Translational Health Research Into Vascular and Neurocognitive Effects of Weight Loss (THRIVE)
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
調査の概要
詳細な説明
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.
研究の種類
入学 (推定)
段階
- フェーズ 4
連絡先と場所
研究連絡先
- 名前：Michael Pileggi, M.Sc.
- 電話番号：514-396-2085
- メール：michael.pileggi@mcgill.ca
研究連絡先のバックアップ
- 名前：Filip Morys
- メール：filip.morys@mcgill.ca
研究場所
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Quebec
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Montreal、Quebec、カナダ、H3A 2B4
- The Montreal Neurological Institute-Hospital
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主任研究者：
- Alain Dagher, MD
-
-
参加基準
適格基準
就学可能な年齢
- 大人
健康ボランティアの受け入れ
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：非ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：Overweight Group (BMI 27 - 40 kg/m2)
semaglutide
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Treatment will be given for 80 weeks.
Dose will be escalated from 0.25 mg to a max of 2.4 mg per week.
他の名前：
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介入なし：Lean group (BMI 20 - 25 kg/m2)
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Serum C-reactive Protein (CRP)
時間枠：Baseline & Change from Baseline
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Fasting serum CRP concentration (mg/L)
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Baseline & Change from Baseline
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Serum Pro-inflammatory Cytokines (Interleukin-6, TNF-α, Interleukin-1β, and IL-1 Receptor Antagonist)
時間枠：Baseline & Change from Baseline
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Fasting serum concentrations of IL-6, TNF-α, IL-1β, and IL-1 receptor antagonist (all in pg/mL)
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Baseline & Change from Baseline
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Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
時間枠：Baseline & Change from Baseline
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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.
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Baseline & Change from Baseline
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Fasting Plasma Glucose
時間枠：Baseline & Change from Baseline
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Venous plasma glucose concentration (mmol/L) following an overnight fast
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Baseline & Change from Baseline
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Glycated Hemoglobin A1c (HbA1c)
時間枠：Baseline & Change from Baseline
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Percentage of glycated hemoglobin (%), reflecting mean blood glucose
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Baseline & Change from Baseline
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Serum Leptin
時間枠：Baseline & Change from Baseline
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Fasting serum leptin concentration (ng/mL)
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Baseline & Change from Baseline
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Serum Ghrelin
時間枠：Baseline & Change from Baseline
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Fasting serum ghrelin concentration (pg/mL)
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Baseline & Change from Baseline
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Serum Adiponectin
時間枠：Baseline & Change from Baseline
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Fasting serum adiponectin concentration (μg/mL)
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Baseline & Change from Baseline
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Fasting Serum Insulin
時間枠：Baseline & Change from Baseline
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Fasting serum insulin concentration (μIU/mL)
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Baseline & Change from Baseline
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Serum Glucagon-Like Peptide-1 (GLP-1)
時間枠：Baseline & Change from Baseline
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Serum total GLP-1 concentration (pmol/L)
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Baseline & Change from Baseline
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Serum C-peptide
時間枠：Baseline & Change from Baseline
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Fasting serum C-peptide concentration (nmol/L)
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Baseline & Change from Baseline
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Serum Lipid Panel (Total Cholesterol, HDL Cholesterol, LDL Cholesterol, Triglycerides, and Non-Esterified Fatty Acids [NEFA])
時間枠：Baseline & Change from Baseline
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Fasting serum concentrations of total cholesterol, HDL, LDL, triglycerides, and NEFA (mmol/L)
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Baseline & Change from Baseline
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Serum Apolipoprotein B (ApoB)
時間枠：Baseline & Change from Baseline
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Fasting serum ApoB concentration (g/L)
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Baseline & Change from Baseline
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Red Blood Cell Phospholipid Fatty Acid Composition
時間枠：Baseline & Change from Baseline
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Proportion of individual fatty acid species in red blood cell membrane phospholipids (expressed as % of total fatty acids)
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Baseline & Change from Baseline
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Cerebral Blood Flow as Measured by Pseudo-Continuous Arterial Spin Labeling (pCASL) MRI
時間枠：Baseline & Change from Baseline
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Regional and whole-brain cerebral blood flow (mL/100g/min) derived from pCASL sequences at 3T MRI
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Baseline & Change from Baseline
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Oxygen Extraction Fraction (OEF) as Measured by Quantitative Susceptibility Mapping (QSM) and T2* MRI
時間枠：Baseline & Change from Baseline
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Whole-brain or regional OEF (dimensionless ratio, 0-1) derived from combined QSM and T2* imaging
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Baseline & Change from Baseline
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Cerebral Metabolic Rate of Oxygen (CMRO₂) as Measured by QSM and T2* MRI
時間枠：Baseline & Change from Baseline
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CMRO₂ (μmol/100g/min) estimated from OEF and cerebral blood flow
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Baseline & Change from Baseline
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Cortical Thickness as Measured by Structural MRI
時間枠：Baseline & Change from Baseline
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Mean cortical thickness (mm) derived from T1-weighted
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Baseline & Change from Baseline
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Grey Matter Volume as Measured by Structural MRI
時間枠：Baseline & Change from Baseline
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Regional and total grey matter volume (cm³) derived from T1-weighted structural MRI
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Baseline & Change from Baseline
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Grey Matter Surface Area as Measured by Structural MRI
時間枠：Baseline & Change from Baseline
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Cortical surface area (cm²) derived from T1-weighted structural MRI
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Baseline & Change from Baseline
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White Matter Fractional Anisotropy (FA) as Measured by Diffusion Tensor Imaging (DTI)
時間枠：Baseline & Change from Baseline
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FA (dimensionless, 0-1) derived from DTI; higher FA indicates greater white matter tract coherence
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Baseline & Change from Baseline
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White Matter Mean Diffusivity (MD) as Measured by Diffusion Tensor Imaging (DTI)
時間枠：Baseline & Change from Baseline
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MD (mm²/s) derived from DTI; higher MD may indicate white matter disruption
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Baseline & Change from Baseline
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White Matter Microstructure as Measured by NODDI (intracellular volume fraction [ICVF], isotropic volume fraction [ISOVF], and Orientation Dispersion Index [ODI])
時間枠：Baseline & Change from Baseline
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ICVF, and ISOVF, ODI (dimensionless, 0-1) derived from NODDI modelling of multi-shell diffusion MRI data
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Baseline & Change from Baseline
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White Matter Hyperintensity Volume as Measured by FLAIR MRI
時間枠：Baseline & Change from Baseline
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Total white matter hyperintensity volume (mL) segmented from T2-weighted FLAIR images
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Baseline & Change from Baseline
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Cerebrovascular Reactivity (CVR) as Measured by BOLD fMRI with End-Tidal CO₂ (EtCO₂) Challenge
時間枠：Baseline & Change from Baseline
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CVR (expressed as % BOLD signal change per mmHg EtCO₂) derived from BOLD fMRI acquired during a hypercapnic EtCO₂ challenge
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Baseline & Change from Baseline
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Neuroinflammation proxy as Measured by T2* relaxation times
時間枠：Baseline & Change from Baseline
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Milliseconds (ms)
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Baseline & Change from Baseline
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Neuromelanin Contrast Ratio in the Substantia Nigra as Measured by Neuromelanin-Sensitive MRI
時間枠：Baseline & Change from Baseline
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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
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Baseline & Change from Baseline
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Intracranial Artery Lumen Diameter as Measured by Time-of-Flight MRA
時間枠：Baseline & Change from Baseline
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Lumen diameter (mm) measured at standardized segments of the ICA, MCA, basilar, and vertebral arteries using 3D TOF-MRA at 3T
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Baseline & Change from Baseline
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Body Mass Index (BMI)
時間枠：Baseline & Change from Baseline
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BMI (kg/m²) calculated from measured height (m) and body weight (kg)
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Baseline & Change from Baseline
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Waist Circumference, Hip Circumference
時間枠：Baseline & Change from Baseline
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circumference (cm)
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Baseline & Change from Baseline
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Waist-to-height ratio, Waist-to-hip ratio
時間枠：Baseline & Change from Baseline
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Unitless
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Baseline & Change from Baseline
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Visceral Adipose Tissue as Measured by MRI
時間枠：Baseline & Change from Baseline
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Visceral adipose tissue volume (mL) quantified by MRI Dixon sequence and Bioimpedance Analysis
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Baseline & Change from Baseline
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Subcutaneous Adipose Tissue as Measured by MRI
時間枠：Baseline & Change from Baseline
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Subcutaneous adipose tissue volume (mL) quantified by MRI
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Baseline & Change from Baseline
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Body Composition
時間枠：Baseline & Change from Baseline
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Whole-body fat as a percentage of total body mass (%), lean mass tissue, muscle mass measured by BIA
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Baseline & Change from Baseline
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Delay Discounting Task Score (Impulsive Choice)
時間枠：Baseline & Change from Baseline
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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.
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Baseline & Change from Baseline
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Penn Line Orientation Test Score (Visual Processing)
時間枠：Baseline & Change from Baseline
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The Penn Line Orientation Test (PLOT) assesses visuospatial processing by asking participants to match line orientations.
Higher scores indicate better visual processing performance.
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Baseline & Change from Baseline
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Penn Progressive Matrices Score (Fluid Intelligence)
時間枠：Baseline & Change from Baseline
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The Penn Progressive Matrices is a nonverbal test of fluid reasoning and abstract problem-solving.
Higher scores indicate greater fluid intelligence.
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Baseline & Change from Baseline
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Oral Reading Recognition Test Score (Language Ability)
時間枠：Baseline & Change from Baseline
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The Oral Reading Recognition Test assesses language ability and reading recognition.
Scores are reported as raw scores; higher scores indicate better language performance.
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Baseline & Change from Baseline
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Penn Word Memory Test Score (Episodic Memory)
時間枠：Baseline & Change from Baseline
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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.
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Baseline & Change from Baseline
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Relational Memory Task Score (Executive Function and Attention)
時間枠：Baseline & Change from Baseline
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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.
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Baseline & Change from Baseline
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Montreal Cognitive Assessment (MoCA) Total Score
時間枠：Baseline & Change from Baseline
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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.
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Baseline & Change from Baseline
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Patient Health Questionnaire-9 (PHQ-9) Depression Score
時間枠：Baseline & Change from Baseline
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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.
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Baseline & Change from Baseline
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Mean Daily Energy Intake, fat, carbohydrate, sugar, protein intake, saturated fatty acids intake as Assessed by 3-Day Food Record.
時間枠：Baseline & Change from Baseline
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Daily energy intake from different macronutrients (kcal/day) derived from a 3-day food record and.
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Baseline & Change from Baseline
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Percentage of calories derived from each of NOVA food classification categories
時間枠：Baseline & Change from Baseline
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Units: Percentage (%)
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Baseline & Change from Baseline
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Healthy Eating Index
時間枠：Baseline & Change from Baseline
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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
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Baseline & Change from Baseline
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Fat Taste Preference Score
時間枠：Baseline & Change from Baseline
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Geometric average of a preferred solution from a Monell 2-series forced choice test.
|
Baseline & Change from Baseline
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Sweet Taste Preference Score
時間枠：Baseline & Change from Baseline
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Geometric average of a preferred solution from a Monell 2-series forced choice test.
|
Baseline & Change from Baseline
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Working memory capacity
時間枠：Baseline & Change from Baseline
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Digits remembered on the digit span and digit span backwards task
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Baseline & Change from Baseline
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Reinforcement learning outcomes
時間枠：Baseline & Change from Baseline
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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. |
Baseline & Change from Baseline
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協力者と研究者
スポンサー
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
その他の研究ID番号
- THRIVE
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
IPD 共有時間枠
IPD 共有アクセス基準
IPD 共有サポート情報タイプ
- STUDY_PROTOCOL
- SAP
- ICF
- ANALYTIC_CODE
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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