Translational Health Research Into Vascular and Neurocognitive Effects of Weight Loss

NCT07592546 | Not Yet Recruiting Phase 4

• 1 other identifier: THRIVE
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn about the nature of brain abnormalities associated with excess body fat in healthy adults aged 35-55. The main questions it aims to answer are:

• Will excessive fat be associated with brain abnormalities on MRI measures?
• Will weight loss change brain health on MRI measures? Participants will:
• Self-administer study drug, semaglutide, once a week for 80 weeks
• Complete metabolic and basic body measurements
• Complete cognitive, mood, and dietary assessments
• Complete questionnaires
• Undergo MRIs

Conditions

Class I/II Obesity

Keywords

weight loss; BMI; Obesity; overweight; obese; semaglutide; Ozempic; Wegovy; GLP-1

Outcome Measures

Primary Outcomes (34)

• Serum C-reactive Protein (CRP)

  Fasting serum CRP concentration (mg/L)

  Baseline & Change from Baseline

• Serum Pro-inflammatory Cytokines (Interleukin-6, TNF-α, Interleukin-1β, and IL-1 Receptor Antagonist)

  Fasting serum concentrations of IL-6, TNF-α, IL-1β, and IL-1 receptor antagonist (all in pg/mL)

  Baseline & Change from Baseline

• Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)

  HOMA-IR is calculated as (fasting glucose \[mmol/L\] × fasting insulin \[μIU/mL\]) / 22.5. The resulting dimensionless value estimates insulin resistance; higher values indicate greater insulin resistance.

  Baseline & Change from Baseline

• Fasting Plasma Glucose

  Venous plasma glucose concentration (mmol/L) following an overnight fast

  Baseline & Change from Baseline

• Glycated Hemoglobin A1c (HbA1c)

  Percentage of glycated hemoglobin (%), reflecting mean blood glucose

  Baseline & Change from Baseline

• Serum Leptin

  Fasting serum leptin concentration (ng/mL)

  Baseline & Change from Baseline

• Serum Ghrelin

  Fasting serum ghrelin concentration (pg/mL)

  Baseline & Change from Baseline

• Serum Adiponectin

  Fasting serum adiponectin concentration (μg/mL)

  Baseline & Change from Baseline

• Fasting Serum Insulin

  Fasting serum insulin concentration (μIU/mL)

  Baseline & Change from Baseline

• Serum Glucagon-Like Peptide-1 (GLP-1)

  Serum total GLP-1 concentration (pmol/L)

  Baseline & Change from Baseline

• Serum C-peptide

  Fasting serum C-peptide concentration (nmol/L)

  Baseline & Change from Baseline

• Serum Lipid Panel (Total Cholesterol, HDL Cholesterol, LDL Cholesterol, Triglycerides, and Non-Esterified Fatty Acids [NEFA])

  Fasting serum concentrations of total cholesterol, HDL, LDL, triglycerides, and NEFA (mmol/L)

  Baseline & Change from Baseline

• Serum Apolipoprotein B (ApoB)

  Fasting serum ApoB concentration (g/L)

  Baseline & Change from Baseline

• Red Blood Cell Phospholipid Fatty Acid Composition

  Proportion of individual fatty acid species in red blood cell membrane phospholipids (expressed as % of total fatty acids)

  Baseline & Change from Baseline

• Cerebral Blood Flow as Measured by Pseudo-Continuous Arterial Spin Labeling (pCASL) MRI

  Regional and whole-brain cerebral blood flow (mL/100g/min) derived from pCASL sequences at 3T MRI

  Baseline & Change from Baseline

• Oxygen Extraction Fraction (OEF) as Measured by Quantitative Susceptibility Mapping (QSM) and T2* MRI

  Whole-brain or regional OEF (dimensionless ratio, 0-1) derived from combined QSM and T2\* imaging

  Baseline & Change from Baseline

• Cerebral Metabolic Rate of Oxygen (CMRO₂) as Measured by QSM and T2* MRI

  CMRO₂ (μmol/100g/min) estimated from OEF and cerebral blood flow

  Baseline & Change from Baseline

• Cortical Thickness as Measured by Structural MRI

  Mean cortical thickness (mm) derived from T1-weighted

  Baseline & Change from Baseline

• Grey Matter Volume as Measured by Structural MRI

  Regional and total grey matter volume (cm³) derived from T1-weighted structural MRI

  Baseline & Change from Baseline

• Grey Matter Surface Area as Measured by Structural MRI

  Cortical surface area (cm²) derived from T1-weighted structural MRI

  Baseline & Change from Baseline

• White Matter Fractional Anisotropy (FA) as Measured by Diffusion Tensor Imaging (DTI)

  FA (dimensionless, 0-1) derived from DTI; higher FA indicates greater white matter tract coherence

  Baseline & Change from Baseline

• White Matter Mean Diffusivity (MD) as Measured by Diffusion Tensor Imaging (DTI)

  MD (mm²/s) derived from DTI; higher MD may indicate white matter disruption

  Baseline & Change from Baseline

• White Matter Microstructure as Measured by NODDI (intracellular volume fraction [ICVF], isotropic volume fraction [ISOVF], and Orientation Dispersion Index [ODI])

  ICVF, and ISOVF, ODI (dimensionless, 0-1) derived from NODDI modelling of multi-shell diffusion MRI data

  Baseline & Change from Baseline

• White Matter Hyperintensity Volume as Measured by FLAIR MRI

  Total white matter hyperintensity volume (mL) segmented from T2-weighted FLAIR images

  Baseline & Change from Baseline

• Cerebrovascular Reactivity (CVR) as Measured by BOLD fMRI with End-Tidal CO₂ (EtCO₂) Challenge

  CVR (expressed as % BOLD signal change per mmHg EtCO₂) derived from BOLD fMRI acquired during a hypercapnic EtCO₂ challenge

  Baseline & Change from Baseline

• Neuroinflammation proxy as Measured by T2* relaxation times

  Milliseconds (ms)

  Baseline & Change from Baseline

• Neuromelanin Contrast Ratio in the Substantia Nigra as Measured by Neuromelanin-Sensitive MRI

  Ratio of T1 signal intensity in the substantia nigra pars compacta relative to a reference region (dimensionless), used as an indirect in vivo measure of neuromelanin content

  Baseline & Change from Baseline

• Intracranial Artery Lumen Diameter as Measured by Time-of-Flight MRA

  Lumen diameter (mm) measured at standardized segments of the ICA, MCA, basilar, and vertebral arteries using 3D TOF-MRA at 3T

  Baseline & Change from Baseline

• Body Mass Index (BMI)

  BMI (kg/m²) calculated from measured height (m) and body weight (kg)

  Baseline & Change from Baseline

• Waist Circumference, Hip Circumference

  circumference (cm)

  Baseline & Change from Baseline

• Waist-to-height ratio, Waist-to-hip ratio

  Unitless

  Baseline & Change from Baseline

• Visceral Adipose Tissue as Measured by MRI

  Visceral adipose tissue volume (mL) quantified by MRI Dixon sequence and Bioimpedance Analysis

  Baseline & Change from Baseline

• Subcutaneous Adipose Tissue as Measured by MRI

  Subcutaneous adipose tissue volume (mL) quantified by MRI

  Baseline & Change from Baseline

• Body Composition

  Whole-body fat as a percentage of total body mass (%), lean mass tissue, muscle mass measured by BIA

  Baseline & Change from Baseline

Secondary Outcomes (13)

• Delay Discounting Task Score (Impulsive Choice)

  Baseline & Change from Baseline

• Penn Line Orientation Test Score (Visual Processing)

  Baseline & Change from Baseline

• Penn Progressive Matrices Score (Fluid Intelligence)

  Baseline & Change from Baseline

• Oral Reading Recognition Test Score (Language Ability)

  Baseline & Change from Baseline

• Penn Word Memory Test Score (Episodic Memory)

  Baseline & Change from Baseline

Study Arms (2)

Overweight Group (BMI 27 - 40 kg/m2)

EXPERIMENTAL

semaglutide

Drug: semaglutide

Lean group (BMI 20 - 25 kg/m2)

NO INTERVENTION

Interventions

semaglutide DRUG

Treatment will be given for 80 weeks. Dose will be escalated from 0.25 mg to a max of 2.4 mg per week.

Also known as: Ozempic, Wegovy

Overweight Group (BMI 27 - 40 kg/m2)

Eligibility Criteria

• Age: 35 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Individuals of age 35-55 years with BMI 27 - 40 kg/m2
• Able to provide informed consent
• Willing to self-inject semaglutide and follow study procedures for its entire duration.
• Individuals of age 35-55 years with BMI 20 - 25 kg/m2
• Able to provide informed consent

You may not qualify if:

• Current type 2 diabetes mellitus;
• Neurological disorders affecting the CNS;
• History or family history of medullary thyroid carcinoma or MEN2 syndrome
• CNS-active medications (outside of medications used to control psychiatric disorders);
• Poorly controlled psychiatric disorders including major depression or previous suicidality;
• Class III obesity (BMI\>40 or BMI\>35 with complications) as these individuals are eligible for bariatric surgery in Canada and will be referred for appropriate medical care;
• Clinical safety blood measures indicative of a medical issue.
• History of weight change \> 5 kg in past 90 days;
• History of pancreatitis
• Previous or planned bariatric surgery;
• Use of another weight loss medication during trial participation and within 90 days before enrolment;
• Female subjects of childbearing potential (i.e., a premenopausal female capable of becoming pregnant) are eligible to enroll if they are either sexually inactive/abstinent or using an effective contraceptive from screening until 4 weeks after the last dose. Medically accepted contraception are hormonal implants, hormonal patches, IDU, diaphragm and spermicide, cervical cape with spermicide, and condom with spermicide.

Sponsors & Collaborators

• Alain Dagher: lead

Study Sites (1)

The Montreal Neurological Institute-Hospital

Montreal, Quebec, H3A 2B4, Canada

Location

MeSH Terms

Conditions

Weight Loss; Obesity; Overweight

Interventions

semaglutide

Condition Hierarchy (Ancestors)

Body Weight Changes; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases

Central Study Contacts

Michael Pileggi, M.Sc.

CONTACT

514-396-2085; michael.pileggi@mcgill.ca

Filip Morys

CONTACT

filip.morys@mcgill.ca

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: The population selected for this trial includes adults aged 35 to 55 years with overweight or obesity (BMI 27-40 kg/m²) and an age- and sex-matched lean control group (BMI 20-25 kg/m²).

Study Record Dates

• First Submitted: May 3, 2026
• First Posted: May 18, 2026
• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): June 1, 2030
• Last Updated: May 22, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: After trial completion with no end date.
• Access Criteria: Researchers will register to the portal and agree to terms and conditions of data use after which they will gain access to the IPD.

Locations

CA (1)