Translational Health Research Into Vascular and Neurocognitive Effects of Weight Loss

Phase 4Not Yet RecruitingNCT07592546

Alain Dagher240 enrolled

Overview

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

We conducted a priori power calculations (80% power, α=0.05) based on published effect sizes (Cohen's d) for the following measures comparing obese to lean participants: hypothalamic neuroinflammation (d=1.52, required n=8/group; Thaler et al. 2012); cerebral metabolic rate of O₂ (d=1.59, required n=8/group; Anwar et al. 2022); oxygen extraction fraction (OEF) (d=0.67, required n=37/group; Anwar et al. 2022); white matter fractional anisotropy (d=0.61, required n=43/group; Daoust et al. 2021); and for the following measures following bariatric surgery: OEF (d=0.47, required n=37; Anwar et al. 2022); cerebral blood flow (d=0.74, required n=17; Anwar et al. 2022); fALFF (d=1.60, required n=6; Zeighami et al. 2021); cortical thickness (d=0.78, required n=8; Bohon et al. 2018). Based on the above, we will assume a conservative minimum sample size of 43 per group to detect changes in brain health. In line with previous clinical trials for weight loss, where 88% of patients completed the trial but 83% adhered to the treatment regimen, we will assume a 15% attrition rate. Therefore, the minimum sample size providing adequate statistical power for sex-stratified analyses will be 50 men and 50 women. We will enroll 60 participants per group to account for an additional 20% dropout, for a total target sample of 120. At full enrollment, this will allow us to detect small to medium effects in brain health with over 90% power (Cohen's d=0.30), and sex-stratified analyses will be powered to detect medium effect sizes (Cohen's d=0.40) with 80% power. If enrollment falls below 100 total participants (50 per group) for feasibility reasons, the sample might be considered insufficient to support confirmatory sex-stratified analyses. In this event, analyses will be conducted in the total sample only. Sex differences may then be examined in an exploratory capacity. This decision rule is pre-specified and will be applied without reference to outcome data. Anwar, Nareen, Wesley J. Tucker, Nancy Puzziferri, T. Jake Samuel, Vlad G. Zaha, Ildiko Lingvay, Jaime Almandoz, et al. 2022. "Cognition and Brain Oxygen Metabolism Improves after Bariatric Surgery-Induced Weight Loss: A Pilot Study." Frontiers in Endocrinology 13 (December): 954127. Bohon, Cara, Luis C. Garcia, and John M. Morton. 2018. "Changes in Cerebral Cortical Thickness Related to Weight Loss Following Bariatric Surgery." Obesity Surgery 28 (8): 2578-82. Daoust, Justine, Joelle Schaffer, Yashar Zeighami, Alain Dagher, Isabel García-García, and Andréanne Michaud. 2021. "White Matter Integrity Differences in Obesity: A Meta-Analysis of Diffusion Tensor Imaging Studies." Neuroscience and Biobehavioral Reviews 129 (October): 133-41. Thaler, Joshua P., Chun Xia Yi, Ellen A. Schur, Stephan J. Guyenet, Bang H. Hwang, Marcelo O. Dietrich, Xiaolin Zhao, et al. 2012. "Obesity Is Associated with Hypothalamic Injury in Rodents and Humans." The Journal of Clinical Investigation 122 (1): 153. Zeighami, Yashar, Sylvain Iceta, Mahsa Dadar, Mélissa Pelletier, Mélanie Nadeau, Laurent Biertho, Annie Lafortune, et al. 2021. "Spontaneous Neural Activity Changes after Bariatric Surgery: A Resting-State FMRI Study." NeuroImage 241 (November): 118419.

Conditions

Class I/II Obesity

Interventions

semaglutideDRUG

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

Eligibility

Sex: ALLMin age: 35 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: Key inclusion criteria for obese group: * 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. Key inclusion criteria for lean control group: * Individuals of age 35-55 years with BMI 20 - 25 kg/m2 * Able to provide informed consent Exclusion Criteria for both groups: * 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; * History of serious medical illness, monogenic obesity, uncontrolled hypertension (sBP\>160 mmHg, dBP\>100 mmHg), active malignancy, illicit substance use, cigarette smoking, diagnosed eating disorder, as listed in the study protocol associated with; Other obesity comorbidities, e.g. hypertension, pre-diabetes (HbA1C = 6% to 6.4%), hyperlipidemia, controlled depressive disorder or anxiety, ADHD, and polycystic ovary syndrome, will not be exclusion criteria as this would reduce the representativeness of our sample. * 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.

Locations (1)

The Montreal Neurological Institute-Hospital

Montreal, Quebec, Canada

Outcomes

Primary Outcomes

Serum C-reactive Protein (CRP)

Fasting serum CRP concentration (mg/L)

Time frame: 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)

Time frame: 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.

Time frame: Baseline & Change from Baseline

Fasting Plasma Glucose

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

Time frame: Baseline & Change from Baseline

Glycated Hemoglobin A1c (HbA1c)

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

Time frame: Baseline & Change from Baseline

Serum Leptin

Fasting serum leptin concentration (ng/mL)

Time frame: Baseline & Change from Baseline

Serum Ghrelin

Fasting serum ghrelin concentration (pg/mL)

Time frame: Baseline & Change from Baseline

Serum Adiponectin

Fasting serum adiponectin concentration (μg/mL)

Time frame: Baseline & Change from Baseline

Central Contacts

Michael Pileggi, M.Sc.

CONTACT

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

Filip Morys

CONTACT

filip.morys@mcgill.ca

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

240

Fasting Serum Insulin

Fasting serum insulin concentration (μIU/mL)

Time frame: Baseline & Change from Baseline

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

Serum total GLP-1 concentration (pmol/L)

Time frame: Baseline & Change from Baseline

Serum C-peptide

Fasting serum C-peptide concentration (nmol/L)

Time frame: 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)

Time frame: Baseline & Change from Baseline

Serum Apolipoprotein B (ApoB)

Fasting serum ApoB concentration (g/L)

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Baseline & Change from Baseline

Cortical Thickness as Measured by Structural MRI

Mean cortical thickness (mm) derived from T1-weighted

Time frame: 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

Time frame: Baseline & Change from Baseline

Grey Matter Surface Area as Measured by Structural MRI

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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Baseline & Change from Baseline

Neuroinflammation proxy as Measured by T2* relaxation times

Milliseconds (ms)

Time frame: 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

Time frame: 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

Time frame: Baseline & Change from Baseline

Body Mass Index (BMI)

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

Time frame: Baseline & Change from Baseline

Waist Circumference, Hip Circumference

circumference (cm)

Time frame: Baseline & Change from Baseline

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

Unitless

Time frame: Baseline & Change from Baseline

Visceral Adipose Tissue as Measured by MRI

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

Time frame: Baseline & Change from Baseline

Subcutaneous Adipose Tissue as Measured by MRI

Subcutaneous adipose tissue volume (mL) quantified by MRI

Time frame: Baseline & Change from Baseline

Body Composition

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

Time frame: Baseline & Change from Baseline

Secondary Outcomes

Delay Discounting Task Score (Impulsive Choice)

The Delay Discounting Task quantifies impulsive choice by measuring preference for smaller immediate versus larger delayed rewards. The discounting rate (k value, log-transformed) is the primary output; higher k values indicate greater impulsivity.

Time frame: Baseline & Change from Baseline

Penn Line Orientation Test Score (Visual Processing)

The Penn Line Orientation Test (PLOT) assesses visuospatial processing by asking participants to match line orientations. Higher scores indicate better visual processing performance.

Time frame: Baseline & Change from Baseline

Penn Progressive Matrices Score (Fluid Intelligence)

The Penn Progressive Matrices is a nonverbal test of fluid reasoning and abstract problem-solving. Higher scores indicate greater fluid intelligence.

Time frame: Baseline & Change from Baseline

Oral Reading Recognition Test Score (Language Ability)

The Oral Reading Recognition Test assesses language ability and reading recognition. Scores are reported as raw scores; higher scores indicate better language performance.

Time frame: Baseline & Change from Baseline

Penn Word Memory Test Score (Episodic Memory)

The Penn Word Memory Test assesses verbal episodic memory via a word recognition paradigm. Performance is reported as percentage of words correctly recognized (0-100%); higher values indicate better episodic memory.

Time frame: Baseline & Change from Baseline

Relational Memory Task Score (Executive Function and Attention)

The Relational Task assesses relational reasoning and executive attention. Performance is reported as \[% correct / reaction time in ms\]; \[higher accuracy / lower reaction time\] indicates better performance.

Time frame: Baseline & Change from Baseline

Montreal Cognitive Assessment (MoCA) Total Score

The MoCA is a brief cognitive screening tool assessing multiple domains including memory, attention, language, and visuospatial ability. Scores range from 0 to 30; higher scores indicate better global cognitive function.

Time frame: Baseline & Change from Baseline

Patient Health Questionnaire-9 (PHQ-9) Depression Score

The PHQ-9 is a 9-item validated self-report questionnaire measuring depressive symptom severity over the preceding 2 weeks. Scores range from 0 to 27; higher scores indicate greater depressive symptom severity.

Time frame: Baseline & Change from Baseline

Mean Daily Energy Intake, fat, carbohydrate, sugar, protein intake, saturated fatty acids intake as Assessed by 3-Day Food Record.

Daily energy intake from different macronutrients (kcal/day) derived from a 3-day food record and.

Time frame: Baseline & Change from Baseline

Percentage of calories derived from each of NOVA food classification categories

Units: Percentage (%)

Time frame: Baseline & Change from Baseline

Healthy Eating Index

The Healthy Eating Index (HEI) measures diet quality on a scale of 0 to 100, where 100 indicates perfect alignment with the Dietary Guidelines for Americans

Time frame: Baseline & Change from Baseline

Fat Taste Preference Score

Geometric average of a preferred solution from a Monell 2-series forced choice test.

Time frame: Baseline & Change from Baseline

Sweet Taste Preference Score

Geometric average of a preferred solution from a Monell 2-series forced choice test.

Time frame: Baseline & Change from Baseline