Semaglutide Effects in Obese Youth With Prediabetes/New Onset Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease

Phase 2RecruitingNCT05067621

Yale University60 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Type 2 Diabetes Mellitus

Eligibility

Sex: ALLMin age: 10 YearsMax age: 21 Years

Medical Language ↔ Plain English

Inclusion Criteria * 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. Exclusion Criteria * 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

Outcomes

Primary Outcomes

Change in Oral Disposition Index (oDI)

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.

Time frame: Baseline and 6 months

Change in Protein Density Fat Fraction (PDFF)

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.

Time frame: Baseline and 6 months

Secondary Outcomes

Change in Oral glucose tolerance test (OGTT) derived biomarkers: oDI

Change in oDI from baseline to 9M after the wash-out period, calculated as the difference between 9M oDI value and baseline oDI value. This is similar to Outcome 1 except measured at 9M.

Time frame: Baseline and 9 months

Change in OGTT derived biomarkers: fasting insulin

Change in fasting insulin calculated as 1/Fasting Insulin \[1/IF\] from baseline to 6M.

Time frame: Baseline and 6 months

Change in OGTT derived biomarkers: fasting insulin

Change in fasting insulin calculated as 1/Fasting Insulin \[1/IF\] from baseline to 9M.

Time frame: Baseline and 9 months

Change in OGTT derived biomarkers: c-peptide

Change in c-peptide from baseline to 6M calculated as \[change in C-peptide from 0-30min\] /\[change in glucose from 0-30 min\]. This computes for early c-peptide response to oral glucose.

Time frame: Baseline and 6 months

Change in OGTT derived biomarkers: c-peptide

Change in c-peptide from baseline to 9M calculated as \[change in C-peptide from 0-30min\] /\[change in glucose from 0-30 min\]. This computes for early c-peptide response to oral glucose.

Time frame: Baseline and 9 months

Change in OGTT derived biomarkers: fasting c-peptide

Change in fasting c-peptide from baseline to 6M calculated as Fasting C-peptide/Fasting Insulin.

Time frame: Baseline and 6 months

Change in OGTT derived biomarkers: fasting c-peptide

Change in fasting c-peptide from baseline to 9M calculated as Fasting C-peptide/Fasting Insulin.

Time frame: Baseline and 9 months

Time to glucose peak

Identification of time to glucose peak during OGTT at baseline.

Time frame: Baseline

Time to glucose peak

Identification of time to glucose peak during OGTT at 6M.

Time frame: 6 months

Time to glucose peak

Identification of time to glucose peak during OGTT at 9M.

Time frame: 9 months

Glucagon levels

Identification of glucagon levels during OGTT at baseline.

Time frame: Baseline

Glucagon levels

Identification of glucagon levels during OGTT at 6M.

Time frame: 6 months

Glucagon levels

Identification of glucagon levels during OGTT at 9M.

Time frame: 9 months

Incretin effect

Estimated as the ratio between total insulin responses during OGTT and IVGTT at the end of treatment and expressed as percentage. It is computed by: \[100% × (AUCins OGTT - AUCins IVGTT)/AUCins OGTT\].

Time frame: 6 months

Incretin effect

Estimated as the ratio between total insulin responses during OGTT and IVGTT at the end of the wash-out period and expressed as percentage. It is computed by: \[100% × (AUCins OGTT - AUCins IVGTT)/AUCins OGTT\].

Time frame: 9 months

Change in Protein Density Fat Fraction (PDFF)

The change in PDFF from baseline to 9M after the wash-out period is calculated as the difference between 9M 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 9M is ≥ 5.8% reduction compared to the placebo group.

Time frame: Baseline and 9 months

Fractional rates of de Novo Lipogenesis (DNL)

It is the measure of contribution of hepatic DNL and plasma free fatty acid reesterification to plasma triglyceride secretion at baseline. It is calculated by F = plasma palmitate enrichment/(22 X plasma deuterium enrichment). F is the fraction of palmitate synthesized during the time between the loading dose of the deuterium-labeled water and the collection time.

Time frame: Baseline

Fractional rates of de Novo Lipogenesis (DNL)

It is the measure of contribution of hepatic DNL and plasma free fatty acid reesterification to plasma triglyceride secretion at 6M. It is calculated by F = plasma palmitate enrichment/(22 X plasma deuterium enrichment). F is the fraction of palmitate synthesized during the time between the loading dose of the deuterium-labeled water and the collection time.

Time frame: 6 months

Fractional rates of de Novo Lipogenesis (DNL)

It is the measure of contribution of hepatic DNL and plasma free fatty acid reesterification to plasma triglyceride secretion at 9M. It is calculated by F = plasma palmitate enrichment/(22 X plasma deuterium enrichment). F is the fraction of palmitate synthesized during the time between the loading dose of the deuterium-labeled water and the collection time.

Time frame: 9 months

Total cholesterol

Measure of total cholesterol in plasma taken at 6M.

Time frame: 6 months

Total cholesterol

Measure of total cholesterol in plasma taken at 9M.

Time frame: 9 months

LDL cholesterol

Measure of LDL cholesterol in plasma taken at 6M.

Time frame: 6 months

LDL cholesterol

Measure of LDL cholesterol in plasma taken at 9M.

Time frame: 9 months

HDL cholesterol

Measure of HDL cholesterol in plasma taken at 6M.

Time frame: 6 months

HDL cholesterol

Measure of LDL cholesterol in plasma taken at 9M.

Time frame: 9 months

Triglycerides

Measures of triglycerides in plasma taken at 6M.

Time frame: 6 months

Triglycerides

Measures of triglycerides in plasma taken at 9M.

Time frame: 9 months

Semaglutide Effects in Obese Youth With Prediabetes/New Onset Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts