Liraglutide Plus Megestrol Acetate in Endometrial Atypical Hyperplasia

Study Overview
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Brief Summary
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To investigate the efficacy of liraglutide plus megestrol acetate in obesity patients with atypical endometrial hyperplasia (AEH)

Detailed Description
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Backgrounds: High-dose progesterone (MA/MPA) or LNG-IUS is the first-line treatment for women with atypical endometrial hyperplasia (AEH) or early endometrioid cancer who want to preserve fertility. About 70-80% of them can achieve complete response (CR) with the median time of 7-8 months. Over 10% of the patients can not achieve CR and choose operation finally. By the way, long-term treatment of progesterone has many side effects. Our previous study showed that overweight (BMI≥25kg/m2) AEH patients had a significantly increased risk of progesterone treatment failure, and the time to achieve CR is significantly prolonged. What's more, the greater the baseline weight of AEH patients, the greater the weight gains after high-dose progesterone treatment. Obese AEH patients have a lower response to high-dose progesterone. Weight management and lifestyle interventions are clearly written into 2020 uterine NCCN guidelines. We also find that metformin may improve insulin resistance in patients with AEH, and shorten time to achieve CR and increase the CR rates. Liraglutide is a GLP-1 receptor agonist (GLP-1RA), which is one of the commonly used hypoglycemic drugs, has been approved for losing weight. And it is applicable for patients with BMI≥30 kg/m2 or ≥27 kg/m2 combined with one of the following: diabetes, hypertension, hyperlipidemia, sleep apnea. Liraglutide acts through improving insulin sensitivity, decreasing glucagon secretion , inhibiting appetite, delaying gastric emptying and improving whole-body inflammation condition. Objective: To investigate whether liraglutide plus MA improve the efficacy of preserving fertility when compared to MA alone in obese women with AEH who want fertility conservation. Design: A pilot prospective randomized controlled study is designed. And this study is open-label. We use SPSS (version 22.0,IBM) to design simple randomization. And participants will be randomly assigned (1:1) to receive MA alone or liraglutide plus MA. Patients in MA alone group will receive MA 160mg po qd and patients in the liraglutide plus MA group will receive liraglutide additionally with dose of 1.8mg/d or the max tolerance dose. All enrolled patients will receive mentoring in weight management and lifestyle improvement. Hysteroscopic assessment will be performed every 12-16 weeks while other indexes will be evaluated every month, including weight, metabolic indications，inbody fat analysis, inflammation indicators and so on. For the efficacy evaluation, CR is defined as the reversion of endometrial atypical hyperplasia to proliferative or secretory endometrium; partial response (PR) is defined as regression to simple or complex hyperplasia without atypia; no response (NR) is defined as the persistence of the disease; and progressive disease (PD) is defined as the appearance of endometrial cancer in patients. Continuous therapies will be needed in PR, NR or PD. Two months of maintenance treatment will be recommended for patients with CR, and participants will be followed up for 2 years. Outcomes: Primary outcome is the CR rates of the two groups (MA alone VS MA+ liraglutide) . secondary outcomes include improvement of weight, insulin resistance, chronic inflammation condition, and time to achieve CR, and safety and side events during the therapy, and the recurrence rates, pregnancy rates and live birth rates in two years.

Official Title
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Megestrol Acetate Versus Liraglutide Plus Megestrol Acetate in Obese Women With Endometrial Atypical Hyperplasia: A Randomized Controlled Pilot Clinical Study

Conditions
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Atypical Endometrial Hyperplasia, Obese, Fertility Issues

Intervention / Treatment
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* Drug: Liraglutide Injection
* Drug: Megestrol Acetate 160 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI (body mass index) ≥28kg/m2 Consent informed and signed Pathologically confirmed as endometrial atypical hyperplasia Have a strong desire to reproduce and ask for fertility preservation or those who insist on keeping the uterus despite no reproductive requirements Have good compliance and follow-up conditions, and patients are willing to follow up in Obstetrics and Gynecology Hospital of Fudan University in time Exclusion Criteria: Diagnosed as type 2 diabetes Diabetic ketoacidosis History of acute pancreatitis Have a history or family history of medullary thyroid carcinoma; multiple endocrine neoplasia syndrome type 2 (MEN2) Combined with severe medical disease or severely impaired liver and kidney function Patients with other types of endometrial cancer or other malignant tumors of the reproductive system; patients with breast cancer or other hormone-dependent tumors that cannot be used with progesterone Those who require hysterectomy or other methods other than conservative treatment with drugs Deep vein thrombosis, stroke, myocardial infarction Smokers (≥15 cigarettes/day)

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: MA alone<br>enrolled patients will receive megestrol acetate 160mg po qd | Drug: Megestrol Acetate 160 MG<br>* 160mg po qd<br>* Other names: Megace;|
| Experimental: MA+liraglutide<br>enrolled patients will receive megestrol acetate 160mg po qd plus liraglutide (1.8mg/d or the max tolerable dosage) | Drug: Liraglutide Injection<br>* Initiate liraglutide with a dose of 0.6 mg daily for one week. After one week at 0.6 mg per day, increase the dose to 1.2 mg daily in a week, and increase the dose to 1.8 mg daily after at least one week of treatment with the 1.2 mg daily dose. If the patients can not tolerate 1.8mg per day, decrease the dose to the max tolerable dose.<br>* Other names: Nuo he li;Drug: Megestrol Acetate 160 MG<br>* 160mg po qd<br>* Other names: Megace;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (CR) rates | The 28-week CR rates will be calculated in two groups | From date of randomization until the date of CR, assessed up to 28 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| weight lose | weight changing in 28-week's intervention, weight will be recorded every 4 weeks. | From date of randomization until the date of CR, assessed up to 28 weeks | 
| changing of insulin resistance | Glycated hemoglobin，Glucose tolerance test，Insulin release test，and C peptide release test will be performed at baseline and 28-week. During 12-16 week, fasting glucose, insulin, glycated hemoglobin and fasting C peptide will be tested once. | From date of randomization until the date of CR, assessed up to 28 weeks. | 
| improvement of chronic inflammation | improvement of chronic inflammation indications in 28 weeks. In detail, indicators including TNF-α、IL-1, IL-6 and Creatine Kinase will be tested at 0,12-16th and 28th week. | From date of randomization until the date of CR, assessed up to 28 weeks | 
| Time of pathological complete response (CR) | Time of histologic regression from AEH to proliferative or secretory endometrium | From date of randomization until the date of CR, assessed up to 2 years. | 
| safety and side effects | Adverse events related with Liraglutide and MA. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 will be recorded, as well as incidence of adverse events. | From date of randomization until the date of CR, assessed up to 2 years. | 
| Relapse rates | All enrolled patients will be followed up for 2 years. During the following-up period, if patients recur after complete regression, they will be counted and the number of recurrence will be divided by number of patients followed up, then we can get the relapse rates.Comparison will be performed between two groups. | up to 2 years after the treatment for each patient | 
| pregnancy outcomes | For patients have a desire for fertility, pregnancies, births and related outcomes will be counted, and the rate of pregnancy will be counted as number of pregnancies/ number of patients trying to fertility in the following period. Comparison will be performed between two groups | up to 2 years after the treatment for each patient |