Multi-centre Study to Compare Efficacy and Safety of AFOLIA and Gonal-f in Women for Assisted Reproductive Treatment

Study Overview
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Brief Summary
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Ther purpose of this study is to show equivalence between AFOLIA and Gonal-f® with regard to the number of oocytes retrieved in women for assisted reproductive treatment.

Official Title
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A Phase III Assessor-blinded Randomized Parallel Group Multi-centre Study to Compare Efficacy and Safety of Two r-hFSH Formulations (AFOLIA Versus Gonal-f) in Women for Assisted Reproductive Treatment

Conditions
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Infertility

Intervention / Treatment
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* Drug: Follitropin alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 20 and 38 years with regular menstrual cycles of 25-35 days First or second cycle in the present series of ART BMI ≥ 18 ≤ 30 kg/m2 Basal FSH < 10 IU/L (cycle day 2-5) E2 levels < 50pg/mL (< 0.18 nmol/L) at the day of FSH administration Antral follicle count (AFC) ≥ 10 to ≤ 25 follicles (sum of both ovaries) Infertility due to any of the following factors: tubal factor, mild endometriosis (ASRM stage 1-2), male factor, unexplained infertility Presence of both ovaries and normal uterine cavity (confirmed by transvaginal ultrasound within 6 months before randomisation) Willingness to participate in the study and to comply with the study protocol Informed consent Exclusion Criteria: Presence of pregnancy History of ≥2 succeeding ART cycles (IVF and/or ICSI) before the study cycle without clinical pregnancy Presence of clinically significant systemic disease Presence of chronic cardiovascular, hepatic, renal or pulmonary disease Presence of uncontrolled endocrine disorder Previous history or presence of severe ovarian hyperstimulation syndrome Presence of polycystic ovaries (PCO) Presence of severe endometriosis (ASRM stage 3 or stage 4) and hydrosalpinx Neoplasia, including tumors of the hypothalamus and pituitary gland Abnormal bleeding of undetermined origin History of poor response to gonadotropin treatment (defined as fewer than 5 oocytes retrieved in a previous attempt) Male infertility without mobile spermatozoa in the ejaculate, that need testicular of epididymal sperm retrieval (MESA/TESE/TESA) Endocrine abnormality such as TSH or prolactin level elevations outside the reference range if clinically relevant at screening Any hormonal treatment within 1 month before the start of the FSH treatment (with the exception of levothyroxin) History of drug, nicotine or alcohol abuse within the last 12 months (> 10 cigarettes/day) Administration of other investigational products within the last month Clinically abnormal findings at Visit 1 Planned PGS/PGD/PBB or assisted hatching Concomitant participation in an other study protocol 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 medication (GnRH agonist, vitrelle®, and Utrogestan®) Presence or history of thrombophlebitis or thromboembolic disorders Presence or history of cerebral haemorrhage Presence or history of porphyria

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 38 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Gonal-f® (Follitropin alfa)<br> | Drug: Follitropin alfa<br>* 150IU per day subcutaneously for a maximum of 16 days<br>|
| Experimental: AFOLIA-150 (Follitropin alfa)<br> | Drug: Follitropin alfa<br>* 150IU per day subcutaneously for a maximum of 16 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Oocytes Retrieved (Per Protocol Population) | As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes | 34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment | 
| Number of Oocytes Retrieved (Intention-to-treat Population) | As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes | 34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Size of Follicles ≥ 12 mm at Day 8 of Stimulation | The number and size of follicles 12 mm or over in diameter at day 8 of stimulation were evaluated as secondary end-point. | Day 8 of stimulation | 
| E2 Concentration at Day 8 and at Day of hCG Administration | The serum concentration of oestradiol was assessed at day 8 and the day of hCG administration. | Day 8 of stimulation and at the day of hCG administration (after max. 16 days of r-FSH treatment) | 
| Total Dose of r-hFSH Administered | Total dose of r-hFSH required was assessed. | Day of hCG administration (after maximum 16 days of r-hFSH treatment) | 
| Quality of Oocytes Retrieved | Number of patients with ovum pick-up | 34-36 hours after hCG administration | 
| Fertilisation Rate of Oocytes | Fertilisation rate was assessed | 1 day after ovum pick-up | 
| Embryo Quality: Mean Number of Blastomeres | Main embryo quality parameter mean number of blastomeres | Day 2 of OPU/fertilisation | 
| Number of Participants With Cryopreserved 2PNs, Embryos/Blastocysts |  | Day 1, 2, 3 and 5 of OPU/fertilisation | 
| Number of Days of r-hFSH Stimulation | Mean duration of stimulation was assessed. | At the day of hCG administration, up to 16 days | 
| Number of Patients With Cycle Cancellation | Number of patients with cycle cancellation was assessed. | Until child birth/miscarriage, up to the end of the study | 
| Number of Patients With Good Response | Good response was defined as patients with an oocyte retrieval of four or more oocytes | Until child birth/miscarriage, up to the end of the study | 
| Implantation Rate | Defined as fetal sac per embryo transferred. | Five to six weeks after oocyte retrieval | 
| Clinical Pregnancy Rate | Presence of at least one intrauterine gestational sac. | Five to six weeks after oocyte retrieval | 
| Ongoing Pregnancy | Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer. | Ten weeks after embryo transfer | 
| Live Birth Rate | Patients with liveborn children | After childbirth with questionnaire | 
| Embryo Quality: Absence of Multinucleation | Main embryo quality parameter absence of multinucleation observed. | Day 3 | 
| Quality of Oocytes Retrieved | Number of patients with transferred blastocysts | At day 4 and 5 | 
| Quality of Oocytes Retrieved | Number of embryos per blastocysts transferred | Day of embryo transfer, either 2, 3 or 5 days after oocyte retrieval | 
| Clinical Pregnancy Rate (Second Treatment Cycle) | Presence of at least one intrauterine gestational sac. | Five to six weeks after oocyte retrieval | 
| Ongoing Pregnancy (Second Treatment Cycle) | Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer. | 10 weeks after embryo transfer | 
| Quality of Oocytes Retrieved | The maturity of the cumulus oophorus was assessed. | After oocyte retrieval, 34 to 36 hours after hCG administration | 
| Quality of Oocytes Retrieved | The nuclear maturity was assessed (Germinal vesicle, Metaphase I, Metaphase II). | After oocyte retrieval, 34 to 36 hours after hCG administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Assisted reproductive treatment, Superovulation, Follitropin alfa, r-hFSH, AFOLIA