## Protocol Section
### Identification Module
**NCT ID:** NCT06416371

**Brief Title:** Retinal Vessel Leakage in Cerebral Small Vessel Disease

**Official Title:** Retinal Vessel Leakage in Cerebral Small Vessel Disease: a Sub-study of the Mild Stroke Study 3

#### Organization Study ID Info
**ID:** AC24000
#### Organization
**Class:** OTHER
**Full Name:** University of Edinburgh
### Status Module
#### Completion Date
**Date:** 2025-07

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-16

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-14

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2025-05

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-05

**Type:** ESTIMATED

**Status Verified Date:** 2024-01

#### Study First Post Date
**Date:** 2024-05-16
**Type:** ACTUAL
**Study First Submit Date:** 2024-01-15
**Study First Submit QC Date:** 2024-05-14
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** University of Edinburgh

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** The goal of this observational study is to learn about leakage from retinal vessels in cerebral small vessel disease. The main questions it aims to answer are:

* Does retinal vessel leakage occur in cerebral small vessel disease?
* If it does, is the severity of retinal vessel leakage similar to the severity of cerebral small vessel disease generally?

Participants will be tested using fluorescein angiography. This involves an intravenous injection of fluorescent dye, and is a very sensitive way to find leakage from retinal blood vessels.

Participants will have already had brain scans and other examinations and tests to measure the severity of their cerebral small vessel disease. Our new retinal images will complement the information from these previous tests.

**Detailed Description:** Cerebral small vessel disease (SVD) is a common cause of stroke and dementia. The molecular causes are unclear, limiting new therapies. Breakdown of the blood-brain barrier (BBB) is characteristic and may damage brain tissue. However, specialist MRI scans to measure BBB breakdown are expensive and time-consuming.

In contrast, measuring leakage from retinal blood vessels is relatively simple. The blood-retina barrier is very similar to the BBB, and SVD is likely to damage retinal and brain blood vessels in the same way. If so, then retinal angiography could be used to study SVD pathogenesis and measure the effect of new treatments with much greater resolution and lower cost than MRI.

We have three aims:

1. Test the feasibility of fluorescein angiography in people with SVD
2. Discover if retinal vessel leakage occurs people with SVD
3. Discover whether the severity of retinal vessel leakage is associated with clinical features of SVD

We will recruit participants from a well-established cohort of people with SVD - the Mild Stroke Study 3 (MSS3).

### Conditions Module

**Conditions:**

- Cerebral Small Vessel Diseases

- Lacunar Stroke

- Vascular Dementia

### Design Module

#### Design Info

**Observational Model:** COHORT

**Time Perspective:** CROSS_SECTIONAL

#### Enrollment Info

**Count:** 40

**Type:** ESTIMATED

**Study Type:** OBSERVATIONAL

### Arms Interventions Module

### Interventions

#### Intervention 1

**Description:** Intravenous injection of sodium fluorescein for angiography of retinal blood vessels

**Name:** Fundus fluorescein angiography, with ultrawide field retinal imaging

**Type:** DIAGNOSTIC_TEST

### Outcomes Module

#### Primary Outcomes

**Description:** The presence and severity of retinal vessel leakage will be measured for each eye in terms of change in pixel brightness over the duration of the angiogram.

**Measure:** Retinal vessel leakage by automated segmentation

**Time Frame:** within one angiogram

**Description:** The presence and severity of retinal vessel leakage will be measured using an manual ordinal grading scale

**Measure:** Retinal vessel leakage by manual grading

**Time Frame:** within one angiogram

#### Secondary Outcomes

**Description:** BBB breakdown is measured by MRI in terms of image enhancement after intravenous gadolinium

**Measure:** Baseline blood-brain barrier breakdown

**Time Frame:** Within one MRI scan

**Description:** This is measured from the most recent structural MRI scan

**Measure:** White matter hyperintensity (WMH) volume adjusted for brain volume

**Time Frame:** Within one MRI scan

**Description:** This is measured by comparing the most recent structural MRI scan with the baseline structural MRI scan

**Measure:** Change in white matter hyperintensity (WMH) volume adjusted for brain volume

**Time Frame:** Difference in MRI scans up to 5 years prior

**Description:** This is measured from the most recent structural MRI scan

**Measure:** Fazekas score

**Time Frame:** Within one MRI scan

**Description:** This is measured by comparing the most recent structural MRI scan with the baseline structural MRI scan

**Measure:** Change in Fazekas score

**Time Frame:** Difference in MRI scans up to 5 years prior

**Description:** BBB breakdown is measured by MRI in terms of image enhancement after intravenous gadolinium

**Measure:** Baseline average leakage in white matter hyperintensities

**Time Frame:** Within one MRI scan

**Description:** BBB breakdown is measured by MRI in terms of image enhancement after intravenous gadolinium

**Measure:** Baseline average leakage in deep grey matter

**Time Frame:** Within one MRI scan

**Description:** BBB breakdown is measured by MRI in terms of image enhancement after intravenous gadolinium

**Measure:** Baseline number of leakage hotspots

**Time Frame:** Within one MRI scan

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Membership in the Mild Stroke Study 3 cohort
* Contrast enhanced MRI within 12 months
* Clear optical media in both eyes, as assessed by study investigator
* Best corrected visual acuity (near vision) ≥N36

Exclusion Criteria:

* Any condition known to cause retinal leakage (i.e., worse than background diabetic retinopathy, retinal vein occlusion, active uveitis, wet age-related macular degeneration, malignant hypertension)
* Previous treatment for retinal leakage (retinal laser, intravitreal anti-VEGF)
* Recent eye surgery
* Shallow anterior chambers as assessed by torch test
* Pregnancy, renal failure
* Severe dementia
* Known allergy to fluorescein
* History of allergy such as food or drug induced urticaria or history of bronchial asthma
* Any other severe or acute medical or psychiatric conditions
* Inability to give informed consent

**Minimum Age:** 18 Years

**Sampling Method:** NON_PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

**Study Population:** Adults \>18 years old with mild ischaemic stroke with a modified Rankin scale (mRS) greater or equal to 2 at recruitment presenting to Edinburgh/Lothian stroke services.

For details see Clancy, et al (2021) Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3. European Stroke Journal 6:81-88. https://doi.org/10.1177/2396987320929617

### IPD Sharing Statement Module

**IPD Sharing:** UNDECIDED

### References Module

#### References

**Citation:** Clancy U, Garcia DJ, Stringer MS, Thrippleton MJ, Valdes-Hernandez MC, Wiseman S, Hamilton OK, Chappell FM, Brown R, Blair GW, Hewins W, Sleight E, Ballerini L, Bastin ME, Maniega SM, MacGillivray T, Hetherington K, Hamid C, Arteaga C, Morgan AG, Manning C, Backhouse E, Hamilton I, Job D, Marshall I, Doubal FN, Wardlaw JM. Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3. Eur Stroke J. 2021 Mar;6(1):81-88. doi: 10.1177/2396987320929617. Epub 2020 Jun 5.

**PMID:** 33817338

**Citation:** MacCormick IJ, Maude RJ, Beare NA, Borooah S, Glover S, Parry D, Leach S, Molyneux ME, Dhillon B, Lewallen S, Harding SP. Grading fluorescein angiograms in malarial retinopathy. Malar J. 2015 Sep 24;14:367. doi: 10.1186/s12936-015-0897-7.

**PMID:** 26403288

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000020521

- Term: Stroke

- ID: D000002561

- Term: Cerebrovascular Disorders

- ID: D000001927

- Term: Brain Diseases

- ID: D000002493

- Term: Central Nervous System Diseases

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000014652

- Term: Vascular Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

- ID: D000003704

- Term: Dementia

- ID: D000019965

- Term: Neurocognitive Disorders

- ID: D000001523

- Term: Mental Disorders

- ID: D000002537

- Term: Intracranial Arteriosclerosis

- ID: D000020765

- Term: Intracranial Arterial Diseases

- ID: D000056784

- Term: Leukoencephalopathies

- ID: D000001161

- Term: Arteriosclerosis

- ID: D000001157

- Term: Arterial Occlusive Diseases

- ID: D000083244

- Term: Thrombotic Stroke

- ID: D000083242

- Term: Ischemic Stroke

- ID: D000020520

- Term: Brain Infarction

- ID: D000007238

- Term: Infarction

- ID: D000007511

- Term: Ischemia

- ID: D000010335

- Term: Pathologic Processes

- ID: D000009336

- Term: Necrosis

### Condition Browse Module - Browse Branches

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BXM

- Name: Behaviors and Mental Disorders

- Abbrev: BC23

- Name: Symptoms and General Pathology

### Condition Browse Module - Browse Leaves

- ID: M22306

- Name: Stroke

- Relevance: LOW

- As Found: Unknown

- ID: M6904

- Name: Dementia

- Relevance: LOW

- As Found: Unknown

- ID: M29437

- Name: Cerebral Small Vessel Diseases

- Relevance: HIGH

- As Found: Cerebral Small Vessel Disease

- ID: M17861

- Name: Dementia, Vascular

- Relevance: HIGH

- As Found: Vascular Dementia

- ID: M29463

- Name: Stroke, Lacunar

- Relevance: HIGH

- As Found: Lacunar Stroke

- ID: M5810

- Name: Cerebrovascular Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M5204

- Name: Brain Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M5742

- Name: Central Nervous System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M17400

- Name: Vascular Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M21836

- Name: Neurocognitive Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M4815

- Name: Mental Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M14473

- Name: Psychotic Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M5786

- Name: Intracranial Arteriosclerosis

- Relevance: LOW

- As Found: Unknown

- ID: M4469

- Name: Arteriosclerosis

- Relevance: LOW

- As Found: Unknown

- ID: M22521

- Name: Intracranial Arterial Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M28591

- Name: Leukoencephalopathies

- Relevance: LOW

- As Found: Unknown

- ID: M4465

- Name: Arterial Occlusive Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M2401

- Name: Thrombotic Stroke

- Relevance: LOW

- As Found: Unknown

- ID: M2400

- Name: Ischemic Stroke

- Relevance: LOW

- As Found: Unknown

- ID: M10543

- Name: Ischemia

- Relevance: LOW

- As Found: Unknown

- ID: M10282

- Name: Infarction

- Relevance: LOW

- As Found: Unknown

- ID: M22305

- Name: Brain Infarction

- Relevance: LOW

- As Found: Unknown

- ID: M12284

- Name: Necrosis

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000059345

- Term: Cerebral Small Vessel Diseases

- ID: D000015140

- Term: Dementia, Vascular

- ID: D000059409

- Term: Stroke, Lacunar

### Misc Info Module

- Version Holder: 2024-05-31
