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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase IIIb Randomized Open-label Study to Compare the Estradiol Level on the Releasing Day in Two Regimen of Cetrotide® 0.25 mg Used From Day 1 or From Day 7 of the Menstrual Cycle (Day 0 or Day 6 of Stimulation) in Polycystic Ovarian (PCO) Women in ART (IVF/ICSI).

Conditions
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Polycystic Ovarian Syndrome

Intervention / Treatment
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* Drug: Cetrorelix acetate
* Drug: Cetrorelix acetate
* Drug: Recombinant Human Choriogonadotropin (r-hCG)
* Drug: Recombinant human follicle stimulating hormone (r-hFSH)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Day 1 protocol<br> | Drug: Cetrorelix acetate<br>* Cetrotide® 0.25 mg will be administered subcutaneously once daily from Day 1 (Day 0 of stimulation period [S0]) until r-hCG day (at least 2 follicles >=17 mm)<br>* Other names: Cetrotide®;Drug: Recombinant Human Choriogonadotropin (r-hCG)<br>* The r-hCG will be administered subcutaneously as a single dose of 250 microgram (mcg) on r-hCG day<br>* Other names: Ovitrelle®;Drug: Recombinant human follicle stimulating hormone (r-hFSH)<br>* Recombinant human follicle stimulating hormone (r-hFSH) will be administered subcutaneously at a dose between 75 and 187.5 international unit (IU) once daily from Day 2 (Day 1 of stimulation period [S1]) until r-hCG day<br>|
| Experimental: Day 7 protocol<br> | Drug: Cetrorelix acetate<br>* Cetrotide® 0.25 mg will be administered subcutaneously once daily from Day 7 (Day 6 of stimulation period [S6]) until r-hCG day (at least 2 follicles >=19 mm)<br>* Other names: Cetrotide®;Drug: Recombinant Human Choriogonadotropin (r-hCG)<br>* The r-hCG will be administered subcutaneously as a single dose of 250 microgram (mcg) on r-hCG day<br>* Other names: Ovitrelle®;Drug: Recombinant human follicle stimulating hormone (r-hFSH)<br>* Recombinant human follicle stimulating hormone (r-hFSH) will be administered subcutaneously at a dose between 75 and 187.5 international unit (IU) once daily from Day 2 (Day 1 of stimulation period [S1]) until r-hCG day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estradiol (E2) Levels on r-hCG Day |  | r-hCG day (end of stimulation cycle [approximately 15 days]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Levels |  | Day 1 | 
| Serum Estradiol (E2) Levels |  | Day 1 | 
| 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 and Quality of Oocytes Retrieved | 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. | Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | 
| Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH) |  | Day 1 up to r-hCG day (end of stimulation cycle [approximately 15 days]) | 
| Percentage of Fertilized Oocytes Retrieved | 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. | Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | 
| Number of Embryos | Embryo is defined as the product of the zygote, two or three days after fertilization of the oocytes. | Day 2-3 post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | 
| Number of Blastocysts | 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. | Day 5-6 post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | 
| Number of Transferred Embryos | Embryo transfer is the procedure in which one or more embryos are placed in the uterus. | Day 2-3 post Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | 
| Implantation Rate | Implantation rate per reporting group was measured as the number of gestational sacs observed, divided by the number of embryos transferred multiplied by 100. | 5 weeks post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | 
| Percentage of Participants With Clinical Pregnancy | 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. | 10 weeks post r-hCG day (end of stimulation cycle [approximately 15 days]) | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Day 1 up to end of study (15 days post last administration of study drug) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cetrorelix acetate; follitropin alfa; human chorionic-gonadotropin alfa; follicular maturation; pregnancy; ovarian stimulation