InfertilityPhase 2NCT01079949
A Phase II Study to Assess the Efficacy and Safety of Luveris® (Lutropin Alfa) in Mid Follicular Phase for Controlled Ovarian Stimulation (COS) in Advanced Reproductive Age
A Phase 2 study testing r-hLH + r-hFSH, r-hFSH and Recombinant Human Choriogonadotropin (r-hCG) in people with Infertility and Ovulation Induction, run by Merck KGaA, Darmstadt, Germany at 1 site in Spain.
Trial summary
Ovarian reserve is related to chronological age; 35 years of age is the accepted threshold for significant decline in assisted reproductive technologies (ART) success with scarce follicular recruitment and poor oocyte retrieval. Read more about this study
- Who is it for?
- Ages 35 to 42 years, women only
- Conditions the study is for
- Infertility, Ovulation Induction
- What is being tested?
- r-hLH + r-hFSH, r-hFSH and Recombinant Human Choriogonadotropin (r-hCG)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 93 participants
- Where
- 1 siteSpain
- Study dates
- Nov 2007to Oct 2010
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 42 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Premenopausal woman, aged 35 to 42 years wanting to become pregnant
- Subjects with FSH baseline plasma levels less than or equal to 10 IU/L (Day 2-5 of the cycle) and with LH and E2 levels within the normal limits of the local laboratory
- Subjects having regular spontaneous menstrual cycle lasting 25-35 days
- Subjects with infertility that is susceptible to treatment with IVF/ICSI
- Subjects to be included in a COS protocol with r-hFSH and GnRHant
- Subjects with partner's sperm suitable for IVF/ICSI according to local laboratory, unless sperm donor is to be used
Show all 13Show fewer
- Subjects with both ovaries
- Subjects with uterine cavity capable of sustaining the implantation of embryo or carrying a pregnancy
- Subjects with normal pap smear (papanicolaou) 6 months prior to be included in the study (signature of informed consent)
- Subjects with body mass index (BMI) less than (<) 30 at the beginning of ovarian stimulation
- Subjects with confirmed absence of pregnancy with the beta-hCG test (urine or blood) before starting the administration of r-hFSH
- Subjects willing to adjust to the protocol for the entire duration of the study
- Subjects who have given informed consent prior to any study-related procedure that is not part of normal medical care
Who cannot join
- Subjects or her partner with known positivity for human immunodeficiency virus (HIV) or Hepatitis-B /Hepatitis-C virus (HBV/HCV)
- Subjects with any systemic illnesses of clinical significance, hypothalamus and pituitary tumors; cancer of ovaries, uterus or breast; hormonal anomalies and/or medical, biochemical, hematological illnesses that, according to the investigator, could interfere with the treatment with gonadotropins
- Subjects with more than 2 previous ART cycles
- Subjects who have cancelled two previous ART cycles
- Subjects with frozen embryos from previous ART cycles
- Subjects with non-specific gynecological bleeding
Show all 12Show fewer
- Subjects with ovaries that are polycystic, increased in size or with cysts of unknown etiology
- Subjects with any contraindication for becoming pregnant and/or carrying pregnancy to term
- Subjects with known allergy to gonadotropin preparations or any of the excipients
- Subjects with drug dependence or history of drug or alcohol abuse in the previous 5 years
- Subjects who have previously entered into this study or simultaneous participation in another clinical drug trial with drugs
- Subjects who are unwilling to or not being able to adjust to the study protocol
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Lutropin Alfa (Luveris®) in Mid Follicular Phase for Controlled Ovarian Stimulation (COS) in Advanced Reproductive Age: Phase II Clinical Trial
Ovarian reserve is related to chronological age; 35 years of age is the accepted threshold for significant decline in assisted reproductive technologies (ART) success with scarce follicular recruitment and poor oocyte retrieval. New therapeutic schemes are sought to improve follicular response in ovarian ageing because of the increasing number of infertile women aged older than 35 years who are trying to get pregnant. The advent of gonadotropin releasing hormone analogue antagonist (GnRHant) offers new perspectives to address the issues related to advanced reproductive age since it prevents premature luteinizing hormone (LH) surges while not causing suppression in the early follicular phase. Gonadotropin releasing hormone analogue antagonists are administered in the latter stage of the ovarian stimulation to prevent LH surge by competitive blockade of gonadotropin releasing hormone (GnRH) receptors, thus producing a marked decrease in LH levels just when the interplay between follicle stimulating hormone (FSH) and LH becomes important to complete follicular development and oocyte competence. Some studies in the past have shown the potential of recombinant human LH (r-hLH) supplementation in women of advanced reproductive age to improve oocyte quality, but these studies are of small size and did not provide data on the physiological mechanism behind the benefit obtained.
This randomized, comparative, parallel controlled Phase II study will be conducted in infertile female subjects aged 35-42 years undergoing in-vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI), to investigate whether the addition of r-hLH (when the lead follicle is greater than [>] 14 millimeter [mm] in size), to the standard protocol with recombinant human FSH (r-hFSH) under GnRHant, improves the number and quality of oocytes retrieved, implantation rate, and pregnancy rate, while assessing the hormonal milieu in the ovarian follicular fluid. Comparison will be performed against ovarian stimulation without addition of r-hLH, that is (i.e.) with r-hFSH under GnRHant alone.
Read the detailed description
Preclinical pharmacology studies have demonstrated that r-hLH has a LH/human chorionic gonadotropin (hCG) receptor affinity similar to pituitary human luteinizing hormone (p-hLH), and is biologically active in-vitro in stimulating steroidogenesis and in promoting oocyte germinal vesicle breakdown. Several clinical studies have investigated the usefulness of r-hLH supplementation in normal ovulatory women undergoing ART and in almost all of them sub-populations of subjects have been identified who will benefit, when r-hLH is added to FSH.
OBJECTIVES
Primary objectives:
- To determine the efficacy of adding r-hLH at mid-follicular phase compared to not adding r-hLH, in women of 35-42 years of age included in a COS with r-hFSH under treatment with a GnRHant for IVF/ICSI, assessed by the number and quality of the oocyte
- To determine the safety of using r-hLH combined with r-hFSH in a protocol with a GnRHant, including incidence of ovarian hyperstimulation syndrome (OHSS) and adverse events (AEs) as well as local tolerability
Secondary objectives:
- To complete the verification of efficacy with additional assessments such as follicular growth, oocyte fertilization, embryo quality and pregnancy rates
- To investigate the underlying mechanism of possible improvement in oocyte quality by means of determining hormone levels (LH, FSH, T, E2, and hCG) levels in follicular fluid
Tertiary objectives:
- This is a phase-II study that did not aim to carry out assessment of pharmacoeconomics or quality of life
All subjects will undergo treatment with r-hFSH at a daily dose of 300-450 IU by subcutaneous route starting on the stimulation Day 1 (S1) until r-hCG administration. Upon detection of a lead follicle > 14 mm in diameter, GnRHant 0.25 milligram (mg)/day subcutaneous administration will be initiated and continued up to r-hCG administration day. Subjects will be then randomly allocated (at any time between S1 and GnRHant initiation day) either to additional treatment with r-hLH at a daily fixed dose of 150 IU or continue treatment with r-hFSH alone. Gonadotropin releasing hormone antagonist and combined treatment with r-hLH plus (+) r-hFSH or r-hFSH alone will be administered until at least one follicle > 18 mm in diameter and two additional follicles > 16 mm in diameter are present and E2 levels are commensurate with the number and size of follicles present. A single injection of 250-500 microgram of r-hCG, will be given to induce final follicular maturation within 36 hours of the last r-hLH and/or r-hFSH injections and on the same day of the last GnRHant morning administration. Oocytes will be retrieved 34-38 hours after r-hCG administration, assessed, and fertilized in-vitro by ICSI. Not more than 3 embryos will be replaced on day 2 or 3 after OPU. The luteal phase will be supported by a daily vaginal administration of natural progesterone, starting after OPU and continuing either up to menstruation or the pregnancy test or, if the subject is pregnant, for at least 30 days after laboratory evidence of pregnancy. Each subject will be followed-up and the treatment outcome (pregnancy or menstruation) will be recorded.
For all subjects who received r-hCG and do not menstruate, a blood sample will be collected for local determination of serum beta-hCG level between post-hCG days 15-20. If positive (beta-hCG > 10 International Unit/liter [IU/L]), it should be confirmed by performing a second test within one week later. An ultrasound scan (US) will be performed at post-hCG days 35-42 on all subjects who will become pregnant provided that no miscarriage has occurred. The number of fetal sacs and fetal heart activity will be recorded. Active follow-up of all pregnancies will be performed, including those subjects withdrawn from the study.
- Conditions
- Infertility, Ovulation Induction
- Being tested
- r-hLH + r-hFSH, r-hFSH, Recombinant Human Choriogonadotropin (r-hCG), GnRH antagonist
- Keywords
- Infertility, Ovulation induction, Luveris, Lutropin alfa, Controlled ovarian stimulation, Reproductive technologies, Assisted
- Medical subject headings
- Infertility, Helping Behavior
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
r-hLH + r-hFSHDrug
Also called Luveris®, Lutropin alfa
Recombinant human follicle stimulating hormone (r-hFSH) injection will be administered subcutaneously once daily from stimulation Day 1(S1) at a starting dose of 300-450 International Unit (IU) and then dose adjusted depending on the ovarian response till recombinant human choriogonadotropin (r-hCG) administration day. Recombinant human luteinizing hormone (r-hLH, Luveris®, Lutropin alfa) injection will be administered subcutaneously once daily at a constant dose of 150 IU with flexible start, depending on the follicular growth (when the lead follicle is greater than 14 mm in size), along with r-hFSH treatment as a separate injection till r-hCG administration day.
r-hFSHDrug
Recombinant human follicle stimulating hormone (r-hFSH) injection will be administered subcutaneously once daily from S1 at a starting dose of 300-450 IU and then dose adjusted depending on the ovarian response till r-hCG administration day.
Recombinant Human Choriogonadotropin (r-hCG)Drug
Also called Ovitrelle®
The r-hCG will be administered as a single dose of 250-500 microgram (mcg) subcutaneously in the same day after the last dose of the GnRH antagonist.
GnRH antagonistDrug
Also called Cetrotide®
The GnRH antagonist will be administered at a starting at a dose of 0.25 milligram (mg) subcutaneously daily in the morning when the ultrasound discovers a follicle of greater than or equal to (>=) 14 mm, and maintained until at least one follicle of >=18 mm and two additional follicles of >=16 mm with appropriate plasma estradiol levels for the number and size of the existing follicles.
| Study group | Role | What they receive |
|---|---|---|
| r-hLH + r-hFSH | Experimental | Not described Receives: Drug: r-hLH + r-hFSH; Drug: Recombinant Human Choriogonadotropin (r-hCG); Drug: GnRH antagonist |
| r-hFSH | Active comparator | Not described Receives: Drug: r-hFSH; Drug: Recombinant Human Choriogonadotropin (r-hCG); Drug: GnRH antagonist |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Oocytes Retrieved
Number of oocytes retrieved per reporting group on the day of ovum pick-up (OPU) (34-38 hours post r-hCG day) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocytes from the ovary of the female participant, enabling fertilization outside the body.
Measured: Ovum pick-up (OPU) day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Number of Mature Oocytes Retrieved
Number of mature oocytes retrieved per reporting group on the day of OPU (34-38 hours post r-hCG day) 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 is assessed based on the presence of a germinal vesicle (GV) or whether oocytes were in metaphase I (Meta-I) or II (Meta-II) stage or atretic.
Measured: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS)
Ovarian Hyper Stimulation Syndrome (OHSS) is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting.
Measured: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])
Number of Cycles Cancelled Due to Risk of Ovarian Hyper Stimulation Syndrome (OHSS)
Ovarian Hyper Stimulation Syndrome (OHSS) is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting.
Measured: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])
Number of Participants With Adverse Events (AEs)
An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.
Measured: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])
Secondary outcomes (14)
Number of Follicles Greater Than or Equal to 14 Millimeter (mm) on Recombinant Human Choriogonadotropin (r-hCG) Day
Measured: r-hCG day (end of stimulation cycle [approximately 9 days])
Endometrial Thickness on Recombinant Human Choriogonadotropin (r-hCG) Day
Endometrial thickness measurement was performed on the day of r-hCG administration.
Measured: r-hCG day (end of stimulation cycle [approximately 9 days])
Number of Fertilized Oocytes (2 Pronuclei [PN])
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 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.
Measured: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Number of Fertilized Oocytes at Stage 2 Pronuclei (2PN) or Higher Than 2PN
Oocytes were fertilized using 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 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. Fertilized oocytes at stage higher then 2PN are those oocytes which consist more than 2 pronuclei like oocyte having 3 pronuclei termed as 3PN, oocyte having 4 pronuclei termed as 4PN.
Measured: Day 35-42 post r-hCG day (end of stimulation cycle [approximately 9 days])
Number and Quality of Embryos
Embryos were classified into 5 different grades (1 to 5) based on their capacity of implantation. Grade 1 embryos were those with best capacity of implantation and Grade 5 embryos were those with worst capacity of implantation.
Measured: Day 2-3 post OPU (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Implantation Rate
Implantation rate was measured as the number of gestational sacs observed, divided by the number of embryos transferred multiplied by 100.
Measured: Day 35-42 post OPU (34-38 hours post r-hCG day {end of stimulation cycle [approximately 9 days]})
Number of Participants With Clinical Pregnancies
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.
Measured: Day 35-42 post r-hCG day (end of stimulation cycle [approximately 9 days])
Number of Participants in Whom Recombinant Human Chorionic Gonadotropin (r-hCG) Was Not Administered Due to Poor Response
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.
Measured: r-hCG day (end of stimulation cycle [approximately 9 days])
Number of Ovarian Stimulation Days
Ovarian stimulation included from first r-hFSH injection (S1) until day on which r-hCG was administered (r-hCG day).
Measured: Day 1 of stimulation period (S1) up to r-hCG day (end of stimulation cycle [approximately 9 days])
Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH)
Measured: Day 1 of stimulation period (S1) up to r-hCG day (end of stimulation cycle [approximately 9 days])
Estradiol (E2) Levels on r-hCG Day
Measured: r-hCG day (end of stimulation cycle [approximately 9 days])
Follicular Levels of Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and Human Chorionic Gonadotropin (hCG) at Ovum Pick up (OPU)
Measured: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Follicular Levels of Estradiol (E2) at Ovum Pick up (OPU)
Measured: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Follicular Levels of Testosterone (T) at Ovum Pick up (OPU)
Measured: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Mar 2010 (estimated)
- Study startNov 2007
- Primary completionOct 2010
- Study completionOct 2010
Why it stopped: Trial was terminated due to low recruitment rate
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for InfertilityStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 93 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merck KGaA, Darmstadt, Germany
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck, S.L., Spain
- Responsible party
- Sponsor
- Investigators
- Medical Responsible, Study director, Merck, S.L., Spain
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01079949
- Sponsor's protocol ID
- 27262
- Other IDs
- 2006-005268-19
- Status last verified
- Jan 2014
- First submitted
- 2 Mar 2010
- Last updated
- 27 Feb 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Lutropin Alfa (Luveris®) in Mid Follicular Phase for Controlled Ovarian Stimulation (COS) in Advanced Reproductive Age: Phase II Clinical Trial
- ClinicalTrials.gov ID
- NCT01079949
- Acronym / sponsor ID
- 27262
- Conditions
- Infertility, Ovulation Induction
- Keywords
- Infertility, Ovulation induction, Luveris, Lutropin alfa, Controlled ovarian stimulation, Reproductive technologies, Assisted
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Trial was terminated due to low recruitment rate
- Enrolment
- 93 participants (actual)
- Lead sponsor
- Merck KGaA, Darmstadt, GermanyIndustry (pharma, biotech, devices)
- Collaborators
- Merck, S.L., Spain
- Study start
- Nov 2007
- Primary completion
- Oct 2010 (actual)
- Study completion
- Oct 2010 (actual)
- First posted
- 3 Mar 2010 (estimated)
- Results
- Posted 20 Feb 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Ovarian reserve is related to chronological age; 35 years of age is the accepted threshold for significant decline in assisted reproductive technologies (ART) success with scarce follicular recruitment and poor oocyte retrieval. New therapeutic schemes are sought to improve follicular response in ovarian ageing because of the increasing number of infertile women aged older than 35 years who are trying to get pregnant. The advent of gonadotropin releasing hormone analogue antagonist (GnRHant) offers new perspectives to address the issues related to advanced reproductive age since it prevents premature luteinizing hormone (LH) surges while not causing suppression in the early follicular phase. Gonadotropin releasing hormone analogue antagonists are administered in the latter stage of the ovarian stimulation to prevent LH surge by competitive blockade of gonadotropin releasing hormone (GnRH) receptors, thus producing a marked decrease in LH levels just when the interplay between follicle stimulating hormone (FSH) and LH becomes important to complete follicular development and oocyte competence. Some studies in the past have shown the potential of recombinant human LH (r-hLH) supplementation in women of advanced reproductive age to improve oocyte quality, but these studies are of small size and did not provide data on the physiological mechanism behind the benefit obtained.
This randomized, comparative, parallel controlled Phase II study will be conducted in infertile female subjects aged 35-42 years undergoing in-vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI), to investigate whether the addition of r-hLH (when the lead follicle is greater than [>] 14 millimeter [mm] in size), to the standard protocol with recombinant human FSH (r-hFSH) under GnRHant, improves the number and quality of oocytes retrieved, implantation rate, and pregnancy rate, while assessing the hormonal milieu in the ovarian follicular fluid. Comparison will be performed against ovarian stimulation without addition of r-hLH, that is (i.e.) with r-hFSH under GnRHant alone.
Detailed description
Preclinical pharmacology studies have demonstrated that r-hLH has a LH/human chorionic gonadotropin (hCG) receptor affinity similar to pituitary human luteinizing hormone (p-hLH), and is biologically active in-vitro in stimulating steroidogenesis and in promoting oocyte germinal vesicle breakdown. Several clinical studies have investigated the usefulness of r-hLH supplementation in normal ovulatory women undergoing ART and in almost all of them sub-populations of subjects have been identified who will benefit, when r-hLH is added to FSH.
OBJECTIVES
Primary objectives:
- To determine the efficacy of adding r-hLH at mid-follicular phase compared to not adding r-hLH, in women of 35-42 years of age included in a COS with r-hFSH under treatment with a GnRHant for IVF/ICSI, assessed by the number and quality of the oocyte
- To determine the safety of using r-hLH combined with r-hFSH in a protocol with a GnRHant, including incidence of ovarian hyperstimulation syndrome (OHSS) and adverse events (AEs) as well as local tolerability
Secondary objectives:
- To complete the verification of efficacy with additional assessments such as follicular growth, oocyte fertilization, embryo quality and pregnancy rates
- To investigate the underlying mechanism of possible improvement in oocyte quality by means of determining hormone levels (LH, FSH, T, E2, and hCG) levels in follicular fluid
Tertiary objectives:
- This is a phase-II study that did not aim to carry out assessment of pharmacoeconomics or quality of life
All subjects will undergo treatment with r-hFSH at a daily dose of 300-450 IU by subcutaneous route starting on the stimulation Day 1 (S1) until r-hCG administration. Upon detection of a lead follicle > 14 mm in diameter, GnRHant 0.25 milligram (mg)/day subcutaneous administration will be initiated and continued up to r-hCG administration day. Subjects will be then randomly allocated (at any time between S1 and GnRHant initiation day) either to additional treatment with r-hLH at a daily fixed dose of 150 IU or continue treatment with r-hFSH alone. Gonadotropin releasing hormone antagonist and combined treatment with r-hLH plus (+) r-hFSH or r-hFSH alone will be administered until at least one follicle > 18 mm in diameter and two additional follicles > 16 mm in diameter are present and E2 levels are commensurate with the number and size of follicles present. A single injection of 250-500 microgram of r-hCG, will be given to induce final follicular maturation within 36 hours of the last r-hLH and/or r-hFSH injections and on the same day of the last GnRHant morning administration. Oocytes will be retrieved 34-38 hours after r-hCG administration, assessed, and fertilized in-vitro by ICSI. Not more than 3 embryos will be replaced on day 2 or 3 after OPU. The luteal phase will be supported by a daily vaginal administration of natural progesterone, starting after OPU and continuing either up to menstruation or the pregnancy test or, if the subject is pregnant, for at least 30 days after laboratory evidence of pregnancy. Each subject will be followed-up and the treatment outcome (pregnancy or menstruation) will be recorded.
For all subjects who received r-hCG and do not menstruate, a blood sample will be collected for local determination of serum beta-hCG level between post-hCG days 15-20. If positive (beta-hCG > 10 International Unit/liter [IU/L]), it should be confirmed by performing a second test within one week later. An ultrasound scan (US) will be performed at post-hCG days 35-42 on all subjects who will become pregnant provided that no miscarriage has occurred. The number of fetal sacs and fetal heart activity will be recorded. Active follow-up of all pregnancies will be performed, including those subjects withdrawn from the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| r-hLH + r-hFSH | Experimental | Drug: r-hLH + r-hFSH, Drug: Recombinant Human Choriogonadotropin (r-hCG), Drug: GnRH antagonist |
| r-hFSH | Active comparator | Drug: r-hFSH, Drug: Recombinant Human Choriogonadotropin (r-hCG), Drug: GnRH antagonist |
Who may qualify
- Ages
- 35 to 42 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (13 listed)
- Premenopausal woman, aged 35 to 42 years wanting to become pregnant
- Subjects with FSH baseline plasma levels less than or equal to 10 IU/L (Day 2-5 of the cycle) and with LH and E2 levels within the normal limits of the local laboratory
- Subjects having regular spontaneous menstrual cycle lasting 25-35 days
- Subjects with infertility that is susceptible to treatment with IVF/ICSI
- Subjects to be included in a COS protocol with r-hFSH and GnRHant
Key exclusion criteria (12 listed)
- Subjects or her partner with known positivity for human immunodeficiency virus (HIV) or Hepatitis-B /Hepatitis-C virus (HBV/HCV)
- Subjects with any systemic illnesses of clinical significance, hypothalamus and pituitary tumors; cancer of ovaries, uterus or breast; hormonal anomalies and/or medical, biochemical, hematological illnesses that, according to the investigator, could interfere with the treatment with gonadotropins
- Subjects with more than 2 previous ART cycles
- Subjects who have cancelled two previous ART cycles
- Subjects with frozen embryos from previous ART cycles
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| r-hLH + r-hFSHAlso: Luveris®, Lutropin alfaRecombinant human follicle stimulating hormone (r-hFSH) injection will be administered subcutaneously once daily from stimulation Day 1(S1) at a starting dose of 300-450 International Unit (IU) and then dose adjusted depending on the ovarian response till recombinant human choriogonadotropin (r-hCG) administration day. Recombinant human luteinizing hormone (r-hLH, Luveris®, Lutropin alfa) injection will be administered subcutaneously once daily at a constant dose of 150 IU with flexible start, depending on the follicular growth (when the lead follicle is greater than 14 mm in size), along with r-hFSH treatment as a separate injection till r-hCG administration day. | Drug | r-hLH + r-hFSH |
| r-hFSHRecombinant human follicle stimulating hormone (r-hFSH) injection will be administered subcutaneously once daily from S1 at a starting dose of 300-450 IU and then dose adjusted depending on the ovarian response till r-hCG administration day. | Drug | r-hFSH |
| Recombinant Human Choriogonadotropin (r-hCG)Also: Ovitrelle®The r-hCG will be administered as a single dose of 250-500 microgram (mcg) subcutaneously in the same day after the last dose of the GnRH antagonist. | Drug | r-hFSH, r-hLH + r-hFSH |
| GnRH antagonistAlso: Cetrotide®The GnRH antagonist will be administered at a starting at a dose of 0.25 milligram (mg) subcutaneously daily in the morning when the ultrasound discovers a follicle of greater than or equal to (>=) 14 mm, and maintained until at least one follicle of >=18 mm and two additional follicles of >=16 mm with appropriate plasma estradiol levels for the number and size of the existing follicles. | Drug | r-hFSH, r-hLH + r-hFSH |
Primary outcome
Number of Oocytes Retrieved
Time frame: Ovum pick-up (OPU) day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Number of oocytes retrieved per reporting group on the day of ovum pick-up (OPU) (34-38 hours post r-hCG day) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocytes from the ovary of the female participant, enabling fertilization outside the body.
Number of Mature Oocytes Retrieved
Time frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Number of mature oocytes retrieved per reporting group on the day of OPU (34-38 hours post r-hCG day) 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 is assessed based on the presence of a germinal vesicle (GV) or whether oocytes were in metaphase I (Meta-I) or II (Meta-II) stage or atretic.
Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS)
Time frame: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])
Ovarian Hyper Stimulation Syndrome (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: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])
Ovarian Hyper Stimulation Syndrome (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 Participants With Adverse Events (AEs)
Time frame: S1 to 1 month ± 1 week post r-hCG day (end of stimulation cycle [approximately 9 days])
An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.
14 secondary outcomes
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 9 days])
Endometrial Thickness on Recombinant Human Choriogonadotropin (r-hCG) Day
Time frame: r-hCG day (end of stimulation cycle [approximately 9 days])
Number of Fertilized Oocytes (2 Pronuclei [PN])
Time frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Number of Fertilized Oocytes at Stage 2 Pronuclei (2PN) or Higher Than 2PN
Time frame: Day 35-42 post r-hCG day (end of stimulation cycle [approximately 9 days])
Number and Quality of Embryos
Time frame: Day 2-3 post OPU (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Implantation Rate
Time frame: Day 35-42 post OPU (34-38 hours post r-hCG day {end of stimulation cycle [approximately 9 days]})
Number of Participants With Clinical Pregnancies
Time frame: Day 35-42 post r-hCG day (end of stimulation cycle [approximately 9 days])
Number of Participants in Whom Recombinant Human Chorionic Gonadotropin (r-hCG) Was Not Administered Due to Poor Response
Time frame: r-hCG day (end of stimulation cycle [approximately 9 days])
Number of Ovarian Stimulation Days
Time frame: Day 1 of stimulation period (S1) up to r-hCG day (end of stimulation cycle [approximately 9 days])
Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH)
Time frame: Day 1 of stimulation period (S1) up to r-hCG day (end of stimulation cycle [approximately 9 days])
Estradiol (E2) Levels on r-hCG Day
Time frame: r-hCG day (end of stimulation cycle [approximately 9 days])
Follicular Levels of Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and Human Chorionic Gonadotropin (hCG) at Ovum Pick up (OPU)
Time frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Follicular Levels of Estradiol (E2) at Ovum Pick up (OPU)
Time frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Follicular Levels of Testosterone (T) at Ovum Pick up (OPU)
Time frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Feb 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Responsible study director
Merck, S.L., Spain
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing r-hLH + r-hFSH, r-hFSH and Recombinant Human Choriogonadotropin (r-hCG) in people with Infertility and Ovulation Induction, run by Merck KGaA, Darmstadt, Germany at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 27 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Feb 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Oocytes Retrieved (time frame: Ovum pick-up (OPU) day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 9 days}])). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Feb 2014.