Clinical trial NCT00696878: Corifollitropin Alfa in Participants Undergoing Repeated Controlled Ovarian Stimulation (COS) Cycles Using a Multiple Dose Gonadatropin Releasing Hormone (GnRH) Antagonist Protocol (Study 38825)(P05714)
Official title: A Phase III, Uncontrolled Trial to Assess the Non-immunogenicity and Safety of Org 36286 in Patients Undergoing Repeated Controlled Ovarian Stimulation Cycles Using a Multiple Dose GnRH Antagonist Protocol
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: In Vitro Fertilization
Keywords: Infertility
Pharmacological effects of drugs
Hormones, Hormone Substitutes and Hormone Antagonists
Pharmacological Actions
Multi-center
Lead sponsor: Organon and Co
Sponsor class: INDUSTRY
First posted: 2008-06-13
Enrollment: 682
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 39
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The objective of the trial is to assess the non-immunogenicity and safety of corifollitropin alfa (also known as Org 36286, SCH 900962 and MK-8962) in participants undergoing repeated COS cycles using a multiple dose GnRH antagonist protocol.

Detailed description: This trial is designed as an open-label, uncontrolled, repeated cycle trial to assess the non-immunogenicity and safety of corifollitropin alfa in participants undergoing repeated COS cycles for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) using a multiple dose GnRH antagonist protocol. The trial period per participant will cover 1, 2 or 3 COS treatment cycles and no more than three (in-between two stimulation cycles) Frozen-Thawed Embryo Transfer (FTET) cycles following either or both of the first two treatment cycles. In each stimulation cycle, participants receive a single injection of corifollitropin alfa and one week later, treatment is continued with a daily dose of any FSH-containing preparation up to the day of (rec)hCG administration for final oocyte maturation. Assessment of anti-corifollitropin alfa antibodies and local tolerance after corifollitropin alfa injection are important safety endpoints in this trial.

Eligibility criteria: Inclusion Criteria:

* Females of couples with an indication for COS and IVF or ICSI;
* \>=18 and \<=39 years of age at the time of signing informed consent;
* Body weight \> 60 kg and body mass index (BMI) \>=18 and \<=29 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 history of ovarian hyperstimulation syndrome (OHSS);
* History of or current polycystic ovary syndrome (PCOS);
* More than 20 basal antral follicles (size: \<11 mm, both ovaries combined) as measured on 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 hydrosalpinx (visible on USS);
* More than three unsuccessful COS cycles since the last established ongoing pregnancy (if applicable);
* History of non- or low ovarian response to FSH/human menopausal gonadotrophin (hMG) treatment;
* FSH \> 12 IU/L or luteinizing hormone (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, including abnormal cervical smear (Papanicolaou \[PAP\]\>=III, cervical intraepithelial neoplasia \[CIN\]\>=1);
* Contraindications for the use of gonadotropins (e.g. tumors, pregnancy/lactation, undiagnosed vaginal bleeding, hypersensitivity, ovarian cysts) or GnRH antagonists (e.g. hypersensitivity, pregnancy/lactation);
* Recent history of or current epilepsy, human immunodeficiency virus (HIV) infection, thrombophilia, diabetes or cardiovascular, gastro-intestinal, hepatic, renal, or pulmonary disease;
* Abnormal karyotyping of the participant or her partner (if karyotyping is performed);
* History or presence of alcohol or drug abuse within 12 months prior to signing informed consent;
* Previous use of corifollitropin alfa;
* Use of hormonal preparations within 1 month prior to screening;
* Administration of investigational drugs within three months prior to signing informed consent.

Primary outcomes:
measure: Percentage of Participants With Clinically Relevant Immunogenicity
timeFrame: Pre-dose (Stimulation Day 1) and up to approximately 40 days post dose in each treatment cycle
measure: Local Tolerance at Injection Site: Number of Participants With no Event of Itching and With Mild, Moderate and Severe Itching in Any of 3 Treatment Cycles
timeFrame: 30 minutes post dose in each treatment cycle
measure: Local Tolerance at Injection Site: Number of Participants With no Event of Pain and With Mild, Moderate and Severe Pain in Any of 3 Treatment Cycles
timeFrame: 30 minutes post dose in each treatment cycle
measure: Local Tolerance at Injection Site: Number of Participants With no Event of Redness and With Mild, Moderate and Severe Redness in Any of 3 Treatment Cycles
timeFrame: 30 minutes post dose in each treatment cycle
measure: Local Tolerance at Injection Site: Number of Participants With no Event of Swelling and With Mild, Moderate and Severe Swelling in Any of 3 Treatment Cycles
timeFrame: 30 minutes post dose in each treatment cycle
measure: Local Tolerance at Injection Site Overall Summary: Number of Participants With no Local Tolerance Event (Itching, Pain, Redness or Swelling) and With a Mild, Moderate and Severe Local Tolerance Event in Any of 3 Treatment Cycles
timeFrame: 30 minutes post dose in each treatment cycle
measure: Number of Participants With AEs
timeFrame: Up to approximately 26 months after first dose of corifollitropin alfa
measure: Number of Participants With Serious AEs (SAEs)
timeFrame: Up to approximately 26 months after first dose of corifollitropin alfa
measure: Number of Participants With Moderate to Severe Ovarian Hyperstimulation Syndrome (OHSS)
timeFrame: Up to approximately 1 month after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), within a treatment cycle
Secondary outcomes:
measure: Amount of (Rec)FSH Needed From Stimulation Day 8 Onwards to Reach the Criterion for Administration of (Rec)hCG
timeFrame: Stimulation Day 8 to day of (rec)hCG administration (approximately Stimulation Day 10), within a treatment cycle
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Stimulation Day 1 During Treatment Cycle 1
timeFrame: Stimulation Day 1 in Treatment Cycle 1
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Stimulation Day 1 During Treatment Cycle 2
timeFrame: Stimulation Day 1 in Treatment Cycle 2
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Stimulation Day 1 During Treatment Cycle 3
timeFrame: Stimulation Day 1 in Treatment Cycle 3
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Stimulation Day 5 or 6 During Treatment Cycle 1
timeFrame: Stimulation Day 5 or 6 in Treatment Cycle 1
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Stimulation Day 5 or 6 During Treatment Cycle 2
timeFrame: Stimulation Day 5 or 6 in Treatment Cycle 2
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Stimulation Day 5 or 6 During Treatment Cycle 3
timeFrame: Stimulation Day 5 or 6 in Treatment Cycle 3
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Stimulation Day 8 During Treatment Cycle 1
timeFrame: Stimulation Day 8 in Treatment Cycle 1
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Stimulation Day 8 During Treatment Cycle 2
timeFrame: Stimulation Day 8 in Treatment Cycle 2
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Stimulation Day 8 During Treatment Cycle 3
timeFrame: Stimulation Day 8 in Treatment Cycle 3
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Day of (Rec)hCG Administration During Treatment Cycle 1
timeFrame: Day of (rec)hCG administration (approximately Stimulation Day 10) in Treatment Cycle 1
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Day of (Rec)hCG Administration During Treatment Cycle 2
timeFrame: Day of (rec)hCG administration (approximately Stimulation Day 10) in Treatment Cycle 2
measure: Number of Follicles ≥11 mm, ≥15 mm and ≥17 mm Documented by Ultrasonography Performed in the Participant on Day of (Rec)hCG Administration During Treatment Cycle 3
timeFrame: Day of (rec)hCG administration (approximately Stimulation Day 10) in Treatment Cycle 3
measure: Number of Oocytes Retrieved in a Participant Among Entire Study Population
timeFrame: Day of oocyte pick-up, 34-36 hours after (rec)hCG administration (approximately Stimulation Day 10), within a treatment cycle
measure: Quality of Oocytes Assessed Prior to Planned ICSI in Treatment Cycle 1
timeFrame: Day of oocyte pick-up, 34-36 hours after (rec)hCG administration (approximately Stimulation Day 10), in Treatment Cycle 1
measure: Quality of Oocytes Assessed Prior to Planned ICSI in Treatment Cycle 2
timeFrame: Day of oocyte pick-up, 34-36 hours after (rec)hCG administration (approximately Stimulation Day 10), in Treatment Cycle 2
measure: Quality of Oocytes Assessed Prior to Planned ICSI in Treatment Cycle 3
timeFrame: Day of oocyte pick-up, 34-36 hours after (rec)hCG administration (approximately Stimulation Day 10), in Treatment Cycle 3
measure: Number of Fertilized Oocytes Obtained in Treatment Cycle 1
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 1
measure: Number of Fertilized Oocytes Obtained in Treatment Cycle 2
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 2
measure: Number of Fertilized Oocytes Obtained in Treatment Cycle 3
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 3
measure: Number of Fertilized Oocytes Obtained That Were Frozen in Treatment Cycle 1
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 1
measure: Number of Fertilized Oocytes Obtained That Were Frozen in Treatment Cycle 2
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 2
measure: Number of Fertilized Oocytes Obtained That Were Frozen in Treatment Cycle 3
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 3
measure: Number of Fertilized Oocytes Obtained That Were Used for Embryo Development in Treatment Cycle 1
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 1
measure: Number of Fertilized Oocytes Obtained That Were Used for Embryo Development in Treatment Cycle 2
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 2
measure: Number of Fertilized Oocytes Obtained That Were Used for Embryo Development in Treatment Cycle 3
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 3
measure: Fertilization Rate
timeFrame: 16-18 hours after start of IVF or ICSI, which occurs on day of oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), within a treatment cycle
measure: Number and Quality of Embryos Obtained at Day 3 After Oocyte Pick-up in Treatment Cycle 1
timeFrame: Day 3 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 1
measure: Number and Quality of Embryos Obtained at Day 3 After Oocyte Pick-up in Treatment Cycle 2
timeFrame: Day 3 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 2
measure: Number and Quality of Embryos Obtained at Day 3 After Oocyte Pick-up in Treatment Cycle 3
timeFrame: Day 3 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 3
measure: Number of Embryos Transferred
timeFrame: At ET, Day 3 or Day 5 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), within a treatment cycle
measure: Number of Participants by Category of Number of Good Quality Embryos Transferred in Treatment Cycle 1
timeFrame: At ET, Day 3 or Day 5 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 1
measure: Number of Participants by Category of Number of Good Quality Embryos Transferred in Treatment Cycle 2
timeFrame: At ET, Day 3 or Day 5 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 2
measure: Number of Participants by Category of Number of Good Quality Embryos Transferred in Treatment Cycle 3
timeFrame: At ET, Day 3 or Day 5 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 3
measure: Number and Quality of Embryos Obtained That Were Frozen in Treatment Cycle 1
timeFrame: Day 3 or Day 5 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 1
measure: Number and Quality of Embryos Obtained That Were Frozen in Treatment Cycle 2
timeFrame: Day 3 or Day 5 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 2
measure: Number and Quality of Embryos Obtained That Were Frozen in Treatment Cycle 3
timeFrame: Day 3 or Day 5 after oocyte pick-up (34-36 hours after [rec]hCG administration [approximately Stimulation Day 10]), in Treatment Cycle 3
measure: Implantation Rate for Participants With ET
timeFrame: Approximately 5-6 weeks after ET, within a treatment cycle
measure: Number of Participants With Biochemical Pregnancy, Clinical Pregnancy, Vital Pregnancy and Ongoing Pregnancy in Any of Treatment Cycles 1, 2 or 3
timeFrame: ≥14 days (for biochemical pregnancy), 5-6 weeks (for clinical pregnancy), 5-6 weeks to 10 weeks (for vital pregnancy) and 10 weeks up to 9 months (for ongoing pregnancy) after ET, within a treatment cycle
measure: Number of Participants With Singleton and Multiple Ongoing Pregnancy in Any of Treatment Cycles 1, 2 or 3
timeFrame: 10 weeks up to 9 months after ET, within a treatment cycle
measure: Number of Participants With Miscarriage Among Participants With Clinical Pregnancy in Any of Treatment Cycles 1, 2 or 3
timeFrame: 5-6 weeks up to 9 months after ET, within a treatment cycle
measure: Number of Participants With Miscarriage Among Participants With Vital Pregnancy in Any of Treatment Cycles 1, 2 or 3
timeFrame: 5-6 weeks up to 9 months after ET, within a treatment cycle
measure: Number of Participants With Ectopic Pregnancy Among Participants With Biochemical Pregnancy in Any of Treatment Cycles 1, 2 or 3
timeFrame: From 2 weeks up to approximately 5-6 weeks after ET, within a treatment cycle
measure: Number of Participants With Ongoing Pregnancy in Any FTET Cycle
timeFrame: 10 weeks up to 9 months after ET within an FTET cycle
measure: Cumulative Ongoing Pregnancy Rate: Percentage of Participants With Ongoing Pregnancy in Treatment Cycles 1, 2 or 3, or in Any FTET Cycle, or Who Had Ongoing Pregnancy That Was a Spontaneous Pregnancy
timeFrame: Up to approximately 26 months after first dose of corifollitropin alfa
measure: Serum Follicle Stimulating Hormone (FSH) Levels in Treatment Cycle 1
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 1
measure: Serum FSH Levels in Treatment Cycle 2
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 2
measure: Serum FSH Levels in Treatment Cycle 3
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 3
measure: Serum Luteinizing Hormone (LH) Levels in Treatment Cycle 1
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 1
measure: Serum LH Levels in Treatment Cycle 2
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 2
measure: Serum LH Levels in Treatment Cycle 3
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 3
measure: Serum Estradiol Levels in Treatment Cycle 1
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 1
measure: Serum Estradiol Levels in Treatment Cycle 2
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 2
measure: Serum Estradiol Levels in Treatment Cycle 3
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 3
measure: Serum Progesterone Levels in Treatment Cycle 1
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 1
measure: Serum Progesterone Levels in Treatment Cycle 2
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 2
measure: Serum Progesterone Levels in Treatment Cycle 3
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 3
measure: Serum Inhibin-B Levels in Treatment Cycle 1
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 1
measure: Serum Inhibin-B Levels in Treatment Cycle 2
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 2
measure: Serum Inhibin-B Levels in Treatment Cycle 3
timeFrame: Pre-dose (Stimulation Day 1) through 2 weeks after ET in Treatment Cycle 3
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
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: Rombauts L, Lambalk CB, Schultze-Mosgau A, van Kuijk J, Verweij P, Gates D, Gordon K, Griesinger G. Intercycle variability of the ovarian response in patients undergoing repeated stimulation with corifollitropin alfa in a gonadotropin-releasing hormone antagonist protocol. Fertil Steril. 2015 Oct;104(4):884-890.e2. doi: 10.1016/j.fertnstert.2015.06.027. Epub 2015 Jul 15.
citation: Norman RJ, Zegers-Hochschild F, Salle BS, Elbers J, Heijnen E, Marintcheva-Petrova M, Mannaerts B; Trust Investigators. Repeated ovarian stimulation with corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for immunogenicity. Hum Reprod. 2011 Aug;26(8):2200-8. doi: 10.1093/humrep/der163. Epub 2011 May 27.