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The goal of this study is to investigate the effects of selective histamine 3 antagonist pitolisant on brain function and cognition in healthy individuals. The main questions it aims to answer are:
Participants will undertake fMRI scanning in addition to a battery of tasks designed to measure cognitive and emotional processing after taking a single dose of pitolisant or placebo. Researchers will compare differences in functional activity, cognition and emotional processing across the pitolisant and placebo groups.
Cognitive and affective processing are underpinned by monoaminergic neurotransmission and neurosteroid systems, yet there are many aspects of these systems that remain unknown in humans. In particular, monoaminergic histamine 3 (H3) receptors are abundant in CNS regions underpinning cognitive processing (prefrontal cortex, hippocampus, and striatum), yet the role of these receptors in humans remains unclear. Evidence from animal models suggests H3R antagonism improves cognitive functioning, however these specific effects are yet to be examined in humans. Similarly, the function of sigma-1 (σ-1) receptors in the brain is not well understood in humans despite strong evidence of pro-cognitive effects in animal models.
The study will investigate the effect of pitolisant, a dual H3R antagonist and σ-1R agonist, on cognitive and affective processing, in addition to changes in functional connectivity. These effects will be measured with a battery of neuropsychological tasks (e.g., Affective Go/No-Go Task; Adaptive dual n-back task), self-rated measures of cognitive function (PDQ), and resting state fMRI and fMRI data acquisition during the verbal n-back and memory encoding tasks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pitolisant | Experimental | Two film-coated tablets (18mg x 2 [36mg]) for oral administration will be encapsulated in an opaque capsule. |
|
| Placebo | Placebo Comparator | Two lactose film-coated tablets (2 x 65mg [125mg]) will be encapsulated in an opaque capsule (identical to the experimental arm drug). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pitolisant 17.8 MG [Wakix] | Drug | Single dose pitoliosant (36mg) |
| |
| Measure | Description | Time Frame |
|---|---|---|
| BOLD signal levels during resting state fMRI sequence | Blood Oxygenation Level Dependent (BOLD) signal level in prior regions of interest (striatum, hippocampus and anterior cingulate cortex) in pilosant group compared with the placebo group | 3-6 hours after single dose of drug or placebo. |
| BOLD signal levels during fMRI memory encoding task | BOLD signal level in prior regions of interest during the task (hippocampus; perirhinal cortex) in pilosant group compared with the placebo group | 3-6 hours after single dose of drug or placebo. |
| BOLD signal levels during fMRI n-back task | BOLD signal level in prior regions of interest during the task (dorsolateral prefrontal cortex; hippocampus; anterior cingulate cortex) in pilosant group compared with the placebo group | 3-6 hours after single dose of drug or placebo. |
| Measure | Description | Time Frame |
|---|---|---|
| Optimal choice selection during loss and reward conditions in Probabilistic Instrumental Learning Task (PILT) | Optimal choice selection during loss and reward conditions in Probabilistic Instrumental Learning Task (PILT) in pilosant group compared with the placebo group | 3-6 hours after single dose of drug or placebo. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Susannah E Murphy, DPhil | University of Oxford | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Psychiatry, University of Oxford | Oxford | United Kingdom |
Data which has been fully de-identified may be shared with other academic and commercial organisations in the future, including those outside of the UK and the EU. Participants will be informed of this and specific consent to this is obtained within the Informed Consent Form.
A few months after all data has been completed (ETA July 2024), unblinding has occurred (ETA April 2024), and all data analyses has been completed (ETA May 2024).
The data will be made publicly available. Access requests will not be required.
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 31, 2023 | Mar 30, 2023 | Prot_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 25, 2023 | Mar 29, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D059445 | Anhedonia |
| ID | Term |
|---|---|
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
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| ID | Term |
|---|---|
| C516975 | pitolisant |
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Participants will be randomly allocated to one of two groups (pitolisant or placebo). This study uses a novel procedure known as variance minimisation (described in Sella, Raz & Cohen Kadosh, 2021) to randomise participants allocation to the two intervention groups based on equalising baseline cognitive functioning and gender. Participants will receive a single dose of the drug (pitolisant, 36mg) or placebo, and undertake fMRI and cognitive/emotional assessment three hours after dose. The study is assessing the effect antagonising the H3 receptor on functional connectivity/cognitive ability, it is not an efficacy or safety study.
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Matched placebo capsule
| Placebo |
| Drug |
Single dose placebo |
|
| Number of inhibited 'no-go' responses during the affective Interference Go/No-Go Task performance |
Number of inhibited 'no-go' responses during the affective Interference Go/No-Go Task in pilosant group compared with the placebo group |
| 3-6 hours after single dose of drug or placebo. |
| Accuracy of target selection on the Colour Change Detection Task | Accuracy of target selection on the Colour Change Detection Task in pilosant group compared with the placebo group | 3-6 hours after single dose of drug or placebo. |
| Accuracy of emotional labeling of facial expressions during the facial emotion recognition task | Accuracy of emotion labels (e.g. disgusted face) assigned by participants to expressive faces during the facial emotion recognition task in pilosant group compared with the placebo group | 3-6 hours after single dose of drug or placebo. |
| Accuracy of target selection during n-back fMRI task | Accuracy of target selection during n-back fMRI task in pilosant group compared with the placebo group | 3-6 hours after single dose of drug or placebo. |
| Accuracy of stimuli labeling (novel or familiar) during fMRI memory encoding task | Accuracy of stimuli labeling (novel or familiar) during fMRI memory encoding task in pilosant group compared with the placebo group | 3-6 hours after single dose of drug or placebo. |
| D013568 | Pathological Conditions, Signs and Symptoms |