Efficacy of Corifollitropin Alfa Versus Follitropin Beta in Aged IVF (In-vitro Fertilization) Patients

• ClinicalTrials.gov Identifier: NCT02466204
• Recruitment Status: Completed
• First Posted: June 9, 2015
• Last Update Posted: August 22, 2017
• Sponsor: Vietnam National University
• Collaborators: Merck Sharp & Dohme Corp.; Mỹ Đức Hospital
• Information provided by (Responsible Party): Manh Tuong Ho, Vietnam National University

Study Description

Brief Summary:

A prospective, randomized, controlled study to explore the efficacy and safety of using either corifollitropin alfa 150 mcg or daily recombinant follicle stimulation hormone (FSH) 300 international unit (IU) for the stimulation treatment of subjects undergoing controlled ovarian stimulation prior to IVF.

The study is designed as a non-inferiority trial. The sample size for this trial of 400 subjects, in both groups, being treated for one IVF cycle is based upon the primary endpoint of the number of oocytes retrieved.

Condition or disease	Intervention/treatment	Phase
Infertility	Drug: corifollitropin alfa; Drug: Follitropin Beta	Phase 4

Detailed Description:

Stimulation regimen and assisted reproductive technology procedures

Corifollitropin Alfa Group: On day 2 or day 3 of the menstrual cycle, a single subcutaneous injection of corifollitropin alfa 150 mg/ 0.5 mL is administered (stimulation day 1).

FSH Group: Daily subcutaneous injections with recombinant FSH (Follitropin Beta) 300 international units (IU) is started on On day 2 or day 3 of the menstrual cycle (stimulation day 1) and continue up to and including stimulation day 7.

From stimulation day 8 onwards, subjects from both treatment groups will continue with a daily subcutaneous dose of FSH up to the day before human chorionic gonadotropin (hCG) administration or gonadotropin releasing hormone agonist administration day. The maximum FSH dose to continue treatment after the first 7 days is 300 IU, but the dose could be reduced when desired.

To prevent premature luteinizing hormone (LH) surges the gonadotropin releasing hormone (GnRH) antagonist (ganirelix acetate subcutaneous injection, 0.25 mg/ 0.5 mL) is administered, starting on stimulation day 5.

As soon as at least three follicles of 17 mm are observed by ultrasound, hCG or a GnRH agonist will be used for final oocyte maturation at the same day. hCG is used if 3-18 follicles and 0.2 mg triptorelin is administered if ≥ 19 follicles >11 mm are observed. About 34-36 hours thereafter, oocyte retrieval followed by IVF or intra-cytoplasmic sperm injection (ICSI) is performed. Three days after oocyte pick-up, 2 to 3 fresh embryos will be transferred. If patients have high progesterone level on day of trigger (progesterone level > 1,5 ng/ml), risk of OHSS and unfavorable endometrium, fresh transfers will be cancelled and freeze all will be recommended.

Patients using hCG for final oocyte maturation will receive luteal phase support with progestogen gel (90 mg once daily) intra-vaginally and estradiol (4 mg/day orally, twice daily) initiated on the day of oocyte retrieval or the day thereafter. Patients, using GnRH agonist for triggering, will have fresh transfer with intense luteal phase support of estradiol and progesterone (receive intense luteal phase support with estradiol and progesterone as the same dose mentioned above and progesterone 50 mg intramuscular injection per day).

Assessments

Patients will return to the clinic for pregnancy test 2 weeks after embryo transfers.

Local tolerance parameters (pain, itching, swelling and redness) are assessed by the clinical staff 30 min after injection for both corifollitropin alfa and FSH injection sites.

Clinical Outcome The primary objective is to show that the corifollitropin alfa regimen, in terms of the number of oocytes retrieved, is equivalent to the reference treatment (predefined equivalence range: -3 to +5 oocytes).

Other clinical parameters will also be evaluated: dose of FSH required, duration of stimulation, number and size of follicles (≥11mm and ≥14 mm), serum hormone levels, fertilization rate, number and quality of embryos obtained, implantation rate, miscarriage rate, and pregnancy rates.

At least 14 days after embryo transfer, a blood pregnancy test is performed. If the pregnancy test is positive, vaginal and/or abdominal ultrasonographic investigation is performed between 35 and 42 days ( 5 to 6 weeks) after embryo transfer to confirm a clinical pregnancy and at least 70 days (≥ 10 weeks) after embryo transfer to confirm an ongoing pregnancy.

Patients will be followed to one year after randomization.

All efficacy analyses will be based on the intent-to-treat (ITT) population, which included all randomized patients who will receive corifollitropin alfa or at least one dose of FSH

Safety endpoints

Occurrence of adverse events, including moderate and severe ovarian hyperstimulation syndrome (OHSS), outcome of local tolerance at injection site assessments will be evaluated as safety endpoints.

The percentage of patients with moderate or severe OHSS and local tolerance is compared between the treatment groups using Fisher's exact test.

Safety analyses will be performed on the all-subjects-treated group, which comprised all the patients who will receive either corifollitropin alfa or FSH.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Efficacy and Safety Study of Corifollitropin Alfa Versus Daily Follitropin Beta for Controlled Ovarian Stimulation in Women 35-42 Years Old With a Body Weight ≥ 50 kg Undergoing IVF Treatment.
• Actual Study Start Date: June 1, 2015
• Actual Primary Completion Date: August 10, 2016
• Actual Study Completion Date: August 15, 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: corifollitropin alfa (long action FSH); corifollitropin alfa 150 mcg subcutaneous injection. Seven days after, combines with recombinant FSH 300 IU daily subcutaneous injection	Drug: corifollitropin alfa; Drug is injected subcutaneously. Seven days after, 300 IU FSH daily injected subcutaneously, until at least two leading ovarian follicles reach 17mm in diameter.; Other Name: Elonva
Active Comparator: Follitropin Beta (recombinant FSH); 300 IU of recombinant FSH, daily subcutaneous injection	Drug: Follitropin Beta; Drug is injected subcutaneously, daily, until at least two leading ovarian follicles reach 17mm in diameter.; Other Name: Puregon

Outcome Measures

Primary Outcome Measures :

1. number of oocytes [ Time Frame: 10 minutes after oocyte retrieval completed ]
   in 10 minutes after oocyte retrieval, total number of oocytes retrieved is counted and recorded

Secondary Outcome Measures :

1. Rate of moderate and severe ovarian hyperstimulation syndrome [ Time Frame: 8 days after oocyte retrieval ]
   symptoms of ovarian hyperstimulation syndrome are followed and recorded until 8 days after oocyte retrieval.
2. Live birth [ Time Frame: at the time of delivery ]
   delivery of live birth
3. number of MII oocytes [ Time Frame: 2 hours after oocyte retrieval completed ]
   Number of mature oocytes collected
4. number of 2PN [ Time Frame: 18 hours after sperm injection ]
   number of two pronuclear (2PN) fertilized oocytes
5. number of mature follicles >11 mm [ Time Frame: on the day of hCG administration ]
   number of mature follicles >11 mm in diameter
6. estradiol level [ Time Frame: on the day of hCG administration ]
   serum level of estradiol
7. FSH dose [ Time Frame: calculated on the day of hCG administration ]
   total dose of FSH
8. implantation rate [ Time Frame: 5 to 6 weeks after embryo transfer ]
   number of sacs with heart beat per total number of embryos transferred
9. Clinical pregnancy [ Time Frame: at 5 to 6 six weeks after embryo transfer ]
   gestational sac on ultrasound
10. Ectopic pregnancy [ Time Frame: 7 to 8 weeks after embryo transfer ]
    The presence of a gestational sac outside the uterine cavity shown on sonography or laparoscopy
11. Miscarriage [ Time Frame: 7 to 12 weeks of gestation ]
    Loss of clinical pregnancy
12. Multiple pregnancy [ Time Frame: at 7 weeks of gestation ]
    more than one gestational sacs or heart beats on ultrasound
13. Ongoing pregnancy [ Time Frame: at 10 weeks after embryo transfer ]
    At least one gestational sac on ultrasound
14. Cumulative ongoing pregnancy [ Time Frame: at 12 months after randomization ]
    Cumulative ongoing pregnancy at 12 months after randomization
15. Pregnancy-induced hypertension [ Time Frame: measured at or after 20 weeks gestation ]
    systolic blood pressure ≥140 mmHg or diastolic pressure ≥90 mmHg on two occasions, two hours apart, or severely elevated single blood pressure measurement requiring antihypertensive medication
16. Pre-eclampsia [ Time Frame: measured at or after 20 weeks gestation ]
    hypertension plus proteinuria or other organ involvement, neurologic or hematologic complications, uteroplacental dysfunction, or fetal growth restriction
17. HELLP syndrome [ Time Frame: measured at or after 20 weeks gestation ]
    Elevated liver enzyme levels (aspartate aminotransferase ≥100 U/L), thrombocytopenia (platelet count <100,000/mm3), elevated serum creatinine level (≥1.5 mg/dL [132.6 μmol/L]) and/or hemolysis (hemoglobin <10 g/dL)
18. Gestational diabetes mellitus [ Time Frame: measured at or after 20 weeks gestation ]
    Diagnosed using a 75g oral glucose tolerance test; fasting: 92 mg/dL [5.1 mmol/L]; 2-hour: 153 mg/dL [8.5 mmol/L]
19. Prematurity [ Time Frame: at 24 weeks gestation, at 32 weeks gestation, at 34 weeks gestation, and at 37 weeks' gestation ]
    preterm birth if any
20. Cumulative live birth [ Time Frame: at 12 months after randomization ]
    cumulative live birth delivery at 12 months after randomization

Eligibility Criteria

• Ages Eligible for Study: 35 Years to 42 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Each subject must be willing and able to provide written informed consent for the study.
• Each subject must be female with years of age ≥35 to ≤42 at the time of recruitment..
• Each subject must have an indication for controlled ovarian stimulation and IVF
• Each subject must have a body weight ≥ 50.0 kg, with a body mass index (BMI) ≥18.0 to ≤32.0 kg/m2.
• Each subject must have a regular spontaneous menstrual cycle with an intra-individual variation not outside the 24 to 35 days range.
• For each subject, ejaculatory sperm must be available (use of donated and/or cryopreserved sperm is allowed; sperm obtained via surgical sperm retrieval is not allowed).
• Each subject must have results of clinical laboratory test (complete blood count, blood chemistries, and urinalysis) within normal limits or clinically acceptable to the investigator, as measured by the local laboratory at screening. A normal cervical smear result, obtained within 12 months, otherwise it must be obtained during screening.
• Each subject must have results of a physical examination, including blood pressure, within normal limits or clinically acceptable limits to the investigator.
• Each subject must have normal ovarian reserve, based on anti-Mullerian hormon (AMH) of 1.38 - 3.25ng/ml or an antral follicle count (AFC) of 7-20, taken within 2 months prior to corifollitropin alfa start.
• Each subject must be able to adhere to dose and visit schedules and willing to disclose any medical events to the investigator.

Exclusion Criteria:

• The subject has a recent (ie, within 3 years) history of/ or any current endocrine abnormality (irrespective whether the patient is stabilized on treatment).
• The subject has a history of ovarian hyper-response (ie, previous IVF cycle with more than 30 follicles ≥11 mm on ultrasound) or ovarian hyperstimulation syndrome (OHSS).
• The subject has a history of/or current polycystic ovary syndrome (PCOS)
• The subject has more 20 basal antral follicles <11 mm (both ovaries combined) as measured on ultrasound in the early follicle phase (menstrual cycle day 2-5).
• The subject has less than 2 ovaries in any other ovarian abnormality (including endometrioma > 10 mm; visible on ultrasound).
• The subject has unilateral or bilateral hydrosalpinx (visible on ultrasound, less clipped).
• The subject has any intra-uterine fibroids >5 cm or any clinically relevant pathology, which could impair embryo implantation or pregnancy continuation.
• The subject has more than three unsuccessful treatment cycles for IVF/ICSI.
• The subject has a history of non- or low avarian response to FSH / Human Menopausal Gonadotropin (hMG) treatment (ie, previous COS cycle cancelled due to insufficient ovarian response or ≤3 oocytes obtained).
• The subject has a history of current miscarriage (3 or more, even when explained).
• The subject has FSH > 15.0 IU/L or LH > 12 .0 IU/L as measured by the local laboratory (sample taken during the early follicle phase: menstrual cycle day 2 to 5).
• The subject has tested positive for human immunodeficiency virus (HIV) or Hepatitis B (results obtained within one year) .
• The subject has contra-indications for the use of gonadotropins (eg, tumors, pregnancy/lactation, undiagnosed vaginal bleeding, hypersensitivity, or ovarian cysts) or GnRH antagonist (eg, hypersensitivity, pregnancy/lactation).
• The subject has a concomitant use of either LH or hMG/urinary FSH preparations in study cycle.
• The subject has a recent history of/or current epilepsy, thrombophilia, diabetes, cardiovascular, gastro-intestinal, hepatic, renal or pulmonary or auto-immune disease requiring regular treatment.
• The subject or the sperm donor has known gene defects, genetic abnormalities, or abnormal karyotyping, relevant for the current indications or for the health of the offspring.
• The subject smokes or has recently stopped smoking (ie, within the last 3 months prior to signing ICF).
• The subject has a history or presence of alcohol or drug abuse within 12 months prior to signing informed consent.
• The subject has an allergy/ sensitivity to investigational drugs or their excipients.
• The subject has used any experimental drugs within 3 months prior to signing informed consent.
• The subject is participating in any other clinical study (excluding surveys).

Contacts and Locations

Locations

Vietnam

My Duc Hospital

Ho Chi Minh City, Vietnam, 70000

Research Center for Genetics and Reproductive Health

Ho Chi Minh City, Vietnam, 70000

Sponsors and Collaborators

Vietnam National University

Merck Sharp & Dohme Corp.

Mỹ Đức Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vuong NL, Pham DT, Phung HT, Giang HN, Huynh GB, Nguyen TTL, Ho MT. Corifollitropin alfa vs recombinant FSH for controlled ovarian stimulation in women aged 35-42 years with a body weight ≥50 kg: a randomized controlled trial. Hum Reprod Open. 2017 Nov 28;2017(3):hox023. doi: 10.1093/hropen/hox023. eCollection 2017.

• Responsible Party: Manh Tuong Ho, Doctor, Vietnam National University
• ClinicalTrials.gov Identifier: NCT02466204
• Other Study ID Numbers: NCKH/CGRH_ 01_2015
• First Posted: June 9, 2015
• Last Update Posted: August 22, 2017
• Last Verified: August 2017

Additional relevant MeSH terms:

Infertility; Follicle Stimulating Hormone; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs