Targeting 18kDa Translocator Protein (TSPO) to Improve Brain Endothelial Cell Function in Cerebral Small Vessel Disease

In healthy people, blood flow to particular areas in the brain increases when the area becomes more active. This ensures that the brain gets enough blood at the right place and time. In people with cerebral small vessel disease (cSVD), this process is disrupted, and the increased blood flow in response to activity is decreased or absent. Damage to the endothelial cells, that form the inner lining of blood vessels, is a key pathological process in cSVD. The aim of this study is to find out whether endothelial cell function and blood flow in cSVD can be improved by altering the function of a protein called TSPO. We will do this by using a drug called XBD173, which binds to TSPO.

This is a double-blind, randomised, crossover study. cSVD patients will be recruited from memory clinics at Imperial College Healthcare NHS Trust. Participants will be invited to the clinical research facility (CRF) at Hammersmith Hospital and randomised to receive XBD173 or matched placebo, twice daily, for 4 weeks. After a 6-week washout, they will be switched to receive the other intervention. The study visits will involve MRI scans and blood tests to assess endothelial cell function.

Healthy volunteers will also be recruited for image optimisation and control data. They will attend for a single MRI scan and not receive XBD173.

Study Overview

• Status: Recruiting
• Conditions: Cerebral Small Vessel Disease
• Intervention / Treatment: Drug: XBD173

• Study Type: Interventional
• Enrollment (Estimated): 106
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: David Owen, PhD; Phone Number: +442033136195; Email: d.owen@imperial.ac.uk
• Study Contact Backup: Name: Daisy Metcalf; Phone Number: +442033136189; Email: d.metcalf@imperial.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Imperial Clinical Research Facility
    • Contact: David Owen, PhD; Phone Number: +442033136195; Email: d.owen@imperial.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Aged 60-90 years inclusive Male or postmenopausal female

- Men are eligible to participate if they are willing to use the contraception methods listed in the PIS, during treatment and for 90 days after the last dose of treatment Able to provide written informed consent prior to any study-mandated procedures AA genotype at rs6971 (TSPO) locus Imaging-based diagnosis of cSVD (Fazekas score of at least 2 for periventricular and 2 for deep white matter) Mild cognitive impairment (MoCA 18-30) Willing to be genotyped at TSPO and ApoE loci

Inclusion Criteria (Healthy Volunteers):

Aged 60-90 years inclusive Male or female Able to provide written informed consent prior to any study-mandated procedures.

Willing to be genotyped at TSPO and ApoE loci

Exclusion Criteria:

History of clinical stroke History of frequent migraines Known Alzheimer's disease, lewy body disease or evidence of non-vascular neurological diseases Conditions affecting safe engagement in the intervention. Conditions preventing completion of study procedures, e.g. severe loss of vision or hearing Clinically-significant renal disease (eGFR <30 ml/min per 1.73m2) Clinically-significant elevation of serum transaminases or known clinically significant liver disease Contraindications to MRI scanning or exposure to gadolinium-based contrast agents Newly commenced (within 2 months of study start) statins, antihypertensives or antiplatelet treatments Severe respiratory disease with chronic hypoxia (sats <92%), known CO2 retention or need for home oxygen therapy.

Use of the following medications or therapies:

• Severe and moderate P450 CY3A4 inhibitors: Boceprevir, Clarithromycin, Cobicistat, Idelalisib, Itraconazole, Ketoconazole, Nelfinavir, Ritonavir, Saquinavir, Telaprevir, Telithromycin, Voriconazole, Aprepitant, Conivaptan, Crizotinib, Diltiazem, Dronedarone, Erythromycin, Fluconazole, Imatinib, Isavuconazole, Nefazodone, Netupitant, Nilotinib, Posaconazole, Tofisopam, Verapamil, Delavirdine.
• Severe and moderate P450 CY3A4 inducers: Carbamazepine, Enzalutamide, Fosphenytoin, Mitotane, Phenytoin, Rifampicin, Bosentan, Efavirenz, St John's wort, Barbiturates, Nevirapine, Primidone, Rifabutin, Rifapentine.
• Oral contraceptives
• Levothyroxine

Exclusion Criteria (Healthy Volunteers):

Contraindications to MRI scanning or exposure to gadolinium-based contrast agents Pregnant women of childbearing potential Clinically significant renal disease (eGFR <30 ml/min per 1.73m2) Severe respiratory disease with chronic hypoxia (sats <92%), known CO2 retention or need for home oxygen therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: XBD173 then Placebo	Drug: XBD173; 4 weeks treatment
Experimental: Placebo then XBD173	Drug: XBD173; 4 weeks treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurovascular coupling	Change in primary visual cortex cerebral blood flow following an alertness task	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurovascular coupling	Change in cerebral blood flow in a ROI generated by a group average mask of regions known to become activated in the frontal and temporal lobes	4 weeks
Blood-brain barrier leak	BBB leak (rate and volume) determined by gadolinium-enhanced DCE-MRI	4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma biomarkers associated with cSVD	hsCRP, fibrinogen, IL6, Tnf, TNFR2, osteoprotegerin, VEGF, PGDF, MMP2/9	4 weeks
Plasma biomarkers associated with endothelial cell activation and dysfunction	VCAM-1, ICAM-1, E-selectin, von Willebrand factor, plasminogen activator inhibitor-1 activity, soluble ROBO4, VEGF-A, NOS3, tissue plasminogen activator, endothelin-1	4 weeks
Plasma biomarkers of continuing neurodegeneration	Neurofilament light chain	4 weeks
Cerebrovascular reactivity in response to CO2 inhalation		4 weeks
Measure of peripheral endothelial cell function		4 weeks

Collaborators and Investigators

• Sponsor: Imperial College London
• Investigators: Study Chair: Paul Matthews, PhD, Imperial College London

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: October 14, 2024
• First Submitted That Met QC Criteria: October 14, 2024
• First Posted (Actual): October 15, 2024

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 14, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases
• Other Study ID Numbers: 24HH8841

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No