placebo group will receive a placebo oral solution 15mg twice daily (BID) for seven days. The study is assessing the effects of fenfluramine on cognitive ability, it is not an efficacy or safety study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fenfluramine<br>Drug: Fenfluramine - 15mg twice daily oral solution for seven days | Drug: Fenfluramine<br>* Fenfluramine (30mg daily) will be dispensed in a cherry flavoured aqueous solution. Fenfluramine is both a serotonin releasing agent and sigma-1 receptor agonist. Fenfluramine is FDA approved for the treatment of Dravet syndrome, a rare form of epilepsy.<br>* Other names: Fenfluramine Hydrochloride (ZX008);|
| Placebo Comparator: Placebo<br>Placebo - 15mg twice daily oral solution for seven days | Other: Placebo<br>* The placebo is a liquid designed to be identical to the interventional drug fenfluramine in terms of both taste and visual appearance. It will be administered at 30mg daily and dispensed in a cherry flavoured aqueous solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Go/No-Go Task performance | Accuracy on the Go/No-Go task | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 
| Change in Auditory Verbal Learning Task | Accuracy on AVLT (number of items recalled across blocks) | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 
| Change in N-back task performance | Accuracy on the N-back task | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in reward sensitivity | Sensitivity to reward as measured by the Probabilistic Instrumental Learning Task (PILT) | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 
| Changes in categorisation of emotional words | Accuracy to categorise positive and negative descriptor words | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 
| Changes in recall of emotional words | Number of words accurately recalled | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 
| Changes in recognition of emotional words | Number of words accurately recognised | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 
| Changes in recognition of emotional facial expressions | Accuracy of emotion labels (e.g. disgusted face) assigned by participants to expressive faces which have appeared on a computer screen for a period of 500ms. | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 
| Changes in visual short term memory on the Oxford Memory Test (OMT) | Accuracy on the Oxford Memory Task | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 
| Changes in visual search ability | Accuracy during contextual cueing task (CCT) | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 
| Changes in control measures of subjective state | Ratings on the Positive and Negative Affect Schedule | Immediately before initial dose (Day 1) and immediately before final visit (Day 7) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug, Cognition, Dravet Syndrome, 5-HT, Sigma-1, Healthy Volunteers