PERgoveriS In Stratified Treatment for Assisted Reproductive Technique

Study Overview
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Brief Summary
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This is a multicenter, multi-national, randomized, open-label comparative trial. After screening, the subjects will start down-regulation treatment on Day 21-22 of the cycle. Down-regulation treatment will start within 2 months following the screening visit. The routine long luteal phase protocol for gonadotropin-releasing hormone (GnRH) agonist treatment will be followed. Once down-regulation has been confirmed, a pregnancy test will be performed just before randomization and start of recombinant human follicle-stimulating hormone (r-hFSH) treatment to rule out any pre-existing pregnancy. If the result is negative, the subject will be randomly assigned to one of the two treatment arms of the trial: GONAL-f®: (Liquid Pen; 300 international unit [IU] of per day) stimulation Day 1-5 followed by Pergoveris® (vial/powder, 300 IU per day) from stimulation Day 6 and until required recombinant human chorionic hormone (r-hCG) criterion is met. The dose can be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice. Pergoveris®: (vial/powder, 300 IU per day) from stimulation Day 1 and until required r-hCG criterion is met. The dose can be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice. Randomization across the two treatment arms will be kept balanced in a 1:1 ratio. Follicular development will be monitored according to the center's standard practice by ultrasound (US) and/or estradiol (E2) levels, until the protocol r-hCG requirement is met (i.e., at least one follicle greater than or equal to [>=] 18 millimeter [mm] and two follicles >=16 mm). After this, a single injection of r-hCG will be administered in order to induce final oocyte maturation. At a time of 34-38 hours after r-hCG administration, oocytes will be recovered vaginally under US monitoring. Oocytes will then be fertilized in vitro and embryos replaced 2-5 days after oocyte recovery. Ovum pick up (OPU), in vitro fertilization (IVF), embryo transfer (ET) and luteal support will be performed as per center's standard practice. A post-treatment safety visit will be performed for all subjects who received r-hCG (pregnant and non- pregnant) on Day 15-20 post-hCG. For subjects who have withdrawn from treatment (i.e. after starting Pergoveris® or Gonal-f® but before hCG is given) this visit will take place 20-30 days after their first Pergoveris® or Gonal-f® treatment injection (excluding pregnancy testing).

Official Title
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A Phase IIIB, Multicentre, Multinational, Randomized, Open-label Trial to Compare the Efficacy and Safety of Ovarian Stimulation With GONAL-f® Day 1 to Day 5 Followed by Pergoveris® Starting Day 6 to Pergoveris® Starting Day 1 in Women Between 36 and 40 Years of Age Undergoing Assisted Reproductive Technique (ART)

Conditions
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Assisted Reproductive Techniques, Reproductive Technology, Assisted

Intervention / Treatment
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* Drug: Gonal-f®
* Drug: Pergoveris®
* Drug: Pergoveris®
* Drug: Recombinant human chorionic gonadotropin (r-hCG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be a female subject justifying an in vitro fertilization and embryo transfer (IVF/ET) treatment Be between her 36th and 40th birthday (both included) at the time of the randomization visit Have early follicular phase (Day 2-4) serum level of basal follicle stimulating hormone (FSH less than or equal to (=<)12 IU/L) measured in the center's local laboratory during the screening period (that is within 2 months prior to down-regulation start) A body mass index (BMI) less than (<) 30 kilogram per square meter (kg/m^2) Have a regular spontaneous ovulatory menstrual cycle between 21 and 35 days in length Be willing and able to comply with the protocol for the duration of the trial Have given written informed consent, prior to any trial-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to her future medical care Have a male partner with semen analysis within the past 6 months prior to randomization considered adequate to proceed with regular insemination or intracytoplasmic sperm injection (ICSI) according to the center's standard practice. If these criteria are not met, the subject can only be entered if donor sperm will be used Other protocol specified inclusion criteria could also apply. Exclusion Criteria: Had >= 2 previous ART cycles with a poor response to gonadotrophin stimulation defined as =< 6 mature follicles and/or =<4 oocytes collected in any previous IVF cycle or previous cycles with a hyper response defined as >= 25 oocytes retrieved Any medical condition, which in the judgment of the investigator may interfere with the absorption, distribution, metabolism or excretion of the drug. In case of doubt, the subject in question should be discussed with Merck Serono's medical responsible Had previous severe ovarian Hyperstimulation Syndrome (OHSS) Polycystic ovary syndrome (PCOS; Rotterdam criteria) to reduce the risk of the occurrence of OHSS Any contraindication to being pregnant and/or carrying a pregnancy to term History of 3 or more miscarriages (early or late miscarriages) due to any cause A clinically significant systemic disease Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus in the trial subject or her male partner Known allergy or hypersensitivity to human gonadotrophin preparations Entered previously into this trial or simultaneous participation in another clinical trial. Pregnancy and lactation period Participation in another clinical trial within the past 30 days Other protocol specified inclusion criteria could also apply.

Ages Eligible for Study
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Minimum Age: 36 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Gonal-f® Plus Pergoveris®<br> | Drug: Gonal-f®<br>* Gonal-f® (follitropin alfa) 300 International Unit (IU) will be administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5).<br>* Other names: Follitropin alfa;Drug: Pergoveris®<br>* Pergoveris® (follitropin alfa and lutropin alfa) 300 IU will be administered subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) administration day (at least 1 follicles >= 18 mm). The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.<br>Drug: Recombinant human chorionic gonadotropin (r-hCG)<br>* 250 microgram of r-hCG will be administered once subcutaneously on r-hCG day (at least 1 follicles >= 18 mm).<br>* Other names: Ovitrelle®;|
| Experimental: Pergoveris®<br> | Drug: Pergoveris®<br>* Pergoveris® (follitropin alfa and lutropin alfa) 300 IU will be administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.<br>Drug: Recombinant human chorionic gonadotropin (r-hCG)<br>* 250 microgram of r-hCG will be administered once subcutaneously on r-hCG day (at least 1 follicles >= 18 mm).<br>* Other names: Ovitrelle®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Oocytes Retrieved | The total number of oocytes retrieved per reporting group on the day of ovum pick-up (OPU) (34-38 hours post r-hCG day) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocytes from the ovary of the female participant, enabling fertilization outside the body. | OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 11 days}]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Dose and Mean Daily Dose of Follicle Stimulating Hormone (FSH) |  | Day 1 up to r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Total Number of Stimulation Treatment Days |  | Day 1 up to r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Implantation Rate | Implantation rate per reporting group was measured as the number of fetal sacs observed, divided by the number of embryos transferred multiplied by 100. | Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Number of Fetal Sacs With Activity | Number of fetal sacs with activity was evaluated by ultrasound scan | Days 35-42 post r-hCG day [end of stimulation cycle {approximately 11 days}]) | 
| Number of Fetal Hearts With Activity | Number of fetal hearts with activity was evaluated by ultrasound scan | Days 35-42 post r-hCG day [end of stimulation cycle {approximately 11 days}]) | 
| Clinical Pregnancy Rate | Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy. Clinical pregnancy rate was reported as total clinical pregnancy rate, clinical pregnancy rate per cycle started and per embryo transfer [ET]). | Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Number of Participants With Cancelled Cycles Due to Excessive or Insufficient Ovarian Response to Treatment | An excessive ovarian response: greater than or equal to 25 oocytes which could put the participant at risk of OHSS; An insufficient ovarian response: defined as 3 or less follicles of greater than or equal to 12 millimeter developing following at least 7 days of treatment. | S1 until Day 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Biochemical Pregnancies Rate | Biochemical pregnancy was defined as the pregnancy diagnosed only by the detection of human chorionic gonadotropin (hCG) in serum or urine and that does not develop into a clinical pregnancy. Participants with beta- hCG concentration greater than 10 international units per liter (IU/L) were considered as biochemical pregnant. | Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Number of Participants With Multiple Pregnancies | Multiple pregnancy was defined as the existence of more than one fetal sac with fetal heart activity. | Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Number of Participants With Early and Late Ovarian Hyper Stimulation Syndrome (OHSS) | Ovarian Hyper Stimulation Syndrome (OHSS) is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting. Early OHSS was defined as the onset of OHSS occurring within 9 days after oocyte retrieval and late OHSS was defined as the onset of OHSS occurring on or after day 10 from oocyte retrieval. | Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Number of Participants With Treatment-emergent Adverse Events | An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. | Day 1 up to days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Systolic and Diastolic Arterial Blood Pressure Assessments |  | Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) | 
| Heart Rate Assessments |  | Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovulation Induction, Ovarian Stimulation, Reproductive Technique, Assisted, Assisted Reproductive Technics, Assisted Reproductive Technique, Reproductive Technology, Assisted