Treating PCOS With Semaglutide vs Active Lifestyle Intervention (TEAL)

Girls with obesity and polycystic ovarian syndrome will receive either glucagon like peptide-1 receptor agonist therapy or a dietary intervention for 12 weeks to decrease the metabolic syndrome, in particular to lower hepatic fat and improve insulin sensitivity.

Study Overview

• Status: Completed
• Conditions: PCOS; NAFLD; Adolescent Obesity
• Intervention / Treatment: Other: Weight loss diet; Drug: Semaglutide 3mg and 7mg [Rybelsus]

Detailed Description

In obese girls with polycystic ovarian syndrome, testosterone and obesity combine to create unique pathology to increase metabolic disease including fatty liver and insulin resistance, which may be mediated by altered glucagon like peptide-1 activity. The investigators will treat girls with obesity and polycystic ovarian syndrome for 4 months with a glucagon like peptide-1 receptor agonist compared to dietary intervention to primarily lower hepatic fat and secondarily improve whole body and adipose insulin sensitivity. Mechanisms of hepatic metabolism, including rates of de novo lipogenesis and relative mitochondrial flux will also be assessed.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anshutz Medical Campus/Children's Hospital Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Sedentary- less than 2 hours of moderate (jogging, swimming etc) exercise a week.
2. BMI equal or greater than the 90th percentile for age and gender
3. PCOS per the most stringent NIH criteria adapted for adolescents (irregular menses >12 months post-menarche and clinical or biochemical hypertestosteronemia
4. Participants cannot be on hormonal contraception, so participants should remain abstinent or use reliable non-hormonal contraception (e.g. copper IUD) for the entire study period. For participants who receive semaglutide, they should avoid pregnancy for at least 2 months after stopping medication to avoid fetal exposure to the medication.

Exclusion Criteria:

1. Diagnosed with or have a family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Family history of medullary thyroid cancer or thyroid nodule palpated by endocrinologist at screening.
2. Use of medications known to affect insulin sensitivity: metformin (cannot have been used in the 3 months prior to screening), oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, HIV medications, hormonal contraception (cannot have been used in the 6 months prior to screening). Dermal patch or vaginal ring contraception methods.Weight loss medications or stimulants. Use of other products containing other GLP-1 agonists.
3. Currently pregnant or breastfeeding women. Development of pregnancy during the study period will necessitate withdrawal from the study.
4. Severe illness requiring hospitalization within 60 days.
5. Diabetes, defined as Hemoglobin A1C > 6.4%
6. BMI percentile less than the 90th percentile for age and sex. Weight >325 lbs. or <84 lbs.
7. Anemia, defined as Hemoglobin < 11 mg/dL
8. Diagnosed major psychiatric or developmental disorder limiting informed consent.
9. Implanted metal devices that are not compatible with MRI
10. Use of blood pressure medications.
11. Known liver disease other than NAFLD or AST or ALT >100 IU/L.
12. Personal history of pancreatitis
13. Known renal disease of any severity or an eGFR at screening of <45ml/min/1.73m2
14. History of severe GI disease (e.g. gastroparesis)
15. History of gallstones
16. Untreated thyroid disease
17. History of hypersensitivity to semaglutide
18. Other causes of hyperandrogenism (example: tumor, CAH) or amenorrhea (untreated thyroid disease, tumor, primary ovarian failure, prolactinoma).
19. Active symptoms or undergoing treatment for anorexia nervosa or binging/purging disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Diet Intervention; Weight loss with dietary intervention	Other: Weight loss diet; Prescribed weight loss diet to match weight loss in Drug arm
Experimental: GLP-1 Intervention; Participants will take a daily oral tablet of semaglutide for 4 months.	Drug: Semaglutide 3mg and 7mg [Rybelsus]; Once daily oral tablet of semaglutide for 4 months; Other Names: GLP-1 receptor agonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Weight	Change in weight will be calculated for each group (diet and semaglutide), and both the absolute and relative weight changes between the two groups will be reported.	Baseline and 12 weeks
Change in Hepatic Fat Fraction	Change from baseline in presence/severity of hepatic fat fraction will be measured with MRI, and calculated via the Dixon method as the proton density hepatic fat fraction, which ranges from 0-75%. A negative value means a decrease in liver fat, and a positive value means an increase in liver fat.	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Whole Body Insulin Sensitivity	Participants will undergo a 75 gram oral glucose tolerance test, and the change from baseline in whole body insulin sensitivity will be expressed as Si, calculated via the oral minimal model.	Baseline and 12 weeks
Change in Rate of De Novo Lipogenesis (DNL)	Change from baseline of the rate of overnight de novo lipogenesis (DNL) will be measured utilizing stable isotope methods with deuterated water, and expressed as the rate of newly synthesized lipids in the serum triglyceride fraction. A negative value means a decrease in newly synthesized lipids after the 12 week intervention, and a positive value means an increase in newly synthesized lipids after the 12 week intervention. A lower value is better.	Baseline and 12 weeks
Change in Adipose Insulin Sensitivity	Change from baseline of adipose insulin sensitivity will be calculated as the percent suppression of free fatty acids, and the nadir of free fatty acids during the oral glucose tolerance test. Percent suppression of FFAs during the OGTT was calculated as fasting FFA minus the minimal FFA value divided by fasting FFA. This was calculated for baseline and after 12-weeks of intervention. The change was calculated by subtracting the final-baseline values. A higher absolute value means there was an improvement in adipose insulin sensitivity after 12-weeks of treatment.	Baseline and 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Percentage of Indirect Glycerol Carbon Contributions to Newly Synthesized Triglycerides and Glucose	This outcome evaluates mitochondrial function and excess tricarboxylic acid (TCA) cycle substrate cycling by measuring indirect carbon contributions to newly synthesized triglycerides and glucose using stable isotope-labeled glycerol. Participants receive orally administered [U-13C3]glycerol mixed in water, and plasma glucose and lipids are analyzed by 13C NMR spectroscopy. Indirect glycerol carbon contribution reflects the fraction of glycerol carbons that first enter the TCA cycle before incorporation into triglycerides and glucose. A decrease in the percentage of indirect contributions is beneficial, indicating decreased oxidative stress resulting from excess TCA cycling.	Baseline and 12 weeks
Change in Free Androgen Index	The Free Androgen Index (FAI) is a test for hyperandrogenism in women, using testosterone and sex hormone binding globulin (SHBG) as markers. The calculation is FAI = Total Testosterone (nmol/ L)) x 100 / Sex Hormone-Binding Globulin (SHBG) (nmol/ L). Typical values for the FAI in women are 7-10, and FAI is usually elevated in women with PCOS. The change in FAI will be calculated after 12 weeks of diet or semaglutide intervention. A negative value means an improvement as there was a decrease in androgen levels after 12 weeks of treatment.	Baseline and 12 weeks

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Melanie Cree-Green, MD, PhD, Children's Hospital Colorado

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2019
• Primary Completion (Actual): October 3, 2023
• Study Completion (Actual): October 3, 2023

Study Registration Dates

• First Submitted: April 15, 2019
• First Submitted That Met QC Criteria: April 16, 2019
• First Posted (Actual): April 18, 2019

Study Record Updates

• Last Update Posted (Estimated): November 25, 2025
• Last Update Submitted That Met QC Criteria: November 12, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Insulin Resistance
• Additional Relevant MeSH Terms: Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Digestive System Diseases; Glucose Metabolism Disorders; Liver Diseases; Hyperinsulinism; Overweight; Obesity; Fatty Liver; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Non-alcoholic Fatty Liver Disease; Insulin Resistance; Pediatric Obesity; Therapeutics; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Diet Therapy; Nutrition Therapy; Diet; semaglutide; Diet, Reducing
• Other Study ID Numbers: 19-0636; 1R01DK120612-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No