Clinical trial NCT05067621: Semaglutide Effects in Obese Youth With Prediabetes/New Onset Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease
Official title: 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 Non-Alcoholic Fatty Liver Disease (NAFLD)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Type 2 Diabetes Mellitus
Impaired Glucose Tolerance
Non-Alcoholic Fatty Liver Disease
Obesity, Childhood
Keywords: Prediabetes
NAFLD
Impaired Glucose Tolerance
Semaglutide
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2021-10-05
Enrollment: 60
Sex: ALL
Minimum age (years): 10
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will undergo baseline tests at the beginning of the study and will be randomized to receive experimental drug or placebo. Dose escalation will be achieved within 16 weeks to reach up to 2.4mg of Semaglutide, weekly, which they will be on for 6 months. All tests will be repeated after 6 months of treatment followed by a wash-out period of 3 months, after which the same tests will be repeated.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Oral Disposition Index (oDI)
timeFrame: Baseline and 6 months
measure: Change in Protein Density Fat Fraction (PDFF)
timeFrame: Baseline and 6 months
Secondary outcomes:
measure: Change in Oral glucose tolerance test (OGTT) derived biomarkers: oDI
timeFrame: Baseline and 9 months
measure: Change in OGTT derived biomarkers: fasting insulin
timeFrame: Baseline and 6 months
measure: Change in OGTT derived biomarkers: fasting insulin
timeFrame: Baseline and 9 months
measure: Change in OGTT derived biomarkers: c-peptide
timeFrame: Baseline and 6 months
measure: Change in OGTT derived biomarkers: c-peptide
timeFrame: Baseline and 9 months
measure: Change in OGTT derived biomarkers: fasting c-peptide
timeFrame: Baseline and 6 months
measure: Change in OGTT derived biomarkers: fasting c-peptide
timeFrame: Baseline and 9 months
measure: Time to glucose peak
timeFrame: Baseline
measure: Time to glucose peak
timeFrame: 6 months
measure: Time to glucose peak
timeFrame: 9 months
measure: Glucagon levels
timeFrame: Baseline
measure: Glucagon levels
timeFrame: 6 months
measure: Glucagon levels
timeFrame: 9 months
measure: Incretin effect
timeFrame: 6 months
measure: Incretin effect
timeFrame: 9 months
measure: Change in Protein Density Fat Fraction (PDFF)
timeFrame: Baseline and 9 months
measure: Fractional rates of de Novo Lipogenesis (DNL)
timeFrame: Baseline
measure: Fractional rates of de Novo Lipogenesis (DNL)
timeFrame: 6 months
measure: Fractional rates of de Novo Lipogenesis (DNL)
timeFrame: 9 months
measure: Total cholesterol
timeFrame: 6 months
measure: Total cholesterol
timeFrame: 9 months
measure: LDL cholesterol
timeFrame: 6 months
measure: LDL cholesterol
timeFrame: 9 months
measure: HDL cholesterol
timeFrame: 6 months
measure: HDL cholesterol
timeFrame: 9 months
measure: Triglycerides
timeFrame: 6 months
measure: Triglycerides
timeFrame: 9 months
Other outcomes:
measure: Changes in liver fibrosis
timeFrame: 6 months
measure: Changes in liver fibrosis
timeFrame: 9 months
Locations:
city: New Haven
country: United States
facility: Pediatric Diabetes Center
state: Connecticut
Study officials:
affiliation: Yale University
name: Sonia Caprio, MD
role: PRINCIPAL_INVESTIGATOR
References: