Lutropin Alfa in Women at Risk of Poor Response

Lutropin Alfa (Luveris®) in Women at Risk of Poor Response Suppressed With Cetrorelix: an Exploratory Trial

Evaluate the effectiveness of adding lutropin alfa (recombinant human luteinizing hormone [r-hLH]) in the middle of the follicular phase compared to no addition, in infertile women at risk of poor response stimulated with follitropin alfa (recombinant Follicle-Stimulating Hormone [r-FSH]) under Gonadotropin Releasing Hormone (GnRH) antagonist in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), in the number and quality of oocytes, follicular development, fertilization oocyte, embryo quality, and pregnancy rate.

Study Overview

• Status: Completed
• Conditions: Ovarian Stimulation
• Intervention / Treatment: Drug: r-FSH; Drug: r-hLH; Drug: Analogous GnRH antagonist; Drug: r-hCG; Drug: Progesterone

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Valencia, Spain
    • Hospital Universitario de La Fe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 38 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Participants who were at risk of poor response by at least one of the following criteria: a) <3 follicles in last cycle, or less than or equal to (</=) 2 metaphase II oocytes, or estradiol (E2) <600 pg/mL; b) Cancellation of previous cycle; c) Early follicular serum Follicle-Stimulating Hormone (FSH) >8.5 milli IU/L
• Participants with normal baseline luteinizing hormone and E2 levels
• Regular menstrual cycles of 25-35 days
• Presence of both ovaries and uterus able to withstand pregnancy

Exclusion Criteria:

• Participants who had any clinically significant disease including known human immunodeficiency virus (HIV), hepatitis-B virus (HBV)/hepatitis-C virus (HCV) positivity
• Participants with more than 3 previous assisted reproductive techniques (ART) cycles
• Participants with polycystic ovaries or cyst of unknown etiology; unexplained gynecological bleeding
• Participants who had any contraindication to being pregnant
• Active substance abuse
• Participants who had simultaneously participated in another clinical drug trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: r-FSH + r-hLH; Lutropin alfa (r-hLH) will be administered at a daily dose of 150 International Units (IU) from the presence of at least one follicle greater than (>) 14 millimeter (mm) to complete ovarian stimulation. Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 milligrams (mg) of recombinant Human Chorionic Gonadotropin (r-hCG) will be administered subcutaneously at 12 hours after the last injection of lutropin alfa and/or follitropin alfa and analogous GnRH antagonist.	Drug: r-FSH; r-FSH will be administered as specified in the arm description.; Other Names: Follitropin alfa; Gonal-F®; Drug: r-hLH; r-hLH will be administered as specified in the arm description.; Other Names: Lutropin alfa; Luveris®; Drug: Analogous GnRH antagonist; Analogous GnRH antagonist will be administered as specified in the arm description.; Other Names: Cetrotide®; Drug: r-hCG; r-hCG will be administered as specified in the arm description.; Drug: Progesterone; Progesterone will be administered as specified in the arm description.
ACTIVE_COMPARATOR: r-FSH; Follitropin alfa (r-FSH) will be administered at an initial dose of 225-450 IU per day (according to standard center practice); the dose will then be adjusted to ovarian response as assessed by ovarian ultrasound and/or serum estradiol. Participants will also receive analogous GnRH antagonist and natural progesterone, as per standard center practice. To complete follicular maturation and trigger ovulation, a single dose of 250 mg of r-hCG will be administered subcutaneously at 12 hours after the last injection of follitropin alfa and analogous GnRH antagonist.	Drug: r-FSH; r-FSH will be administered as specified in the arm description.; Other Names: Follitropin alfa; Gonal-F®; Drug: Analogous GnRH antagonist; Analogous GnRH antagonist will be administered as specified in the arm description.; Other Names: Cetrotide®; Drug: r-hCG; r-hCG will be administered as specified in the arm description.; Drug: Progesterone; Progesterone will be administered as specified in the arm description.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Oocytes Retrieved		At the end of stimulation (Day 2 up to Day 8)
Number of Follicles Greater Than (>) 14 Millimeter (mm) in Diameter		At the end of stimulation (Day 2 up to Day 8)
Oocytes Recovery Rate	Oocytes recovery rate (oocytes per >14 mm follicle) is defined as number of oocytes retrieved divided by number of follicles >14 mm in diameter.	At the end of stimulation (Day 2 up to Day 8)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oocyte Nuclear Maturity Rate	Oocyte nuclear maturity rate (metaphase II oocytes per retrieved oocyte) is defined as number of metaphase II oocytes divided by total number of oocytes retrieved.	At the end of stimulation (Day 2 up to Day 8)
Fertilization Rate	The fertilization rate (2 pronuclei [PN] fertilized oocytes per inseminated oocyte) was defined as number of 2 PN fertilized oocytes divided by number of inseminated oocytes.	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Number of Embryos by Quality	Embryo quality was graded according to morphological classification of Veeck. Grade 1: even blastomeres with no fragmentation; Grade 2: even blastomeres with slight fragmentation (less than 20%); Grade 3: uneven size blastomeres with no fragmentation; Grade 4: even or uneven size blastomeres with moderate fragmentation (20-25%); and Grade 5: unrecognizable blastomeres with severe fragmentation (>50%).	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Number of Embryos Transferred by In Vitro Fertilization (IVF)		Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Number of Participants With Positive Pregnancy Test	The beta Human Chorionic Gonadotropin (beta-hCG) test was used as pregnancy test.	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Number of Participants With Clinical Pregnancy	A clinical pregnancy is a pregnancy that is confirmed by both pregnancy test (beta-hCG test) and sonographic confirmation of a gestational sac or heartbeat (fetal sac).	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Implementation Rate	Implementation rate (clinical pregnancy/embryo transferred) was defined as the number of clinical pregnancies divided by number of embryos transferred.	Up to 35-45 days after administration of r-hCG (r-hCG administration = Day 2 to Day 8)
Plasma Level of Estradiol		At the time of r-hCG administration (any days between Day 2 to Day 8)
Endometrial Thickness		At the time of r-hCG administration (any days between Day 2 to Day 8)
Duration of Ovarian Stimulation	Duration of ovarian stimulation was defined as the time from start of study treatment to time of r-hCG administration.	Randomization to Day 8
rFSH Cumulative Dose		Randomization to Day 8
Plasma Levels of LH		At the time of r-hCG administration (any days between Day 2 to Day 8)
Number of Participants in Whom At Least 1 Stimulation Cycle Was Cancelled		Randomization to Day 8

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• M.J. Fernández Ramírez, A. Monzó, T. García-Gimeno, J.M. Rubio, V. Montañana, C. Duque, G. Herrero, A. Romeu. Role of LH administration during the follicullar phase in women with risk of low response in ovarian stimulation with FSH and cetrorelix for IVF, REVISTA IBEROAMERICANA DE FERTILIDAD, Vol. 23- nº 5 - Septiembre-Octubre 2006

Helpful Links

• Results publication in spanish language

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 7, 2005
• Primary Completion (ACTUAL): January 30, 2007
• Study Completion (ACTUAL): January 30, 2007

Study Registration Dates

• First Submitted: April 26, 2010
• First Submitted That Met QC Criteria: April 27, 2010
• First Posted (ESTIMATE): April 28, 2010

Study Record Updates

• Last Update Posted (ACTUAL): August 28, 2018
• Last Update Submitted That Met QC Criteria: July 30, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Intracytoplasmic sperm injection; Reproductive techniques, assisted; Lutropin alfa; Fertilization in vitro
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Progestins; Cetrorelix; Progesterone
• Other Study ID Numbers: IMP26170 (INI25954); 2005-002229-30 (EUDRACT_NUMBER)