Class I/II Obesity
Conditions
Keywords
weight loss, BMI, Obesity, overweight, obese, semaglutide, Ozempic, Wegovy, GLP-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
Detailed description
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.
Interventions
DRUGsemaglutide
Treatment will be given for 80 weeks. Dose will be escalated from 0.25 mg to a max of 2.4 mg per week.
Sponsors
Alain Dagher
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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).
Eligibility
Sex/Gender
ALL
Age
35 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum C-reactive Protein (CRP) | Baseline & Change from Baseline | Fasting serum CRP concentration (mg/L) |
| Serum Pro-inflammatory Cytokines (Interleukin-6, TNF-α, Interleukin-1β, and IL-1 Receptor Antagonist) | Baseline & Change from Baseline | Fasting serum concentrations of IL-6, TNF-α, IL-1β, and IL-1 receptor antagonist (all in pg/mL) |
| Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | Baseline & Change from Baseline | 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. |
| Fasting Plasma Glucose | Baseline & Change from Baseline | Venous plasma glucose concentration (mmol/L) following an overnight fast |
| Glycated Hemoglobin A1c (HbA1c) | Baseline & Change from Baseline | Percentage of glycated hemoglobin (%), reflecting mean blood glucose |
| Serum Leptin | Baseline & Change from Baseline | Fasting serum leptin concentration (ng/mL) |
| Serum Ghrelin | Baseline & Change from Baseline | Fasting serum ghrelin concentration (pg/mL) |
| Serum Adiponectin | Baseline & Change from Baseline | Fasting serum adiponectin concentration (μg/mL) |
| Fasting Serum Insulin | Baseline & Change from Baseline | Fasting serum insulin concentration (μIU/mL) |
| Serum Glucagon-Like Peptide-1 (GLP-1) | Baseline & Change from Baseline | Serum total GLP-1 concentration (pmol/L) |
| Serum C-peptide | Baseline & Change from Baseline | Fasting serum C-peptide concentration (nmol/L) |
| Serum Lipid Panel (Total Cholesterol, HDL Cholesterol, LDL Cholesterol, Triglycerides, and Non-Esterified Fatty Acids [NEFA]) | Baseline & Change from Baseline | Fasting serum concentrations of total cholesterol, HDL, LDL, triglycerides, and NEFA (mmol/L) |
| Serum Apolipoprotein B (ApoB) | Baseline & Change from Baseline | Fasting serum ApoB concentration (g/L) |
| Red Blood Cell Phospholipid Fatty Acid Composition | Baseline & Change from Baseline | Proportion of individual fatty acid species in red blood cell membrane phospholipids (expressed as % of total fatty acids) |
| Cerebral Blood Flow as Measured by Pseudo-Continuous Arterial Spin Labeling (pCASL) MRI | Baseline & Change from Baseline | Regional and whole-brain cerebral blood flow (mL/100g/min) derived from pCASL sequences at 3T MRI |
| Oxygen Extraction Fraction (OEF) as Measured by Quantitative Susceptibility Mapping (QSM) and T2* MRI | Baseline & Change from Baseline | Whole-brain or regional OEF (dimensionless ratio, 0-1) derived from combined QSM and T2\* imaging |
| Cerebral Metabolic Rate of Oxygen (CMRO₂) as Measured by QSM and T2* MRI | Baseline & Change from Baseline | CMRO₂ (μmol/100g/min) estimated from OEF and cerebral blood flow |
| Cortical Thickness as Measured by Structural MRI | Baseline & Change from Baseline | Mean cortical thickness (mm) derived from T1-weighted |
| Grey Matter Volume as Measured by Structural MRI | Baseline & Change from Baseline | Regional and total grey matter volume (cm³) derived from T1-weighted structural MRI |
| Grey Matter Surface Area as Measured by Structural MRI | Baseline & Change from Baseline | Cortical surface area (cm²) derived from T1-weighted structural MRI |
| White Matter Fractional Anisotropy (FA) as Measured by Diffusion Tensor Imaging (DTI) | Baseline & Change from Baseline | FA (dimensionless, 0-1) derived from DTI; higher FA indicates greater white matter tract coherence |
| White Matter Mean Diffusivity (MD) as Measured by Diffusion Tensor Imaging (DTI) | Baseline & Change from Baseline | MD (mm²/s) derived from DTI; higher MD may indicate white matter disruption |
| White Matter Microstructure as Measured by NODDI (intracellular volume fraction [ICVF], isotropic volume fraction [ISOVF], and Orientation Dispersion Index [ODI]) | Baseline & Change from Baseline | ICVF, and ISOVF, ODI (dimensionless, 0-1) derived from NODDI modelling of multi-shell diffusion MRI data |
| White Matter Hyperintensity Volume as Measured by FLAIR MRI | Baseline & Change from Baseline | Total white matter hyperintensity volume (mL) segmented from T2-weighted FLAIR images |
| Cerebrovascular Reactivity (CVR) as Measured by BOLD fMRI with End-Tidal CO₂ (EtCO₂) Challenge | Baseline & Change from Baseline | CVR (expressed as % BOLD signal change per mmHg EtCO₂) derived from BOLD fMRI acquired during a hypercapnic EtCO₂ challenge |
| Neuroinflammation proxy as Measured by T2* relaxation times | Baseline & Change from Baseline | Milliseconds (ms) |
| Neuromelanin Contrast Ratio in the Substantia Nigra as Measured by Neuromelanin-Sensitive MRI | Baseline & Change from Baseline | 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 |
| Intracranial Artery Lumen Diameter as Measured by Time-of-Flight MRA | Baseline & Change from Baseline | Lumen diameter (mm) measured at standardized segments of the ICA, MCA, basilar, and vertebral arteries using 3D TOF-MRA at 3T |
| Body Mass Index (BMI) | Baseline & Change from Baseline | BMI (kg/m²) calculated from measured height (m) and body weight (kg) |
| Waist Circumference, Hip Circumference | Baseline & Change from Baseline | circumference (cm) |
| Waist-to-height ratio, Waist-to-hip ratio | Baseline & Change from Baseline | Unitless |
| Visceral Adipose Tissue as Measured by MRI | Baseline & Change from Baseline | Visceral adipose tissue volume (mL) quantified by MRI Dixon sequence and Bioimpedance Analysis |
| Subcutaneous Adipose Tissue as Measured by MRI | Baseline & Change from Baseline | Subcutaneous adipose tissue volume (mL) quantified by MRI |
| Body Composition | Baseline & Change from Baseline | Whole-body fat as a percentage of total body mass (%), lean mass tissue, muscle mass measured by BIA |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Delay Discounting Task Score (Impulsive Choice) | Baseline & Change from Baseline | 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. |
| Penn Line Orientation Test Score (Visual Processing) | Baseline & Change from Baseline | The Penn Line Orientation Test (PLOT) assesses visuospatial processing by asking participants to match line orientations. Higher scores indicate better visual processing performance. |
| Penn Progressive Matrices Score (Fluid Intelligence) | Baseline & Change from Baseline | The Penn Progressive Matrices is a nonverbal test of fluid reasoning and abstract problem-solving. Higher scores indicate greater fluid intelligence. |
| Oral Reading Recognition Test Score (Language Ability) | Baseline & Change from Baseline | The Oral Reading Recognition Test assesses language ability and reading recognition. Scores are reported as raw scores; higher scores indicate better language performance. |
| Penn Word Memory Test Score (Episodic Memory) | Baseline & Change from Baseline | 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. |
| Relational Memory Task Score (Executive Function and Attention) | Baseline & Change from Baseline | 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. |
| Montreal Cognitive Assessment (MoCA) Total Score | Baseline & Change from Baseline | 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. |
| Patient Health Questionnaire-9 (PHQ-9) Depression Score | Baseline & Change from Baseline | 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. |
| Mean Daily Energy Intake, fat, carbohydrate, sugar, protein intake, saturated fatty acids intake as Assessed by 3-Day Food Record. | Baseline & Change from Baseline | Daily energy intake from different macronutrients (kcal/day) derived from a 3-day food record and. |
| Percentage of calories derived from each of NOVA food classification categories | Baseline & Change from Baseline | Units: Percentage (%) |
| Healthy Eating Index | Baseline & Change from Baseline | 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 |
| Fat Taste Preference Score | Baseline & Change from Baseline | Geometric average of a preferred solution from a Monell 2-series forced choice test. |
| Sweet Taste Preference Score | Baseline & Change from Baseline | Geometric average of a preferred solution from a Monell 2-series forced choice test. |
| Working memory capacity | Baseline & Change from Baseline | Digits remembered on the digit span and digit span backwards task |
| Reinforcement learning outcomes | Baseline & Change from Baseline | Choose-A accuracy (reward learning) Proportion of test-phase trials on which participants select stimulus A (the most frequently rewarded stimulus, 80% positive feedback) when paired with novel stimuli, indexing the bias to learn from positive feedback / approach the best option. Avoid-B accuracy (punishment learning) Proportion of test-phase trials on which participants avoid stimulus B (the most frequently punished stimulus, 80% negative feedback) when paired with novel stimuli, indexing the bias to learn from negative feedback / avoid the worst option. |
Countries
Canada
Contacts
CONTACTMichael Pileggi, M.Sc.
CONTACTFilip Morys
Outcome results
None listed