Clinical trial NCT05316493: Weight Management Plus LNG-IUS/Megestrol Acetate in Endometrial Atypical Hyperplasia
Official title: Weight Management Plus Levonorgestrel Intrauterine System or Megestrol Acetate in Endometrial Atypical Hyperplasia: Multiple Single-arm, Prospective and Open-label Clinical Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Atypical Endometrial Hyperplasia
Fertility Issues
Overweight and Obesity
Lead sponsor: Fudan University
Sponsor class: OTHER
First posted: 2022-04-07
Enrollment: 172
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: All enrolled participants will receive enhanced lifestyle management to control weight and take LNG-IUS or Megestrol Acetate (MA) for treating EAH
Primary purpose: TREATMENT

Brief summary: To investigate the efficacy of weight management plus levonorgestrel intrauterine system (LNG-IUS) or megestrol acetate (MA) in obese patients with endometrial atypical hyperplasia (EAH) asking for conservative therapy.

Detailed description: Background:

High-efficacy progesterone, such as levonorgestrel intrauterine system (LNG-IUS), megestrol acetate (MA), and medroxyprogesterone acetate(MPA), is the first-line treatment for women with endometrial atypical hyperplasia (EAH) who want to preserve fertility. About 70% to 80% of those patients can achieve complete remission (CR) with a median CR time of about 6 months, but about 20% to 30% of those patients get no response or need longer time to get CR (over one year or even longer).

Overweight or obesity is an independent risk factor for fertility-sparing treatment response and pregnancy outcomes in young females with EAH or early endometrioid cancer (EEC). Evidence showed that obesity can cause lower CR rates and longer time to get CR and lower birth rates in EAH or EEC patients asking for conservative therapy. Weight management has been proved to improve metabolic disorders, ovarian functions, and pregnancy outcomes. Metformin, as a diabetes drug, has been proved to increase CR rates in EAH or EEC patients treated with MA for fertility. Weight management has raised more and more attention and has been proved to benefit metabolic and pregnancy outcomes. Based on previous research and published studies, the hypothesise is that weight management plus progestin therapy may raise CR rates and pregnancy outcomes in young female EAH patients asking for fertility conservation.

Enhanced lifestyle management (diet control, exercise, and daily behavioral guidance) may improve metabolic conditions, increase CR rates and pregnancy outcomes in obese EAH patients who want to preserve fertility. Till now, no similar studies were found, so this study is designed to explore the efficacy of weight control in EAH fertility-sparing patients to provide new evidence for improving conservative treatment.

Objective:

To investigate whether weight management plus LNG-IUS/MA can improve the efficacy of preserving fertility in obese EAH women who want fertility conservation.

Design:

This study is designed according to Simon's Two-Stage Design. Based on BMI and treatment plans, four single-arms are designed. This study is prospective, open-label. EAH Patients requiring conservation treatment with BMI ≥ 24 kg/m2 will be recruited in this study and they will be divided into four arms, the first group recruits overweight (24kg/ m2≤BMI\<28kg/m2) patients treated with LNG-IUS, the second group recruits overweight (24kg/ m2≤BMI\<28kg/m2) patients treated with MA, the third group recruits obese (BMI≥28kg/m2) patients treated with LNG-IUS, and the last group recruits obese (BMI≥28kg/m2) patients treated with MA. The sample size is calculated based on Simon's Two-Stage Design and previous CR rates. All enrolled patients will receive enhanced lifestyle management to control weight and take LNG-IUS/MA for treating EAH. Hysteroscopic examination, metabolic and inflammatory indicators will be performed every 12 to16 weeks while other indexes will be evaluated every month, including weight, heart rates, blood pressure, body fat tests, and so on. For the progestin efficacy evaluation, CR is defined as the remission of EAH 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 disease progression in patients. Two months' 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 four arms. Secondary outcomes include pregnancy rates, live birth rates, weight loss, insulin resistance, chronic inflammation indicators, time to achieve CR and recurrence rates, and so on. Safety and side events during the whole trial will be monitored in two years.

Eligibility criteria: Inclusion Criteria:

1.18 years≤age≤45years 2.BMI (body mass index) ≥24kg/m2 3.Consent informed and signed 4.Pathologically confirmed as endometrial atypical hyperplasia. Patients with endometrial specimens obtained by endometrial biopsy, diagnostic curettage or hysteroscopy and diagnosed histologically as endometrial atypical hyperplasia. If specimens are from other hospitals, they must be counseled or reconfirmed by the Department of Pathology of the Obstetrics and Gynecology Hospital of Fudan University.

5.Have a strong desire to reproduce and ask for fertility preservation or those who insist on keeping the uterus despite no reproductive requirements.

6.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:

1. Combined with severe medical disease or liver or kidney dysfunction: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level elevates to 3 times or more of the upper limit of normal, kidney dysfunction (creatinine clearance \< 30 mL/min)
2. Patients are diagnosed with other malignant tumors of the reproductive system; patients with breast cancer or other hormone-dependent tumors that cannot be used with progesterone.
3. Those who have received high doses of high potency progestin or oral contraceptives within the last 3 months (or those on maintenance medication).
4. Those who require hysterectomy or other methods other than conservative treatment.
5. Known or suspected pregnancy.
6. Those who has contraindications to use progestin.
7. Deep vein thrombosis, stroke, myocardial infarction.
8. Severe joint lesions that prevent walking or movement.
9. untreated or recurrent pelvic inflammatory disease (PID)
10. an untreated or uncontrolled pelvic infection (vaginal, cervical, uterine);
11. Cervical dysplasia
12. Congenital or acquired uterine abnormalities, including uterine fibroid tumors or conditions that affect the shape of the uterus
13. allergic to the LNG-IUS components
14. uterine cavity is too large (average uterine diameter is over 7 cm) or have a history of LNG-IUS falling out.

Notes: the last 6 criteria are only applied for patients with LNG-IUS.

Primary outcomes:
measure: Pathological complete response (CR) rates
timeFrame: From date of recruitment until the date of CR, assessed up to 28 weeks.
Secondary outcomes:
measure: Pregnancy outcomes
timeFrame: up to 2 years after complete response of the last participant
measure: Weight change
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Body composition change
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Blood pressures change
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Heart rates change
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Blood glucose change
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Blood lipids change
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Insulin resistance change
timeFrame: Baseline，3months and 6months after enrolled.
measure: Ovarian reserve function
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Quality of life change
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Impact of Weight on Quality of Life
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Physical activities change
timeFrame: From date of recruitment, assessed up to 28 weeks.
measure: Chronic inflammatory index (TNF-α) change
timeFrame: baseline, 3 months and 6 months after treatment.
measure: Chronic inflammatory index (IL-1) change
timeFrame: baseline, 3 months and 6 months after treatment.
measure: Chronic inflammatory index (IL-6) change
timeFrame: baseline, 3 months and 6 months after treatment.
measure: Time of pathological complete response (CR)
timeFrame: From date of recruitment until the date of CR, assessed up to 2 years.
measure: Incidence of adverse events
timeFrame: From date of recruitment until the date of CR, assessed up to 2 years.
measure: Relapse rates
timeFrame: up to 2 years after the treatment for each patient
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Obstetrics and Gynecology Hospital of Fudan University
Study officials:
affiliation: Obstetrics & Gynecology Hospital of Fudan University
name: XIAOJUN CHEN, PhD
role: PRINCIPAL_INVESTIGATOR
References: