Cumulative Pregnancy Rate With Lower and Higher Gonadotropin Dose During IVF Among Poor Responders

Study Overview
=================
Brief Summary
-----------------
Controlled ovarian hyperstimulation (COH) is an important step during in vitro fertilization (IVF). Its aim optimally is to recruit 10-15 oocytes. When deciding on the actual treatment, different stimulation protocols, various stimulating agents and wide range of gonadotropin dose can one choose from. Prior to the decision on the actual stimulation protocol and gonadotropin (Gn) dose the patient's expected response to stimulation is assessed primarily using ovarian reserve markers. Most medications used during stimulation exert their effect in a dose-dependent manner hence with a higher Gn dose one would expect a better response, more oocytes. More oocytes could translate into more embryos and potentially a higher pregnancy rate. The currently available evidence however does not support this practice as randomized controlled trials (RCT) have failed to show that the use of higher Gn dose results in higher pregnancy, live-birth rates. These studies however identified patients based on different criteria, compared different stimulation protocols and various Gn doses. There are only two RCTs that compared cumulative live birth rates (fresh + frozen embryo transfers) and they identified poor responders based on different criteria and used different drug regimens. Therefore, the aim of our study is to compare cumulative IVF clinical pregnancy rates using a lower and a higher gonadotropin dose among poor responders identified based on universally accepted criteria.

Detailed Description
-----------------
The investigators will enroll patients who, based on their initial evaluation, reproductive history or prior fertility treatment, have a proper indication to undergo in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI) treatment. A basic infertility evaluation includes: 1.) hormonal evaluation of ovarian function, including ovarian reserve testing (anti-Müllerian hormone [AMH] level, antral follicle count [AFC]), 2) transvaginal ultrasound evaluation of female internal genital organs, 3) evaluation of the uterine cavity (hysterosalpingogram, saline sonohysterogram or hysteroscopy), 4) cervical cancer screening, 5) cervical culture for Chlamydia, 6) serologic testing for HIV, hepatitis B, C, syphilis (both partners), 7) semen analysis, 8) male andrological exam, 9) if needed male hormonal +/- genetic testing. IVF-ICSI treatment is started for advanced maternal age, diminished ovarian reserve (DOR), unexplained infertility after failed intrauterine inseminations, male factor infertility, endometriosis. The investigators plan to recruit: - infertile patients between the ages of 18-42 who require IVF-ICSI treatment and are identified as poor responders based on: a) AMH: 0.3-1.2 ng/ml or AFC <5, b) AMH>1.2 ng/ml or AFC≥5 but the retrieval of ≤ 4 oocytes during previous IVF treatment. (POSEIDON category III-IV, Alviggi et al. Fertility Sterility 2016) Further inclusion criteria: regular menstrual cycles (24-35 days) body mass index (BMI): 18-35 kg/m2 no more than 3 previous failed IVF/ICSI treatments no more than 2 previous cancelled stimulations for IVF due to poor response motile sperm with normal morphology obtained from the ejaculate or from testicular biopsy intact uterine cavity Exclusion criteria: age <18 or >42 years short (<24 days), or long (>35 days) menstrual cycles irregular uterine cavity presence of hydrosalpinx positive HIV, hepatitis B, C screening tests BMI <18 or > 35 kg/m2 planned preimplantation genetic testing of the embryos planned elective cryopreservation medical, gynecologic or surgical contraindication to IVF treatment lack of consent Methods: prospective, multicenter (5 centers), randomized controlled trial comparing a higher or lower gonadotropin (Gn) dose treatment. In both the low and high groups two different drug regimens (follitropin alpha + hp human menopausal gonadotropin or follitropin delta + hp human menopausal gonadotropin) will be used. 150 IU follitropin alpha was shown to be equally effective to 10 mcg follitropin delta. Therefore, the investigators expect similar response (oocyte yield) with the two regimens within the high and low Gn dose groups but the study design still will allow the investigators to compare the two follitropin medications too, which is a secondary aim. Lower-dose group: 150 IU follitropin alpha + 75 IU highly purified human menopausal gonadotropin (hpHMG) 10 mcg follitropin delta + 75 IU hpHMG Higher-dose group: 225 IU follitropin alpha + 150 IU hpHMG 15 mcg follitropin delta + 150 IU hpHMG Treatment protocol: The stimulation will get started on day 2 or 3 of the spontaneous menstrual cycle, or on the 5th day after oral contraceptive pill use or after luteal estradiol pretreatment. During the stimulation ultrasound +/- serum hormone measurements will be used to monitor response. The first ultrasound is scheduled for day 5 or 6 of stimulation. At the time of the ultrasound blood test for serum estradiol is planned too. At the time of the last scan serum estradiol and progesterone levels will be measured. According to the study protocol the patient will continue with the assigned medication dose throughout her treatment. Dose increase is not allowed. If there is evidence for hyper-response [estradiol level > 4000 pmol/l on day 6 or more than 15 follicles over 10 mm any time during the stimulation] the dose can be reduced. As soon as two or more follicles reach >17 mm in diameter human chorionic gonadotropin (hCG) or gonadotropin-releasing hormone agonits [GnRH a] trigger injection will be used and 35-36 hours later transvaginal ultrasound guided follicle aspiration will be performed. The luteal phase will be supported by vaginal progesterone starting on the day after the retrieval. IVF or ICSI fertilization will be performed based on the semen parameters or previous fertilization records. The day after the retrieval the success of fertilization will be checked and the embryo(s) will be transferred 2-5 days after the retrieval. Embryo(s) will be transferred transcervically using soft transfer catheters under ultrasound guidance using the afterload technique. Surplus good quality embryos will be cryopreserved using vitrification. Elective cryopreservation (no transfer in the fresh cycle) will be performed if: 1) risk of ovarian hyperstimulation syndrome, 2) serum progesterone level over 1.5 ng/ml [5.5 nmol/l] prior to the oocyte collection, 3) any complications between the retrieval and planned fresh transfer (bleeding, infection, illness). 12-14 days after the transfer serum human chorionic gonadotropin (HCG) measurement will determine whether implantation has occurred. If the test is positive in 2-3 weeks a vaginal ultrasound will be done to determine the size, location and number of gestational sacs. Viable pregnancies will be referred to a formal prenatal care around week 8-9 of pregnancy. Delivery and perinatal outcome data will be collected by phone call after the delivery. If the fresh IVF cycle is not successful but embryos have been cryopreserved then the patient will undergo a frozen embryo transfer treatment cycle either in her own cycle, or in a minimally stimulated or completely artificial cycle. The care of the patients will not differ from the care of non-study patients in terms of potential medication dose, the number of clinic visits, retrieval and embryology procedures as well as prenatal care. Randomization: Randomization will be performed according to a computer generated list. (www.randomizer.org) The planned sample size is 700 patients (350 in both the low- and high-dose groups). Sample size calculation: In order to determine the sample size, the investigators calculated with a 20% pregnancy rate in a patient population that fits the inclusion-exclusion criteria. The investigators expect higher oocyte yield in the higher dose group that should result in more available embryos and therefore more frozen embryo transfers. The investigators calculate that this could increase the cumulative pregnancy rate by 50%. The investigators also believe that about 20% of the patients will drop out for various reasons. Therefore, 350 participants are needed in both arms of the study. Statistical analysis: After the enrollment of the first 350 patients, a planned interim analysis will be performed to decide whether the planned sample size is sufficient to achieve our goal. Logistic regression analysis using a generalized, mixed linear model will be used to assess the impact of various Gn doses on pregnancy rates. Chi-square test will be used to test significance and OR will be calculated. Data will be collected for the following parameters: Age Cycle day 3 follicle stimulating hormone (FSH), estradiol level anti-Müllerian hormone (AMH) antral follicle count (AFC) Indication for IVF: male, tubal, unexplained, endometriosis, diminished ovarian reserve Smoking (yes-no) Body mass index Cycle number (fresh + frozen together) Estradiol level on day 6 Estradiol + progesterone level at the last scan Number of follicles >10 mm at the end of stimulation Stimulation duration Endometrial thickness Gn dose (daily, total) Trigger mechanism (HCG vs. GnRh agonist) Sperm parameters Oocyte number Mature (MII) oocyte number Proportion of mature oocytes (MII/ oocyte number) IVF vs. ICSI fertilization Number of fertilized (2 pronuclei (PN)) oocytes Fertilization rate per oocyte Fertilization rate per mature oocyte The number of good quality embryos (morphology better than score 6B2 on day 3, or score >2BB on day 5) and proportion of good morphology embryos among all embryos Number of transferred embryos Number of cryopreserved embryos Pregnancy rate (positive hCG) Clinical pregnancy rate (sac with viable embryo in it) Cumulative pregnancy rate (fresh + frozen embryo transfers) Pregnancy/ neonatal outcome

Official Title
-----------------
Cumulative Pregnancy Rate With Lower and Higher Dose of Gonadotropin During Controlled Ovarian Hyperstimulation During IVF Among Expected Poor Responders: a Prospective, Randomized Controlled Trial

Conditions
-----------------
Infertility, Ovarian Dysfunction

Intervention / Treatment
-----------------
* Drug: Follitropin Alfa
* Drug: Follitropin delta
* Drug: human menopausal gonadotropin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Expected poor responder based on: AMH: 0.3-1.2 ng/ml or AFC <5, AMH>1.2 ng/ml or AFC≥5 but the retrieval of ≤ 4 oocytes during previous IVF treatment. motile sperm with normal morphology obtained from the ejaculate of testicular biopsy no more than 3 previous failed IVF cycles (if the patient had 2 or more previous cycles cancelled for poor response she cannot be included) BMI: 18-35 kg/m2 regular 24-35 day cycles intact uterine cavity indication for in vitro fertilisation treatment (tubal factor, male factor, low ovarian reserve, endometriosis, unexplained infertility) age 18-421 yrs Exclusion Criteria: presence of hydrosalpinx positive HIV, hepatitis B, C screening tests planned preimplantation genetic testing of the embryos planned elective cryopreservation lack of consent not meeting the inclusion criteria

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lower gonadotropin dose stimulation<br>Low-dose group: 150 IU follitropin alpha + 75 IU highly purified human menopausal gonadotropin (hpHMG) 10 mcg follitropin delta + 75 IU hpHMG | Drug: Follitropin Alfa<br>* lower dose gonadotropin (follitropin alpha/ follitropin delta + hpHMG) vs. higher dose stimulation (Follitropin alpha/delta + hpHMG)<br>* Other names: Gonal F (Merck Europe B.V.);Drug: Follitropin delta<br>* lower dose gonadotropin (follitropin alpha/ follitropin delta + hpHMG) vs. higher dose stimulation (Follitropin alpha/delta + hpHMG)<br>* Other names: Rekovelle (Ferring Pharmaceuticals A/S, Denmark);Drug: human menopausal gonadotropin<br>* lower dose gonadotropin (follitropin alpha/ follitropin delta + hpHMG) vs. higher dose stimulation (Follitropin alpha/delta + hpHMG)<br>* Other names: Menopur (Ferring Pharmaceuticals A/S, Denmark);|
| Experimental: Higher gonadotropin dose stimulation<br>High-dose group: 225 IU follitropin alpha + 150 IU highly purified human menopausal gonadotropin (hpHMG) 15 mcg follitropin delta + 150 IU hpHMG | Drug: Follitropin Alfa<br>* lower dose gonadotropin (follitropin alpha/ follitropin delta + hpHMG) vs. higher dose stimulation (Follitropin alpha/delta + hpHMG)<br>* Other names: Gonal F (Merck Europe B.V.);Drug: Follitropin delta<br>* lower dose gonadotropin (follitropin alpha/ follitropin delta + hpHMG) vs. higher dose stimulation (Follitropin alpha/delta + hpHMG)<br>* Other names: Rekovelle (Ferring Pharmaceuticals A/S, Denmark);Drug: human menopausal gonadotropin<br>* lower dose gonadotropin (follitropin alpha/ follitropin delta + hpHMG) vs. higher dose stimulation (Follitropin alpha/delta + hpHMG)<br>* Other names: Menopur (Ferring Pharmaceuticals A/S, Denmark);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulative clinical pregnancy rate | an ultrasound confirmation of an intrauterine gestational sac with an embryo with detectable heartbeat in it after the fresh + if available frozen embryo transfer treatments | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical pregnancy rate | an ultrasound confirmation of an intrauterine gestational sac with an embryo with detectable heartbeat in it in the fresh cycle | 12 months | 
| clinical pregnancy rate with follitropin alpha vs. follitropin delta | an ultrasound confirmation of an intrauterine gestational sac with an embryo with | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
follitropin alpha, follitropin delta, high-dose gonadotropin, clinical pregnancy, cumulative pregnancy rate, gonadotropin