Recombinant Follicle-stimulating Hormone in Treatment for Infertility

Study Overview
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Brief Summary
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This is a randomized multi-centre, assessor-blind, parallel-group study to be conducted in 250 women in the age group of 20 to 39 years (both inclusive), who are indicated to undergo COS as part of assisted reproductive technology (ART). The participant will receive r-hFSH, fixed-dose for 5 days, and day 6 onwards the dose may be adjusted for a single cycle of COS followed by ART procedures, and post-ART follow-up for ongoing pregnancy. The primary and secondary outcomes will be captured on days as per protocol. Adverse events will be noted for safety evaluation.

Official Title
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A Randomized, Parallel-group, Multi-Center, Assessor-blind Phase 3 Study to Compare the Efficacy, Safety and Ease of Use of Two Follicle Stimulating Hormone -Human Recombinant (r-hFSH) 900 IU (66.0 μg) / 1.5mL Solution for Injection in Prefilled Pen (Foligraf®- Manufactured by BSV and Gonal-f® Manufactured by Merck Serono) in Subjects Undergoing Controlled Ovarian Stimulation for Assisted Reproductive Technology

Conditions
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Female Infertility

Intervention / Treatment
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* Drug: Recombinant Human Follicle Stimulating Hormone 900 IU (66.0 μg) / 1.5mL Solution for Injection in Prefilled Pen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has indication ART using COS. Subject has regular menstrual cycle of 21-35 days. Subject has one of the following: FSH level <10 IU/L and Estradiol levl <80 pg/mL at day 2 or 3 Anti-mullerian hormone (AMH) level between 1 to 3.5 ng/mL during the menstrual cycle Subject has an antral follicle count (AFC) of 10- 25, follicle ≤10 mm in diameter before ovarian stimulation Subject has a BMI ≥18 and <30 kg/m2 Subject has results of clinical laboratory tests within normal reference range Subject and her partner are willing to provide written informed consent and comply Exclusion Criteria Details Subject has history of >2 failed ART cycles Subject with history of any endocrine abnormality, with documented hormone levels outside the reference range, which are clinically relevant, at screening Subject with a history of ovarian hyper-response (i.e., previous COS cycle with >25 follicles of ≥11 mm in diameter on USG) or OHSS Subject with documented polycystic ovarian syndrome (PCOS) at the time of screening Subject with only one ovary or ovarian abnormality (including endometrioma >10 mm; visible on USG), at screening Subject with documented severe endometriosis (American Society of Reproductive Medicine stage 3 or stage 4) or hydrosalpinx, at screening Subject with submucosal fibroids ≥5 cm or any other clinically relevant pathology, which could impair embryo implantation or pregnancy continuation, at screening Subject with a history of extrauterine pregnancy within 3 months of screening Subject with history of poor response to gonadotropin treatment (retrieval of <4 oocytes) in the previous ART cycle Subject with history of ≥3 miscarriages, at any time prior to screening Subject who has tested positive for Human Immunodeficiency Virus, Hepatitis B or Hepatitis C at screening Subject known to be allergic, hypersensitive, or intolerant to any of the preparations of r hFSH or its excipients, that will be used in the study Subject with contraindications to the use of gonadotropins (e.g., tumours, undiagnosed vaginal bleeding, or ovarian cysts) or gonadotropin-releasing hormone (GnRH) antagonists Subject with a history of epilepsy, thrombophilia, cardiovascular, gastrointestinal, hepatic, renal, pulmonary, auto-immune disease, or any active infection, requiring treatment which at the investigator's discretion might interfere with the study Subject with history of malignancy Subject who smokes or has stopped smoking within the last 3 months prior to screening Subject with history of alcohol or drug abuse within 12 months prior to screening Subject who has received any treatment listed below within 5 half-lives prior to screening: Any agent(s) known to affect ovulation (e.g., neuroleptics); Drugs known or suspected to be teratogenic in nature.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 39 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
Interventional Model Description: This is a Randomized, Parallel-group, Multi-Center, Assessor-blind Phase 3 Study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test group<br>Foligraf 900 IU (66.0 μg) / 1.5mL Solution for Injection in Prefilled Pen Follicle Stimulating Hormone (Human Recombinant) manufactured by Bharat Serums and Vaccines Ltd | Drug: Recombinant Human Follicle Stimulating Hormone 900 IU (66.0 μg) / 1.5mL Solution for Injection in Prefilled Pen<br>* fixed-dose of 225 IU/day, subcutaneous (SC), daily, for 5 days. further dosage will be adjusted till adequate follicular development.<br>* Other names: Gonal-f;|
| Active Comparator: Reference group<br>Gonal-f Recombinant Human Follicle Stimulating Hormone | Drug: Recombinant Human Follicle Stimulating Hormone 900 IU (66.0 μg) / 1.5mL Solution for Injection in Prefilled Pen<br>* fixed-dose of 225 IU/day, subcutaneous (SC), daily, for 5 days. further dosage will be adjusted till adequate follicular development.<br>* Other names: Gonal-f;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of oocytes retrieved | Number of oocytes retrieved | Oocyte pick up - up to   34 to 36 hours after human chorionic gonadotropin (hCG) administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pregnancy rate | Clinical pregnancy rate | 4 weeks after embryo transfer (ET) | 
| Ongoing Pregnancy rate | Ongoing pregnancy rate | 11±1 weeks after ET | 
| Cycle cancellation rate | Cycle cancellation rate | at Stimulation phase up to 20 days, oocyte pick up up to   34 to 36 hours after hCG administration, ET anytime up to 8 weeks | 
| Total Doseof r-hFSH | Total dose of r-hFSH (in IU) required for ovarian stimulation; | at end of stimulation up to 20 days | 
| Number of Days of r-hFSH stimulation | Number of days of r-hFSH stimulation | at end of stimulation up to 20 days | 
| Number of subject Change in Dosage | Proportion of subjects requiring change in dose | post Day 6 till end of stimulation up to 20 days | 
| Hormonal Investigation | Estradiol, Luteinizing, Progesterone, and inhibin b levels | Day 6 | 
| Follicle size on Day 6 | Number of follicles with size <11mm, Number of follicles with size 11- 14 mm, Number of follicles with size15 mm, Number of follicles with size16 mm, Number of follicles with size17 mm and Number of follicles with size ≥18 mm | Day 6 | 
| Follicle size at HCG administration | Number of follicles with size <11mm, Number of follicles with size 11- 14 mm, Number of follicles with size15 mm, Number of follicles with size16 mm, Number of follicles with size17 mm and Number of follicles with size ≥18 mm mm) | Day of hCG administration anytime upto 3 weeks | 
| Endometrium thickness | Endometrial thickness (mm) | day 6 | 
| Endometrium at HCG administration | Endometrial thickness (mm) | day of hCG injection (anytime upto 3 weeks) | 
| Number of Matured oocytes | Proportion of matured oocytes | Oocyte pick up   34 to 36 hours after hCG administration | 
| Number of good quality embryos | Number of good quality embryos | ET day (up to 8 weeks) | 
| Number of Adverse events | Number of treatment-emergent adverse events (TEAE) reported | Baseline, 1st day of stimulation, day 6 , end of stimulation up to 20 days, hCG administration, oocyte pick up   34 to 36 hours after hCG administration, ET up to 8 weeks, clinical pregnancy (after 4 weeks of ET),  12 weeks after ET | 
| Specific adverse events | The number of patients with ovarian hyperstimulation syndrome (OHSS) reported | Day 1 of Stimulation till  12 weeks after ET | 
| Exploratory | Ease of use of Pen - comparison of total score of Questionnaire to user of rhFSH pen | End of stimulation up to 20 days | 
| Evaluation of immunogenicity (antibody) of r-hFSH | Evaluation of immunogenicity of r-hFSH, comparison of antibody titre against r-hFSH in both groups | Baseline, 4 weeks and 12 weeks |