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)

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

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.

Study Overview

• Status: Completed
• Conditions: In Vitro Fertilization
• Intervention / Treatment: Drug: Corifollitropin alfa; Drug: Placebo RecFSH / follitropin beta; Biological: RecFSH / Follitropin beta (Days 8 to hCG); Drug: Ganirelix; Biological: hCG; Biological: Progesterone; Biological: RecFSH / Follitropin beta (Days 1 to 7); Drug: Placebo Corifollitropin alfa

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1509
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 36 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 150 µg Corifollitropin Alfa; 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; 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.; Other Names: Org 36286; SCH 900962; MK-8962; Drug: Placebo RecFSH / follitropin beta; 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.; Biological: RecFSH / Follitropin beta (Days 8 to hCG); From Stimulation Day 8 onwards a daily SC dose of 200 IU recFSH was administered up to and including the Day of hCG.; Other Names: Puregon / Follistim AQ Cartridge; Drug: Ganirelix; On Stimulation Day 5 a daily SC injection of 0.25 mg was started, which continued up to and including the day of hCG; Other Names: Orgalutran/ Ganirelix Acetate Injection; Biological: hCG; 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; Other Names: Pregnyl / urinary hCG; Biological: Progesterone; 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.
ACTIVE_COMPARATOR: 200 IU recFSH; 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 8 to hCG); From Stimulation Day 8 onwards a daily SC dose of 200 IU recFSH was administered up to and including the Day of hCG.; Other Names: Puregon / Follistim AQ Cartridge; Drug: Ganirelix; On Stimulation Day 5 a daily SC injection of 0.25 mg was started, which continued up to and including the day of hCG; Other Names: Orgalutran/ Ganirelix Acetate Injection; Biological: hCG; 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; Other Names: Pregnyl / urinary hCG; Biological: Progesterone; 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.; Biological: RecFSH / Follitropin beta (Days 1 to 7); Daily SC injections with 200 IU fixed dose recFSH were started on Stimulation Day 1 and continued up to and including Stimulation Day 7.; Other Names: Puregon / Follistim AQ Cartridge; Drug: Placebo Corifollitropin alfa; 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.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Organon and Co

Publications and helpful links

General Publications

• Lawrenz B, Beligotti F, Engelmann N, Gates D, Fatemi HM. Impact of gonadotropin type on progesterone elevation during ovarian stimulation in GnRH antagonist cycles. Hum Reprod. 2016 Nov;31(11):2554-2560. doi: 10.1093/humrep/dew213. Epub 2016 Sep 12.
• Zandvliet AS, Prohn M, de Greef R, van Aarle F, McCrary Sisk C, Stegmann BJ. Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation. Br J Clin Pharmacol. 2016 Jul;82(1):74-82. doi: 10.1111/bcp.12939. Epub 2016 May 31.
• Griesinger G, Verweij PJ, Gates D, Devroey P, Gordon K, Stegmann BJ, Tarlatzis BC. Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol. PLoS One. 2016 Mar 7;11(3):e0149615. doi: 10.1371/journal.pone.0149615. eCollection 2016.
• Broekmans FJ, Verweij PJ, Eijkemans MJ, Mannaerts BM, Witjes H. Prognostic models for high and low ovarian responses in controlled ovarian stimulation using a GnRH antagonist protocol. Hum Reprod. 2014 Aug;29(8):1688-97. doi: 10.1093/humrep/deu090. Epub 2014 Jun 5.
• Leader A, Devroey P, Witjes H, Gordon K. Corifollitropin alfa or rFSH treatment flexibility options for controlled ovarian stimulation: a post hoc analysis of the Engage trial. Reprod Biol Endocrinol. 2013 Jun 11;11:52. doi: 10.1186/1477-7827-11-52.
• Fauser BC, Alper MM, Ledger W, Schoolcraft WB, Zandvliet A, Mannaerts BM; Engage Investigators. Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF. Reprod Biomed Online. 2010 Nov;21(5):593-601. doi: 10.1016/j.rbmo.2010.06.032. Epub 2010 Jun 30.
• Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC; ENGAGE Investigators. A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod. 2009 Dec;24(12):3063-72. doi: 10.1093/humrep/dep291. Epub 2009 Aug 14. Erratum In: Hum Reprod. 2014 May;29(5):1116-20.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 27, 2006
• Primary Completion (ACTUAL): November 19, 2007
• Study Completion (ACTUAL): January 15, 2008

Study Registration Dates

• First Submitted: June 11, 2008
• First Submitted That Met QC Criteria: June 11, 2008
• First Posted (ESTIMATE): June 13, 2008

Study Record Updates

• Last Update Posted (ACTUAL): February 3, 2022
• Last Update Submitted That Met QC Criteria: February 1, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Infertility; Randomized; Double-blind; Multi-center; Hormones; Non-inferiority; Multi-national; Active-controlled; Pharmacological effect of drugs; Hormone substitutes and hormone antagonists; Pharmacological actions
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Progestins; Follicle Stimulating Hormone; Progesterone; Ganirelix
• Other Study ID Numbers: P05787; 2004-004771-11 (EUDRACT_NUMBER); 38819 (OTHER: Organon); 8962-011 (OTHER: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Study Data/Documents

1. CSR Synopsis