Administration of Follicle-stimulating Hormone (FSH) and Low Dose Human Chorionic Gonadotropin (hCG) for Oocyte Maturity While Decreasing hCG Exposure in In Vitro Fertilization (IVF) Cycles
Condition: Infertility
MeSH terms: Infertility
Study type: Interventional
Phase: Phase 3

Summary: 
      This is a randomized, double-blind, single center clinical trial study to compare oocyte
      competence and risk of ovarian hyperstimulation syndrome (OHSS) after receiving the standard
      dose of human chorionic gonadotropin (hCG) ovulation trigger or a lower dose of hCG plus
      concomitant follicle stimulating hormone (FSH) co-trigger in women undergoing in vitro
      fertilization (IVF).
    

Detailed description: 
      The success rate of assisted reproductive technology (ART) has dramatically increased due to
      the improvements in embryo culture, laboratory conditions, and optimization of different
      ovarian stimulation protocols. Recent data shows that if hCG is not administered for oocyte
      maturation, severe OHSS is very rare. However, with gonadotropin releasing hormone (GnRH)
      agonist cycles, hCG is required. Previous studies have revealed that a smaller dose of hCG
      used for ovulation trigger versus the standard dose can have the same effect on the induction
      of final oocyte maturation and can possibly reduce the risk of OHSS . However, the minimal
      dose required of hCG to maintain maximal success rates of IVF is not known as it has not been
      adequately studied in randomized controlled trials. Interestingly, our previous randomized
      controlled study revealed that concomitant administration of FSH and hCG (10,000 IU), a more
      physiological process, improved developmental oocyte competence. In that study, there was no
      OHSS in the group that received the FSH co-trigger. A subsequent study performed a randomized
      trial to determine if FSH co-trigger reduced the incidence of OHSS and found that, it may
      prevent OHSS. Additionally, our own clinical experience (unpublished data) reveals that
      administering 1,500 IU hCG plus 450 IU FSH co-trigger is enough to promote adequate (i.e.
      non-inferior) oocyte maturation while not increasing the risk of developing OHSS in high risk
      patients. Given these findings, we propose a further modification of ovulation trigger with
      decreased exposure to hCG. Our objective is to determine if concomitant administration of FSH
      with a decreased dose of hCG versus a standard dose of hCG alone for ovulation will promote
      adequate oocyte maturation and quality, while decreasing the risk of OHSS. The selected FSH
      dose of 450 IU is thought to parallel the physiologic FSH surge observed in a natural cycle.
      We have chosen 1,500 IU as the designated low dose of hCG based on previous studies showing
      that even hCG doses as low as 2,000 IU allows oocytes to undergo maturation as well as our
      own clinical experience that has demonstrated adequate oocyte maturity and fertilization in
      patients chosen to receive 1,500 IU of hCG, due to the risk of OHSS.

      Study participants will be recruited from the Reproductive Endocrinology and Infertility
      Clinic at University of California at San Francisco Center for Reproductive Health. Couples
      undergoing IVF will be offered participation in the study.

      Approximately 100 subjects will be randomized at the time of enrollment to receive either the
      standard dose of hCG alone or low dose hCG (1,500 IU) + FSH (450 IU) for oocyte maturation
      trigger by the research coordinator. There will be about 50 subjects in each study arm.

      Each subject will undergo a standard IVF stimulation protocol chosen by their primary
      physician. Study participants will receive a syringe (prepared by the research coordinator)
      on the day of ovulation trigger containing either the standard dose of hCG or low dose hCG +
      FSH according to the randomization. The subjects will be triggered with the following:

        1. Control arm: Standard dose of hCG (10,000 or 5,000 IU) or

        2. Experimental arm: hCG 1,500 IU SQ + FSH 450 IU SQ.

      For the control arm, the standard hCG dose will be given based on the estradiol (E2) level.
      If the E2 level is less than 3,500 pg/ml then we will trigger with 10,000 IU of hCG. If the
      E2 level is more than 3,500 pg/ml but less than 5,000 pg/ml then we will trigger with 5,000
      IU.

      Interventions to prevent OHSS in high risk patients:

      Any patients in either arm with an E2 serum level >5,000 pg/ml on the day of expected trigger
      administration will be excluded from the study. These patients will be individually assessed
      by their primary physician. Their primary physician will decide the safest trigger option
      based on the patient's risk of OHSS. From our own clinical experience, we expect that <5% of
      subjects will have an E2 serum level of >5,000 pg/ml and be excluded.

      The hCG and FSH trigger shots for each patient will be prepared by one unblinded physician
      the same day the patient will administer the medications. The subjects will self-administer
      the ovulation trigger at the designated time given by the primary physician.

      The oocyte retrieval will be performed 36 hours after the oocyte maturation trigger. All egg
      retrievals will be performed using transvaginal ultrasound and the associated needle guide in
      the standard fashion. Both the physician and the laboratory personnel will be blinded to the
      study. All visible follicles will be aspirated. The first follicle from each ovary on every
      patient will be aspirated and the system (needle and tubing) will be flushed into a separate
      tube prior to aspirating the remaining follicles so that direct correlation of follicular
      size to oocyte recovery maturation, and embryo development can be separately assessed.
      Additionally, the follicular fluid from the first aspirate will be collected for future
      hormone assays. Oocyte stripping will be performed under the standard protocol. The status of
      oocyte maturation at the time of stripping (approximately 38-40 hours after hCG
      administration) and at the end of the intracytoplasmic sperm injection (ICSI) procedure
      (approximately 40-42 hours after hCG administration) will be recorded. Fertilization will be
      assessed 16-19 hours after insemination. The embryos will be transferred to growth media and
      cultured with standard protocols.

      Subjects will return 12 hours after trigger (T+1), at oocyte retrieval (T+2), and 5 days
      after trigger (T+5) to assess serum levels of estradiol, progesterone, hCG, FSH, LH, and
      vascular endothelial growth factor (VEGF), as appropriate, based on the study visit day.

      To assess the incidence of OHSS, patients will be evaluated objectively by a change in the
      abdominal circumference as well as subjectively by clinical symptomatology based on patient's
      bloating symptoms.

      Prior to starting the stimulation, the abdominal circumference (C) and body weight (BW) will
      also be measured in centimeters at the baseline ultrasound visit (C baseline, BW baseline).
      Five days after the oocyte retrieval the abdominal circumference and body weight will again
      be measured in centimeters (C stimulated, BW stimulated). The difference in the abdominal
      circumference and body weight will be calculated as follows: C baseline - C stimulated = CΔ.;
      BW baseline - BW stimulated = BWΔ.

      The patient's clinical symptoms will be evaluated based on a bloating score reported by each
      patient before the trigger shot is administered and then 5 days after the oocyte retrieval
      will be determined. A venipuncture will also be obtained for hormone assays 5 days after
      oocyte retrieval.

      Patients diagnosed with OHSS will be managed by a physician as clinically indicated. The
      number of follow-up clinic visits and hospitalizations secondary to symptoms of OHSS will be
      recorded.
    

Intervention name(s): Low dose hCG plus FSH co-trigger; Standard dose of hCG
Intervention type(s): Drug; Drug
Intervention description(s): Low dose hCG (1,500 IU) plus FSH (450 IU) co-trigger; Standard dose of hCG (10,000 or 5,000 IU) trigger
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Infertility; In vitro fertilization; IVF