Clinical trial NCT01968317
Conditions: Endometrial Atypical Hyperplasia Endometrial Adenocarcinoma
Keywords: Endometrial Atypical Hyperplasia Endometrial Adenocarcinoma Conservative Medication
Sponsor: Xiaojun Chen
Start date: 2013-10-01; Completion date: 2017-10-01
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Megestrol acetate and metformin intervention 2: Megestrol acetate
Intervention descriptions: intervention 1: Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months. intervention 2: Patients will receive megestrol acetate 160 mg by mouth daily for 3 months.

Protocol documents:
Prot_SAP_000.pdf: 
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Megestrol Acetate plus Metformin to Megestrol Acetate 
in Patients  
with Endometrial Atypical Hyperplasia  
or Early Stage Endometrial Adenocarcinoma 
 
 
ClinicalTrials.gov ID: NCT01968317 
Date: 17/June/2020 
 
 


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Synopsis of protocol 
 
Enrolment criteria 
 
Eligible patients will be women who 1) were 18-45 years old; 2) pathologically 
diagnosed with AEH or EEC (endometroid, grade I, without myometrial invasion) 
for the first time; 3) willing to preserve their fertility; 4) have no signs of 
suspicious endometrial invasion or extrauterine metastasis by enhanced 
magnetic resonance imaging (MRI), enhanced computed tomography (CT) or 
transvaginal ultrasonography (TVUS); 5) have no contraindication for metformin, 
MA or pregnancy; 6) have no hormone or metformin treatment within six 
months before the trial; 7) not pregnant when participating in the trial; 8) have 
good compliance for the treatment.  
 
The exclusion criteria were patients who have either of followed conditions: 1) 
allergy history or contraindications for MA or metformin; 2) being pregnant 
when initiating the study 3) alcoholism, severe infection, severe chronical 
diseases (dysfunction of heart, liver, lung or kidney); 4) with high risk of 
thrombosis; 5) recurrent AEH or EC; 6) other malignancy history. 
 
All patients will be pathologically diagnosed by endometrial biopsy through 
dilation and curettage (D&C) with or without hysteroscopy (HSC). Pathologic 
diagnosis will be confirmed by two experienced gynecological pathologists 
according to the World Health Organization (WHO) pathological classification 
(2014). If their opinions differ, a seminar will be held in the pathological 
department for the final diagnosis. This study is approved by the Ethics 
Committees of Obstetrics and Gynecology Hospital of Fudan University. Before 
initiation of study procedures, written informed consent will be obtained from 
each patient regarding risks of conservative treatments and agreement of using 
their clinical data for research purpose. 
 
Randomization and masking 
AEH and EEC patients will be firstly stratified, and then both randomly assigned 
(1:1) to receive MA treatment (control group) or metformin plus MA treatment 
(experimental group) until complete regression or disease progression or 
unacceptable side effects, whichever occurrs first. A computer-based procedure 
of simple randomization (SPSS for Mac, version 20·0; IBM) will be used for 
participant enrollment and randomization. Before an individual is successfully 
enrolled, her treatment assignment will remain concealed. This trial will be open 
label: patients and study physicians were aware of treatment assignment. 
 
Outcomes 
The primary end point is the accumulate CR rate within three months of 


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treatment. The accumulate CR rate within six, nine, twelve months of treatment, 
time to CR, adverse events, recurrence rate and pregnancy rate in two years are 
secondary end points.  
 
Statistical analysis 
For primary endpoint, a baseline CR rate of 25% in MA group and an expected CR 
rate of 50% in MA/metformin group were expected according to results in our 
previous pilot study, with a power of 0·9 at a two-sided significance level of 0·05, 
requiring an accrual 150 eligible patients (lost follow-up rate <5%). Relapse rate 
will be calculated among patients who achieved CR. Pregnancy rates will be 
evaluated among patients who planned to conceive once achieving CR. 
Continuous variables will be summarized by means and standard deviations, or 
median and interquartile range (IQR). Categorical variables will be presented as 
frequency with percentage. The intra-group differences of continuous variables 
will be investigated by Student's t-test or Mann-Whitney U test where 
appropriate. Chi-square test or Fisher's exact test will be used to analyze the 
difference between categorical variables. Adjusted Odds ratios (OR) and 95% CI 
will be estimated with Logistic regression model. Estimates of time to CR will be 
calculated using the Kaplan-Meier method. A 2-tailed p value of less than 0.05 
will be considered as statistically significant. SPSS 20·0 (SPSS, Inc., Chicago, IL, 
USA) will be used for all the statistical analyses.