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

Phase 3

Completed

Conditions: Infertility

Interventions: Drug: AFOLIA
Drug: Gonal-f® RFF

Registration Number: NCT01687712

Lead Sponsor: Fertility Biotech AG

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 1100

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AFOLIA	AFOLIA	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.
Gonal-f® RFF	Gonal-f® RFF	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.

Primary Outcome Measures

Name	Time	Method
Clinical Pregnancy Rate After One Cycle of Treatment - ITT Population	Six weeks post embryo transfer	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.
Clinical Pregnancy Rate After One Cycle of Treatment - PP Population	Six weeks post embryo transfer	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.

Secondary Outcome Measures

Name	Time	Method
Exposure to r-hFSH Injections: Days of r-hFSH Stimulation - Cycle 1	Measured at discretionary visits between Days 9 and 15 after FSH starts	The number of days of r-hFSH stimulation a subject received during Cycle 1.
Exposure to r-hFSH Injections: Total Dose of r-hFSH (IU) - Cycle 1	Measured at discretionary visits between Days 9 and 15 after FSH starts.	The total dose of r-hFSH that subjects received during Cycle 1.
Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2	Measured either 3 days after ooctye pick up (Visit 9) or 18 +/- 1 days after oocyte pick up (Visit 10).	Summary of the number of subjects with mild, moderate and severe OHSS. The total number of subjects with OHSS is also included.
Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3	Measured either 3 days after ooctye pick up (Visit 9) or 18 +/- 1 days after oocyte pick up (Visit 10).	Summary of the number of subjects with mild, moderate and severe OHSS. The total number of subjects with OHSS is also included.
Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - 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).	Measurement of the number of subjects with detectable specific serum binding to FSH by surface Plasmon resonance during Cycle 1.
Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - 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).	Measurement of the number of subjects with detectable specific serum binding to FSH by surface Plasmon resonance during Cycle 2.
Exposure to r-hFSH Injections: Daily Dose of r-hFSH (IU) - Cycle 1	Measured at discretionary visits between Days 9 and 15 after FSH starts.	The mean dose of r-hFSH that subjects received in a day during Cycle 1.
Number of Oocytes Retrieved - Cycle 1	Visit 8, 34-36 hours after hCG administration	The number of oocytes retrieved per subject, following hCG administration in Cycle 1.
Local and Systemic Adverse Events: Dermal Response to Injection - Cycle 1	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).	Number of subjects reporting at least one dermal response to r-hFSH injection and number of subjects reporting no dermal responses.
Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1	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).	Dermal response to r-hFSH injection as assessed by the investigator and categorized according to severity of reaction
Overall Summary of Adverse Events (AEs) - Cycle 1	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).	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
Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1	Measured either 3 days after ooctye pick up (Visit 9) or 18 +/- 1 days after oocyte pick up (Visit 10).	Summary of the number of subjects with mild, moderate and severe OHSS. The total number of subjects with OHSS is also included.
Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - 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).	Measurement of the number of subjects with detectable specific serum binding to FSH by surface Plasmon resonance during Cycle 3.

Trial Locations

Locations (22): Shady Grove Fertility RSC
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Rockville, Maryland, United States
Fertility Centers of Illinois
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Chicago, Illinois, United States
Fertility Associates of Memphis
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Memphis, Tennessee, United States
In Via Fertility Specialists
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Hoffman Estate, Illinois, United States
Center for Assisted Reproduction
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Bedford, Texas, United States
Texas Fertility Center
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Austin, Texas, United States
Fertility Specialists of Houston
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Houston, Texas, United States
Jones Institute for Reproductive Medicine
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Norfolk, Virginia, United States
Houston Fertility Institute
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Houston, Texas, United States
Reproductive Associates of Delaware
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Newark, Delaware, United States
Physicians Research Group
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Tempe, Arizona, United States
FL Fertility Institution
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Tampa, Florida, United States
Georgia Reproductive Specialists
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Atlanta, Georgia, United States
HRC Fertility
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Encino, California, United States
Cooper Institute of Reproductive Hormonal Disorders, P.C.
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Marlton, New Jersey, United States
Shady Grove Fertility RSC, Chesterbrook, PA
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Chesterbrook, Pennsylvania, United States
Nevada Center for Reproductive Medicine
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Reno, Nevada, United States
University of Penn
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Philadelphia, Pennsylvania, United States
Institute for Reproductive Health
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Cincinnati, Ohio, United States
Main Line Fertility Center
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Bryn Mawr, Pennsylvania, United States
Abington Reproductive Medicine
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Abington, Pennsylvania, United States
Center of Reproducitve Medicine
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Webster, Texas, United States