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Weight Management Plus LNG-IUS/Megestrol Acetate in Endometrial Atypical Hyperplasia

Primary Purpose

Atypical Endometrial Hyperplasia, Fertility Issues, Overweight and Obesity

Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Intensive Lifestyle Intervention (ILI)
Megestrol Acetate 160 MG Oral Tablet
Levonorgestrel-Releasing Intrauterine Contraceptive System (Mirena), 52 Mg
Sponsored by
Xiaojun Chen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Atypical Endometrial Hyperplasia

Eligibility Criteria

18 Years - 45 Years (Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • Obstetrics and Gynecology Hospital of Fudan UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

overweight MA+ILI

overweight LNG-IUS+ILI

obese MA+ILI

obese LNG-IUS+ILI

Arm Description

enrolled overweight (24kg/m2≤BMI<28kg/m2) patients will receive megestrol acetate 160mg po qd plus weight management

enrolled overweight (24kg/m2≤BMI<28kg/m2) patients will be treated with LNG-IUS plus weight management

enrolled obese (BMI≥28kg/m2) patients will receive megestrol acetate 160mg po qd plus weight management

enrolled obese (BMI≥28kg/m2) patients will be treated with LNG-IUS plus weight management

Outcomes

Primary Outcome Measures

Pathological complete response (CR) rates
The 28-week CR rates will be calculated in four arms

Secondary Outcome Measures

Pregnancy outcomes
For participants 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.
Weight change
The investigators will record body weight every month and calculate its change in kilograms.
Body composition change
The investigators will detect body composition with InBody machine and calculate changes of the indicated indexes.
Blood pressures change
Record blood pressures (systolic and diastolic pressures) every 12-16 weeks and count the change during the trial.
Heart rates change
Record heart rates (beats per minute) every 12-16 weeks and count the change.
Blood glucose change
Assess fasting glucose levels each 3 to 4 months and calculate changes in mmol/L.
Blood lipids change
Assess blood lipids levels each 3 to 4 months and calculate changes during the trial.
Insulin resistance change
Test fasting insulin levels each 3 to 4 months, and count HOMA-IR index (Homeostatic Model Assessment for Insulin Resistance) with fasting insulin and fasting glucose as follow: Insulin (pmol/L)*glucose (mmol/L)/22.5, and compare the HOMA-IR change during the treatment.
Ovarian reserve function
Detect serum Anti-Mullerian Hormone (AMH) each 3 or 4 months and calculate its change.
Quality of life change
Collect the questionnaire SF-36 and count scores change through conservative treatment.
Impact of Weight on Quality of Life
Collect questionnaire IWQOL- LITE and count scores change through conservative treatment.
Physical activities change
Collect physical activities questionnaire(IPAQ) and compare scores changes through conservative treatment.
Chronic inflammatory index (TNF-α) change
The investigators will detect the levels of TNF-α (fmol/ml) in serum and calculate changes through the whole treatment period.
Chronic inflammatory index (IL-1) change
The investigators will detect serum index IL-1 in U/ml and calculate changes through the whole treatment period.
Chronic inflammatory index (IL-6) change
The investigators will detect serum index IL-6 in U/ml and calculate changes through the whole treatment period.
Time of pathological complete response (CR)
Time of histologic regression from EAH to proliferative or secretory endometrium
Incidence of adverse events
Adverse events related with MA, LNG-IUS and weight control. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 will be recorded, as well as incidence of adverse events.
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 the investigators can get the relapse rates.

Full Information

First Posted
March 23, 2022
Last Updated
May 27, 2023
Sponsor
Xiaojun Chen
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1. Study Identification

Unique Protocol Identification Number
NCT05316493
Brief Title
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

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 13, 2022 (Actual)
Primary Completion Date
February 28, 2024 (Anticipated)
Study Completion Date
February 28, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Xiaojun Chen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atypical Endometrial Hyperplasia, Fertility Issues, Overweight and Obesity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
All enrolled participants will receive enhanced lifestyle management to control weight and take LNG-IUS or Megestrol Acetate (MA) for treating EAH
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
172 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
overweight MA+ILI
Arm Type
Experimental
Arm Description
enrolled overweight (24kg/m2≤BMI<28kg/m2) patients will receive megestrol acetate 160mg po qd plus weight management
Arm Title
overweight LNG-IUS+ILI
Arm Type
Experimental
Arm Description
enrolled overweight (24kg/m2≤BMI<28kg/m2) patients will be treated with LNG-IUS plus weight management
Arm Title
obese MA+ILI
Arm Type
Experimental
Arm Description
enrolled obese (BMI≥28kg/m2) patients will receive megestrol acetate 160mg po qd plus weight management
Arm Title
obese LNG-IUS+ILI
Arm Type
Experimental
Arm Description
enrolled obese (BMI≥28kg/m2) patients will be treated with LNG-IUS plus weight management
Intervention Type
Behavioral
Intervention Name(s)
Intensive Lifestyle Intervention (ILI)
Other Intervention Name(s)
Weight Management
Intervention Description
dietary guidance, exercise guidance, lifestyle intervention
Intervention Type
Drug
Intervention Name(s)
Megestrol Acetate 160 MG Oral Tablet
Other Intervention Name(s)
yilizhi
Intervention Description
enrolled participants will take Megestrol Acetate 160mg daily
Intervention Type
Drug
Intervention Name(s)
Levonorgestrel-Releasing Intrauterine Contraceptive System (Mirena), 52 Mg
Other Intervention Name(s)
manyuele
Intervention Description
enrolled patients will be treated with LNG-IUS.
Primary Outcome Measure Information:
Title
Pathological complete response (CR) rates
Description
The 28-week CR rates will be calculated in four arms
Time Frame
From date of recruitment until the date of CR, assessed up to 28 weeks.
Secondary Outcome Measure Information:
Title
Pregnancy outcomes
Description
For participants 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.
Time Frame
up to 2 years after complete response of the last participant
Title
Weight change
Description
The investigators will record body weight every month and calculate its change in kilograms.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Body composition change
Description
The investigators will detect body composition with InBody machine and calculate changes of the indicated indexes.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Blood pressures change
Description
Record blood pressures (systolic and diastolic pressures) every 12-16 weeks and count the change during the trial.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Heart rates change
Description
Record heart rates (beats per minute) every 12-16 weeks and count the change.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Blood glucose change
Description
Assess fasting glucose levels each 3 to 4 months and calculate changes in mmol/L.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Blood lipids change
Description
Assess blood lipids levels each 3 to 4 months and calculate changes during the trial.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Insulin resistance change
Description
Test fasting insulin levels each 3 to 4 months, and count HOMA-IR index (Homeostatic Model Assessment for Insulin Resistance) with fasting insulin and fasting glucose as follow: Insulin (pmol/L)*glucose (mmol/L)/22.5, and compare the HOMA-IR change during the treatment.
Time Frame
Baseline,3months and 6months after enrolled.
Title
Ovarian reserve function
Description
Detect serum Anti-Mullerian Hormone (AMH) each 3 or 4 months and calculate its change.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Quality of life change
Description
Collect the questionnaire SF-36 and count scores change through conservative treatment.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Impact of Weight on Quality of Life
Description
Collect questionnaire IWQOL- LITE and count scores change through conservative treatment.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Physical activities change
Description
Collect physical activities questionnaire(IPAQ) and compare scores changes through conservative treatment.
Time Frame
From date of recruitment, assessed up to 28 weeks.
Title
Chronic inflammatory index (TNF-α) change
Description
The investigators will detect the levels of TNF-α (fmol/ml) in serum and calculate changes through the whole treatment period.
Time Frame
baseline, 3 months and 6 months after treatment.
Title
Chronic inflammatory index (IL-1) change
Description
The investigators will detect serum index IL-1 in U/ml and calculate changes through the whole treatment period.
Time Frame
baseline, 3 months and 6 months after treatment.
Title
Chronic inflammatory index (IL-6) change
Description
The investigators will detect serum index IL-6 in U/ml and calculate changes through the whole treatment period.
Time Frame
baseline, 3 months and 6 months after treatment.
Title
Time of pathological complete response (CR)
Description
Time of histologic regression from EAH to proliferative or secretory endometrium
Time Frame
From date of recruitment until the date of CR, assessed up to 2 years.
Title
Incidence of adverse events
Description
Adverse events related with MA, LNG-IUS and weight control. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 will be recorded, as well as incidence of adverse events.
Time Frame
From date of recruitment until the date of CR, assessed up to 2 years.
Title
Relapse rates
Description
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 the investigators can get the relapse rates.
Time Frame
up to 2 years after the treatment for each patient

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
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: 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) 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. Those who have received high doses of high potency progestin or oral contraceptives within the last 3 months (or those on maintenance medication). Those who require hysterectomy or other methods other than conservative treatment. Known or suspected pregnancy. Those who has contraindications to use progestin. Deep vein thrombosis, stroke, myocardial infarction. Severe joint lesions that prevent walking or movement. untreated or recurrent pelvic inflammatory disease (PID) an untreated or uncontrolled pelvic infection (vaginal, cervical, uterine); Cervical dysplasia Congenital or acquired uterine abnormalities, including uterine fibroid tumors or conditions that affect the shape of the uterus allergic to the LNG-IUS components 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
WEIWEI SHAN, PhD
Phone
8613817813106
Email
danweiwei7468@fckyy.org.cn
First Name & Middle Initial & Last Name or Official Title & Degree
XIAOJUN CHEN, PhD
Phone
8613601680784
Email
cxjlhjj@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
XIAOJUN CHEN, PhD
Organizational Affiliation
Obstetrics & Gynecology Hospital of Fudan University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Obstetrics and Gynecology Hospital of Fudan University
City
Shanghai
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
WEIWEI SHAN, PhD
Phone
13817813106
Email
fdsww1024@sina.cn
First Name & Middle Initial & Last Name & Degree
DANDAN JU, MD
Phone
021-33189900-8408

12. IPD Sharing Statement

Plan to Share IPD
No

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Weight Management Plus LNG-IUS/Megestrol Acetate in Endometrial Atypical Hyperplasia

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