Analysis of Two Therapeutic With Cetrotide® in Polycystic Ovarian (PCO) Women in Assisted Reproductive Technology (ART)

Phase 3

Completed

Conditions: Polycystic Ovarian Syndrome

Interventions: Drug: Cetrorelix acetate
Drug: Recombinant Human Choriogonadotropin (r-hCG)
Drug: Recombinant human follicle stimulating hormone (r-hFSH)

Registration Number: NCT01185704

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: This is a randomized open-label study to compare between in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes of the two regimen of Cetrotide® (Cetrorelix acetate) which are 0.25 milligram (mg) used from Day 1 or Day 7 of the menstrual cycle (Day 0 or Day 6 of stimulation) in polycystic ovarian (PCO) women in assisted reproductive technology (ART).

Detailed Description: Polycystic ovarian syndrome population is an androgenic syndrome characterized by a wide spectrum of clinical manifestations such as obesity, hirsutism, insulin resistance, diabetes and presence of specific ultrasonic features.

Cetrotide®, cetrorelix acetate, is an antagonist of luteinizing-hormone-releasing hormone (LHRH). Cetrotide® is registered in 70 countries (including France) for the prevention of premature ovulation in subjects undergoing a controlled ovarian stimulation, followed by oocyte pick-up and ARTs. Ovitrelle®, active ingredient human chorionic-gonadotropin alfa, is administered to trigger final follicular maturation and luteinization after stimulation of follicular growth.

OBJECTIVES

Primary objective:

* To compare the hormonal level of plasmatic estradiol on the releasing day (day of r-hCG administration) induced by Cetrotide® 0.25 mg/day started on Day 1 (Group A: Day 1) or on Day 7 (Group B: Day 7) of the menstrual cycle (Day 0 (S0) or Day 6 (S6) of stimulation) in PCO subjects undergoing IVF/ICSI procedures.

Secondary objectives:

* To compare the hormonal changes during the stimulation induced by Cetrotide® in A and B Groups

* To assess by ultrasound scans (US) the follicular development induced by Cetrotide® in A and B Groups

* To assess biological and clinical outcomes induced by Cetrotide® in A and B Groups

* To monitor safety of Cetrotide in A and B Groups

The trial will be conducted on an outpatient basis. Once each subject has met all eligibility criteria, they will be randomly assigned in one of the two treatment groups.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 136

Inclusion Criteria

Female subjects with PCO or Polycystic ovary syndrome (PCOS) according to the revised 2003 Rotterdam Consensus
Female subjects suitable for IVF/ICSI, undergoing first or second attempt
18-35 years old, Body Mass Index (BMI) less than or equal to 32, non-smoking at least from Visit 0 (V0)
Normal FSH value (less than 10 international unit per liter [IU/L]) on Day 3 of spontaneous cycle within 12 months prior to the trial
Anti Mullerian Hormone (AMH) value (greater than 1.5 nanogram per milliliter [ng/mL]) of a spontaneous cycle within 12 months prior to the trial or at least at V0
No history of active genito-urinary infection
Normal thyroid function (or adequate substitution for at least 3 months)
Negative cervical papanicolaou test within the last 12 months prior to study entry
No gonadotropins, for at least one month prior to the trial
No metformin therapy for at least one month prior to Visit 1 (V1)
Subject who is able to participate in the trial and has provided written, informed consent.

Exclusion Criteria

Ongoing pregnancy, any pregnancy within 3 months prior to study entry, or any contraindication to pregnancy or carrying pregnancy to term
Drilling 3 months prior to V0
Uterine malformation, diethylstilbestrol syndrome, synechia
Female subjects with World Health Organization (WHO) Type I or III anovulation
Female subjects with hyperprolactinemia
Female subjects with more than 2 recurrent miscarriages (early or late, and for any reasons)
Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus, for subject or partner
Abnormal gynecological bleeding of undetermined origin
History of major thromboembolic disease
Endometriosis (Grade III or IV)
Presence or history of malignant tumors and related treatment
Known case of tumors of the hypothalamus or pituitary gland
Clinically significant systemic disease or clinically significant abnormal hematology, chemistry, or urinalysis results at screening
Known allergic reaction or hypersensitivity to Cetrotide® or Ovitrelle®
Any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years
Participation in another clinical trial within 3 months prior to study entry.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Day 1 protocol	Recombinant Human Choriogonadotropin (r-hCG)	-
Day 1 protocol	Recombinant human follicle stimulating hormone (r-hFSH)	-
Day 7 protocol	Recombinant Human Choriogonadotropin (r-hCG)	-
Day 7 protocol	Recombinant human follicle stimulating hormone (r-hFSH)	-
Day 1 protocol	Cetrorelix acetate	-
Day 7 protocol	Cetrorelix acetate	-

Primary Outcome Measures

Name	Time	Method
Estradiol (E2) Levels on r-hCG Day	r-hCG day (end of stimulation cycle [approximately 15 days])

Secondary Outcome Measures

Name	Time	Method
Serum Estradiol (E2) Levels	Day 1
Percentage of Participants With Clinical Pregnancy	10 weeks post r-hCG day (end of stimulation cycle [approximately 15 days])	Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It excludes ectopic pregnancy.
Serum Progesterone (P4) Levels	Day 1
Anti Mullerian Hormone (AMH) Levels	Day 0
Number of Follicles Greater Than or Equal (>=) to 17 mm (For Day 1 Protocol) or 19 mm (For Day 7 Protocol) on r-hCG Day	r-hCG day (end of stimulation cycle [approximately 15 days])
Number of Embryos	Day 2-3 post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])	Embryo is defined as the product of the zygote, two or three days after fertilization of the oocytes.
Number of Blastocysts	Day 5-6 post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])	Blastocyst is an embryo, five or six days after fertilization, with an inner cell mass, outer layer of trophectoderm and a fluid-filled blastocoele cavity.
Number of Transferred Embryos	Day 2-3 post Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])	Embryo transfer is the procedure in which one or more embryos are placed in the uterus.
Implantation Rate	5 weeks post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])	Implantation rate per reporting group was measured as the number of gestational sacs observed, divided by the number of embryos transferred multiplied by 100.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Day 1 up to end of study (15 days post last administration of study drug)	An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. To avoid the participant/event combination double-count AEs and SAEs are reported separately.
Number and Quality of Oocytes Retrieved	Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])	Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocytes from the ovary of the female participant, enabling fertilization outside the body. Oocytes were classified into 4 different categories based on their quality: mature, fractured, immature and inseminated oocytes.
Percentage of Fertilized Oocytes Retrieved	Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])	Oocytes were fertilized using Intra-cytoplasmic Sperm Injection (ICSI) technique which is an IVF procedure in which a single sperm is injected directly into an egg under a microscope.
Serum Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Levels	Day 1
Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH)	Day 1 up to r-hCG day (end of stimulation cycle [approximately 15 days])