Potential Benefit of r-hLH Addition in Patients Aged 35 to 40 Under Ovarian Stimulation Treatment

An Exploratory, Randomized, Open-label, Controlled Study to Evaluate the Potential Benefit of r-hLH Addition in Patients Aged 35 to 40 Under Ovarian Stimulation Treatment

This will be an exploratory, prospective, randomized, open-label and controlled trial to evaluate the potential benefit of r-hFSH:r-hLH 2:1 co-treatment starting from COS D1 versus r-hFSH alone in patients aged 35 to 40 under ovarian stimulation treatment.

After signing informed consent form (ICF), all eligible participants will be randomly assigned in a 1:1 ratio to either treatment or control group, and GnRH antagonist protocol will be used in both treatment and control groups.

Study Overview

• Status: Not yet recruiting
• Conditions: Infertility
• Intervention / Treatment: Drug: Recombinant Human Follitropin Alfa Solution for Injection (Gonal-f®); Drug: Recombinant Human Lutropin alfa for Injection (r-hLH, Luveris®)

Detailed Description

This will be an exploratory, prospective, randomized, open-label and controlled trial to evaluate the potential benefit of r-hFSH:r-hLH 2:1 co-treatment starting from COS D1 versus r-hFSH alone in patients aged 35 to 40 under ovarian stimulation treatment.

After signing informed consent form (ICF), all eligible participants will be randomly assigned in a 1:1 ratio to either treatment or control group, and GnRH antagonist protocol will be used in both treatment and control groups.

1. Treatment group: The r-hFSH starting dose will be based on the patient's profile and physician's experience. r-hLH will be added at a ratio of 2:1 starting from day 1 of r-hFSH administration; the dose of r-hFSH during COS will be adjusted by the physician based on clinical experience and the patient's ovarian response, and the r-hFSH: r-hLH dose will be 2:1, continuing to 24~48 hours prior to trigger drug injection.
2. Control group: r-hFSH alone will be administrated for ovarian stimulation. The r-hFSH starting dose will be based on the patient's profile and physician's experience. The dose of r-hFSH during COS will be adjusted by the physician based on clinical experience and the patient's ovarian response, continuing to 24~48 hours prior to trigger drug injection.

The estimated treatment duration is 11 days from the first day of COS until 24~48 h prior to trigger drug injection, and this may vary depending on individual circumstances.

Follicular development, serum E2 and P levels will be monitored during COS according to the investigator site's ART practice until the criteria to administer trigger drug are met to induce final oocyte maturation. Trigger drug administration is to be performed according to the site's routine clinical practice.

Oocyte pick-up (OPU), IVF/ICSI, ET, and luteal phase support (LPS) will be performed according to the site's routine practice. LPS will be started after oocyte retrieval in fresh embryo transfer.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Haixiang Sun, Dr.; Phone Number: 13851622008; Email: stevensunz@163.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210008
      • Nanjing Drum Tower Hospital
      • Contact: Haixiang Sun, Dr.; Phone Number: +8683106666

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 35 to 40 (including 40)
• 18.5<BMI<28 kg/m2
• AFC up to 14
• First or second ART cycle
• Planned for ovarian stimulation with GnRH-antagonist for down-regulation
• Ejaculated sperm

Exclusion Criteria:

• Contraindications to ART treatment
• History of two or more spontaneous miscarriages
• History of two or more implantation failures after fresh or frozen-warmed embryo transfers
• Diagnosis of severe endometriosis
• Patients with endocrine and metabolic diseases (diabetes mellitus, hypogonadotropic amenorrhea, genital system tumors, hyperprolactinemia, etc.)
• Confirmed chromosomal abnormalities

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment group; The r-hFSH starting dose will be based on the patient's profile and physician's experience. r-hLH will be added at a ratio of 2:1 starting from day 1 of r-hFSH administration; the dose of r-hFSH during COS will be adjusted by the physician based on clinical experience and the patient's ovarian response, and the r-hFSH: r-hLH dose will be 2:1, continuing to 24~48 hours prior to trigger drug injection. For both groups, daily injection of 0.25 mg of cetrorelix (Cetrotide®, Merck Serono S.A.) will be administrated subcutaneously when at least one follicle with diameter ≥ 14 mm or serum LH level exceeds 10 IU/L or LH level is 2 folder than basal LH level or P level exceeds 0.8 ng/ml, continuing until ovulation triggering day. Cetrorelix can be administrated earlier in patients with advanced age or diminished ovarian reserve according to judgment of clinicians.	Drug: Recombinant Human Follitropin Alfa Solution for Injection (Gonal-f®); As a r-hFSH agent, Gonal-f® is used for COS. It is a prefilled ready to use pen device containing follitropin alfa for injection and is designed for subcutaneous self-administration by patients undergoing COS for ART. It is available as dose presentations of 150 IU and 450 IU. The investigators and/or his/her delegate/s will explain the use of Gonal-f® prefilled pen. Gonal-f® will be prescribed by the investigator based on clinical diagnosis and treatment routines, and will not be provided free of charge.; Drug: Recombinant Human Lutropin alfa for Injection (r-hLH, Luveris®); This product is a white freeze-dried powder and a colorless and clear injection solvent, and stored away from light under 25℃ in the original packaging. Luveris® will be provided free of charge.
Active Comparator: Control group; r-hFSH alone will be administrated for ovarian stimulation. The r-hFSH starting dose will be based on the patient's profile and physician's experience. The dose of r-hFSH during COS will be adjusted by the physician based on clinical experience and the patient's ovarian response, continuing to 24~48 hours prior to trigger drug injection. For both groups, daily injection of 0.25 mg of cetrorelix (Cetrotide®, Merck Serono S.A.) will be administrated subcutaneously when at least one follicle with diameter ≥ 14 mm or serum LH level exceeds 10 IU/L or LH level is 2 folder than basal LH level or P level exceeds 0.8 ng/ml, continuing until ovulation triggering day. Cetrorelix can be administrated earlier in patients with advanced age or diminished ovarian reserve according to judgment of clinicians.	Drug: Recombinant Human Lutropin alfa for Injection (r-hLH, Luveris®); This product is a white freeze-dried powder and a colorless and clear injection solvent, and stored away from light under 25℃ in the original packaging. Luveris® will be provided free of charge.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Good quality embryo rate (cleavage stage)	Cleavage stage good-quality embryos are defined as embryos derived from normally fertilized zygotes with 7~9 cells on day 3 post-fertilization, stage-specific cell size, less than 10% fragmentation, and no multinucleation. Cleavage stage good-quality embryo rate is defined as the number of cleavage stage good-quality embryos divided by the number of normally fertilized zygotes. Embryos will be assessed by two independent experienced embryologists to minimize intra-observation variability.	Day 3 after fertilization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of oocytes	Number of oocytes is defined as the total number of oocytes obtained through transvaginal ultrasound guided puncture on the day of OPU. All follicles with an estimated diameter of ≥12 mm should be punctured.	24 hours after Oocytes pick up
Number of MII oocytes (analyzed in ICSI subgroup only)	Number of MII oocyte is defined as the total number of an oocyte at metaphase of meiosis II, exhibiting the first polar body and with the ability to become fertilized	24 hours after Oocytes pick up
Total r-hFSH dose	Total r-hFSH dose is defined as the total dose of r-hFSH used for subcutaneous injection during COS period.	24 hours after ovulation triggering
Fertilization rate	IVF normal fertilization rate is defined as the number of oocytes with 2PN and 2PB divided by the number of COCs inseminated.; ICSI normal fertilization rate is defined as the number of oocytes with 2PN and 2PB divided by the number of MII oocytes injected.	24 hours after fertilization
Blastocyst development rate	Blastocyst development rate is defined as the proportion of blastocysts observed at 116 ± 2 h post-insemination as a function of the number of normally fertilized oocytes.	5 days after fertilization, up to 7 days
Utilizable embryo rate	Utilizable embryo rate is defined as the number of embryos (or blastocysts) suitable for transfer or cryopreservation as a function of the number of normally fertilized (2PN) oocytes observed on Day 1.	5 days after fertilization, up to 7 days
Implantation rate	Implantation rate is defined as the number of gestational sacs observed divided by the number of embryos transferred using transvaginal ultrasound 4~6 weeks after embryo transfer.	At 4-6 weeks of amenorrhea after customized timing of embryo transfer
Clinical pregnancy rate (per transfer cycle and per oocyte retrieval cycle)	Clinical pregnancy rate is defined as the number of clinical pregnancies expressed per 100 initiated cycles, aspiration cycles, or embryo transfer cycles. Clinical pregnancy is defined as the presence of gestational sac (intrauterine or ectopic) using ultrasound examination at 4~6 weeks after embryo transfer.	At 4-6 weeks of amenorrhea after customized timing of embryo transfer
Ongoing pregnancy rate	Ongoing pregnancy rate is defined as the number of intrauterine pregnancies continued for 12 gestational weeks divided by the number of embryo transfer cycles.	At 12 weeks of amenorrhea after customized timing of embryo transfer
Ovarian sensitivity index (OSI)	OSI is defined as the total r-hFSH dose divided by the number of oocytes retrieved.	24 hours after fertilization
Follicular output rate (FORT)	FORT is defined as the number of pre-ovulatory follicles (16~22 mm) on the day of trigger divided by the AFC (3~8 mm)	24 hours after fertilization
Follicle oocyte index (FOI)	FOI is defined as the number of total oocytes retrieved divided by the AFC	24 hours after fertilization
Safety Assessments	AE, SAE and OHSS	During the COS cycle (average cycle range 11 days), Up to 12 weeks after transfer

Collaborators and Investigators

• Sponsor: Nanjing University
• Investigators: Principal Investigator: Haiming Xia, Dr., The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2024
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): January 30, 2027

Study Registration Dates

• First Submitted: August 5, 2024
• First Submitted That Met QC Criteria: August 22, 2024
• First Posted (Actual): August 26, 2024

Study Record Updates

• Last Update Posted (Actual): August 27, 2024
• Last Update Submitted That Met QC Criteria: August 25, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: recombinant human LH; recombinant human FSH; ovarian stimulation treatment; advanced maternal age population
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Infertility; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Follicle Stimulating Hormone
• Other Study ID Numbers: MS700642_0020

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