Ovarian Hyperstimulation Syndrome
Conditions
Keywords
OHSS, GnRH agonist trigger, low dose hCG, PCOS, IVF
Brief summary
This a prospective randomized double blind study involving patients at high risk of OHSS development with peak serum E2 levels \< 4,000 pg/ml comparing the ongoing pregnancy rates in patients who receive adjuvant hCG 1,000 IU at the time of GnRH agonist trigger or adjuvant hCG 1,500 IU 35 hours after GnRH agonist trigger.
Detailed description
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian hyperstimulation which may result in significant morbidity and rarely mortality as well as significant financial and psychological distress. GnRH agonist trigger has been shown to be effective in OHSS prevention. However, the adoption of its use has not been widely accepted in view of concerns regarding potential impairment of implantation. Intensive luteal phase supplementation with estrogen (E2) and progesterone (P) is important due to the strong evidence of abnormal luteal phase serum E2 and P profiles. However, it has been shown that optimal conception rates is not achieved for high risk patients with peak serum E2 \< 4,000 pg/ml despite aggressive steroidal supplementation. It has been proposed that the use of adjuvant low dose hCG at the time of GnRH agonist trigger or 35 hours later will rescue some of the corpora lutea and help improve corpora lutea function and improve pregnancy rates. The study will evaluate patients at high risk of OHSS development with peak serum E2 \< 4,000 pg/mL to determine whether timing of low dose hCG administration affects ongoing pregnancy rates or risk of OHSS. Markers of corpus luteum function such as serum 17 hydroxy-progesterone and prorenin during the luteal phase and early pregnancy will help elucidate further the effect of adjuvant low dose hCG with GnRH agonist trigger on corpus luteum function.
Interventions
DRUGhCG
Adjuvant low dose hCG 1,000 IU administered at the time of GnRH agonist trigger
Sponsors
Merck Sharp & Dohme LLC
UConn Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 39 Years
Healthy volunteers
Yes
Inclusion criteria
* Normal baseline serum follicle stimulating hormone, polycystic ovarian syndrome (PCOS), Polycystic ovarian morphology, Previous high responder or previous OHSS, must have \> 14 follicles of over 11 mm in diameter and with peak serum E2 levels \< 4,000 pg/mL on the day of trigger of oocyte maturation.
Exclusion criteria
* Hypothalamic dysfunction, Patients with \< 14 follicles \< 11 mm in diameter, peak serum E2 levels \>= 4,000 pg/mL.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ongoing Pregnancy | Through time of study completion, on average 1-2years | Positive serum pregnancy test and ultrasound evidence of fetal pole and fetal heart rate . |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ovarian Hyperstimulation Syndrome | Within 4 weeks of oocyte retrieval | Evaluation of symptoms and signs of OHSS at 9 days after trigger of oocyte maturation. Patients who also present with symptoms of OHSS wil also be evaluated for OHSS within 4 weeks after oocyte maturation. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Markers of Corpus Luteum Function | Within 60 days after trigger of oocyte maturation | A subset of patients (20 patients in each group) will have serum frozen for subsequent analysis of 17 hydroxy progesterone and prorenin. |
| Proportion of Patients With Abdominal Distension | Within 2 weeks after trigger of oocyte maturation | Patients will complete a questionnaire to determine if there is a difference in the effect of the intervention on the quality of life (abdominal distension) of the patients from the day of trigger of oocyte maturation until menses or positive pregnancy test. |
Countries
United States
Participant flow
Pre-assignment details
All patients that met initial study criteria were enrolled and consented before starting ovarian stimulation. Final randomization occurred during stimulation. Therefore patients who were enrolled and consented may drop out before randomization, either because they did not meet the final inclusion criteria in did not undergo IVF.
Participants by arm
| Arm | Count |
|---|---|
| hCG Given at Time of GnRHa Trigger Adjuvant low dose hCG 1,000 IU administered at the time of GnRH agonist trigger.
Placebo administered 35 hours after GnRH agonist trigger
hCG: Adjuvant low dose hCG 1,000 IU administered at the time of GnRH agonist trigger | 26 |
| hCG Given 35 Hours After GnRHa Trigger Placebo administered at the time of GnRH agonist trigger
Adjuvant low dose hCG 1,500 IU administered 35 hours after GnRH agonist trigger.
hCG: Adjuvant low dose hCG 1,500 IU administered 35 hours after GnRH agonist trigger | 31 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 8 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | hCG Given 35 Hours After GnRHa Trigger | Total | hCG Given at Time of GnRHa Trigger |
|---|---|---|---|
| Age, Continuous | 32.2 years STANDARD_DEVIATION 3.4 | 31.8 years STANDARD_DEVIATION 3.4 | 31.3 years STANDARD_DEVIATION 3.3 |
| Anti Mullerian Hormone (AMH) | 8.4 ng/ml STANDARD_DEVIATION 4.9 | 8.35 ng/ml STANDARD_DEVIATION 5.2 | 8.3 ng/ml STANDARD_DEVIATION 5.8 |
| Body Mass Index (BMI) | 27.4 kg/m^2 STANDARD_DEVIATION 5.5 | 26.9 kg/m^2 STANDARD_DEVIATION 5.2 | 26.3 kg/m^2 STANDARD_DEVIATION 4.8 |
| Follicle Stimulating Hormone (FSH) | 5.2 IU/L STANDARD_DEVIATION 1.6 | 5.5 IU/L STANDARD_DEVIATION 2.1 | 5.6 IU/L STANDARD_DEVIATION 1.7 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Sex: Female, Male Female | 31 Participants | 57 Participants | 26 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 31 |
| other Total, other adverse events | 0 / 26 | 0 / 31 |
| serious Total, serious adverse events | 1 / 26 | 1 / 31 |
Outcome results
Primary
Ongoing Pregnancy
Positive serum pregnancy test and ultrasound evidence of fetal pole and fetal heart rate .
Time frame: Through time of study completion, on average 1-2years
Population: per protocol analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| hCG Given at Time of GnRHa Trigger | Ongoing Pregnancy | 15 participants |
| hCG Given 35 Hours After GnRHa Trigger | Ongoing Pregnancy | 19 participants |
Secondary
Ovarian Hyperstimulation Syndrome
Evaluation of symptoms and signs of OHSS at 9 days after trigger of oocyte maturation. Patients who also present with symptoms of OHSS wil also be evaluated for OHSS within 4 weeks after oocyte maturation.
Time frame: Within 4 weeks of oocyte retrieval
Population: Women with normal or high response to IVF, peak estradiol on day of trigger less than 4000 pg/mL.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| hCG Given at Time of GnRHa Trigger | Ovarian Hyperstimulation Syndrome | 1 Participants |
| hCG Given 35 Hours After GnRHa Trigger | Ovarian Hyperstimulation Syndrome | 3 Participants |
p-value: <0.05Fisher Exact
Other Pre-specified
Markers of Corpus Luteum Function
A subset of patients (20 patients in each group) will have serum frozen for subsequent analysis of 17 hydroxy progesterone and prorenin.
Time frame: Within 60 days after trigger of oocyte maturation
Population: Subset of women included in larger study, normal or high responders, peak estradiol level less than 4000 pg/mL on day of trigger.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| hCG Given at Time of GnRHa Trigger | Markers of Corpus Luteum Function | Early luteal 17-OH-Progesterone | 13.68 ng/mL | Standard Deviation 11 |
| hCG Given at Time of GnRHa Trigger | Markers of Corpus Luteum Function | Day 16 Prorenin | 1.13 ng/mL | Standard Deviation 0.8 |
| hCG Given 35 Hours After GnRHa Trigger | Markers of Corpus Luteum Function | Early luteal 17-OH-Progesterone | 21.77 ng/mL | Standard Deviation 8.5 |
| hCG Given 35 Hours After GnRHa Trigger | Markers of Corpus Luteum Function | Day 16 Prorenin | 2.22 ng/mL | Standard Deviation 1.6 |
p-value: 0.04t-test, 2 sided
Other Pre-specified
Proportion of Patients With Abdominal Distension
Patients will complete a questionnaire to determine if there is a difference in the effect of the intervention on the quality of life (abdominal distension) of the patients from the day of trigger of oocyte maturation until menses or positive pregnancy test.
Time frame: Within 2 weeks after trigger of oocyte maturation
Population: Some patients did not complete the questionnaire. Abdominal distension analyzed
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| hCG Given at Time of GnRHa Trigger | Proportion of Patients With Abdominal Distension | Abdominal distension | 2 Participants |
| hCG Given at Time of GnRHa Trigger | Proportion of Patients With Abdominal Distension | abdominal pain | 1 Participants |
| hCG Given 35 Hours After GnRHa Trigger | Proportion of Patients With Abdominal Distension | Abdominal distension | 11 Participants |
| hCG Given 35 Hours After GnRHa Trigger | Proportion of Patients With Abdominal Distension | abdominal pain | 9 Participants |