Safety and Efficacy of Pre-defined, Fixed Dose of Gonal-f Pen Based on Subject Baseline Characteristics in Subjects Undergoing in Vitro Fertilization (IVF)

Study Overview
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Brief Summary
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Clinical validation of the assisted reproductive technology (ART) treatment guidelines, which determine the optimal dose of recombinant human follicle stimulating hormone (r-hFSH) based on subject baseline characteristics/predictors of ovarian response.

Official Title
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A Phase IIIB/IV, Open Label Study to Assess the Efficacy and Safety of a Pre-defined, Fixed Dose of Gonal-f® (Filled-by-Mass in a Prefilled Pen) Based on Subject Baseline Characteristics, for Ovarian Stimulation in Subjects Undergoing in Vitro Fertilization (IVF)

Conditions
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Infertility

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Be an infertile subject justifying an in-vitro fertilization/embryo transfer (IVF/ET) treatment. Have a male partner with semen analysis within the past six months prior to study entry 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. Be between her 18th and 35th birthday (35 not included). Have a regular spontaneous ovulatory menstrual cycle between 21 and 35 days in length. Have early follicular phase (Day 2-4) serum levels within the last 3 months prior to study entry of: Follicle stimulating hormone (FSH) greater than or equal to (>=) 12 International units per liter (IU/L), and Oestradiol (E2) within center's local normal laboratory range values. Presence of both ovaries. Have a uterine cavity without abnormalities, which, in the investigator's opinion, could impair embryo implantation or pregnancy evolution as assessed within the last 3 years using ultrasound (US), hysteroscopy (HSC), or hysterosalpingography (HSG). Have a negative cervical papanicolaou (PAP) test within the last 6 months prior to study entry. Have at least one wash-out cycle (defined as >= 30 days since the last dose of clomiphene citrate or gonadotrophin treatment) since the last ART cycle and/or clomiphene citrate or gonadotrophin treatment prior to starting gonadotrophin releasing hormone (GnRH) agonist therapy. Have a negative pregnancy test prior to beginning GnRH agonist therapy. Be willing and able to comply with the protocol for the duration of the study. Have given written informed consent, prior to any study-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. Exclusion Criteria: Had 2 previous ART cycles with a poor response to gonadotrophin stimulation, defined as less than or equal to (<=) 5 mature follicles and/or <=3 oocytes collected in any previous IVF cycle or hyper response, defined as >=25 oocytes retrieved. Any medical condition, which in the judgement 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 Serono's Therapeutic Director. Had previous severe ovarian hyperstimulation syndrome (OHSS). A body mass index (BMI) greater than (>) 30 kilogram per square meter (kg/m^2) Any contraindication to being pregnant and/or carrying a pregnancy to term. Extra-uterine pregnancy within the last 3 months. History of 3 or more miscarriages (early or late miscarriages) due to any cause. Tumours of the hypothalamus and pituitary gland. Ovarian enlargement or cyst of unknown aetiology. Ovarian, uterine or mammary cancer. A clinically significant systemic disease. Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus. Abnormal gynaecological bleeding of undetermined origin. Known allergy or hypersensitivity to human gonadotrophin preparations. Any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years. Entered previously into this study or simultaneous participation in another clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 34 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gonal-f 112.5 IU<br> | Drug: Gonal-f<br>* GONAL-f (follitropin alfa) will be administered subcutaneously based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle.<br>* Other names: Recombinant Human Follicle Stimulating Hormone (r-hFSH);Drug: Recombinant human chorionic gonadotrophin (r-hCG)<br>* When at least 1 follicle greater than or equal to (>=) 18 millimeter (mm) and 2 follicles >=16 mm in diameter develop, 250 microgram (mcg) of recombinant human chorionic gonadotrophin (r-hCG) will be administered.<br>|
| Experimental: Gonal-f 37.5 IU<br> | Drug: Gonal-f<br>* GONAL-f (follitropin alfa) will be administered subcutaneously based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle.<br>* Other names: Recombinant Human Follicle Stimulating Hormone (r-hFSH);Drug: Recombinant human chorionic gonadotrophin (r-hCG)<br>* When at least 1 follicle greater than or equal to (>=) 18 millimeter (mm) and 2 follicles >=16 mm in diameter develop, 250 microgram (mcg) of recombinant human chorionic gonadotrophin (r-hCG) will be administered.<br>|
| Experimental: Gonal-f 75 IU<br> | Drug: Gonal-f<br>* GONAL-f (follitropin alfa) will be administered subcutaneously based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle.<br>* Other names: Recombinant Human Follicle Stimulating Hormone (r-hFSH);Drug: Recombinant human chorionic gonadotrophin (r-hCG)<br>* When at least 1 follicle greater than or equal to (>=) 18 millimeter (mm) and 2 follicles >=16 mm in diameter develop, 250 microgram (mcg) of recombinant human chorionic gonadotrophin (r-hCG) will be administered.<br>|
| Experimental: Gonal-f 150 IU<br> | Drug: Gonal-f<br>* GONAL-f (follitropin alfa) will be administered subcutaneously based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle.<br>* Other names: Recombinant Human Follicle Stimulating Hormone (r-hFSH);Drug: Recombinant human chorionic gonadotrophin (r-hCG)<br>* When at least 1 follicle greater than or equal to (>=) 18 millimeter (mm) and 2 follicles >=16 mm in diameter develop, 250 microgram (mcg) of recombinant human chorionic gonadotrophin (r-hCG) will be administered.<br>|
| Experimental: Gonal-f 187.5 IU<br> | Drug: Gonal-f<br>* GONAL-f (follitropin alfa) will be administered subcutaneously based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle.<br>* Other names: Recombinant Human Follicle Stimulating Hormone (r-hFSH);Drug: Recombinant human chorionic gonadotrophin (r-hCG)<br>* When at least 1 follicle greater than or equal to (>=) 18 millimeter (mm) and 2 follicles >=16 mm in diameter develop, 250 microgram (mcg) of recombinant human chorionic gonadotrophin (r-hCG) will be administered.<br>|
| Experimental: Gonal-f 225 IU<br> | Drug: Gonal-f<br>* GONAL-f (follitropin alfa) will be administered subcutaneously based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle.<br>* Other names: Recombinant Human Follicle Stimulating Hormone (r-hFSH);Drug: Recombinant human chorionic gonadotrophin (r-hCG)<br>* When at least 1 follicle greater than or equal to (>=) 18 millimeter (mm) and 2 follicles >=16 mm in diameter develop, 250 microgram (mcg) of recombinant human chorionic gonadotrophin (r-hCG) will be administered.<br>|
| Experimental: Gonal-f 262.5 IU<br> | Drug: Gonal-f<br>* GONAL-f (follitropin alfa) will be administered subcutaneously based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle.<br>* Other names: Recombinant Human Follicle Stimulating Hormone (r-hFSH);Drug: Recombinant human chorionic gonadotrophin (r-hCG)<br>* When at least 1 follicle greater than or equal to (>=) 18 millimeter (mm) and 2 follicles >=16 mm in diameter develop, 250 microgram (mcg) of recombinant human chorionic gonadotrophin (r-hCG) will be administered.<br>|
| Experimental: Gonal-f 300 IU<br> | Drug: Gonal-f<br>* GONAL-f (follitropin alfa) will be administered subcutaneously based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle.<br>* Other names: Recombinant Human Follicle Stimulating Hormone (r-hFSH);Drug: Recombinant human chorionic gonadotrophin (r-hCG)<br>* When at least 1 follicle greater than or equal to (>=) 18 millimeter (mm) and 2 follicles >=16 mm in diameter develop, 250 microgram (mcg) of recombinant human chorionic gonadotrophin (r-hCG) will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Oocytes Retrieved | Mean number of oocytes retrieved on the day of ovum pick up (OPU) was calculated. Oocyte retrieval was a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects. | Ovum pick up day (34 to 38 hours post r-hCG administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH) | As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects. | up to end of stimulation cycle (approximately 31 days) | 
| Mean Number of Ovarian Stimulation Days | The mean number of stimulation days were determined based on the treatment administration information collected in the case report form. Ovarian stimulation included time from first r-hFSH injection (stimulation Day) until day on which r-hCG was administered (r-hCG day). As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects. | up to end of stimulation cycle (approximately 31 days) | 
| Percentage of Cycles Cancelled Due to Excessive or Inadequate Response to r-hFSH | As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects. | up to end of stimulation cycle (approximately 31 days) | 
| Number of Subjects Needing Dose Adjustment | Number of subjects needing increase in dose, decrease in dose or increase and decrease both in dose were reported. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects. | 6 days post r-hFSH treatment | 
| Mean Daily Recombinant Human Follicle Stimulating Hormone (r-hFSH) Dose | As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects. | up to end of stimulation cycle (approximately 31 days) | 
| Embryo Implantation Rate | Embryo implantation rate was measured as the number of gestational sacs observed divided by the number of embryos transferred multiplied by 100. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects. | 35-42 days post r-hCG administration | 
| Overall Pregnancy Rate, Clinical Rate and Multiple Pregnancy Rate | Overall pregnancy rate was defined as the percentage of subjects with serum beta-hCG levels greater than 10 IU/L. Clinical pregnancy rate was defined as the percentage of subjects with at least 1 ultrasound confirmed gestational sac, with or without foetal heart activity. Multiple pregnancy rate was defined as the percentage of subjects with more than 1 ultrasound confirmed gestational sac in the uterus with fetal heart activity. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects. | 35-42 days post r-hCG administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infertility, Assisted Reproductive Technology (ART), Ovarian stimulation