A Randomised, Phase II, Comparative Study With a Parallel Control for Evaluating the Efficacy and Safety of Combined Treatment of Lutropin Alpha and Recombinant Human Luteinizing Hormone in the Middle of the Controlled Ovarian Stimulation Follicular Phase in Women With Reduced Ovarian Reserve

This study has been completed.
Sponsor:
Information provided by:
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01110707
First received: April 22, 2010
Last updated: July 15, 2014
Last verified: April 2010
  Purpose

This was a prospective, randomised, Phase II, comparative study with a parallel control for evaluating the efficacy and safety of combined treatment of recombinant human follicle stimulating hormone (r-hFSH) and recombinant human luteinizing hormone (r-hLH). The combined treatment was administered at the middle of the follicular phase in subjects undergoing in-vitro fertilisation (IVF) through intracytoplasmic sperm injection (ICSI) and transfer of embryos (ET).

Few evidences suggest that aged subjects have more possibilities of obtaining a benefit from the combined use of FSH and LH. This study was designed to find out whether the addition of r-hLH on the sixth day of stimulation with r-hFSH in conventional protocol improves the assisted reproduction in terms of quality of recovered oocytes, implantation rates and pregnancy rates in subjects.


Condition Intervention Phase
Infertility
Ovulation Induction
Drug: Recombinant human follicle stimulating hormone
Drug: Recombinant human luteinizing hormone (Luveris)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Lutropin Alpha in the Middle of the Controlled Ovarian Stimulation Follicular Phase in Women With Reduced Ovarian Reserve: Comparative Study, in Phase II, With Parallel Control

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Proportion of oocytes in metaphase II (M-II) (recovered M-II/oocytes) [ Time Frame: From baseline until the pregnancy or menstruation confirmation (During this time frame data were collected and the time point depended on the duration of the cycle of each subject ) ] [ Designated as safety issue: No ]
  • Safety [ Time Frame: From baseline until the pregnancy or menstruation confirmation (During this time frame data were collected and the time point depended on the duration of the cycle of each subject ) ] [ Designated as safety issue: Yes ]
    Incidence and severity of the adverse occurrences, including local reactions at the r-hFSH and r-hLH injection area, the incidence and severity of OHSS, the number of cancelled cycles (suspension of the administering of r-hCG) due to the risk of OHSS and the results of the laboratory tests)


Secondary Outcome Measures:
  • Secondary efficacy parameters [ Time Frame: From baseline until the pregnancy or menstruation confirmation (During this time frame data were collected and the time point depended on the duration of the cycle of each subject ) ] [ Designated as safety issue: No ]
    Fertilised oocytes; number and grade of the embryos; implantation rate per transferred embryo; number of confirmed pregnancies using bio-chemical and clinical criteria; average number of follicles > 14 mm the day r-hCG was administered or the day this treatment was suspended; endometrial thickness on the day r-hCG was administered; number of cycles cancelled due to an unsatisfactory response and the total oocytes recovered.


Enrollment: 138
Study Start Date: January 2005
Study Completion Date: May 2007
Primary Completion Date: May 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: r-hFSH + r-hLH
The subjects were administered r-hLH per day sc from Day 6 of COS, while they continued receiving r-hFSH treatment with a separate injection which was initiated after achieving pituitary desensibilisation with GnRH-a. Administration of both r-hFSH and r-hLH was suspended 36 hours before administering r-hCG.
Drug: Recombinant human follicle stimulating hormone
After the pituitary desensibilization, all subjects were administered 300-450 IU of r-hFSH per day sc; afterwards, the dosage was adjusted according to the ovarian response. The administration of r-hFSH was terminated within the 36 hours prior to the administration of r-hCG.
Drug: Recombinant human luteinizing hormone (Luveris)
On the sixth day of COS, subjects assigned to the group r-hFSH + r-hLH were administered 150 IU r-hLH per day sc while they continue r-hFSH treatment with a separate injection. Administration of r-hLH was also suspended 36 hours before administering r-hCG.
Other Name: Luveris
Active Comparator: r-hFSH alone
The subjects continued receiving r-hFSH treatment alone which was initiated after achieving pituitary desensibilisation with GnRH-a . Administration of r-hFSH was suspended 36 hours before administering r-hCG.
Drug: Recombinant human follicle stimulating hormone
After the pituitary desensibilization, all subjects were administered 300-450 IU of r-hFSH per day sc; afterwards, the dosage was adjusted according to the ovarian response. The administration of r-hFSH was terminated within the 36 hours prior to the administration of r-hCG.

Detailed Description:

Delayed pregnancy and women of 35 years or more have important limitations regarding the success of IVF. It represents a real challenge for assisted reproduction due to the risk of achieving unsatisfactory follicular recruitment and growth, which would result in the controlled ovarian stimulation (COS). It is a common practice to start COS with high doses of FSH in aged subjects when gonadotropin releasing hormone (GnRH) agonist protocols are used. With the combination of r-hFSH and r-hLH for COS in a non-selected group of subjects undergoing IVF, no significant statistical differences were obtained with respect to the use of r-hFSH alone. The analysis of the subpopulation with deep pituitary suppression or those who required elevated doses of r-hFSH indicated that the use of r-hLH can be positive in terms of the quality of oocytes and increase in pregnancy rates. Preliminary data had been published in favour of adding r-hLH as rescue treatment to increase the quality of oocytes in young subjects subjected to IVF, who present little response to the conventional doses of FSH, which indicates a strong suppression of the endogenous LH.

OBJECTIVES

  • To evaluate the efficacy of adding r-hLH in the middle of the follicular phase compared to the non addition of r-hLH in subjects, subjected to COS with r-hFSH for practicing IVF/ICSI and ET, in terms of the quality of oocytes, follicular development, fertilisation of the oocytes, quality of embryos and pregnancy rates
  • To evaluate the safety of r-hLH when combined with r-hFSH for the symptom listed in the above objective, including the incidence of ovarian hyperstimulation syndrome (OHSS), general adverse occurrences and local reactions at the injection area

This study was performed on an out-patient basis where all the subjects received one treatment cycle of pituitary desensibilization with GnRH agonist (GnRH-a). The desensibilization was commenced at the middle of the luteinic phase (long protocol). Once the decrease in pituitary activity was confirmed using estradiol (E2) < 50 pg/ml (180 pmol/l) as criteria, COS was initiated with an r-hFSH dosage of 300-450 IU administered subcutaneously (sc). On Day 6 of stimulation (S6), subjects were randomly assigned to an additional treatment with r-hLH with a fixed dosage of 150 IU or were continued to be treated with r-hFSH alone. The first dose of r-hLH was administered late in the evening on the day the randomisation was carried out (S6).

The combined treatment with r-hLH + r-hFSH or treatment with r-hFSH alone was administered until the follicular development was adequate as judged by the investigator (evaluated through ovarian ultrasound and determination of the serum levels of E2). A sole injection of 250 mcg of human recombinant chorionic gonadotropin (r-hCG) was administered in order to achieve the follicular maturation within the 36 hours following the last dose of r-hFSH, r-hLH and GnRH-a. The r-hCG was not administered until at least one follicle has reached an average diameter > 18 mm and other follicles of diameter > 16 mm and the E2 levels are proportional in number and size to the follicles that are present. The oocytes were collected 34-38 hours after administering the r-hCG and were evaluated and fertilised in-vitro through ICSI. No more than 3 embryos were implanted on Days 2-4 after the oocyte retrieval(ovum pick-up).

The luteinic phase was supported through the daily administration of natural progesterone via the vaginal route, starting after the ovum pick-up (OPU) and continuing until the moment of menstruation or until the pregnancy test; or, if the subject is pregnant, for at least 30 days after obtaining a positive result in the laboratory pregnancy test. A monitoring of subjects was carried out and the result of the treatment was recorded (pregnancy or menstruation).

  Eligibility

Ages Eligible for Study:   35 Years to 40 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

All subjects must meet the following inclusion criteria within the 6 months prior to starting the pituitary suppression unless otherwise specified:

  • Premenopausic woman aged between 35 and 40 years that wishes to become pregnant
  • Subjects with basal serum level (beginning of the follicular phase, Day 2-5) of FSH < 10 IU/l determined within the 6 months prior as well as LH and E2 levels within the normal interval according to standard data for the area where the study was carried out
  • Subjects with a regular menstrual cycles between 25-35 days
  • Subjects with infertility that justifies treatment with IVF/ET or ICSI
  • Subjects undergoing COS with r-hFSH using a long protocol with GnRH-a
  • Sperm availability from the subject's current partner unless it is planned to use sperm from a donor
  • Subjects with both ovaries
  • Subjects with uterine cavity capable of withstanding the implantation of the embryo and pregnancy
  • Subjects whose vaginal smear (PAP) was normal within the 3 years prior to starting the stimulation
  • Subjects with body mass index (BMI) between 18 and 30 at the time of participation in the study
  • Subjects in whom at least 30 days have elapsed since the last dose of clomiphene citrate or gonadotropins before beginning treatment with GnRH-a
  • Subjects with a negative pregnancy test result using the beta human chorionic gonadotropin (beta-hCG) test (in urine or blood) before beginning treatment with GnRH-a
  • Subjects willing to and capable of following the protocol during the entire study
  • Subjects who have provided informed written consent before carrying out any procedure related with the study (that is not part of the normal medical treatment followed by the subject)

Exclusion Criteria:

  • Subject who were human immunodeficiency virus, hepatitis B and C virus positive
  • Subjects suffering from any clinically important systematic disease, hypothalmic or pituitary tumour, ovarian, uterine or breast cancer, endocrinopathy and/or medical alterations, biochemical or hematological that as per the investigators judgement, may interfere with the gonadotropin treatment
  • Subjects who have been subjected to more than 2 assisted reproductive cycles in the past
  • Subjects who have cancelled 2 cycles in the past
  • Subjects who have cryopreserved embryos from previous assisted reproductive cycles
  • Subjects with non explained vaginal haemorrhages
  • Subjects with polycystic ovary, enlarged ovary or ovarian cysts of unknown aetiology
  • Subjects with any contraindication for getting pregnant or taking the pregnancy to full term
  • Subjects with known allergy to the gonadotropin preparations or any of its excipients
  • Subjects with current drug use or prior personal history of alcohol, drug or psychiatric drug dependency in the past five years
  • Subjects with prior participation in this study or simultaneous participation in a different clinical study with a medication under investigation
  • Subjects who were not willing to or incapable of following the study protocol
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01110707

Locations
Spain
Hospital de Cruces, Plaza de Cruces, 12, 48903
Vizcaya, Spain
Sponsors and Collaborators
Merck KGaA
Investigators
Study Director: Enrique Granados Merck Serono, Spain
  More Information

Publications:
Responsible Party: Dr. S. Burgues, Medical Director, Departamento Medico, Serono Spain S.A., an affiliate of Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT01110707     History of Changes
Other Study ID Numbers: IMP 25186
Study First Received: April 22, 2010
Last Updated: July 15, 2014
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Merck KGaA:
Reproductive technology, Assisted
Recombinant human follicle stimulating hormone (r-hFSH)
Recombinant leutinizing hormone (r-hLH)
Ovulation induction
Infertility

Additional relevant MeSH terms:
Infertility
Genital Diseases, Male
Genital Diseases, Female
Hormones
Follicle Stimulating Hormone
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 29, 2014