Clinical trial NCT05356104: GLP-1 Analogue in Preventing Progression of Small Vessel Disease (GAPP-SVD)
Official title: GLP-1 Analogue in Preventing Progression of Small Vessel Disease (GAPP-SVD) - A Pilot Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Cerebral Small Vessel Disease
Keywords: cSVD
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
First posted: 2022-05-02
Enrollment: 110
Sex: ALL
Minimum age (years): 55
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 110 patients with cSVD of Age-Related White Matter Changes Scale of 2 or 3 will be randomized into "treatment arm" with GLP-1R agonist and standard medical therapy, and "control" arm with standard medical therapy alone in a 1:1 ratio. In this 78 weeks pilot study, investigators shall evaluate the tolerability and safety profile of exenatide, a GLP-1R agonist in SVD patients, together with changes in clinical, imaging and sonographic parameters.
Primary purpose: TREATMENT

Brief summary: Cerebral small vessel disease (cSVD), a result of neurovascular cell dysfunction, is a major cause of stroke, dementia and mobility problems worldwide. Vascular risk factor control alone may not be sufficient to prevent the development of vascular cognitive impairment (VCI) in patients with cSVD according to previous clinical trials.

The presence of glucagon-like peptide-1 receptor (GLP-1R) in cerebral microglia may reveal a potential therapeutic target for prevention of cSVD progression and its disabling clinical outcomes. At the cellular and animal experimentation levels, GLP-1R agonist demonstrated reversal of some pathogenic processes in cSVD. However, its application to cSVD patients remains to be elucidated.

Investigator aims to investigate the safety and efficacy of GLP-1R agonist in patients with moderate-to-severe cSVD.

Detailed description: In this single-center, open-label (assessor blinded), randomized controlled study, 110 patients with cSVD of Age-Related White Matter Changes Scale of 2 or 3 will be randomized into "treatment arm" with GLP-1R agonist and standard medical therapy, and "control" arm with standard medical therapy alone in a 1:1 ratio. In this 78 weeks pilot study, investigators shall evaluate the tolerability and safety profile of exenatide, a GLP-1R agonist in SVD patients, together with changes in clinical, imaging and sonographic parameters.

Clinical and biochemical measures will be assessed at baseline, 12 weeks, 26 weeks and 52 weeks. Transcranial Doppler Ultrasound (TCD) will be performed at baseline, 12 weeks, 26 weeks, 52 weeks and 78 weeks. MRI will be performed at baseline and 78 weeks

Eligibility criteria: Inclusion Criteria:

1. Chinese ethnicity;
2. Age 55 to 80 years old;
3. Age-Related White Matter Change (ARWMC) Scale of 2 or early 3 in FLAIR MRI;
4. Modified Functional Ambulation Classification 5 or above;
5. Montreal Cognitive Assessment (MoCA) score \< 25;
6. Both diabetic and non-diabetic patient are eligible;
7. Patient who understands the purpose and requirements of the study, and able to provide an informed consent;

Exclusion Criteria:

1. Dementia or MoCA score lower than 2nd percentile of the age and education adjusted cutoff ;
2. Cerebral white matter changes unrelated to neurodegenerative, e.g. CADASIL, X-linked adrenoleukodystrophy, metabolic diseases, multiple sclerosis, etc.;
3. Contraindication to GLP-1R agonist, including thyroid carcinoma, pancreatic pathology, proliferative retinopathy, hypersensitivity to GLP-1R agonist and history of family history of multiple endocrine neoplasia;
4. BMI \<18.5kg/m2;
5. Contraindication to proposed imaging, e.g. chronic kidney disease (KDNIGO) stage 4 or above, acute kidney injury, hypersensitivity to gadolinium-based contrast, non-MRI conditional implants or prosthesis;
6. Medical condition that would not allow the patient to adhere to the protocol or complete the study.;
7. Patient with established neurodegenerative disorders (e.g. Parkinson's Disease, Alzheimer's Disease, etc.);
8. Pregnancy.

Primary outcomes:
measure: Change of Brain Peak Width of Skeletonized Mean Diffusivity
timeFrame: Baseline and week 78
Secondary outcomes:
measure: Number of recurrent stroke
timeFrame: Baseline and week 78
measure: Change of Hong Kong MOntreal Cognitive Assessment
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change The Chinese Geriatric Depression Scale 30
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of Pittsburgh sleep quality index
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of Hong Kong List Learning Test
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of Neuropsychiatric Inventory
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of disability assessment for dementia
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of Gait
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of balance
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of Pulsatility Index
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of Breath Holding Index
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of DNA methylation
timeFrame: Baseline, week 12, week 26, week 52 and week 78
measure: Change of neurovascular inflammation
timeFrame: Baseline, week 12, week 26, week 52 and week 78
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Chinese University of Hong Kong
Study officials:
affiliation: Chinese University of Hong Kong
name: Bonaventure Yiu Ming Ip, MBChB
role: PRINCIPAL_INVESTIGATOR
References: