Semaglutide, 2.4mg, Once Weekly: Effects on Beta-cell Preservation and Reduction of Intrahepatic Triglyceride Content in Obese Youth With Prediabetes (IGT)/Early Type 2 Diabetes (T2D) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 60
- 试验地点
- 2
- 主要终点
- Change in Oral Disposition Index (oDI)
研究概览
简要总结
The purpose of this study is to understand the role of GLP-1 in the pathogenesis of T2D in youth and explore their potential salutary effects and ability to delay the progressive loss of ß-cell function and reduce hepatic steatosis in youth with prediabetes/new onset T2D and NAFLD.
详细描述
In a recent publication by the TODAY Group Study, it was reported that "diabetes-related complications appear early in youth-onset T2D and accumulate rapidly at a mean age of 26.4 years," and 60.1% of participants developed at least one microvascular complication. The same has been reported in RISE Studies and was suggested that the rapid decline in β-cell function and its insensitivity to two of the most frequently used treatments for T2D in pediatrics is further aggravated by the rising prevalence in NAFLD. These alarming results indicate a pressing need for effective and innovative approaches at preserving β-cell function and reducing hepatic steatosis in obese youth in order to prevent disease progression and associated complications.
This study will provide mechanistic insights in support of a GLP-1 analog, Semaglutide, 2.4 mg weekly, therapy for prediabetes, new onset T2D and NAFLD in youth. The study design is a randomized, double-blind, placebo-controlled, clinical trial (RCT) using Semaglutie (Wegovy up to 2.4mg) for 6 months followed by a wash-out period of 3 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Yale Investigational Drug Services Pharmacy will handle the masking of drug and placebo pens.
入排标准
- 年龄范围
- 10 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects diagnosed with Pre-impaired glucose tolerance (pre-IGT) (2h glucose ≥ 130 mg/dl to ≤ 200 mg/dl post-OGTT) OR impaired glucose tolerance (2h glucose ≥140 to <200 mg/dl post-OGTT OR HbA1c ≥5.7% to <6.5%), OR new-onset T2D (≤24 months duration, 2h glucose >200 and HbA1c >6.5% to10%) treated with stable metformin dose (stable metformin dose is defined as at least 1000 mg daily or the maximum tolerated dose for 12 months or less)
- •PDFF of ≥ 8%
- •Male or female, aged 10 to <21 years at the day of randomization, in puberty (pubertal stage will be assessed by pediatric Endocrinologists Dr. Samuels and Dr. Hu) (girls and boys: Tanner stage II-IV); girls who begin menstruating must have a negative pregnancy test during the study
- •Weight ≥ 54kg
- •BMI ≥ 85% but ≤ 40 kg/m2
- •Good general health (normal kidney function, amylase, and lipase levels)
- •Informed consent from a legally acceptable representative (LAR) and child assent from the subject obtained before any trial-related activities (trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial)
- •Ability and willingness to adhere to the protocol including self-measurement of plasma glucose according to the protocol.
排除标准
- •Known or suspected hypersensitivity to trial product(s) or related products.
- •Receipt of any investigational medicinal product within 30 days before screening.
- •Prepubertal participants (Tanner stage 1)
- •Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing potential and not using highly effective contraceptive methods.
- •Having a diagnosis of:
- •Type 1 diabetes o Maturity onset diabetes of the young (MODY) o History or presence of Pancreatitis (acute or chronic) o Presence of endocrinopathies (e.g., Cushing syndrome) o Cardiac, renal or pulmonary or other chronic illness o Known history of heart disease (including history of clinically significant arrhythmias or conduction delays on ECG, or new clinically significant arrhythmias or conduction delays on ECG identified at visit 1) o Family or personal history of MEN type 2 or medullary thyroid carcinoma (family is defined as a first-degree relative)o Any other disorder which, in the opinion of the investigator, might jeopardize subject's safety or compliance with the protocol
- •Any laboratory safety parameter at screening outside the below extended laboratory ranges: o Baseline creatinine >1.0mg o Hypertriglyceridemia)(>500 mg/dl)
- •Calcitonin equal or above 50 ng/L at screening o Body Mass Index (BMI) ≤ 25.0 at the screening visit o ALT ≥5 times the upper normal limit (UNL) o Creatinine >UNL for age in children unless renal function is proven normal by further assessments at the discretion of the investigator
- •Known hypoglycemic unawareness.
- •Recurrent severe hypoglycemic episodes within the last year as judged by the investigator.
- •Uncontrolled hypertension treated or untreated >99th percentile for age and gender in children and adolescents.
- •Treatment with any medication for the indication of diabetes other than stated in the inclusion criteria in a period of 90 days before screening.
- •Taking medication, based on the investigator's judgement, that may cause significant weight gain or loss (e.g., antipsychotic, steroid, anti-obesity medication).
- •Presence or history of malignant neoplasm within 5 years prior to the day of screening.Basal and squamous cell skin cancer and any carcinoma in-situ is allowed.
- •Positive insulinoma associated-protein 2 (IA-2) antibodies or anti-glutamic acid decarboxylase (anti-GAD) antibodies.
- •Mental health:
- •History of major depressive disorder within 2 years before screening
- •Diagnosis of other severe psychiatric disorders (e.g., schizophrenia, bipolar disorder)
- •A Patient Health Questionnaire-9 (PHQ-9) score of ≥15 at screening
- •A lifetime history of suicidal attempt
- •Suicidal behavior within 30 days before screening
- •Suicidal ideation corresponding to type 4 or 5 based on the Columbia-Suicide Severity
- •Rating Scale (C-SSRS) within the past 30 days before screening
- •Participants with confirmed diagnosis of bulimia nervosa disorder
研究组 & 干预措施
Placebo
The placebo pen is almost exactly the same as the Wegovy subcutaneous injection except it does not contain the active ingredient, Semaglutide.
干预措施: Placebo (Drug)
Receive treatment
Semaglutide (Wegovy) pen is a subcutaneous injection
干预措施: Semaglutide Pen Injector (Drug)
结局指标
主要结局
Change in Oral Disposition Index (oDI)
时间窗: Baseline and 6 months
The oDI value is the product of total responsivity index and insulin sensitivity. The change in oDI from baseline to 6M on treatment is calculated as the difference between 6M oDI value and baseline oDI value. The oDI measures the ability of beta-cell to respond to a glucose stimulus.
Change in Protein Density Fat Fraction (PDFF)
时间窗: Baseline and 6 months
The change in PDFF from baseline to 6M on treatment is calculated as the difference between 6M PDFF value and Baseline PDFF. It provides an accurate, non-invasive, reproducible, quantitative, and precise estimation of liver fat content. The expected changes in MRI-PDFF from baseline to 6M is ≥ 5.8% reduction compared to the placebo group.
次要结局
- Triglycerides(9 months)
- Change in Oral glucose tolerance test (OGTT) derived biomarkers: oDI(Baseline and 9 months)
- Change in OGTT derived biomarkers: fasting insulin(Baseline and 9 months)
- Change in OGTT derived biomarkers: c-peptide(Baseline and 9 months)
- Change in OGTT derived biomarkers: fasting c-peptide(Baseline and 9 months)
- Time to glucose peak(9 months)
- Glucagon levels(9 months)
- Incretin effect(9 months)
- Change in Protein Density Fat Fraction (PDFF)(Baseline and 9 months)
- Fractional rates of de Novo Lipogenesis (DNL)(9 months)
- Total cholesterol(9 months)
- LDL cholesterol(9 months)
- HDL cholesterol(9 months)
- Change in OGTT derived biomarkers: fasting insulin(Baseline and 6 months)
- Change in OGTT derived biomarkers: c-peptide(Baseline and 6 months)
- Change in OGTT derived biomarkers: fasting c-peptide(Baseline and 6 months)
- Time to glucose peak(Baseline)
- Time to glucose peak(6 months)
- Glucagon levels(Baseline)
- Glucagon levels(6 months)
- Incretin effect(6 months)
- Fractional rates of de Novo Lipogenesis (DNL)(Baseline)
- Fractional rates of de Novo Lipogenesis (DNL)(6 months)
- Total cholesterol(6 months)
- LDL cholesterol(6 months)
- HDL cholesterol(6 months)
- Triglycerides(6 months)