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

Sponsor
Xiaojun Chen (Other)
Overall Status
Completed
CT.gov ID
NCT01968317
Collaborator
Fudan University (Other), Shanghai 6th People's Hospital (Other), Zhejiang Cancer Hospital (Other), Shanghai Changning Maternity & Infant Health Hospital (Other)
150
5
2
48
30
0.6

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Megestrol acetate and metformin
  • Drug: Megestrol acetate
Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
150 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Megestrol Acetate Plus Metformin to Megestrol Acetate in Patients With Endometrial Atypical Hyperplasia or Early Stage Endometrial Adenocarcinoma
Study Start Date :
Oct 1, 2013
Actual Primary Completion Date :
Oct 1, 2017
Actual Study Completion Date :
Oct 1, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: 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.

Drug: 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.
Other Names:
  • Megestrol acetate: Megace
  • Metformin: Fortamet, Glucophage
  • Experimental: 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.

    Drug: Megestrol acetate
    Patients will receive megestrol acetate 160 mg by mouth daily for 3 months.
    Other Names:
  • Megestrol acetate: Megace
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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.

    2. 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.

    3. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 45 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    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

    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Obstetrics and Gynecology Hospital, Fudan University Shanghai Shanghai China 200011
    2 Fudan University Shanghai Cancer Center Shanghai Shanghai China 200032
    3 Shanghai Changning Maternity & Infant Health Hospital Shanghai Shanghai China
    4 Shanghai Sixth People's Hospital Shanghai Shanghai China
    5 Zhejiang Cancer Hospital Hangzhou Zhejiang China

    Sponsors and Collaborators

    • Xiaojun Chen
    • Fudan University
    • Shanghai 6th People's Hospital
    • Zhejiang Cancer Hospital
    • Shanghai Changning Maternity & Infant Health Hospital

    Investigators

    • Study Chair: Xiaojun Chen, PhD, Obstetrics & Gynecology Hospital of Fudan University

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Xiaojun Chen, Deputy Secretary of the Party committee, Fudan University
    ClinicalTrials.gov Identifier:
    NCT01968317
    Other Study ID Numbers:
    • 134119a4500
    First Posted:
    Oct 24, 2013
    Last Update Posted:
    Sep 14, 2021
    Last Verified:
    Sep 1, 2021
    Keywords provided by Xiaojun Chen, Deputy Secretary of the Party committee, Fudan University
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details 307 patients from Obstetrics and Gynaecology Hospital of Fudan University (Shanghai, China) were enrolled to this study between October 2013 to October 2017, including 237 patients with atypical endometrial hyperplasia (AEH) and 70 patients with well-differentiated endometrioid endometrial cancer (EEC).
    Pre-assignment Detail 157 of 307 enrolled patients were deemed ineligible, including 28 patients with hysterectomy history, 31 patients with AEH/EEC history, 67 patients with progestin use history, 10 patients refusing to attend this trial, 21 patients transferred to other hospital were excluded from this trial.
    Arm/Group Title Megestrol Acetate and Metformin Megestrol Acetate
    Arm/Group Description 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 and metformin: Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months. 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. Megestrol acetate: Patients will receive megestrol acetate 160 mg by mouth daily for 3 months.
    Period Title: Overall Study
    STARTED 76 74
    COMPLETED 76 74
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Megestrol Acetate and Metformin Megestrol Acetate Total
    Arm/Group Description 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 and metformin: Patients will receive metformin 500 mg by mouth third daily and megestrol acetate 160 mg by mouth daily for 3 months. 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. Megestrol acetate: Patients will receive megestrol acetate 160 mg by mouth daily for 3 months. Total of all reporting groups
    Overall Participants 76 74 150
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    32.0
    (4.5)
    33.4
    (5.2)
    32.6
    (4.9)
    Sex: Female, Male (Count of Participants)
    Female
    76
    100%
    74
    100%
    150
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    76
    100%
    74
    100%
    150
    100%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    White
    0
    0%
    0
    0%
    0
    0%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    China
    76
    100%
    74
    100%
    150
    100%

    Outcome Measures

    1. Primary Outcome
    Title Cumulative CR Rates Within 16 Weeks
    Description 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.
    Time Frame 16 weeks after initial treatment

    Outcome Measure Data

    Analysis Population Description
    In MA+metformin group, 9 cases were excluded in primary analysis for 1 asking for surgery and 8 missing hysteroscopic evaluation. In MA group, 16 cases were excluded for 1 asking for surgery and 15 missing hysteroscopic evaluation.
    Arm/Group Title Megestrol Acetate and Metformin Megestrol Acetate
    Arm/Group Description Patients will receive metformin 500 mg by mouth three times daily and megestrol acetate 160 mg by mouth daily. Hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded. Patients will receive megestrol acetate 160 mg by mouth daily. Hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded.
    Measure Participants 67 58
    Count of Participants [Participants]
    23
    30.3%
    12
    16.2%
    2. Secondary Outcome
    Title Cumulative CR Rates Within 32 Weeks
    Description 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.
    Time Frame 32 weeks after initial treatment

    Outcome Measure Data

    Analysis Population Description
    In MA+metformin group, 6 cases were excluded in this analysis for 3 asking for surgery and 3 missing hysteroscopic evaluation. In MA group, 8 cases were excluded for 2 asking for surgery and 6 missing hysteroscopic evaluation.
    Arm/Group Title Megestrol Acetate and Metformin Megestrol Acetate
    Arm/Group Description Patients will receive metformin 500 mg by mouth three times daily and megestrol acetate 160 mg by mouth daily. Hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded. Patients will receive megestrol acetate 160 mg by mouth daily. Hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded.
    Measure Participants 70 66
    Count of Participants [Participants]
    52
    68.4%
    45
    60.8%
    3. Secondary Outcome
    Title Recurrence Rate
    Description 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.
    Time Frame through study completion, a median time of 33 months

    Outcome Measure Data

    Analysis Population Description
    In MA+metformin group, 3 cases were excluded in this analysis for surgery, 3 for lost to follow-up, and 1 for still in treatment. In MA group, 2 cases were excluded for surgery and 6 for lost to follow-up.
    Arm/Group Title Megestrol Acetate and Metformin Megestrol Acetate
    Arm/Group Description Patients will receive metformin 500 mg by mouth three times daily and megestrol acetate 160 mg by mouth daily. Hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded. Patients will receive megestrol acetate 160 mg by mouth daily. Hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded.
    Measure Participants 69 66
    Count of Participants [Participants]
    7
    9.2%
    6
    8.1%
    4. Secondary Outcome
    Title Pregnancy Rate
    Description All patients were followed up till February 2019. The pregnancy rate was calculated only in women who planned for parenthood immediately after achieving CR.
    Time Frame through study completion, a median time of 33 months

    Outcome Measure Data

    Analysis Population Description
    In MA+metformin group only 31 cases wanted to have a baby, and that in MA group were 37.
    Arm/Group Title Megestrol Acetate and Metformin Megestrol Acetate
    Arm/Group Description Patients will receive metformin 500 mg by mouth three times daily and megestrol acetate 160 mg by mouth daily. Hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded. Patients will receive megestrol acetate 160 mg by mouth daily. Hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded.
    Measure Participants 37 31
    Count of Participants [Participants]
    19
    25%
    15
    20.3%

    Adverse Events

    Time Frame 32 weeks
    Adverse Event Reporting Description
    Arm/Group Title Megestrol Acetate and Metformin Megestrol Acetate
    Arm/Group Description Patients will receive metformin 500 mg by mouth three times daily and megestrol acetate 160 mg by mouth daily. After initiating the treatment, hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded. Patients will receive megestrol acetate 160 mg by mouth daily for 3 months.After initiating the treatment, hysteroscopic evaluation was performed every 3 months during the therapy to evaluate the endometrial condition, and the findings will be recorded.
    All Cause Mortality
    Megestrol Acetate and Metformin Megestrol Acetate
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/76 (0%) 0/74 (0%)
    Serious Adverse Events
    Megestrol Acetate and Metformin Megestrol Acetate
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/76 (0%) 0/74 (0%)
    Other (Not Including Serious) Adverse Events
    Megestrol Acetate and Metformin Megestrol Acetate
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 47/76 (61.8%) 46/74 (62.2%)
    Congenital, familial and genetic disorders
    Uterine hemorrhage 6/76 (7.9%) 6 13/74 (17.6%) 13
    Endocrine disorders
    Weight gain 29/76 (38.2%) 29 34/74 (45.9%) 34
    Gastrointestinal disorders
    Diarrhea 12/76 (15.8%) 12 3/74 (4.1%) 3
    Nausea 8/76 (10.5%) 8 4/74 (5.4%) 4
    Constipation 1/76 (1.3%) 1 1/74 (1.4%) 1
    General disorders
    Insomnia 2/76 (2.6%) 2 3/74 (4.1%) 3
    Anorexia 5/76 (6.6%) 5 0/74 (0%) 0
    Nervous system disorders
    Dizziness 7/76 (9.2%) 7 7/74 (9.5%) 7
    Renal and urinary disorders
    Increased nocturnal urine 15/76 (19.7%) 15 20/74 (27%) 20
    Skin and subcutaneous tissue disorders
    Hyperhidrosis 10/76 (13.2%) 10 10/74 (13.5%) 10
    Allergic reaction 8/76 (10.5%) 8 5/74 (6.8%) 5
    Vascular disorders
    Breast pain OR Abdominal pain 17/76 (22.4%) 17 20/74 (27%) 20

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Xiaojun Chen
    Organization Obstetrics and Gynecology Hospital of Fudan University
    Phone 33189900
    Email xiaojunchen2013@sina.com
    Responsible Party:
    Xiaojun Chen, Deputy Secretary of the Party committee, Fudan University
    ClinicalTrials.gov Identifier:
    NCT01968317
    Other Study ID Numbers:
    • 134119a4500
    First Posted:
    Oct 24, 2013
    Last Update Posted:
    Sep 14, 2021
    Last Verified:
    Sep 1, 2021