Phase III Study Comparing Efficacy and Safety of AFOLIA vs Gonal-f® RFF in Women (35 to 42) Undergoing IVF

Study Overview
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Brief Summary
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The purpose of this study is to show that AFOLIA, a recombinant manufactured human follicle stimulating hormone (r-hFSH) has a similar efficacy and safety profile compared to Gonal-f® RFF.

Detailed Description
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Comparison of the clinical pregnancy rate in the AFOLIA group compared to the US approved Gonal-f® RFF Redi-ject group as the primary endpoint. Comparison of the number and size of follicles, the number of cycle cancellation, the hormone parameters and adverse events in the AFOLIA group compared to the Gonal-f® RFF group as secondary endpoints.

Official Title
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Phase III Investigator and Assessor Blinded 1:1 Randomized, Parallel-group Multicenter Study to Compare Efficacy and Safety of Two r-hFSH Formulations (AFOLIA vs Gonal-f® RFF) in Normal Ovulatory Women 35 to 42 Years Old Undergoing in Vitro Fertilization

Conditions
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Infertility

Intervention / Treatment
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* Drug: AFOLIA
* Drug: Gonal-f® RFF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 35 to 42 years of age Indication for controlled ovarian stimulation and IVF or intracytoplasmic sperm injection (ICSI) Regular menstrual cycles (25-35 days) History of a maximum of two fresh cycle treatments in the present series of assisted reproductive technologies (ART) at the day of first screening (thawed cycles are not subject to that criteria) Body mass index (BMI) ≥18 and ≤38 kg/m2 Basal FSH <12 IU/L (cycle day 2-5) Antral follicle count (AFC) ≥ 10 to ≤20 follicles with a diameter of <11mm (sum of both ovaries) as measured on ultrasound (US) in the early follicular phase (menstrual cycle day 2-5) Documented history of infertility due to any of the following factors: tubal factor, mild endometriosis (American Society for Reproductive Medicine [ASRM] stage 1-2), male factor, unexplained infertility Presence of both ovaries by ultrasonography and normal uterine cavity (confirmed by hysterosalpingography, saline infusion sonography or hysteroscopy within 6 months before randomization) Male partner with semen analysis that is at least adequate for ICSI within 6 months prior to patient beginning down-regulation (invasive or surgical sperm retrieval, donor and/or cryopreserved sperm may be used) Willingness to participate in the study and to comply with the study protocol Signed informed consent prior to screening Exclusion Criteria: Presence of pregnancy History of or active polycystic ovary syndrome (PCOS) AFC >20 follicles with a diameter of <11 mm (both ovaries combined) as measured on US in the early follicular phase (menstrual cycle day 2-5) History of >2 unsuccessful fresh ART retrieval cycles Presence of uncontrolled endocrine disorder Previous history or presence of severe OHSS Intrauterine fibroids ≥5 cm or otherwise clinically relevant pathology that could impair embryo implantation or pregnancy continuation History of recurrent spontaneous abortion (3 or more, even when unexplained) Presence of severe endometriosis (ASRM stage 3 or stage 4) or hydrosalpinx Neoplasia, including tumors of the hypothalamus and pituitary gland Abnormal bleeding of undetermined origin History of extrauterine pregnancy in the previous 3 months Known allergy or hypersensitivity to progesterone or to any of the excipients (including peanut oil) of the additional study medications (GnRH agonist, Ovidrel®, and Crinone 8%®) History of poor response to gonadotropin treatment (defined as fewer than 5 oocytes retrieved in a previous attempt) Any hormonal treatment within 1 month before the start of the FSH treatment, with the exception of levothyroxine) Egg donor Administration of other investigational products within the previous month Clinically abnormal findings at Visit 1 Concomitant participation in another study protocol

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 42 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AFOLIA<br>One subcutaneous injection of 225IU AFOLIA (follitropin alfa) per day (initial dose) for the first 5 days. From day 6 dose could be adjusted up (to a max of 450IU per day) or down (to a min of 75IU per day) in multiple increments of 37.5IU. | Drug: AFOLIA<br>* 225IU subcutaneously, starting at the day of successful down-regulation for the first 5 days, followed by a treatment period with an increased dose until the point of ovulation induction has been reached<br>* Other names: Follitropin-alfa;|
| Active Comparator: Gonal-f® RFF<br>One subcutaneous injection of 225IU Gonal-f® RFF (follitropin alfa) per day (initial dose) for the first 5 days. From day 6 dose could be adjusted up (to a max of 450IU per day) or down (to a min of 75IU per day) in multiple increments of 37.5IU. | Drug: Gonal-f® RFF<br>* 225IU subcutaneously, starting at the day of successful down-regulation for the first 5 days, followed by a treatment period with an increased dose until the point of ovulation induction has been reached<br>* Other names: Follitropin-alfa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Pregnancy Rate After One Cycle of Treatment - ITT Population | Clinical pregnancy was defined as presence of at least one intrauterine gestational sac and fetal heart activity as demonstrated by vaginal ultrasound at six weeks (42 +/- 1 day) post ET (Visit 11). The clinical pregnancy rate is the proportion of subjects who achieve clinical pregnancy, relative to the number of patients in the ITT population of the respective treatment arm. | Six weeks post embryo transfer | 
| Clinical Pregnancy Rate After One Cycle of Treatment - PP Population | Clinical pregnancy was defined as presence of at least one intrauterine gestational sac and fetal heart activity as demonstrated by vaginal ultrasound at six weeks (42 +/- 1 day) post ET (Visit 11). The clinical pregnancy rate is the proportion of subjects who achieve clinical pregnancy, relative to the number of patients in the PP population of the respective treatment arm. | Six weeks post embryo transfer | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exposure to r-hFSH Injections: Days of r-hFSH Stimulation - Cycle 1 | The number of days of r-hFSH stimulation a subject received during Cycle 1. | Measured at discretionary visits between Days 9 and 15 after FSH starts | 
| Exposure to r-hFSH Injections: Total Dose of r-hFSH (IU) - Cycle 1 | The total dose of r-hFSH that subjects received during Cycle 1. | Measured at discretionary visits between Days 9 and 15 after FSH starts. | 
| Exposure to r-hFSH Injections: Daily Dose of r-hFSH (IU) - Cycle 1 | The mean dose of r-hFSH that subjects received in a day during Cycle 1. | Measured at discretionary visits between Days 9 and 15 after FSH starts. | 
| Number of Oocytes Retrieved - Cycle 1 | The number of oocytes retrieved per subject, following hCG administration in Cycle 1. | Visit 8, 34-36 hours after hCG administration | 
| Local and Systemic Adverse Events: Dermal Response to Injection - Cycle 1 | Number of subjects reporting at least one dermal response to r-hFSH injection and number of subjects reporting no dermal responses. | Measure recorded in the Patient Diary which is maintained through entire FSH treatment, from FSH Start through to Day 16 after start of FSH (16 days). | 
| Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1 | Dermal response to r-hFSH injection as assessed by the investigator and categorized according to severity of reaction | Measure recorded in the Patient Diary which is maintained through entire FSH treatment, from FSH through to Day 16 after start of FSH (16 days). | 
| Overall Summary of Adverse Events (AEs) - Cycle 1 | Summary of AEs, including the number of subjects experiencing to following during Cycle 1: At least one AE At least one treatment related AE At least one serious AE At least one AE leading to discontinuation of study drug At least one AE due to pregnancy complication | Measured from the start of FSH treatment through to either the end FSH treatment + 30 days (up to 46 days) or to the last Telephone Follow-up / Live Birth Questionnaire on pregnancy outcome (if applicable) (up to 10 months). | 
| Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1 | Summary of the number of subjects with mild, moderate and severe OHSS. The total number of subjects with OHSS is also included. | Measured either 3 days after ooctye pick up (Visit 9) or 18 +/- 1 days after oocyte pick up (Visit 10). | 
| Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2 | Summary of the number of subjects with mild, moderate and severe OHSS. The total number of subjects with OHSS is also included. | Measured either 3 days after ooctye pick up (Visit 9) or 18 +/- 1 days after oocyte pick up (Visit 10). | 
| Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3 | Summary of the number of subjects with mild, moderate and severe OHSS. The total number of subjects with OHSS is also included. | Measured either 3 days after ooctye pick up (Visit 9) or 18 +/- 1 days after oocyte pick up (Visit 10). | 
| Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Measurement of the number of subjects with detectable specific serum binding to FSH by surface Plasmon resonance during Cycle 1. | Immunogenicity samples were taken at baseline, Visit 5 (8 days after start of treatment), Visit 9 (5 days after the end of FSH treatment), Visit 10 (18 +/- 1 days after oocyte retrieval), and Visit 11 (42 +/- 1 days after embryo transfer). | 
| Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Measurement of the number of subjects with detectable specific serum binding to FSH by surface Plasmon resonance during Cycle 2. | Immunogenicity samples were taken at baseline, Visit 5 (8 days after start of treatment), Visit 9 (5 days after the end of FSH treatment), Visit 10 (18 +/- 1 days after oocyte retrieval), and Visit 11 (42 +/- 1 days after embryo transfer). | 
| Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Measurement of the number of subjects with detectable specific serum binding to FSH by surface Plasmon resonance during Cycle 3. | Immunogenicity samples were taken at baseline, Visit 5 (8 days after start of treatment), Visit 9 (5 days after the end of FSH treatment), Visit 10 (18 +/- 1 days after oocyte retrieval), and Visit 11 (42 +/- 1 days after embryo transfer). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IVF, In vitro fertilization, Controlled ovarian stimulation, Follitropin, AFOLIA, Finox