Value of LNG-IUS as Fertility-preserving Treatment of EAH and EC

Sponsor

West China Second University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03463252

Collaborator

(none)

224

Enrollment

Location

Arms

153

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Primary end points:

This clinical trial is aimed to analyze the effectiveness of Levonorgestrel-Releasing Intrauterine System (LNG-IUS, Mirena®) in the fertility-sparing treatment of atypical endometrial hyperplasia and early endometrial carcinoma, including pathology response and pregnancy outcome.

Second end points:

To analyze the appearances of side-effects.

Condition or Disease	Intervention/Treatment	Phase
Endometrial Cancer Atypical Endometrial Hyperplasia	Drug: Progesterone Device: Mirena® Drug: GnRH agonist	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

224 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Value of Levonorgestrel-Releasing Intrauterine System (LNG-IUS) in the Fertility-preserving Treatment of Atypical Endometrial Hyperplasia and Early Endometrial Carcinoma

Actual Study Start Date :

Apr 1, 2018

Anticipated Primary Completion Date :

Dec 30, 2025

Anticipated Study Completion Date :

Dec 30, 2030

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: MPA for EC without progesterone contraindication The enrolled patient (endometrial cancer without contraindication of oral high dose progesterone) is allocated to one of three groups, MPA only, MPA+LNG-IUS, LNG-IUS only, by randomization. Continuous treatment for 3 months is one cycle. Hysteroscopic evaluation and biopsy will procedure every cycle. Patients with partial response or in stable condition, after 2 cycles, will receive continuous treatment for one more cycle again. Patients with complete response after 2 or 3 cycles are encouraged to pregnancy. The consideration of giving up fertility-sparing treatment is recommended: 1) if patient have documented progression on the biopsies; 2) if endometrial cancer is still present after 3 cycles.	Drug: Progesterone MPA oral 250mg-500mg qd for 3 months per cycle Other Names: medroxyprogesterone acetate (MPA)
Experimental: MPA+Mirena® for EC without contraindication The enrolled patient (endometrial cancer without contraindication of oral high dose progesterone) is allocated to one of three groups, MPA only, MPA+LNG-IUS, LNG-IUS only, by randomization. Continuous treatment for 3 months is one cycle. Hysteroscopic evaluation and biopsy will procedure every cycle. Patients with partial response or in stable condition, after 2 cycles, will receive continuous treatment for one more cycle again. Patients with complete response after 2 or 3 cycles are encouraged to pregnancy. The consideration of giving up fertility-sparing treatment is recommended: 1) if patient have documented progression on the biopsies; 2) if endometrial cancer is still present after 3 cycles.	Drug: Progesterone MPA oral 250mg-500mg qd for 3 months per cycle Other Names: medroxyprogesterone acetate (MPA) Device: Mirena® levonorgestrel intrauterine sustained release system (LNG-IUS) placed in uterus for 3 months per cycle Other Names: LNG-IUS
Experimental: Mirena® for EC without contraindication The enrolled patient (endometrial cancer without contraindication of oral high dose progesterone) is allocated to one of three groups, MPA only, MPA+LNG-IUS, LNG-IUS only, by randomization. Continuous treatment for 3 months is one cycle. Hysteroscopic evaluation and biopsy will procedure every cycle. Patients with partial response or in stable condition, after 2 cycles, will receive continuous treatment for one more cycle again. Patients with complete response after 2 or 3 cycles are encouraged to pregnancy. The consideration of giving up fertility-sparing treatment is recommended: 1) if patient have documented progression on the biopsies; 2) if endometrial cancer is still present after 3 cycles.	Device: Mirena® levonorgestrel intrauterine sustained release system (LNG-IUS) placed in uterus for 3 months per cycle Other Names: LNG-IUS
Active Comparator: GnRH agonist+Mirena® for EC with contraindication The enrolled patient (endometrial cancer with contraindication of oral high dose progesterone) is allocated to either GnRH-a+ LNG-IUS or only LNG-IUS by randomization. Continuous treatment for 3 months is one cycle. Hysteroscopic evaluation and biopsy will procedure every cycle. Patients with partial response or in stable condition, after 2 cycles, will receive continuous treatment for one more cycle again. Patients with complete response after 2 or 3 cycles are encouraged to pregnancy. The consideration of giving up fertility-sparing treatment is recommended: 1) if patient have documented progression on the biopsies; 2) if endometrial cancer is still present after 3 cycles.	Device: Mirena® levonorgestrel intrauterine sustained release system (LNG-IUS) placed in uterus for 3 months per cycle Other Names: LNG-IUS Drug: GnRH agonist GnRH-a intramuscular injection 3.75mg once a month for 3 months per cycle Other Names: GnRH-a
Experimental: Mirena® for EC with contraindication The enrolled patient (endometrial cancer with contraindication of oral high dose progesterone) is allocated to either GnRH-a+ LNG-IUS or only LNG-IUS by randomization. Continuous treatment for 3 months is one cycle. Hysteroscopic evaluation and biopsy will procedure every cycle. Patients with partial response or in stable condition, after 2 cycles, will receive continuous treatment for one more cycle again. Patients with complete response after 2 or 3 cycles are encouraged to pregnancy. The consideration of giving up fertility-sparing treatment is recommended: 1) if patient have documented progression on the biopsies; 2) if endometrial cancer is still present after 3 cycles.	Device: Mirena® levonorgestrel intrauterine sustained release system (LNG-IUS) placed in uterus for 3 months per cycle Other Names: LNG-IUS
Active Comparator: Mirena® for EAH without progesterone contraindication The enrolled patient (atypical endometrial hyperplasia without contraindication of oral high dose progesterone) is allocated to either MPA or LNG-IUS by randomization. Continuous treatment for 3 months is one cycle. Hysteroscopic evaluation and biopsy will procedure every cycle. Patients with partial response or in stable condition, after 2 cycles, will receive continuous treatment for one more cycle again. Patients with complete response after 2 or 3 cycles are encouraged to pregnancy. The consideration of giving up fertility-sparing treatment is recommended: 1) if patient have documented progression on the biopsies; 2) if EAH is still present after 3 cycles.	Device: Mirena® levonorgestrel intrauterine sustained release system (LNG-IUS) placed in uterus for 3 months per cycle Other Names: LNG-IUS
Experimental: MPA for EAH without progesterone contraindication The enrolled patient (atypical endometrial hyperplasia without contraindication of oral high dose progesterone) is allocated to either MPA or LNG-IUS by randomization. Continuous treatment for 3 months is one cycle. Hysteroscopic evaluation and biopsy will procedure every cycle. Patients with partial response or in stable condition, after 2 cycles, will receive continuous treatment for one more cycle again. Patients with complete response after 2 or 3 cycles are encouraged to pregnancy. The consideration of giving up fertility-sparing treatment is recommended: 1) if patient have documented progression on the biopsies; 2) if EAH is still present after 3 cycles.	Drug: Progesterone MPA oral 250mg-500mg qd for 3 months per cycle Other Names: medroxyprogesterone acetate (MPA)
Active Comparator: Mirena® for EAH with progesterone contraindication The enrolled patient (atypical endometrial hyperplasia with contraindication of oral high dose progesterone) is allocated to either GnRH-a+ LNG-IUS or only LNG-IUS by randomization. Continuous treatment for 3 months is one cycle. Hysteroscopic evaluation and biopsy will procedure every cycle. Patients with partial response or in stable condition, after 2 cycles, will receive continuous treatment for one more cycle again. Patients with complete response after 2 or 3 cycles are encouraged to pregnancy. The consideration of giving up fertility-sparing treatment is recommended: 1) if patient have documented progression on the biopsies; 2) if EAH is still present after 3 cycles.	Device: Mirena® levonorgestrel intrauterine sustained release system (LNG-IUS) placed in uterus for 3 months per cycle Other Names: LNG-IUS
Experimental: GnRH-a+Mirena® for EAH with progesterone contraindication The enrolled patient (atypical endometrial hyperplasia with contraindication of oral high dose progesterone) is allocated to either GnRH-a+ LNG-IUS or only LNG-IUS by randomization. Continuous treatment for 3 months is one cycle. Hysteroscopic evaluation and biopsy will procedure every cycle. Patients with partial response or in stable condition, after 2 cycles, will receive continuous treatment for one more cycle again. Patients with complete response after 2 or 3 cycles are encouraged to pregnancy. The consideration of giving up fertility-sparing treatment is recommended: 1) if patient have documented progression on the biopsies; 2) if EAH is still present after 3 cycles.	Device: Mirena® levonorgestrel intrauterine sustained release system (LNG-IUS) placed in uterus for 3 months per cycle Other Names: LNG-IUS Drug: GnRH agonist GnRH-a intramuscular injection 3.75mg once a month for 3 months per cycle Other Names: GnRH-a

Outcome Measures

Primary Outcome Measures

Pathologic Response [6-12 months]
Pathologic response to medicine treatment is categorized as complete response (CR), partial response (PR), no change (NC), and progressive disease (PD). CR is defined as the absence of any hyperplastic or cancerous lesion. PR is defined as the residual lesion with degeneration and atrophy of endometrial glands. NC is defined as residual lesion without degeneration or atrophy of endometrial glands. PD is defined as the appearance of endometrial cancer for EAH and grade 2 (G2) or 3 for EC.
Pregnancy Rate [7-144 months]
The percentage of successful pregnancies in the CR patients.
Live Birth Rate [16-144 months]
The percentage of successfully alive baby delivery in the pregnant patients.

Secondary Outcome Measures

Side-Affects Rate [1-144 months]
The appearances of side-effects include weight gain, irregular vaginal bleeding, breast pain, appetite changes, nausea, vomiting, rash, jaundice, thromboembolism, hypertension, liver dysfunction, kidney dysfunction, glucose intolerance, and diabetes.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 40 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

For Patients With Endometrial Cancer：

Inclusion Criteria:

≤40 years of age:
Having a strong desire for fertility preservation;
Histological diagnosis is confirmed as well-differentiated (grade 1) endometrioid adenocarcinoma by the designated gynecological pathologists, and the progesterone receptors (PgRs) is positive in immunohistochemistry;
Disease limited to the endometrium (stage 1A) on MRI;
Serum CA125/199 level is within normal limit (Laparoscopic exploration to rule out ovarian tumor or another metastasis if necessary);
Patients should have undergone counseling to learn fertility-preserving treatment is not standard of care for the treatment of EC, volunteered to participate in this study, signed the informed consent form, and agreed to participated in clinical follow-up.

Exclusion Criteria:

Patients have allergies or contraindications (except for thromboembolic disease, liver dysfunction, hypertension, and diabetes) for the involved drugs;
Patients have lynch syndrome (LS);
Patients have contraindications for pregnancy;
Patients have serious underlying disease, malignancies at other site(s), acute liver or kidney disease, acute liver or kidney diseases, acute or subacute genital tract infections and congenital or acquired abnormal uterine development (that may make intrauterine device placement impossible);
Patients refuse to participate in clinical follow-up or sign the informed consent form.

For Patients With Endometrial atypical hyperplasia：

Inclusion Criteria:

≤ 40 years of age
Having a strong desire for fertility preservation
Histological diagnosis is confirmed as atypical endometrial hyperplasia (EAH) by the designated gynecological pathologists
Having volunteered to participate in this study, signed the informed consent form, and agreed to participate in clinical follow-up

Exclusion Criteria:

Patients have allergies or contraindications (except for thromboembolic disease, liver dysfunction, hypertension, and diabetes) for the involved drugs
Patients have contraindications for pregnancy
Patients have serious underlying disease, malignancies at other site(s), acute liver or kidney disease, acute or subacute genital tract infections, and congenital or acquired abnormal uterine development (that may make intrauterine device placement impossible)
Patients refuse to participate in clinical follow-up or sign the informed consent form.