Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00696800
First received: June 11, 2008
Last updated: August 21, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
In Vitro Fertilization
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
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Percentage of Participants With an Ongoing Pregnancy (Ongoing Pregnancy Rate) [ Time Frame: Assessed at least 10 weeks after embryo transfer (up to 1 year) ] [ Designated as safety issue: No ]
    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.

  • Mean Number of Oocytes Retrieved [ Time Frame: Up to 36 hours after administration of hCG (up to 1 year) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Median Amount of Recombinant FSH Needed to Induce Multifollicular Development Starting at Day 1 [ Time Frame: From Day 1 to day of hCG treatment (up to 1 year) ] [ Designated as safety issue: No ]
    The amount of recFSH administered for a participant to reach 3 follicles >= 17 mm, starting from treatment Day 1 onwards.

  • Median Amount of Recombinant FSH Needed to Induce Multifollicular Development Starting at Day 8 [ Time Frame: From Day 8 to Day of hCG treatment (up to 1 year) ] [ Designated as safety issue: No ]
    The amount of recFSH administered for a participant to reach 3 follicles >= 17 mm, starting from treatment Day 8 onwards.

  • Serum FSH Levels During Stimulation [ Time Frame: Up to day of hCG treatment (up to 1 year) ] [ Designated as safety issue: No ]
    Mean serum FSH are presented over one Controlled Ovarian Stimulation (COS) cycle: from Day 1 (Pre-dose) up to the day of hCG treatment.

  • Serum Luteinizing Hormone (LH) Levels During Stimulation [ Time Frame: Up to day of hCG treatment (up to 1 year) ] [ Designated as safety issue: No ]
    Mean serum LH levels are presented over one COS cycle: from Day 1 (Pre-dose) up to the day of hCG treatment.

  • Serum Estradiol (E2) Levels During Stimulation [ Time Frame: Up to day of hCG treatment (up to 1 year) ] [ Designated as safety issue: No ]
    Mean serum E2 levels are presented over one COS cycle: from Day 1 (Pre-dose) up to the day of hCG treatment.

  • Serum Progesterone (P) Levels During Stimulation [ Time Frame: Up to day of hCG treatment (up to 1 year) ] [ Designated as safety issue: No ]
    Mean serum P levels are presented over one COS cycle: from Day 1 (Pre-dose) up to day of hCG treatment

  • Serum Inhibin-B Levels During Stimulation [ Time Frame: Up to day of hCG treatment (up to 1 year) ] [ Designated as safety issue: No ]
    Mean serum Inhibin-B levels are presented over one COS cycle: from Day 1 (Pre-dose) up to day of hCG treatment

  • Number of Follicles Categorized by Size on Stimulation Day 1 [ Time Frame: On Day 1 of treatment (up to 1 year) ] [ Designated as safety issue: No ]
    Ovaries were assessed during stimulation by ultrasonographic investigation (USS), and the mean number of follicles are categorized by their size.

  • Number of Follicles Categorized by Size on Stimulation Day 5 [ Time Frame: On Day 5 of treatment (up to 1 year) ] [ Designated as safety issue: No ]
    Ovaries were assessed during stimulation by USS, and the mean number of follicles are categorized by their size.

  • Number of Follicles Categorized by Size on Stimulation Day 8 [ Time Frame: On Day 8 of treatment (up to 1 year) ] [ Designated as safety issue: No ]
    Ovaries were assessed during stimulation by USS, and the mean number of follicles are categorized by their size.

  • Number of Follicles Categorized by Size on the Day of hCG [ Time Frame: Day of HCG treatment (up to 1 year) ] [ Designated as safety issue: No ]
    Ovaries were assessed during stimulation by USS, and the mean number of follicles are categorized by their size.

  • Number of Cumulus-oocyte-complexes [ Time Frame: Up to 36 hours after administration of hCG (up to 1 year) ] [ Designated as safety issue: No ]
    Prior to IVF the mean number of cumulus-oocyte-complexes used for IVF was assessed

  • Number of Oocytes Assessed Prior to Intracytoplasmic Sperm Injection (ICSI) [ Time Frame: Up to 36 hours after administration of hCG (up to 1 year) ] [ Designated as safety issue: No ]
    The number of oocytes used for ICSI was assessed, and categorized based on their quality

  • Percentage of Fertilized Oocytes (Fertilization Rate) [ Time Frame: Up to 18 hours after start of fertilization (up to 1 year) ] [ Designated as safety issue: No ]
    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

  • Number of Embryos Obtained on Day 3 Categorized by Quality [ Time Frame: Post fertilization Day 3 (up to 1 year) ] [ Designated as safety issue: No ]
    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.

  • Number of Embryos Transferred on Day 3 [ Time Frame: Post fertilization Day 3 (up to 1 year) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Gestational Sacs (Implantation Rate) [ Time Frame: Up to 6 weeks after embryo transfer (up to 1 year) ] [ Designated as safety issue: No ]
    The implantation rate is 100 times the number of gestational sacs assessed by USS after embryo transfer, divided by the number of embryos transferred.

  • Percentage of Participants With a Miscarriage (Miscarriage Rate) Per Clinical Pregnancy [ Time Frame: Up to day of miscarriage (up to 1 year) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With a Miscarriage (Miscarriage Rate) Per Vital Pregnancy [ Time Frame: Up to day of miscarriage (up to 1 year) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With a Biochemical Pregnancy (Pregnancy Rate) Per Attempt [ Time Frame: Two weeks after embryo transfer (up to 1 year) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With a Biochemical Pregnancy (Pregnancy Rate) Per Embryo Transfer [ Time Frame: Two weeks after embryo transfer (up to 1 year) ] [ Designated as safety issue: No ]
    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.


Enrollment: 1509
Study Start Date: June 2006
Study Completion Date: January 2008
Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • MK-8962
  • SCH 900962
  • Org 36286
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 Name: 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 Name: 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 Name: 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 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 Name: 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.
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 Name: 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 Name: 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 Name: 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.

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

Ages Eligible for Study:   18 Years to 36 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00696800

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

No publications provided by Merck Sharp & Dohme Corp.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00696800     History of Changes
Other Study ID Numbers: P05787, 2004-004771-11, 38819, 8962-011
Study First Received: June 11, 2008
Results First Received: August 6, 2014
Last Updated: August 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Merck Sharp & Dohme Corp.:
Infertility
Pharmacological effect of drugs
Hormones
Hormone substitutes and hormone antagonists
Pharmacological actions
Randomized
Multi-center
Multi-national
Double-blind
Active-controlled
Non-inferiority

Additional relevant MeSH terms:
Follicle Stimulating Hormone
Ganirelix
Hormones
Progesterone
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Pharmacologic Actions
Physiological Effects of Drugs
Progestins

ClinicalTrials.gov processed this record on November 19, 2014