Open-Label TD study to evaluate VMAT2 blockade using PET
Research type
Research Study
Full title
An Open-label Positron Emission Tomography Study to Evaluate the Effects of Vesicular Monoamine Transporter 2 Receptor (VMAT2) Blockade on the Dopamine Neurotransmitter System in Subjects with Tardive Dyskinesia Study No.: NBI-98854-1726
IRAS ID
288817
Contact name
Oliver D Howes
Contact email
Sponsor organisation
Neurocrine Biosciences Inc.
Duration of Study in the UK
2 years, 0 months, 0 days
Research summary
Summary of Research
This research study is looking at the effects of reducing the activity of a protein called VMAT2 on brain messengers in people who have an abnormal involuntary movement disorder called Tardive Dyskinesia (TD).
The purpose of this research study is to determine if reducing the activity of this protein reduces brain dopamine function and how this relates to movements. The study uses a medication called valbenazine to reduce the activity of VMAT2 and brain imaging using Positron Emission Tomography (PET) imaging with the radiotracers [18F]DOPA and [18F]AV-133. The radiotracers are being used as a way to index how dopamine is being processed in the brain as this is linked to movement disorders such as TD.
Up to 25 people aged 21 - 85 will undergo assessments at the Screening Visit, including a brain magnetic resonance imaging (MRI scan), analysis of gene variants, and assessments of TD severity, to determine eligibility.
There will be two baseline PET imaging visits to allow a [18F]DOPA scan and a [18F]AV-133 PET scan. Blood samples to evaluate valbenazine levels will be taken during the scans. There will also be some baseline clinical assessments. Eligible candidates will self-administer valbenazine for up to 45 days, each day as a capsule. The dose to be taken will start at 40 mg for one week and then increase to 80 mg if there are no side effects and the team will check in to determine safety and progress. There will be two on-treatment PET imaging visits with a repeat of the same scans as before. Self-administration of valbenazine will stop after the final treatment PET imaging visit. Approximately 1 week later, there'll be a Safety Follow-up Visit to have safety assessments performed.
The study will last up to approximately 16 weeks for each volunteer.
Summary of Results
Valbenazine is an inhibitor of vesicular monoamine transporter 2 (VMAT2), which is a protein present in synapses (the connections between nerve cells) that is involved in the packaging and release of certain neurotransmitters, including dopamine, serotonin and noradrenaline. It is used to treat certain movement disorders, in particular tardive dyskinesia, which is causes by long-term exposure to antipsychotic medication. We found that administration of valbenazine had no effect on dopamine synthesis as measured through 18F-fluorodopa positron emission tomography (PET), however a previous study did show an increase in PHNO binding following valbenazine, suggesting a decrease in presynaptic dopamine release. We did see that valbenazine reduced binding of the PET tracer AV-133 to the VMAT2 protein, showing successful binding of the drug to the protein.
REC name
East of Scotland Research Ethics Service REC 1
REC reference
20/ES/0107
Date of REC Opinion
30 Nov 2020
REC opinion
Further Information Favourable Opinion