Recombinant Follicle-stimulating Hormone in Treatment for Infertility (REFRESH)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Female Infertility
• Intervention / Treatment: Drug: Recombinant Human Follicle Stimulating Hormone 900 IU (66.0 μg) / 1.5mL Solution for Injection in Prefilled Pen

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 3

Contacts and Locations

Study Locations

• India
  • Uttar Pradesh
    • Varanasi, Uttar Pradesh, India, 221007
      • Om Research Center Om Surgical Center and Maternity Home

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 39 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject has indication ART using COS.
• Subject has regular menstrual cycle of 21-35 days.

• Subject has one of the following:

  1. FSH level <10 IU/L and Estradiol levl <80 pg/mL at day 2 or 3
  2. 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:

  1. Any agent(s) known to affect ovulation (e.g., neuroleptics);
  2. Drugs known or suspected to be teratogenic in nature.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test group; 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; fixed-dose of 225 IU/day, subcutaneous (SC), daily, for 5 days. further dosage will be adjusted till adequate follicular development.; Other Names: Gonal-f; Foligraf
Active Comparator: Reference group; 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; fixed-dose of 225 IU/day, subcutaneous (SC), daily, for 5 days. further dosage will be adjusted till adequate follicular development.; Other Names: Gonal-f; Foligraf

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bharat Serums and Vaccines Limited

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2022
• Primary Completion (Estimated): August 31, 2023
• Study Completion (Estimated): November 30, 2023

Study Registration Dates

• First Submitted: January 23, 2022
• First Submitted That Met QC Criteria: February 23, 2022
• First Posted (Actual): March 4, 2022

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 31, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Infertility; Infertility, Female; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Follicle Stimulating Hormone; Hormones
• Other Study ID Numbers: BSV_rhFSH_20_09

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No