Treating PCOS With Semaglutide vs Active Lifestyle Intervention (TEAL)

• ClinicalTrials.gov Identifier: NCT03919929
• Recruitment Status: Active, not recruiting
• First Posted: April 18, 2019
• Last Update Posted: January 26, 2024
• Sponsor: University of Colorado, Denver
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
PCOS; Adolescent Obesity; NAFLD	Drug: Semaglutide 3mg and 7mg [Rybelsus]; Other: Weight loss diet	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treating PCOS With Semaglutide vs Active Lifestyle Intervention
• Actual Study Start Date: May 3, 2019
• Estimated Primary Completion Date: July 2024
• Estimated Study Completion Date: July 2024

Arms and Interventions

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 Name: GLP-1 receptor agonist

Outcome Measures

Primary Outcome Measures :

1. Change in Hepatic Fat Fraction [ Time Frame: Baseline and 12 weeks ]
   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%.
2. Change in Weight [ Time Frame: Baseline and 12 weeks ]
   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.

Secondary Outcome Measures :

1. Change in Rate of De Novo Lipogenesis [ Time Frame: Baseline and 12 weeks ]
   Change from baseline of the rate of overnight de novo lipogenesis will be measured utilizing stable isotope methods with deuterated water, and expressed as the rate of newly synthesized lipids in the serum triglyceride fraction.
2. Change in Whole Body Insulin Sensitivity [ Time Frame: Baseline and 12 weeks ]
   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.
3. Change in Adipose Insulin Sensitivity [ Time Frame: Baseline and 12 weeks ]
   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.

Other Outcome Measures:

1. Evaluation of Mitochondrial function via change in ratios of direct to indirect hepatic carbon flux in newly synthesized triglycerides [ Time Frame: Baseline and 12 weeks ]
   OSTT with UC13 glycerol baseline and 12 weeks
2. Change in Free Androgen Index [ Time Frame: Baseline and 12 weeks ]
   The Free Androgen Index (FAI) is a test for hyperandrogenism in women, using testosterone and sex hormone binding globulin (SHBG) as markers. 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.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Colorado

University of Colorado Anshutz Medical Campus/Children's Hospital Colorado

Aurora, Colorado, United States, 80045

Sponsors and Collaborators

University of Colorado, Denver

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Melanie Cree-Green, MD, PhD; Children's Hospital Colorado

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03919929
• Other Study ID Numbers: 19-0636; 1R01DK120612-01A1 ( U.S. NIH Grant/Contract )
• First Posted: April 18, 2019
• Last Update Posted: January 26, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Colorado, Denver:

Insulin Resistance

Additional relevant MeSH terms:

Pediatric Obesity; Obesity; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Semaglutide; Glucagon-Like Peptide-1 Receptor Agonists; Hypoglycemic Agents; Physiological Effects of Drugs