A Study to Investigate the Efficacy and Safety of a Single Injection of Corifollitropin Alfa (Organon 36286) for Ovarian Stimulation Using Daily Recombinant Follicle Stimulating Hormone (FSH) as Reference (P05787)

Study Overview
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Brief Summary
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To investigate the efficacy and safety of a single injection of 150 μg Corifollitropin Alfa (Organon 36286) to induce multifollicular development for controlled ovarian stimulation using daily recombinant FSH (recFSH) as a reference. The primary hypothesis is that a single injection of Corifollitropin Alfa is non-inferior to daily treatment with recFSH in initiating multifollicular growth.

Detailed Description
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This is a randomized, double-blind, active-controlled, non-inferiority clinical trial investigating the efficacy and safety of a new treatment regimen with Corifollitropin Alfa, a recombinant gonadotropin applied to initiate and sustain follicular stimulation in controlled ovarian stimulation for Assisted Reproductive Technology (ART). For this regimen, participants receive a single injection of Corifollitropin Alfa and one week later, treatment is continued with daily recFSH up to the day of triggering final oocyte maturation. In the reference group participants receive daily injections of recFSH up to the day of triggering final oocyte maturation. Non-inferiority in ongoing pregnancy rates (assessed at least 10 weeks after embryo transfer) will be the primary endpoint for this trial. The number of oocytes retrieved will be analyzed as co-primary endpoint.

Official Title
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A Phase III, Randomized, Double-Blind, Active-Controlled, Non-Inferiority Clinical Trial to Investigate the Efficacy and Safety of a Single Injection of Org 36286 (Corifollitropin Alfa) to Induce Multifollicular Development for Controlled Ovarian Stimulation Using Daily Recombinant FSH as Reference

Conditions
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In Vitro Fertilization

Intervention / Treatment
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* Drug: Corifollitropin alfa
* Biological: RecFSH / Follitropin beta (Days 1 to 7)
* Drug: Placebo Corifollitropin alfa
* Drug: Placebo RecFSH / follitropin beta
* Biological: RecFSH / Follitropin beta (Days 8 to hCG)
* Drug: Ganirelix
* Biological: hCG
* Biological: Progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females of couples with an indication for Controlled Ovarian Stimulation (COS) and in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI); >=18 and <=36 years of age at the time of signing informed consent; Body weight > 60 and <=90 kg and body mass index (BMI) >=18 and <=32 kg/m^2; Normal menstrual cycle length: 24-35 days; Availability of ejaculatory sperm (use of donated and/or cryopreserved sperm is allowed); Willing and able to sign informed consent. Exclusion Criteria: History of/or any current (treated) endocrine abnormality; History of ovarian hyper-response or ovarian hyperstimulation syndrome (OHSS); History of/or current polycystic ovary syndrome (PCOS); More than 20 basal antral follicles <11 mm (both ovaries combined) as measured on ultrasound scan (USS) in the early follicular phase (menstrual cycle day 2-5); Less than 2 ovaries or any other ovarian abnormality (including endometrioma > 10 mm; visible on USS); Presence of unilateral or bilateral hydrosalphinx (visible on USS); Presence of any clinically relevant pathology affecting the uterine cavity or fibroids >=5 cm; More than three unsuccessful IVF cycles since the last established ongoing pregnancy (if applicable); History of non- or low ovarian response to FSH/ human menopausal gonadotropin (hMG) treatment; History of recurrent miscarriage (3 or more, even when unexplained); FSH > 12 IU/L or LH > 12 IU/L as measured by the local laboratory (sample taken during the early follicular phase: menstrual cycle day 2-5); Any clinically relevant abnormal laboratory value based on a sample taken during the screening phase; Contraindications for the use of gonadotropins (e.g. tumors, pregnancy/lactation, undiagnosed vaginal bleeding, hypersensitivity, ovarian cysts); Recent history of/or current epilepsy, human immunodeficiency virus (HIV) infection, diabetes, cardiovascular, gastro-intestinal, hepatic, renal or pulmonary disease; Abnormal karyotyping of the patient or her partner (if karyotyping is performed); Smoking more than 5 cigarettes per day; History or presence of alcohol or drug abuse within 12 months prior to signing informed consent; Previous use of Org 36286; Use of hormonal preparations within 1 month prior to randomization; Hypersensitivity to any of the concomitant medication prescribed as part of the treatment regimen in this protocol; Administration of investigational drugs within three months prior to signing informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 36 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 150 µg Corifollitropin Alfa<br>Participants received a single subcutaneous (SC) injection of 150 µg Corifollitropin Alfa (org 36286) on day 2 or 3 of the menstrual cycle (Stimulation Day 1); 7 daily SC injections from Stimulation Days 1 to 7 with placebo-recFSH; followed by daily SC injections with 200 IU recFSH up to the day of hCG. Daily SC injections of Ganirelix were administered from Stimulation Day 5 to the day of hCG; at which time a single dose of hCG was given when 3 follicles >= 17 mm. On the day of oocyte pick up (OPU) daily doses of progesterone were started and continued for up to 6 weeks or menses. | Drug: Corifollitropin alfa<br>* On the morning of day 2 or 3 of the menstrual cycle (Stimulation Day 1), a single SC injection of 150 μg (0.5 mL) Corifollitropin Alfa was administered in the abdominal wall.<br>* Other names: Org 36286;Drug: Placebo RecFSH / follitropin beta<br>* Identical ready-for-use solution, but without the active ingedient, supplied in cartridges for SC injection with the Follistim Pen. Daily SC injections were started on Stimulation Day 1 and continued up to and including Stimulation Day 7.<br>Biological: RecFSH / Follitropin beta (Days 8 to hCG)<br>* From Stimulation Day 8 onwards a daily SC dose of 200 IU recFSH was administered up to and including the Day of hCG.<br>* Other names: Puregon / Follistim AQ Cartridge;Drug: Ganirelix<br>* On Stimulation Day 5 a daily SC injection of 0.25 mg was started, which continued up to and including the day of hCG<br>* Other names: Orgalutran/ Ganirelix Acetate Injection;Biological: hCG<br>* When 3 follicles >= 17 mm were observed by USS, a single dose of 10,000 IU/USP hCG was administered; or, for those at risk for Ovarian Hyperstimulation Syndrome (OHSS), a lower dose of 5,000 IU/USP<br>* Other names: Pregnyl / urinary hCG;Biological: Progesterone<br>* On the day of OPU, luteal phase support was started by administering micronized progesterone of at least 600 mg/day vaginally, or at least 50 mg/day intramuscular (IM), which continued for at least 6 weeks, or up to menses.<br>|
| Active Comparator: 200 IU recFSH<br>Participants received a single SC injection of placebo Corifollitropin Alfa on day 2 or 3 of the menstrual cycle (Stimulation Day 1); 7 daily SC injections with 200 IU recFSH from Stimulation Days 1 to 7; followed by daily SC injections with 200 IU recFSH up to the day of hCG. Daily SC injections of Ganirelix were given from Stimulation Day 5 to the day of hCG; at which time a single dose of hCG was administered when 3 follicles >= 17 mm. On the day of OPU daily doses of progesterone were started and continued for up to 6 weeks or menses. | Biological: RecFSH / Follitropin beta (Days 1 to 7)<br>* Daily SC injections with 200 IU fixed dose recFSH were started on Stimulation Day 1 and continued up to and including Stimulation Day 7.<br>* Other names: Puregon / Follistim AQ Cartridge;Drug: Placebo Corifollitropin alfa<br>* Pre-filled syringe containing an identical solution when compared to Corifollitropin Alfa. On the morning of day 2 or 3 of the menstrual cycle (Stimulation Day 1), a single SC injection was administered in the abdominal wall.<br>Biological: RecFSH / Follitropin beta (Days 8 to hCG)<br>* From Stimulation Day 8 onwards a daily SC dose of 200 IU recFSH was administered up to and including the Day of hCG.<br>* Other names: Puregon / Follistim AQ Cartridge;Drug: Ganirelix<br>* On Stimulation Day 5 a daily SC injection of 0.25 mg was started, which continued up to and including the day of hCG<br>* Other names: Orgalutran/ Ganirelix Acetate Injection;Biological: hCG<br>* When 3 follicles >= 17 mm were observed by USS, a single dose of 10,000 IU/USP hCG was administered; or, for those at risk for Ovarian Hyperstimulation Syndrome (OHSS), a lower dose of 5,000 IU/USP<br>* Other names: Pregnyl / urinary hCG;Biological: Progesterone<br>* On the day of OPU, luteal phase support was started by administering micronized progesterone of at least 600 mg/day vaginally, or at least 50 mg/day intramuscular (IM), which continued for at least 6 weeks, or up to menses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Ongoing Pregnancy (Ongoing Pregnancy Rate) | An ongoing pregnancy is a fetus with heart activity at least 10 weeks after embryo transfer as assessed by Ultrasound Scan (USS) or Doppler or is confirmed by live birth. The ongoing pregnancy rate is 100 times the number of participants with an ongoing pregnancy after embryo transfer, divided by the total number of participants who started treatment. Calculations were made per attempt, meaning that participants who did not have embryo transfers were considered not pregnant. | Assessed at least 10 weeks after embryo transfer (up to 1 year) | 
| Mean Number of Oocytes Retrieved | Up to 36 hours after receiving hCG, cumulus-oocyte-complexes were retrieved. Mean numbers retrieved were calculated per attempt, meaning that if a participant did not reach this stage in In Vitro Fertilization (IVF) treatment, zero values were imputed. | Up to 36 hours after administration of hCG (up to 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Amount of Recombinant FSH Needed to Induce Multifollicular Development Starting at Day 1 | The amount of recFSH administered for a participant to reach 3 follicles >= 17 mm, starting from treatment Day 1 onwards. | From Day 1 to day of hCG treatment (up to 1 year) | 
| Median Amount of Recombinant FSH Needed to Induce Multifollicular Development Starting at Day 8 | The amount of recFSH administered for a participant to reach 3 follicles >= 17 mm, starting from treatment Day 8 onwards. | From Day 8 to Day of hCG treatment (up to 1 year) | 
| Serum FSH Levels During Stimulation | Mean serum FSH are presented over one Controlled Ovarian Stimulation (COS) cycle: from Day 1 (Pre-dose) up to the day of hCG treatment. | Up to day of hCG treatment (up to 1 year) | 
| Serum Luteinizing Hormone (LH) Levels During Stimulation | Mean serum LH levels are presented over one COS cycle: from Day 1 (Pre-dose) up to the day of hCG treatment. | Up to day of hCG treatment (up to 1 year) | 
| Serum Estradiol (E2) Levels During Stimulation | Mean serum E2 levels are presented over one COS cycle: from Day 1 (Pre-dose) up to the day of hCG treatment. | Up to day of hCG treatment (up to 1 year) | 
| Serum Progesterone (P) Levels During Stimulation | Mean serum P levels are presented over one COS cycle: from Day 1 (Pre-dose) up to day of hCG treatment | Up to day of hCG treatment (up to 1 year) | 
| Serum Inhibin-B Levels During Stimulation | Mean serum Inhibin-B levels are presented over one COS cycle: from Day 1 (Pre-dose) up to day of hCG treatment | Up to day of hCG treatment (up to 1 year) | 
| Number of Follicles Categorized by Size on Stimulation Day 1 | Ovaries were assessed during stimulation by ultrasonographic investigation (USS), and the mean number of follicles are categorized by their size. | On Day 1 of treatment (up to 1 year) | 
| Number of Follicles Categorized by Size on Stimulation Day 5 | Ovaries were assessed during stimulation by USS, and the mean number of follicles are categorized by their size. | On Day 5 of treatment (up to 1 year) | 
| Number of Follicles Categorized by Size on Stimulation Day 8 | Ovaries were assessed during stimulation by USS, and the mean number of follicles are categorized by their size. | On Day 8 of treatment (up to 1 year) | 
| Number of Follicles Categorized by Size on the Day of hCG | Ovaries were assessed during stimulation by USS, and the mean number of follicles are categorized by their size. | Day of HCG treatment (up to 1 year) | 
| Number of Cumulus-oocyte-complexes | Prior to IVF the mean number of cumulus-oocyte-complexes used for IVF was assessed | Up to 36 hours after administration of hCG (up to 1 year) | 
| Number of Oocytes Assessed Prior to Intracytoplasmic Sperm Injection (ICSI) | The number of oocytes used for ICSI was assessed, and categorized based on their quality | Up to 36 hours after administration of hCG (up to 1 year) | 
| Percentage of Fertilized Oocytes (Fertilization Rate) | The fertilization rate is 100 times the number of fertilized 2 pro-nuclei (2PN) oocytes obtained, divided by the number of oocytes fertilized by IVF or ICSI | Up to 18 hours after start of fertilization (up to 1 year) | 
| Number of Embryos Obtained on Day 3 Categorized by Quality | Embryos obtained on Day 3 were categorized by their qualiity as follows: Grade 1: excellent: No fragmentation, 6-10 cells, and equal blastomere size taking the impact of cell division into account. Grade 2: good: < 20% fragmentation, 6-10 cells, and equal blastomere size taking the impact of cell division into account. Grade 3: fair: 20-50% fragmentation and/or less than 6 cells and/or multinucleation (if observed). Other Grade: Embryos that do not qualify as Grades 1, 2 or 3. Grades 1 and 2 are considered good quality. | Post fertilization Day 3 (up to 1 year) | 
| Number of Embryos Transferred on Day 3 | After fertilization, the mean number of embryos transferred on Day 3 were assessed. Total and good quality embryos are presented, with good quality embryos, Grades 1 and 2, defined as the following: Grade 1: excellent: No fragmentation, 6-10 cells, and equal blastomere size taking the impact of cell division into account. Grade 2: good: < 20% fragmentation, 6-10 cells, and equal blastomere size taking the impact of cell division into account. | Post fertilization Day 3 (up to 1 year) | 
| Percentage of Gestational Sacs (Implantation Rate) | The implantation rate is 100 times the number of gestational sacs assessed by USS after embryo transfer, divided by the number of embryos transferred. | Up to 6 weeks after embryo transfer (up to 1 year) | 
| Percentage of Participants With a Miscarriage (Miscarriage Rate) Per Clinical Pregnancy | The miscarriage rate is 100 times the number of miscarriages, divided by the number of clinical pregnancies assessed by USS. A clinical pregnancy is the presence of at least one gestational sac or confirmed by live birth. | Up to day of miscarriage (up to 1 year) | 
| Percentage of Participants With a Miscarriage (Miscarriage Rate) Per Vital Pregnancy | The miscarriage rate is 100 times the number of miscarriages, divided by the number of vital pregnancies assessed by USS. A vital pregnancy is the presence of at least one fetus with heart activity. | Up to day of miscarriage (up to 1 year) | 
| Percentage of Participants With a Biochemical Pregnancy (Pregnancy Rate) Per Attempt | Biochemical pregnancy was assessed by measuring serum or urinary hCG. Per attempt means that if a participant did not reach the stage of pregnancy assessment zero values were imputed. The pregnancy rate is 100 times the number of participants with pregnancies detected, divided by the number of participants assessed. | Two weeks after embryo transfer (up to 1 year) | 
| Percentage of Participants With a Biochemical Pregnancy (Pregnancy Rate) Per Embryo Transfer | Biochemical pregnancy was assessed for participants who had embryo transfer by measuring serum or urinary hCG. The pregnancy rate is 100 times the number of participants with pregnancies detected, divided by the number of participants assessed. | Two weeks after embryo transfer (up to 1 year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infertility, Pharmacological effect of drugs, Hormones, Hormone substitutes and hormone antagonists, Pharmacological actions, Randomized, Multi-center, Multi-national, Double-blind, Active-controlled, Non-inferiority