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

Study Overview
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Brief Summary
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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.

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

Conditions
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Endometrial Hyperplasia

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Placebo
* Drug: Progestin
* Behavioral: Telemedicine behavioral weight intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of histologically confirmed complex atypical endometrial hyperplasia. Patients with a previous diagnosis of 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 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. Exclusion Criteria: 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 or type 2 diabetes. Acute decompensation of glycemic control. Acute coronary or cerebrovascular event in the previous 30 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. Current, active treatment for any malignant neoplasm 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. History of diabetic retinopathy. Recent history of pancreatitis, defined as less than 4 weeks prior to enrollment. History of suicidal attempts or active suicidal ideation. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. Pregnant and/or breastfeeding. Participants must have a negative serum pregnancy test within 7 days of date of registration. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL, they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration, or they are receiving anti-retrovirals that affect progestin levels. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Semaglutide + progestin<br>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 0.24 mg up to 2.4 mg). Will receive a telemedicine behavioral intervention delivered by a psychologist. At each session, patients will self-report weight, number of days they kept a food journal during the past week, average daily caloric intake for the week, number of days exercised for the week, total number of minutes of moderate physical activity, and average number of steps per day for the week | Drug: Semaglutide<br>* 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.<br>Drug: Progestin<br>* Released via the levonorgestrel-releasing IUD.<br>Behavioral: Telemedicine behavioral weight intervention<br>* Weekly telephone calls during the first month, biweekly during the next 5 months, and then monthly for the last 7 months (13 months total). Each telephone session will be 30 minutes long.<br>|
| Active Comparator: Arm 2: Placebo + Progestin<br>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 receive a telemedicine behavioral intervention delivered by a psychologist. At each session, patients will self-report weight, number of days they kept a food journal during the past week, average daily caloric intake for the week, number of days exercised for the week, total number of minutes of moderate physical activity, and average number of steps per day for the week | Drug: Placebo<br>* 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.<br>Drug: Progestin<br>* Released via the levonorgestrel-releasing IUD.<br>Behavioral: Telemedicine behavioral weight intervention<br>* Weekly telephone calls during the first month, biweekly during the next 5 months, and then monthly for the last 7 months (13 months total). Each telephone session will be 30 minutes long.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with atypia-free biopsy with uterine preservation |  | At 2 years (or exit from study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Atypia-free survival |  | Through completion of follow-up (estimated to be 4 years) | 
| Endometrial cancer-free survival |  | 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) | The CWIES is a 15-item self-report measure evaluating stress reactions and traumatic experiences, specifically inquiring about cancer worry-specific distress. Range of values for each individual item will be a Likert Scale from 0-5. 0=not at all and 5=often. The higher the score, the more cancer-worry specific distress the participant has. | At enrollment, 12 months, and end of treatment (estimated to be 2 years) | 
| Change in Impact of Weight on Quality of Life (IWQOL-Lite) | The IWQOL-Lite provides a total score and scores for five subscales: physical function, self-esteem, sexual life, public distress and work. Scores range from 0 to 100 with lower scores indicating greater impairment. | At enrollment, 12 months, and end of treatment (estimated to be 2 years) |