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

Study Overview
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Brief Summary
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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
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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 Additionally, our own clinical experience (unpublished data) reveals that administering 1,500 IU hCG plus 450 IU FSH co-trigger is enough to promote adequate (i.e. non-inferior) oocyte maturation while not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: Control arm: Standard dose of hCG (10,000 or 5,000 IU) or 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.

Official Title
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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

Conditions
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Infertility

Intervention / Treatment
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* Drug: Low dose hCG plus FSH co-trigger
* Drug: Standard dose of hCG


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 41 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose hCG plus FSH co-trigger<br>On the day of ovulation trigger the patient will receive hCG 1,500 IU SQ plus FSH 450 IU SQ | Drug: Low dose hCG plus FSH co-trigger<br>* Low dose hCG (1,500 IU) plus FSH (450 IU) co-trigger<br>|
| Active Comparator: Standard dose of hCG alone<br>On the day of ovulation trigger the patient will receive standard dose of hCG (10,000 or 5,000 IU SQ) | Drug: Standard dose of hCG<br>* Standard dose of hCG (10,000 or 5,000 IU) trigger<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Fertilization Proportion (i.e. Total Competent Proportion) | The number of fertilized oocytes (2-pronuclei) after standard in vitro fertilization or intra-cytoplasmic sperm injection divided by the total number of oocytes retrieved as a measure of oocyte competence. | 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Oocytes Retrieved | The total number of oocytes recovered at the oocyte retrieval. | 1 day | 
| Number of MII Oocytes | The number of metaphase 2 oocytes (MII) recovered which can only be calculated in patients that underwent intracytoplasmic sperm injection. | 1 day | 
| Total Oocyte Maturity Rate | Oocyte maturity rate was determined by the number of meta phase 2 (MII) oocytes divided by the number of oocytes retrieved. This outcome was only assessed in patients undergoing intracytoplasmic sperm injection (ICSI). | 1 day | 
| Mature Oocyte Recovery Proportion | Mature oocyte recovery proportion is defined as the number of MIIs divided by the total number of follicles greater or equal to 13mm in size on trigger day. | 1 day | 
| ICSI Fertilization Rate | ICSI fertilization rate was determined by the number of 2 pro-nuclei (2PN) divided by the number of MII oocytes. This was only assessed in patients undergoing ICSI. | 2 days | 
| High Quality Cleavage-stage Embryos | Good quality embryo development was compared between trigger groups by calculating the ratio of good quality embryos to the total number of cleavage-stage embryos. A good quality cleavage-stage embryo was defined by having a cell number of 7 to 10 and <10% of cell fragmentation based on a modified Veeck's grading system. | 4 days | 
| High Quality Blastocyst Embryos | A high quality blastocyst was defined as grade 3 or higher expansion plus inner cell mass and trophectoderm grading of A or B based on Gardner's criteria. The number describes the degree of embryo expansion on a scale from 1-6. As the embryo expands, the degree of expansion increases. The first letter indicates on a scale from A to C (A being the highest) the quality of the inner cell mass. The second letter is also on a scale from A to C (A being the highest) and indicates the quality of the trophectoderm. | 6 days | 
| Livebirth Rate From All Fresh Transfers | Livebirth rate (LBR) was defined as a liveborn at the time of the analysis. Pregnancy outcomes were calculated for all fresh transfers. | 10 months | 
| Bloating Score | Change in bloating scores from day of baseline ultrasound to post-trigger day 5. The patient's clinical symptoms will be evaluated based on a bloating score reported by each patient on the day of ovulation trigger and then 5 days after the oocyte retrieval will be determined. The bloating score will range on a scale from 0-5. The number describes the degree of bloating and will increase as the degree of bloating increases. The bloating score will be determined as follows: 0 - No bloating - Mild bloating. Able to continue daily activities without discomfort. - Mild to moderate bloating. Able to continue daily activities but with mild discomfort. - Moderate bloating. Able to continue daily activities but with moderate discomfort. - Moderate to severe bloating. Difficulty performing daily activities. - Severe bloating. Abdomen feels very tense and unable to perform daily activities. | 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 | 
| Abdominal Circumference | Change in abdominal circumference (in centimeters) from day of baseline ultrasound to post-trigger day 5. | 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 | 
| Body Weight | Change in body weight from day of baseline ultrasound to post-trigger day 5. | 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 | 
| Serum hCG T+1 | Blood samples were collected about 12 hours after trigger (T+1) to assess the serum concentration of human chorionic gonadotropin (hCG). | 1 day | 
| Serum FSH T+1 | Blood samples were collected about 12 hours after trigger (T+1) to assess the serum concentration of follicle stimulating hormone (FSH). | 1 day | 
| Serum P4 on T+1 | Blood samples were collected about 12 hours after trigger (T+1) to assess the serum concentration of Progesterone (P4). | 1 day | 
| Serum E2 on T+1 | Blood samples were collected about 12 hours after trigger (T+1) to assess the serum concentration of estradiol (E2). | 1 day | 
| Serum LH on T+1 | Blood samples were collected about 12 hours after trigger (T+1) to assess the serum concentration of luteinizing hormone (LH). | 1 day | 
| Serum hCG on T+2 | Blood samples were collected about 2 days after trigger (T+2) to assess the serum concentration of human chorionic gonadotropin (hCG). | 2 days | 
| Serum FSH on T+2 | Blood samples were collected 2 days after trigger (T+2) to assess the serum concentration of follicle stimulating hormone (FSH). | 2 days | 
| Serum P4 on T+2 | Blood samples were collected 2 days after trigger (T+2) to assess the serum concentration of progesterone (P4). | 2 days | 
| Serum E2 on T+2 | Blood samples were collected 2 days after trigger (T+2) to assess the serum concentration of estradiol (E2). | 2 days | 
| Serum HCG on T+5 | Blood samples were collected 5 days after trigger (T+5) to assess the serum concentration of human chorionic gonadotropin (hCG). | 5 days | 
| Serum FSH on T+5 | Blood samples were collected 5 days after trigger (T+5) to assess the serum concentration of follicle stimulating hormone (FSH). | 5 days | 
| Serum LH on T+5 | Blood samples were collected about 5 days after trigger (T+5) to assess the serum concentration of luteinizing hormone (LH). | 5 days | 
| Follicular hCG | Follicular fluid was individually aspirated at oocyte retrieval from the lead follicle in each ovary using a single lumen needle. The mean concentration between right and left follicles collected was compared to assess the follicular concentration of human chorionic gonadotropin (hCG). | 2 days | 
| Follicular FSH | Follicular fluid was individually aspirated at oocyte retrieval from the lead follicle in each ovary using a single lumen needle. The mean concentration between right and left follicles collected was compared to assess the follicular concentration of follicle stimulating hormone (FSH). | 2 days | 
| Follicular P4 | Follicular fluid was individually aspirated at oocyte retrieval from the lead follicle in each ovary using a single lumen needle. The mean concentration between right and left follicles collected was compared to assess the follicular concentration of progesterone (P4). | 2 days | 
| Follicular E2 | Follicular fluid was individually aspirated at oocyte retrieval from the lead follicle in each ovary using a single lumen needle. The mean concentration between right and left follicles collected was compared to assess the follicular concentration of estradiol (E2). | 2 days | 
| Follicular VEGF | Follicular fluid was individually aspirated at oocyte retrieval from the lead follicle in each ovary using a single lumen needle. The mean concentration between right and left follicles collected was compared to assess the follicular concentration of vascular endothelial growth factor (VEGF). | 2 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infertility, In vitro fertilization, IVF