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

NCT06643013 | Recruiting DMC

• 1 other identifier: 24HH8841
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cerebral Small Vessel Disease

Outcome Measures

Primary Outcomes (1)

• Neurovascular coupling

  Change in primary visual cortex cerebral blood flow following an alertness task

  4 weeks

Secondary Outcomes (2)

• Neurovascular coupling

  4 weeks

• Blood-brain barrier leak

  4 weeks

Other Outcomes (5)

• Plasma biomarkers associated with cSVD

  4 weeks

• Plasma biomarkers associated with endothelial cell activation and dysfunction

  4 weeks

• Plasma biomarkers of continuing neurodegeneration

  4 weeks

Study Arms (2)

XBD173 then Placebo

EXPERIMENTAL

Drug: XBD173

Placebo then XBD173

EXPERIMENTAL

Drug: XBD173

Interventions

XBD173 DRUG

4 weeks treatment

Placebo then XBD173; XBD173 then Placebo

Eligibility Criteria

• Age: 60 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Imperial College London: lead

Study Sites (1)

Imperial Clinical Research Facility

London, United Kingdom

RECRUITING

MeSH Terms

Conditions

Cerebral Small Vessel Diseases

Interventions

N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Paul Matthews, PhD

  Imperial College London

  STUDY CHAIR

Central Study Contacts

David Owen, PhD

CONTACT

+442033136195; d.owen@imperial.ac.uk

Daisy Metcalf

CONTACT

+442033136189; d.metcalf@imperial.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 14, 2024
• First Posted: October 15, 2024
• Study Start: October 1, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2028
• Last Updated: October 15, 2024

Record last verified: 2024-10

Locations

GB (1)