Clinical trial NCT05172999: Loxenatide Plus LNG-IUS in Endometrial Atypical Hyperplasia
Official title: A Randomized Controlled Pilot Study of Polyethylene Glycol Loxenatide Plus LNG-IUS in Women With Endometrial Atypical Hyperplasia
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Atypical Endometrial Hyperplasia
Obesity
Fertility Issues
Keywords: atypical endometrial hyperplasia, obesity, fertility
Lead sponsor: Fudan University
Sponsor class: OTHER
First posted: 2021-12-29
Enrollment: 30
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 study if polyethylene glycol loxenatide plus levonorgestrel-releasing intrauterine system (LNG-IUS) will improve response rates in patients with endometrial atypical hyperplasia.

Detailed description: Background: Obesity or overweight is associated with lower treatment response and longer time to achieve complete response(CR) in patients with atypical endometrial hyperplasia (AEH) who want to preserve fertility, as evidenced by our research and lots of published studies. The larger the baseline weight of AEH patients, the more the weight gains after high-dose progesterone treatment. Obese AEH patients have a lower response to high-dose progesterone.

Losing weight may help improve treatment response. Weight management and lifestyle intervention have been written into 2020 uterine NCCN (National Comprehensive Cancer Network) guidelines. Our research showed that metformin may improve insulin resistance in patients with AEH, and shorten time to achieve CR, and increase the CR rates. Theoretically, Losing weight can improve the chronic inflammatory environment in the endometrium and whole body and improve metabolic disorder which help patients achieve CR.

LNG-IUS will be adopted in this research. Though LNG-IUS and high-dose progesterone have similar efficacy in treating AEH patients, long-term treatment of progesterone has many side effects. Compared to oral progesterone, LNG-IUS has fewer side effects and fewer effects on weight gaining.

GLP-1 receptor agonist (GLP-1RA), which is one of the commonly used hypoglycemic drugs, has been approved for weight control. Loxenatide is the first Chinese-produced long-acting GLP-1R agonist. It is applicable for diabetes patients. In the USA, some GLP-1RA has been applied for losing weight, such as liraglutide and semaglutide. GLP-1RA acts through improving insulin sensitivity, decreasing glucagon secretion, inhibiting appetite, delaying gastric emptying, and improving whole-body inflammation condition. Loxenatide plus LNG-IUS may improve the efficacy of preserving fertility in obese AEH patients through help patients lose weight.

Objective: To investigate whether loxenatide plus LNG-IUS improves the efficacy of preserving fertility when compared to LNG-IUS 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 software (version 22.0, IBM) to perform simple randomization and get randomized numbers. And participants will be randomly assigned (1:1) to receive LNG-IUS alone or loxenatide plus LNG-IUS. Patients in LNG-IUS alone group will accept LNG-IUS insertion as treatment and the other group cases will be treated with loxneatide plus LNG-IUS.

All enrolled patients will receive basic medical treatment in weight management and lifestyle improvement support, no enhanced interventions. Hysteroscopic assessment, metabolic and inflammatory indications will be performed every 12-16 weeks, while other indexes (weight, body composition change, side effects, and so on) will be evaluated every month.

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 (LNG-IUS alone verse LNG-IUS+ loxenatide) in 16-week. Secondary outcomes include CR rates in 32 weeks, assessment of ovarian functions, 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
* Known or suspected pregnancy
* Currently suffering from pelvic inflammatory disease or diagnosed as pelvic inflammatory disease
* Lower reproductive system infection
* abnormal cervical dysplasia
* Congenital or acquired uterine abnormalities, including fibroids that deform the uterine cavity
* Allergic to any parts of LNG-IUS components
* The uterine cavity is too large (average diameter is over 7cm) or the history of LNG-IUS falling off

Primary outcomes:
measure: Pathological complete response (CR) rates
timeFrame: From date of randomization until the date of CR, assessed up to 16 weeks.
Secondary outcomes:
measure: 32-week complete response (CR) rates
timeFrame: From date of randomization until the date of CR, assessed up to 32 weeks.
measure: weight change
timeFrame: From date of randomization until the date of CR, assessed up to 32weeks.
measure: changing of insulin resistance
timeFrame: From date of randomization until the date of CR, assessed up to 32weeks.
measure: change of chronic inflammation status
timeFrame: From date of randomization until the date of CR, assessed up to 32 weeks.
measure: change of ovarian functions
timeFrame: From date of randomization until 6 months after treatment is over
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:
city: Shanghai
country: China
facility: Obstetrics & Gynecology Hospital of Fudan University
state: Shanghai
Study officials:
affiliation: Obstetrics & Gynecology Hospital of Fudan University
name: XIAOJUN CHEN, PhD
role: PRINCIPAL_INVESTIGATOR
References: