Clinical trial NCT00696800: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: In Vitro Fertilization
Keywords: Infertility
Pharmacological effect of drugs
Hormones
Hormone substitutes and hormone antagonists
Pharmacological actions
Randomized
Multi-center
Multi-national
Double-blind
Active-controlled
Non-inferiority
Lead sponsor: Organon and Co
Sponsor class: INDUSTRY
First posted: 2008-06-13
Enrollment: 1509
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 36
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With an Ongoing Pregnancy (Ongoing Pregnancy Rate)
timeFrame: Assessed at least 10 weeks after embryo transfer (up to 1 year)
measure: Mean Number of Oocytes Retrieved
timeFrame: Up to 36 hours after administration of hCG (up to 1 year)
Secondary outcomes:
measure: Median Amount of Recombinant FSH Needed to Induce Multifollicular Development Starting at Day 1
timeFrame: From Day 1 to day of hCG treatment (up to 1 year)
measure: Median Amount of Recombinant FSH Needed to Induce Multifollicular Development Starting at Day 8
timeFrame: From Day 8 to Day of hCG treatment (up to 1 year)
measure: Serum FSH Levels During Stimulation
timeFrame: Up to day of hCG treatment (up to 1 year)
measure: Serum Luteinizing Hormone (LH) Levels During Stimulation
timeFrame: Up to day of hCG treatment (up to 1 year)
measure: Serum Estradiol (E2) Levels During Stimulation
timeFrame: Up to day of hCG treatment (up to 1 year)
measure: Serum Progesterone (P) Levels During Stimulation
timeFrame: Up to day of hCG treatment (up to 1 year)
measure: Serum Inhibin-B Levels During Stimulation
timeFrame: Up to day of hCG treatment (up to 1 year)
measure: Number of Follicles Categorized by Size on Stimulation Day 1
timeFrame: On Day 1 of treatment (up to 1 year)
measure: Number of Follicles Categorized by Size on Stimulation Day 5
timeFrame: On Day 5 of treatment (up to 1 year)
measure: Number of Follicles Categorized by Size on Stimulation Day 8
timeFrame: On Day 8 of treatment (up to 1 year)
measure: Number of Follicles Categorized by Size on the Day of hCG
timeFrame: Day of HCG treatment (up to 1 year)
measure: Number of Cumulus-oocyte-complexes
timeFrame: Up to 36 hours after administration of hCG (up to 1 year)
measure: Number of Oocytes Assessed Prior to Intracytoplasmic Sperm Injection (ICSI)
timeFrame: Up to 36 hours after administration of hCG (up to 1 year)
measure: Percentage of Fertilized Oocytes (Fertilization Rate)
timeFrame: Up to 18 hours after start of fertilization (up to 1 year)
measure: Number of Embryos Obtained on Day 3 Categorized by Quality
timeFrame: Post fertilization Day 3 (up to 1 year)
measure: Number of Embryos Transferred on Day 3
timeFrame: Post fertilization Day 3 (up to 1 year)
measure: Percentage of Gestational Sacs (Implantation Rate)
timeFrame: Up to 6 weeks after embryo transfer (up to 1 year)
measure: Percentage of Participants With a Miscarriage (Miscarriage Rate) Per Clinical Pregnancy
timeFrame: Up to day of miscarriage (up to 1 year)
measure: Percentage of Participants With a Miscarriage (Miscarriage Rate) Per Vital Pregnancy
timeFrame: Up to day of miscarriage (up to 1 year)
measure: Percentage of Participants With a Biochemical Pregnancy (Pregnancy Rate) Per Attempt
timeFrame: Two weeks after embryo transfer (up to 1 year)
measure: Percentage of Participants With a Biochemical Pregnancy (Pregnancy Rate) Per Embryo Transfer
timeFrame: Two weeks after embryo transfer (up to 1 year)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.