Clinical trial NCT02310919: 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
Official title: Concomitant Administration of FSH With a Low Dose of hCG (1,500 IU) Has Equivalent Oocyte Developmental Competence While Decreasing the Exposure to hCG in IVF Cycles: A Double Blind Randomized Control Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infertility
Keywords: Infertility
In vitro fertilization
IVF
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Ferring Pharmaceuticals
First posted: 2014-12-08
Enrollment: 105
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 41
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria: The target population includes couples undergoing IVF. All eligible couples will be asked to join the study. Study participants will be recruited from the Reproductive Endocrinology Clinic at University of California at San Francisco Center for Reproductive Health. Patients receiving any type of stimulation protocol for IVF will be offered participation in the study.

Exclusion Criteria:

* Age \>41 years old
* Antral Follicle Count (AFC; 2-10 mm) \< 8
* Body Mass Index \> 30 kg/m2
* History of ≥ 2 prior canceled IVF cycles secondary to poor response
* Diagnosis of cancer
* Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow-up, or interpretation of study results
* Undergoing embryo co-culture
* Use of any of the following medications: Growth Hormone, Sildenafil, or Aspirin (except if being used for hypercoagulable state)
* Severe male factor infertility diagnosis. Male factor infertility diagnosis should be cleared for eligibility by the PI based on previous patient history of fertilization outcomes and/or expected fertilization outcomes of the cause of male factor infertility based on known scientific data.
* Ovulation trigger less than or greater than 36 hours to oocyte retrieval
* Serum estradiol level \>5,000 pg/ml on the day of expected trigger due to high risk of OHSS

Primary outcomes:
measure: Total Fertilization Proportion (i.e. Total Competent Proportion)
timeFrame: 2 days
Secondary outcomes:
measure: Number of Oocytes Retrieved
timeFrame: 1 day
measure: Number of MII Oocytes
timeFrame: 1 day
measure: Total Oocyte Maturity Rate
timeFrame: 1 day
measure: Mature Oocyte Recovery Proportion
timeFrame: 1 day
measure: ICSI Fertilization Rate
timeFrame: 2 days
measure: High Quality Cleavage-stage Embryos
timeFrame: 4 days
measure: High Quality Blastocyst Embryos
timeFrame: 6 days
measure: Livebirth Rate From All Fresh Transfers
timeFrame: 10 months
measure: Bloating Score
timeFrame: about 16 days (varies by subject), accounts for the median length of IVF stimulation in this study being 11 days from baseline to 5 days post trigger
measure: Abdominal Circumference
timeFrame: about 16 days (varies by subject), accounts for the median length of IVF stimulation in this study being 11 days from baseline to 5 days post trigger
measure: Body Weight
timeFrame: about 16 days (varies by subject), accounts for the median length of IVF stimulation in this study being 11 days from baseline to 5 days post trigger
measure: Serum hCG T+1
timeFrame: 1 day
measure: Serum FSH T+1
timeFrame: 1 day
measure: Serum P4 on T+1
timeFrame: 1 day
measure: Serum E2 on T+1
timeFrame: 1 day
measure: Serum LH on T+1
timeFrame: 1 day
measure: Serum hCG on T+2
timeFrame: 2 days
measure: Serum FSH on T+2
timeFrame: 2 days
measure: Serum P4 on T+2
timeFrame: 2 days
measure: Serum E2 on T+2
timeFrame: 2 days
measure: Serum HCG on T+5
timeFrame: 5 days
measure: Serum FSH on T+5
timeFrame: 5 days
measure: Serum LH on T+5
timeFrame: 5 days
measure: Follicular hCG
timeFrame: 2 days
measure: Follicular FSH
timeFrame: 2 days
measure: Follicular P4
timeFrame: 2 days
measure: Follicular E2
timeFrame: 2 days
measure: Follicular VEGF
timeFrame: 2 days
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Mitchell Rosen, M.D.
role: PRINCIPAL_INVESTIGATOR
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