Megestrol Acetate Plus Metformin to Megestrol Acetate in Patients With Endometrial Atypical Hyperplasia or Early Stage Endometrial Adenocarcinoma

Phase 2

Completed

• Conditions: Endometrial Adenocarcinoma; Endometrial Atypical Hyperplasia
• Interventions: Drug: Megestrol acetate and metformin; Drug: Megestrol acetate

• Registration Number: NCT01968317
• Lead Sponsor: Xiaojun Chen

Brief Summary

The purpose of this study is to see if megestrol acetate plus metformin will be more effective in returning the endometrial tissue to a normal state than megestrol acetate alone in patients with endometrial atypical hyperplasia or early stage endometrial adenocarcinoma.

Detailed Description

After diagnosed of endometrial atypical hyperplasia(EAH) or type I endometrial cancer(EC) by dilatation and curettage (D\&C) or hysteroscopy, patients will be enrolled. Age, waist circumstances, blood pressure, basic history of infertility, blood pressure, serum lipid level and side effects will be collected. Blood tests, including triglycerides, high density lipoprotein-cholesterol, fasting blood glucose, liver and kidney function will be performed before treatment to evacuate their metabolic conditions.

Patients are randomized to 1 of 2 treatment groups. Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months on Arm I. Patients will receive megestrol acetate 160 mg PO daily for 3 months on Arm II. Then an hysteroscope will be used to evaluate the endometrial condition, and the findings will be recorded. For patients with EAH, complete response (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. EAH after treatment will be defined as PR in patients with EC. Continuous therapies will be needed in PR, NR or PD.

After completion of study treatment, 3 months of maintenance treatment will be recommended for patients with CR, and they will be followed up for 2 years.

In addition, we've already had a pilot study in 19 patients primarily diagnosed of endometrial atypical hyperplasia from August 2012 to April 2013. 10 patients were in Arm I and 9 patients were in Arm II. Metabolic syndrome were evaluated among all subjects. After treatment, megestrol acetate plus metformin worked better than megestrol acetate alone. But two arms showed no difference in NR patients, which may suggest metformin just worked as an antitumor drug more than an insulin sensitizer. More supportive researches are needed to verify it.

Study Timeline

• Study Start: 2013-10
• Study First Submitted: 2013-10-16
• Study First Submitted QC: 2013-10-20
• Study First Posted: 2013-10-24
• Primary Completion: 2017-10
• Study Completion: 2017-10
• Results First Submitted: 2020-11-26
• Results First Submitted QC: 2021-08-17
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-10
• Results First Posted: 2021-09-13
• Last Update Posted: 2021-09-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 150

Inclusion Criteria

• Be between the ages of 18-45 years old

• Primarily have a confirmed diagnosis of endometrial atypical hyperplasia based upon D&C or hysteroscopy

  • OR primarily have a confirmed diagnosis of endometrial adenocarcinoma(G1, low tumor grade), based upon D&C or hysteroscopy, and three MRI parameters shows there's no myometrial invasion, extension beyond corpus, or enlarged lymph nodes

• Have a desire for remaining reproductive function or uterus

• Need to be able to undergo correlative treatment and follow-up

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Exclusion Criteria

• Have a history of serious liver or renal dysfunction
• Have a confirmed diagnosis of malignant tumor in genital system
• Have taken oral contraceptive or other medicine for the treatment of endometrial hyperplasia in the past 6 months
• Ask for removal of the uterus or other conservative treatment
• serum CA-125 > 35 Um/L

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Megestrol acetate and metformin	Megestrol acetate and metformin	Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months.Then an hysteroscope will be used to evaluate the endometrial condition, and the findings will be recorded.
Megestrol acetate	Megestrol acetate	Patients will receive megestrol acetate 160 mg by mouth daily for 3 months.Then an hysteroscope will be used to evaluate the endometrial condition, and the findings will be recorded.

Primary Outcome Measures

Name	Time	Method
Cumulative CR Rates Within 16 Weeks	16 weeks after initial treatment	The primary objective was to determine whether metformin plus MA would be associated with a higher CR rate at 3 months of treatment compared with MA alone. However, for patients who eventually underwent the first and second hysteroscopies for endometrium evaluation within 16 weeks of the treatment, the cumulative CR rates within 16 weeks (16w-CR) were analysed as first end point instead of the CR rate at 3 months.; Complete response was defined as the reversion of AEH/EEC to proliferative or secretory endometrium in pathology.

Secondary Outcome Measures

Name	Time	Method
Pregnancy Rate	through study completion, a median time of 33 months	All patients were followed up till February 2019. The pregnancy rate was calculated only in women who planned for parenthood immediately after achieving CR.
Cumulative CR Rates Within 32 Weeks	32 weeks after initial treatment	One of the secondary objectives was between-group comparisons of the cumulative CR rate at 6 months treatment. However, for patients who eventually underwent the second hysteroscopies for endometrium evaluation within 32 weeks of the treatment, the cumulative CR rates within 32 weeks (32w-CR rates) were analysed as secondary end point instead of the CR rate at 6 months.
Recurrence Rate	through study completion, a median time of 33 months	All patients were followed up till February 2019. Statistics of patients who didn't accept hysterectomy and were not lost to follow up were analyzed.

Trial Locations

Locations (5)

Obstetrics and Gynecology Hospital, Fudan University; 🇨🇳 Shanghai, Shanghai, China

Shanghai Changning Maternity & Infant Health Hospital; 🇨🇳 Shanghai, Shanghai, China

Shanghai Sixth People's Hospital; 🇨🇳 Shanghai, Shanghai, China

Zhejiang Cancer Hospital; 🇨🇳 Hangzhou, Zhejiang, China

Fudan University Shanghai Cancer Center; 🇨🇳 Shanghai, Shanghai, China