Clinical trial NCT04683237: Liraglutide Plus Megestrol Acetate in Endometrial Atypical Hyperplasia
Official title: Megestrol Acetate Versus Liraglutide Plus Megestrol Acetate in Obese Women with Endometrial Atypical Hyperplasia: a Randomized Controlled Pilot Clinical Study
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
PHASE3
Conditions: Atypical Endometrial Hyperplasia
Obese
Fertility Issues
Lead sponsor: Fudan University
Sponsor class: OTHER
Collaborators: name: Huashan Hospital
First posted: 2020-12-24
Enrollment: 0
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Pathological complete response (CR) rates
timeFrame: From date of randomization until the date of CR, assessed up to 28 weeks.
Secondary outcomes:
measure: weight lose
timeFrame: From date of randomization until the date of CR, assessed up to 28 weeks
measure: changing of insulin resistance
timeFrame: From date of randomization until the date of CR, assessed up to 28 weeks.
measure: improvement of chronic inflammation
timeFrame: From date of randomization until the date of CR, assessed up to 28 weeks
measure: Time of pathological complete response (CR)
timeFrame: From date of randomization until the date of CR, assessed up to 2 years.
measure: safety and side effects
timeFrame: From date of randomization until the date of CR, assessed up to 2 years.
measure: Relapse rates
timeFrame: up to 2 years after the treatment for each patient
measure: pregnancy outcomes
timeFrame: up to 2 years after the treatment for each patient
Other outcomes:
Locations:
Study officials:
affiliation: Obstetrics & Gynecology Hospital of Fudan University
name: xiaojun chen
role: PRINCIPAL_INVESTIGATOR
References: