Primary Prevention and Uterine Preservation in Premenopausal Women With Obesity and Endometrial Hyperplasia

NCT05829460 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 202402083
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The investigators hypothesize that combined treatment with the GLP-1R agonist semaglutide 2.4 mg and levonorgestrel intrauterine device (LNG-IUD), compared to LNG-IUD alone, will result in improved likelihood of uterine preservation, sustained weight loss, improved endometrial and metabolomic response to progestin, and improved quality of life in premenopausal women with endometrial hyperplasia who desire uterine preservation.

Conditions

Endometrial Hyperplasia

Outcome Measures

Primary Outcomes (1)

• Number of patients with endometrial hyperplasia free biopsy with uterine preservation

  At 2 years (or exit from study)

Secondary Outcomes (5)

• Time to resolution of endometrial hyperplasia (EH)

  Through completion of follow-up (estimated to be 4 years)

• Change in weight

  From baseline to 2 years

• Change in Cancer Worry Impact of Events Scale (CWIES)

  At enrollment, 12 months, and end of treatment (estimated to be 2 years)

• Change in Impact of Weight on Quality of Life (IWQOL-Lite)

  At enrollment, 12 months, and end of treatment (estimated to be 2 years)

• Hyperplasia-free survival

  Through completion of follow-up (estimated to be 4 years)

Study Arms (2)

Arm 1: Semaglutide + progestin

EXPERIMENTAL

* The progestin will be delivered via the levonorgestrel-releasing IUD and it is standard of care. * Will receive injectable pens containing semaglutide and will be self-administered on a weekly basis for up to 104 weeks. Dosing will be escalated during weeks 1 through 16 (start at 0.25 mg up to 2.4 mg). * Will be enrolled in a behavioral weight program that is optional to attend. The program will be delivered in a closed-group format. The group program will consist of 12 consecutive 60 minute weekly visits, and will recur every three months such that participants can join the soonest available Week 1 session after study enrollment. Each group session will focus on providing education and cognitive/behavioral strategies to achieve a healthier, reduced-calorie diet and a more physically active lifestyle. Cognitive/behavioral strategies will consist of goal setting, problem solving, cognitive restructuring, stimulus control, and stress management.

Drug: Semaglutide; Drug: LNG-IUD (Progestin); Behavioral: Telemedicine behavioral weight program

Arm 2: Placebo + Progestin

ACTIVE COMPARATOR

* The progestin will be delivered via the levonorgestrel-releasing IUD and it is standard of care. * Will receive injectable pens containing the placebo and will be self-administered on a weekly basis for up to 104 weeks. * Will be enrolled in a behavioral weight program that is optional to attend. The program will be delivered in a closed-group format. The group program will consist of 12 consecutive 60 minute weekly visits, and will recur every three months such that participants can join the soonest available Week 1 session after study enrollment. Each group session will focus on providing education and cognitive/behavioral strategies to achieve a healthier, reduced-calorie diet and a more physically active lifestyle. Cognitive/behavioral strategies will consist of goal setting, problem solving, cognitive restructuring, stimulus control, and stress management.

Drug: Placebo; Drug: LNG-IUD (Progestin); Behavioral: Telemedicine behavioral weight program

Interventions

LNG-IUD (Progestin) DRUG

Released via the levonorgestrel-releasing IUD.

Arm 1: Semaglutide + progestin; Arm 2: Placebo + Progestin

Semaglutide DRUG

This medication is self-administered as a subcutaneous injection in the abdomen, thigh, or upper arm; injection site should be rotated when using the same body region.

Arm 1: Semaglutide + progestin

Placebo DRUG

This medication is self-administered as a subcutaneous injection in the abdomen, thigh, or upper arm; injection site should be rotated when using the same body region.

Arm 2: Placebo + Progestin

Telemedicine behavioral weight program BEHAVIORAL

Optional to attend.

Arm 1: Semaglutide + progestin; Arm 2: Placebo + Progestin

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Diagnosis of histologically confirmed non-atypical endometrial hyperplasia (EH) or complex atypical endometrial hyperplasia (AEH).
• Patients with a previous diagnosis of EH or AEH who are already being followed with conservative management with oral or LNG-IUD progestin therapy are eligible provided they have not previously been on a GLP-1R agonist within 3 months prior to enrollment.
• For patients with a previous diagnosis of EH or AEH who have been placed on progestin prior to study entry, the duration of IUD or oral progestin use prior to trial entry should be less than or equal to 6 months.
• Premenopausal woman with a uterus.
• At least 18 years of age and no more than 45 years of age.
• Interested in uterine preservation/fertility-sparing treatment.
• BMI ≥ 30 kg/m2.
• Prior or current receipt of progestin is allowed as above. Willingness to undergo placement of LNG-IUD at the time of study entry.
• Prior or current receipt of metformin is allowed.
• Ability to understand and willingness to sign an IRB approved written informed consent document.

You may not qualify if:

• Prior use of GLP-1 receptor agonist (exenatide, liraglutide, or other) or pramlintide or any DPP-4 inhibitor in the 3 months prior to date of registration.
• History of type 1 diabetes.
• History of type 2 diabetes requiring use of insulin.
• Acute decompensation of glycemic control.
• Concomitant use of other weight management drugs or drugs for short-term weight loss.
• History of surgery or use of a device to treat obesity.
• Uncontrolled thyroid disease
• Acute coronary or cerebrovascular event in the previous 60 days.
• Currently planned coronary, carotid, or peripheral artery revascularization.
• Chronic heart failure (NYHA class IV).
• Evidence of renal dysfunction as defined by creatinine clearance \< 60 ml/minute.
• History of solid organ transplant or awaiting solid organ transplant.
• Diagnosis of any malignant neoplasm or current, active treatment with chemotherapy or radiation.
• Family or personal history of multiple endocrine neoplasia syndrome type 2 (MEN 2) or familial medullary thyroid carcinoma (MTC).
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to progestin, semaglutide, or other agents used in the study.

Sponsors & Collaborators

• Novo Nordisk A/S: collaborator
• Washington University School of Medicine: lead

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Endometrial Hyperplasia

Interventions

semaglutide; Progestins

Condition Hierarchy (Ancestors)

Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Andrea R Hagemann, M.D., MSCI

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: Participant and pathologist
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be randomized on a 1:1 basis to either progestin + semaglutide 2.4 mg or progestin + placebo. Randomization will be stratified by previous progestin and metformin use.

Study Record Dates

• First Submitted: April 12, 2023
• First Posted: April 25, 2023
• Study Start: March 12, 2025
• Primary Completion (Estimated): April 30, 2030
• Study Completion (Estimated): April 30, 2032
• Last Updated: January 12, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share