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A Clinical Trial to Determine the Effect of Lutropin Alfa on Embryo Quality and Implantation Rate in Advanced Reproductive Age

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ClinicalTrials.gov Identifier: NCT01075815
Recruitment Status : Terminated
First Posted : February 25, 2010
Results First Posted : November 20, 2012
Last Update Posted : February 13, 2014
Sponsor:
Collaborator:
Merck, S.L., Spain
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

Tracking Information
First Submitted Date  ICMJE February 24, 2010
First Posted Date  ICMJE February 25, 2010
Results First Submitted Date  ICMJE August 29, 2012
Results First Posted Date  ICMJE November 20, 2012
Last Update Posted Date February 13, 2014
Study Start Date  ICMJE November 2008
Actual Primary Completion Date October 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 19, 2012)
Implantation Rate [ Time Frame: Day 35-42 post ovum pick-up (OPU) (34-38 hours post recombinant human choriogonadotropin day {end of stimulation cycle}[approximately 28 days]) ]
Implantation rate was measured as the number of gestational sacs observed, divided by the number of embryos transferred.
Original Primary Outcome Measures  ICMJE
 (submitted: February 24, 2010)
Implantation rate [ Time Frame: Baseline till two months after OPU ]
Number of clinical pregnancies (ultrasound evidence of sac) by the number of embryos transferred
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 19, 2012)
  • Mean Number of Follicles Greater Than or Equal to 14 Millimeter (mm) on Recombinant Human Choriogonadotropin (r-hCG) Day [ Time Frame: r-hCG day (end of stimulation cycle [approximately 28 days]) ]
  • Mean Number of Oocytes Retrieved [ Time Frame: 34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) ]
    Mean number of oocytes retrieved per reporting group on the day of OPU (34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body.
  • Number of Mature Oocytes Retrieved [ Time Frame: 34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) ]
    Number of mature oocytes retrieved per reporting group on the day of OPU (34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body. The nuclear maturity was evaluated based on the presence of a germinal vesicle (GV) or whether oocytes were in metaphase I (Meta-I) or II (Meta-II) stage.
  • Number of Fertilized Oocytes (2 Pronuclei [PN]) [ Time Frame: 34-38 hours post r-hCG day (end of stimulation cycle [approximately 28 days]) ]
    Oocytes were fertilized using Intra-cytoplasmic Sperm Injection (ICSI) technique which is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. The appearance of two 2PN is the first sign of successful fertilization as observed during in vitro fertilization, and is usually observed after ICSI. The zygote is then termed 2PN.
  • Number and Quality of Embryos [ Time Frame: Day 2-3 post OPU (34-38 hours post r-hCG day {end of stimulation cycle}[approximately 28 days]) ]
    Embryos were graded according to Spanish Association for the Study of Reproductive Biology (ASEBIR) criteria into different categories: (A) optimal quality with maximum capacity for implantation, (B) good quality with a high capacity for implantation, (C) regular with low possibility of implantation and (D) poor quality with very little possibility of implantation.
  • Number of Participants With Biochemical Pregnancies [ Time Frame: 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ]
    Biochemical pregnancy was defined as a pregnancy diagnosed only by the detection of hCG in serum or urine and that does not develop into a clinical pregnancy.
  • Number of Participants With Clinical Pregnancies [ Time Frame: 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ]
    Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy.
  • Total Dose of Recombinant Follicle Stimulating Hormone (r-FSH) [ Time Frame: 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ]
  • Estradiol (E2) Levels on r-hCG Day [ Time Frame: r-hCG day (end of stimulation cycle [approximately 28 days]) ]
  • Number of Ovarian Stimulation Days [ Time Frame: S1 up to r-hCG day (end of stimulation cycle [approximately 28 days]) ]
    Ovarian stimulation included from first rFSH injection (S1) until day on which r-hCG was administered (r-hCG day). This period was divided into 2 parts: the first period in which 300 International Unit (IU) rFSH dose was constant and which covered from S1 to Day 4 of stimulation period (S4); the second period in which the rFSH dose could be adjusted depending on the ovarian response and which began on S4 and finished on the day on which the criteria for administration of r-hCG to induce the final follicular maturation were met.
  • Number of Recombinant Human Choriogonadotropin (r-hCG) Cycles Cancelled Due to Poor Response [ Time Frame: Up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ]
    Poor response was defined as 3 or less follicles of greater than or equal to 12 mm developing following at least 7 days of study treatment.
  • Total Number of Births [ Time Frame: Up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ]
    Total number of births per reporting group was calculated.
  • Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
  • Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) [ Time Frame: Baseline up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ]
    OHSS is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting.
  • Number of Cycles Cancelled Due to Risk of Ovarian Hyper Stimulation Syndrome (OHSS) [ Time Frame: Baseline up to 2 months after OPU (34-38 hours post r-hCG day {end of stimulation cycle} [approximately 28 days]) ]
    OHSS is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 24, 2010)
  • Secondary efficacy variables [ Time Frame: Baseline till two months after OPU ]
    Number of follicles on r-hCG day or cancellation; number of oocytes retrieved and their maturity; number of fertilized (2PN) oocytes; fertilisation rate; number and quality of embryos; number of clinical pregnancies; number of cycles cancelled due to poor response; stimulation days; total dose of r-FSH; estardiol (E2) levels on r-hCG day.
  • Adverse events [ Time Frame: Baseline till pregnancy assessment ]
  • Tolerability/safety [ Time Frame: Baseline till two months after OPU ]
    Incidence of OHSS; number of cycles cancelled (hCG not administered) due to risk of OHSS; adverse events, including local tolerance and local laboratory parameters.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Clinical Trial to Determine the Effect of Lutropin Alfa on Embryo Quality and Implantation Rate in Advanced Reproductive Age
Official Title  ICMJE Exploratory Study to Determine the Effect of Lutropin Alfa on Embryo Quality and Their Implantation in Women of Advanced Reproductive Age
Brief Summary This is a multicentric, open, randomized, comparative trial aimed to assess the influence of recombinant luteinizing hormone (r-LH) supplementation during controlled ovarian stimulation (COS) in advanced reproductive age in terms of improved embryo competence which allows to transfer less embryos to avoid high grade multiple pregnancy without reducing the pregnancy rate.
Detailed Description

This study will be carried out by the Grupo de Interés de Salud Embrionaria (GISE) group (part of the Spanish Fertility Society) who uses strict criteria to select the embryos most suitable for successful transference.

OBJECTIVES

Primary objective:

  • To determine the benefit of r-LH supplementation in COS prior to in-vitro fertilization (IVF)/intracytosolic sperm injection (ICSI) in advanced reproductive age, in terms of embryo competence to implant, as compared against no r-LH supplementation

Secondary objectives:

To evaluate the benefit of r-LH supplementation in COS, in terms of:

  • follicular development
  • length of the stimulation
  • oocyte number and their maturity
  • fertilization rate
  • embryo number and quality
  • gestational sacs
  • abortion
  • ongoing pregnancies
  • local and systemic safety of r-LH administration

The study will consist of 2 groups randomized in 1:1 ratio and each subject would be followed up until the confirmation of her pregnancy status. Each subject will be administered gonadotropin releasing hormone (GnRH) agonist subcutaneously daily from previous mid luteal phase to r-hCG administration as a standard practice to achieve down regulation. Each subject will also be administered recombinant follicle stimulating hormone (r-FSH) at a starting dose of 300 IU from S1 up to ovarian stimulation completion (r-hCG day) as a part of standard practice. In addition to the above concurrent therapies, one group will be administered experimental treatment (Luveris®) and the other group (control group) will not be administered any other drug (control treatment) during the stimulation period from stimulation start (S1) up to ovarian stimulation completion or stimulation cancellation respectively. Ovarian stimulation on an average takes 11 days and it is expected that stimulation period will not be extended beyond 15 days. A single injection of r-hCG will be administered intramuscularly or subcutaneously after the last injection of Luveris or r-FSH to achieve final follicular maturation. After, 34-36 hours of administration of r-hCG OPU will be done for oocyte retrieval and embryo transfer (ET) will be conducted within 5 days from OPU. Subjects will also be provided luteal support with natural progesterone and will be followed until delivery or miscarriage. Ultrasound and estradiol (E2) assessment of follicular growth will be conducted at various time points during the stimulation period with or without treatment adjustment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Infertility
  • Ovulation Induction
Intervention  ICMJE
  • Drug: Recombinant human luteinizing hormone (rhLH)
    Other Names:
    • Luveris®
    • Lutropin alfa
  • Drug: Recombinant follicle-stimulating hormone (rFSH)
Study Arms  ICMJE
  • Experimental: rFSH + rhLH
    Recombinant human luteinizing hormone (rhLH,Luveris®) injection 150 IU subcutaneously daily along with rFSH 300 IU subcutaneously daily from S1 to S4 and then rFSH dose can be adjusted depending on the ovarian response till r-hCG administration day.
    Interventions:
    • Drug: Recombinant human luteinizing hormone (rhLH)
    • Drug: Recombinant follicle-stimulating hormone (rFSH)
  • Active Comparator: rFSH
    rFSH injection 300 IU subcutaneously daily from S1 to S4 and then dose can be adjusted depending on the ovarian response till r-hCG administration day.
    Intervention: Drug: Recombinant follicle-stimulating hormone (rFSH)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: December 8, 2011)
76
Original Estimated Enrollment  ICMJE
 (submitted: February 24, 2010)
134
Actual Study Completion Date  ICMJE October 2010
Actual Primary Completion Date October 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pre-menopausal female subject aged greater than (>) 35 years
  • Subjects with baseline FSH serum level less than or equal to (<=) 10 IU/liter (l), LH and E2 levels within local normal range and plasma prolactin levels < 30 nanogram/milliliter (ng/ml)
  • Subjects with regular spontaneous menstrual cycles of 25-35 days
  • Subjects with infertility justifying IVF/ICSI-ET treatment
  • Subjects programmed for COS with r-FSH under GnRH agonist protocol
  • Sperm from current male partner suitable for IVF/ICSI according to local lab, unless sperm donor is foreseen
  • Subjects with presence of both ovaries
  • Subjects whose uterine cavity is able to sustain embryo implantation or pregnancy
  • Subjects with normal papanicolaou test (PAP) smear within previous 3 years
  • Subjects with body mass index (BMI) < 30 at stimulation start
  • Subjects who receive confirmation of not being pregnant by a negative beta-hCG test (urine or blood) prior to starting r-FSH administration
  • Subjects willing and able to comply with the protocol for the duration of the study
  • Subjects who have given informed consent prior to any study-related procedure not part of normal medical care

Exclusion Criteria:

  • Subjects or her male partners who are known to be human immunodeficiency virus, hepatitis B virus or hepatitis C virus positive
  • Subjects with any clinically significant systemic disease; tumors of the hypothalamus and pituitary gland; ovarian, uterine or mammary cancer; hormonal abnormality and/or medical, biochemical, hematological condition which in the judgment of the investigator may interfere with gonadotropin treatment
  • Subjects with more than 2 previous assisted reproductive technologies (ART) cycles
  • Subjects in which previous cycles were cancelled due to poor response (< 3 antral follicles after 15 day of stimulation)
  • Subjects with cryopreserved embryos from previous ART cycles
  • Subjects with unexplained gynecological bleeding
  • Subjects with polycystic ovaries, ovarian enlargement or cyst of unknown etiology
  • Subjects known to have any contraindication to being pregnant and/or carrying pregnancy to term
  • Subjects with known allergy to gonadotrophin preparations or any of the excipients
  • Subjects known to have any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years
  • Subjects with previous entry into this study or simultaneous participation in another clinical drug trial
  • Subjects who have refused to or inability to comply with the protocol
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 35 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01075815
Other Study ID Numbers  ICMJE 700642-500
2008-002281-55 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Merck KGaA, Darmstadt, Germany
Study Sponsor  ICMJE Merck KGaA, Darmstadt, Germany
Collaborators  ICMJE Merck, S.L., Spain
Investigators  ICMJE
Study Director: Medical Responsible Merck, S.L., Spain
PRS Account Merck KGaA, Darmstadt, Germany
Verification Date January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP