Infertility
Conditions
Keywords
IVF, In vitro fertilization, Controlled ovarian stimulation, Follitropin, AFOLIA, Finox
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.
Interventions
DRUGAFOLIA
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
DRUGGonal-f® RFF
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
Sponsors
Fertility Biotech AG
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
35 Years to 42 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
Countries
United States
Participant flow
Recruitment details
1548 subjects were enrolled, 1101 subjects were randomized and 1100 received Investigational Medicinal Product (IMP) at 22 investigational sites in the United States.
Pre-assignment details
After the informed consent was signed, each subject received a subject identification number and underwent the down-regulation procedure. After a successful downregulation, subjects were centrally randomized in a 1:1 ratio to one of the treatment groups, AFOLIA or Gonal-f®RFF.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 549 |
| 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. | 551 |
| Total | 1,100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Cycle 1 | Abortion | 3 | 0 |
| Cycle 1 | Early Pregnancy Loss | 43 | 60 |
| Cycle 1 | Ectopic Pregnancy | 5 | 5 |
| Cycle 1 | Heterotropic Pregnancy | 1 | 0 |
| Cycle 1 | Intrauterine Fetal Death | 0 | 1 |
| Cycle 1 | Lost to Follow-up | 1 | 1 |
| Cycle 1 | Miscarriage/Spontaneous Abortion | 9 | 14 |
| Cycle 1 | Not Biochemically Pregnant | 386 | 348 |
| Cycle 2 | Early Pregnancy Loss | 18 | 16 |
| Cycle 2 | Ectopic Pregnancy | 0 | 1 |
| Cycle 2 | Miscarriage/Spontaneous Abortion | 0 | 1 |
| Cycle 2 | Not Biochemically Pregnant | 74 | 77 |
| Cycle 2 | Still Birth | 1 | 0 |
| Cycle 3 | Early Pregnancy Loss | 1 | 2 |
| Cycle 3 | Ectopic Pregnancy | 1 | 0 |
| Cycle 3 | Miscarriage/Spontaneous Abortion | 1 | 0 |
| Cycle 3 | Not Biochemically Pregnant | 21 | 22 |
Baseline characteristics
| Characteristic | AFOLIA | Total | Gonal-f® RFF |
|---|---|---|---|
| Age, Continuous | 37.7 years STANDARD_DEVIATION 2.16 | 37.8 years STANDARD_DEVIATION 2.17 | 37.8 years STANDARD_DEVIATION 2.18 |
| Age, Customized 35-37 | 275 Participants | 551 Participants | 276 Participants |
| Age, Customized 38-40 | 201 Participants | 395 Participants | 194 Participants |
| Age, Customized 41-42 | 73 Participants | 154 Participants | 81 Participants |
| BMI Category (kg/m^2) >=18 to <25 | 279 Participants | 524 Participants | 245 Participants |
| BMI Category (kg/m^2) >=25 to <30 | 150 Participants | 334 Participants | 184 Participants |
| BMI Category (kg/m^2) >=30 to <=38 | 109 Participants | 221 Participants | 112 Participants |
| BMI Category (kg/m^2) >38 | 3 Participants | 7 Participants | 4 Participants |
| BMI Category (kg/m^2) Unknown or Not Reported | 8 Participants | 14 Participants | 6 Participants |
| BMI (kg/m^2) | 25.92 kg/m^2 STANDARD_DEVIATION 4.738 | 26.15 kg/m^2 STANDARD_DEVIATION 4.765 | 26.38 kg/m^2 STANDARD_DEVIATION 4.784 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 96 Participants | 174 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 452 Participants | 925 Participants | 473 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| FSH at screening | 7.98 international units (IU) STANDARD_DEVIATION 4.636 | 7.87 international units (IU) STANDARD_DEVIATION 3.7 | 7.76 international units (IU) STANDARD_DEVIATION 2.433 |
| Height (m) | 1.643 meters STANDARD_DEVIATION 0.066 | 1.642 meters STANDARD_DEVIATION 0.0672 | 1.642 meters STANDARD_DEVIATION 0.0684 |
| Infertility Duration | 4.1 years STANDARD_DEVIATION 4.61 | 4.1 years STANDARD_DEVIATION 4.58 | 4.2 years STANDARD_DEVIATION 4.54 |
| LH at screening | 5.77 international units (IU) STANDARD_DEVIATION 3.36 | 5.76 international units (IU) STANDARD_DEVIATION 2.93 | 5.74 international units (IU) STANDARD_DEVIATION 2.44 |
| Number of previous fresh ART cycles [N(%)] 0 | 441 Participants | 881 Participants | 440 Participants |
| Number of previous fresh ART cycles [N(%)] 1 | 81 Participants | 158 Participants | 77 Participants |
| Number of previous fresh ART cycles [N(%)] 2 | 20 Participants | 50 Participants | 30 Participants |
| Number of previous fresh ART cycles [N(%)] ≥3 | 7 Participants | 11 Participants | 4 Participants |
| Primary Cause of Infertility Male Factor | 189 Participants | 367 Participants | 178 Participants |
| Primary Cause of Infertility Mild Endometriosis | 59 Participants | 104 Participants | 45 Participants |
| Primary Cause of Infertility Other | 28 Participants | 69 Participants | 41 Participants |
| Primary Cause of Infertility Tubal Factor | 138 Participants | 307 Participants | 169 Participants |
| Primary Cause of Infertility Unexplained Infertility | 225 Participants | 431 Participants | 206 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 40 Participants | 88 Participants | 48 Participants |
| Race (NIH/OMB) Black or African American | 61 Participants | 118 Participants | 57 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 12 Participants | 4 Participants |
| Race (NIH/OMB) White | 435 Participants | 875 Participants | 440 Participants |
| Sex: Female, Male Female | 549 Participants | 1100 Participants | 551 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight (kg) | 70.01 kilograms STANDARD_DEVIATION 13.803 | 70.57 kilograms STANDARD_DEVIATION 13.828 | 71.12 kilograms STANDARD_DEVIATION 13.844 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 549 | 1 / 551 | 0 / 109 | 0 / 120 | 0 / 28 | 0 / 24 |
| other Total, other adverse events | 403 / 549 | 391 / 551 | 69 / 109 | 66 / 120 | 13 / 28 | 12 / 24 |
| serious Total, serious adverse events | 32 / 549 | 31 / 551 | 2 / 109 | 6 / 120 | 3 / 28 | 0 / 24 |
Outcome results
Primary
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.
Time frame: Six weeks post embryo transfer
Population: Intention to treat population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Clinical Pregnancy Rate After One Cycle of Treatment - ITT Population | Yes | 114 Participants |
| AFOLIA | Clinical Pregnancy Rate After One Cycle of Treatment - ITT Population | No | 435 Participants |
| Gonal-f® RFF | Clinical Pregnancy Rate After One Cycle of Treatment - ITT Population | Yes | 138 Participants |
| Gonal-f® RFF | Clinical Pregnancy Rate After One Cycle of Treatment - ITT Population | No | 413 Participants |
Comparison: The null and alternative hypotheses are as follows:~H0: p2- p1 \> ∆ and H1: p2- p1 ≤ ∆,~where p1 is the clinical pregnancy rate in the AFOLIA treatment group, p2 is the clinical pregnancy rate in the Gonal f® treatment group, and Δ is the non-inferiority margin of 8%.95% CI: [-1.3, 8.7]
Primary
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.
Time frame: Six weeks post embryo transfer
Population: Per-protocol population, defined as a subset of the ITT population composed of all patients without any major protocol deviation (i.e. one which would affect the primary efficacy endpoint assessment).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Clinical Pregnancy Rate After One Cycle of Treatment - PP Population | Yes | 108 Participants |
| AFOLIA | Clinical Pregnancy Rate After One Cycle of Treatment - PP Population | No | 378 Participants |
| Gonal-f® RFF | Clinical Pregnancy Rate After One Cycle of Treatment - PP Population | Yes | 125 Participants |
| Gonal-f® RFF | Clinical Pregnancy Rate After One Cycle of Treatment - PP Population | No | 369 Participants |
Comparison: The null and alternative hypotheses are as follows:~H0: p2- p1 \> ∆ and H1: p2- p1 ≤ ∆,~where p1 is the clinical pregnancy rate in the AFOLIA treatment group, p2 is the clinical pregnancy rate in the Gonal f® treatment group, and Δ is the non-inferiority margin of 8%.95% CI: [-2.5, 8.1]
Secondary
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.
Time frame: Measured either 3 days after ooctye pick up (Visit 9) or 18 +/- 1 days after oocyte pick up (Visit 10).
Population: Safety population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1 | Total Number of Subjects with OHSS | 13 Participants |
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1 | Number of Subjects with Mild OHSS | 6 Participants |
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1 | Number of Subjects with Moderate OHSS | 5 Participants |
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1 | Number of Subjects with Severe OHSS | 2 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1 | Number of Subjects with Severe OHSS | 2 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1 | Total Number of Subjects with OHSS | 12 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1 | Number of Subjects with Moderate OHSS | 6 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 1 | Number of Subjects with Mild OHSS | 4 Participants |
Secondary
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.
Time frame: Measured either 3 days after ooctye pick up (Visit 9) or 18 +/- 1 days after oocyte pick up (Visit 10).
Population: Safety population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2 | Total Number of Subjects with OHSS | 1 Participants |
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2 | Number of Subjects with Mild OHSS | 1 Participants |
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2 | Number of Subjects with Moderate OHSS | 0 Participants |
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2 | Number of Subjects with Severe OHSS | 0 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2 | Number of Subjects with Severe OHSS | 0 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2 | Total Number of Subjects with OHSS | 3 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2 | Number of Subjects with Moderate OHSS | 2 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 2 | Number of Subjects with Mild OHSS | 1 Participants |
Secondary
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.
Time frame: Measured either 3 days after ooctye pick up (Visit 9) or 18 +/- 1 days after oocyte pick up (Visit 10).
Population: Safety population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3 | Total Number of Subjects with OHSS | 0 Participants |
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3 | Number of Subjects with Mild OHSS | 0 Participants |
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3 | Number of Subjects with Moderate OHSS | 0 Participants |
| AFOLIA | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3 | Number of Subjects with Severe OHSS | 0 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3 | Number of Subjects with Severe OHSS | 0 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3 | Total Number of Subjects with OHSS | 0 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3 | Number of Subjects with Moderate OHSS | 0 Participants |
| Gonal-f® RFF | Adverse Events of Special Interest: Ovarian Hyperstimulation Syndrome (OHSS) - Cycle 3 | Number of Subjects with Mild OHSS | 0 Participants |
Secondary
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.
Time frame: Measured at discretionary visits between Days 9 and 15 after FSH starts.
Population: Intention to treat population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AFOLIA | Exposure to r-hFSH Injections: Daily Dose of r-hFSH (IU) - Cycle 1 | 292.1 international unit (IU) | Standard Deviation 57.9 |
| Gonal-f® RFF | Exposure to r-hFSH Injections: Daily Dose of r-hFSH (IU) - Cycle 1 | 297.5 international unit (IU) | Standard Deviation 56.97 |
Secondary
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.
Time frame: Measured at discretionary visits between Days 9 and 15 after FSH starts
Population: Intention to treat population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AFOLIA | Exposure to r-hFSH Injections: Days of r-hFSH Stimulation - Cycle 1 | 10.8 days | Standard Deviation 1.72 |
| Gonal-f® RFF | Exposure to r-hFSH Injections: Days of r-hFSH Stimulation - Cycle 1 | 11.0 days | Standard Deviation 1.67 |
Secondary
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.
Time frame: Measured at discretionary visits between Days 9 and 15 after FSH starts.
Population: Intention to treat population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AFOLIA | Exposure to r-hFSH Injections: Total Dose of r-hFSH (IU) - Cycle 1 | 3209.2 international unit (IU) | Standard Deviation 1008.05 |
| Gonal-f® RFF | Exposure to r-hFSH Injections: Total Dose of r-hFSH (IU) - Cycle 1 | 3343.6 international unit (IU) | Standard Deviation 1005.08 |
Secondary
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
Time frame: 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).
Population: Safety population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1 | No evidence of irritation | 28 Participants |
| AFOLIA | Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1 | Minimal erythema, barely perceptible | 2 Participants |
| AFOLIA | Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1 | Definited Erythema, readily visible; minimal edema | 0 Participants |
| AFOLIA | Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1 | Definite Edema | 1 Participants |
| Gonal-f® RFF | Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1 | Definite Edema | 0 Participants |
| Gonal-f® RFF | Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1 | No evidence of irritation | 25 Participants |
| Gonal-f® RFF | Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1 | Definited Erythema, readily visible; minimal edema | 1 Participants |
| Gonal-f® RFF | Local and Systemic Adverse Events: Dermal Response to Injection by Severity - Cycle 1 | Minimal erythema, barely perceptible | 7 Participants |
Secondary
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.
Time frame: 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).
Population: Safety population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Local and Systemic Adverse Events: Dermal Response to Injection - Cycle 1 | Subjects who reported at least one dermal response | 37 Participants |
| AFOLIA | Local and Systemic Adverse Events: Dermal Response to Injection - Cycle 1 | Subjects who reported no dermal responses | 512 Participants |
| Gonal-f® RFF | Local and Systemic Adverse Events: Dermal Response to Injection - Cycle 1 | Subjects who reported at least one dermal response | 42 Participants |
| Gonal-f® RFF | Local and Systemic Adverse Events: Dermal Response to Injection - Cycle 1 | Subjects who reported no dermal responses | 509 Participants |
Secondary
Number of Oocytes Retrieved - Cycle 1
The number of oocytes retrieved per subject, following hCG administration in Cycle 1.
Time frame: Visit 8, 34-36 hours after hCG administration
Population: Intention to treat population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AFOLIA | Number of Oocytes Retrieved - Cycle 1 | 11.3 Oocytes retrieved | Standard Deviation 6.76 |
| Gonal-f® RFF | Number of Oocytes Retrieved - Cycle 1 | 11.2 Oocytes retrieved | Standard Deviation 6.63 |
Comparison: The null and alternative hypotheses are as follows:~H0: p2- p1 = 0 and H1: p2- p1 ≠0,~where p1 is the least squares adjusted mean number of oocytes retrieved in the AFOLIA treatment group and p2 is the least squares adjusted mean number of oocytes retrieved in the Gonal f® treatment group.p-value: 0.612ANCOVA
Secondary
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.
Time frame: 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).
Population: Safety population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization. Percentages are based on the number of subjects in the safety population with data at the respective visit.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Visit 5 | 1 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Visit 10 | 1 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Visit 9 | 1 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Visit 11 | 0 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Baseline | 1 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Visit 11 | 1 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Baseline | 1 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Visit 5 | 1 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Visit 9 | 1 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 1 | Visit 10 | 1 Participants |
Secondary
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.
Time frame: 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).
Population: Safety population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization. Percentages are based on the number of subjects in the safety population with data at the respective visit.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Visit 5 | 0 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Visit 10 | 0 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Visit 9 | 0 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Visit 11 | 0 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Baseline | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Visit 11 | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Baseline | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Visit 5 | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Visit 9 | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 2 | Visit 10 | 0 Participants |
Secondary
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.
Time frame: 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).
Population: Safety population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization. Percentages are based on the number of subjects in the safety population with data at the respective visit.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Visit 5 | 0 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Visit 10 | 0 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Visit 9 | 0 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Visit 11 | 0 Participants |
| AFOLIA | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Baseline | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Visit 11 | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Baseline | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Visit 5 | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Visit 9 | 0 Participants |
| Gonal-f® RFF | Number of Subjects With Detectable Specific Serum Binding to FSH by Surface Plasmon Resonance - Cycle 3 | Visit 10 | 0 Participants |
Secondary
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
Time frame: 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).
Population: Safety population, defined as all randomized subjects who received at least one dose of study treatment, based on their randomization.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AFOLIA | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one treatment related AE | 202 Participants |
| AFOLIA | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one AE leading to discontinuation | 2 Participants |
| AFOLIA | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one serious adverse event | 32 Participants |
| AFOLIA | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one AE due to pregnancy complication | 29 Participants |
| AFOLIA | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one AE | 403 Participants |
| Gonal-f® RFF | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one AE due to pregnancy complication | 30 Participants |
| Gonal-f® RFF | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one AE | 391 Participants |
| Gonal-f® RFF | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one treatment related AE | 197 Participants |
| Gonal-f® RFF | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one serious adverse event | 31 Participants |
| Gonal-f® RFF | Overall Summary of Adverse Events (AEs) - Cycle 1 | At least one AE leading to discontinuation | 1 Participants |