Treating PCOS With Semaglutide vs Active Lifestyle Intervention

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03919929

Acronym

TEAL

Enrollment

Registered

2019-04-18

Start date

2019-05-03

Completion date

2023-10-03

Last updated

2025-11-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Adolescent Obesity, NAFLD, PCOS

Keywords

Insulin Resistance

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.

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.

Interventions

DRUGSemaglutide 3mg and 7mg [Rybelsus]

Once daily oral tablet of semaglutide for 4 months

OTHERWeight loss diet

Prescribed weight loss diet to match weight loss in Drug arm

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

12 Years to 21 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Change in Hepatic Fat Fraction	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%. A negative value means a decrease in liver fat, and a positive value means an increase in liver fat.
Change in Weight	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

Measure	Time frame	Description
Change in Adipose Insulin Sensitivity	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. 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.
Change in Whole Body Insulin Sensitivity	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.
Change in Rate of De Novo Lipogenesis (DNL)	Baseline and 12 weeks	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.

Other

Measure	Time frame	Description
Change in Percentage of Indirect Glycerol Carbon Contributions to Newly Synthesized Triglycerides and Glucose	Baseline and 12 weeks	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.
Change in Free Androgen Index	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. 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.

Countries

United States

Participant flow

Pre-assignment details

There were 5 participants who screen failed, and 4 participants who withdrew due to not tolerating the study medication.

Participants by arm

Arm	Count
Diet Intervention Weight loss with dietary intervention Weight loss diet: Prescribed weight loss diet to match weight loss in Drug arm	17
GLP-1 Intervention Participants will take a daily oral tablet of semaglutide for 4 months. Semaglutide 3mg and 7mg \[Rybelsus\]: Once daily oral tablet of semaglutide for 4 months	38
Total	55

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Screen Failure	0	5
Overall Study	Withdrawal by Subject	0	4

Baseline characteristics

Characteristic	Diet Intervention	GLP-1 Intervention	Total
Age, Continuous	14.44 years STANDARD_DEVIATION 1.55	15.65 years STANDARD_DEVIATION 1.71	15.20 years STANDARD_DEVIATION 1.64
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants	18 Participants	27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants	20 Participants	28 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Region of Enrollment United States	17 participants	38 participants	55 participants
Sex: Female, Male Female	17 Participants	38 Participants	55 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 17	0 / 38
other Total, other adverse events	0 / 17	0 / 38
serious Total, serious adverse events	0 / 17	0 / 38

Outcome results

Primary

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.