Reproductive Techniques, AssistedPhase 3Luveris in ARTNCT01071200
Study to Evaluate if the Addition of r-hLH (Luveris®) to FSH From Day 8 of Ovarian Stimulation is Able to Decrease Total FSH Dose and to Improve Cycle Outcome in Infertile Women Undergoing ART, Who Required High FSH Dose in a Previous Cycle
A Phase 3 study testing Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH) and r-hFSH in people with Reproductive Techniques, Assisted, run by Merck KGaA, Darmstadt, Germany at 1 site in Italy.
Trial summary
The present study was designed to investigate, in hyporesponder subjects, that required in a previous assisted reproductive technologies (ART) cycle follicle stimulating hormone (FSH) >3500 International Unit (IU), the possibility to decrease through recombinant human luteinizing hormone (r-hLH) supplementation, the… Read more about this study
- Who is it for?
- Ages 18 to 40 years, women only
- Conditions the study is for
- Reproductive Techniques, Assisted
- What is being tested?
- Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH) and r-hFSH
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 133 participants
- Where
- 1 siteItaly
- Study dates
- Mar 2005to Apr 2009
- Phase
- Phase 3
- 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 18 to 40 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Pre-menopausal infertile woman, aged 18 to 40 years inclusive, who wishes to conceive
- Regular, spontaneous menstrual cycle of 25-35 days
- Body mass index (BMI) ≤ 28
- FSH ≤ 10 IU/L (follicular phase, days 2-5)
- Prolactin (PRL) within the normal ranges
- Evidence of both ovaries by ultrasound scan
Show all 12Show fewer
- Women undergoing IVF-Embryo Transfer (ET) or ICSI, down regulated with Gonadotropin releasing hormone analogues (GnRHa) (daily dose) under controlled ovarian hyperstimulation (COH) with FSH
- Washout > 90 days from last dose of clomiphene or gonadotrophin, before ongoing COH cycle
- Only one previous IVF-ET or ICSI cycle (in the last 9 months preceding the ongoing COH cycle) resulted in a hypo-response properly documented (from 6 to 12 oocytes with a total FSH dose ≥ 4000 IU)
- Negative pregnancy hCG test (urine or blood sample) before the ongoing COH cycles
- Willing and able to comply with the protocol for the duration of the study
- Written informed consent before applying any procedure related to the study protocol, which is not part of routine medical care, with the understanding that consent may be withdrawn by the subject at any time, without prejudice on their future medical care
Who cannot join
- Oligo/Anovulatory cycles (World Health Organization [WHO] I and II)
- Male partner azoospermia (assessed within the last 12 months)
- Follicular phase (day 2-5) FSH > 10 IU/L even if only once observed in the medical history
- Abnormal cervical cytology (assessed within the last 12 months)
- History of unexplained gynecologic hemorrhage
- Any contraindication to pregnancy
Show all 13Show fewer
- Known allergy to gonadotrophin
- Any clinically important systemic disease (e.g. insulin-dependent diabetes mellitus, epilepsy, serious migraine, intermittent purpura, hepatic, renal or cardiovascular disease, serious corticoid-dependent asthma) which constitutes a contraindication to gonadotropin use
- Any medical condition which, according to the investigator's judgement, may affect the absorption, distribution, metabolism or excretion of the drug. In case of doubt, inclusion of the subject in question should be discussed with the Medical Responsible of Serono
- Known Human Immunodeficiency Virus (HIV) positivity
- Any substance abuse or history of drugs or alcohol abuse within the past 5 years
- Prior inclusion in the present study or simultaneous inclusion in a clinical study of another drug
- Refusal or inability to comply with the protocol
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase III, Multicentric, Randomized, Open, Comparative Study to Evaluate if the Addition of Recombinant Human Luteinising Hormone [r-hLH (Luveris®)] to Follicle Stimulating Hormone (FSH) From Day 8 of Ovarian Stimulation is Able to Decrease Total FSH Dose and to Improve Cycle Outcome in Infertile Women Undergoing Assisted Reproduction Technology (ART), Who Required High FSH Dose in a Previous Cycle
The present study was designed to investigate, in hyporesponder subjects, that required in a previous assisted reproductive technologies (ART) cycle follicle stimulating hormone (FSH) >3500 International Unit (IU), the possibility to decrease through recombinant human luteinizing hormone (r-hLH) supplementation, the FSH amount per oocytes retrieved and in the mean time to improve the overall cycle outcome.
Read the detailed description
Recombinant human follicle stimulating hormone (r-hFSH), which totally lacks LH activity, is widely used to induce multiple follicle development in women under pituitary desensitization, in order to submit them to treatment with assisted reproduction techniques (ART). Clinical experience from hypogonadotropic-hypogonadic women suggests that while FSH alone is sufficient to induce follicle development, LH plays a significant part in final follicle maturation, estrogen synthesis and optimal endometrium growth.
This was a phase III, multicentre, randomized, open-label comparative study to evaluate if the addition of r-hLH (Luveris) in a 2:1 ratio to FSH from day 8 of ovarian stimulation is able to decrease the total FSH dose and to improve cycle outcome in 250 infertile women undergoing ART, who required high FSH dose in a previous cycle (≥ 3500 IU). Subjects who have met all the inclusion criteria, achieved pituitary desensitization and started controlled ovarian hyperstimulation (COH) treatment with FSH, on stimulation day 8 (S8) received an identification number and will be allocated to one of the two following arms:
Arm : FSH + r-hLH (2:1 ratio of FSH:r-hLH), Arm : FSH alone. Treatment with Luveris was commenced on day 8 (S8) and continued until injection of hCG or cancellation of the treatment cycle.
Monitoring of stimulation, FSH dose escalation, criteria for injection of hCG, ovum pick up, embryo transfer and pregnancy confirmation took place according to standard management practice. The in-vitro fertilization (IVF) or intracytosolic sperm injection (ICSI) procedure, including luteal phase support, was performed according to each centres' normal procedures.
The subjects were followed up and the treatment outcome (menstruation or pregnancy) was recorded. The delivery outcome for any pregnant subjects was recorded in the Case Report Form (CRF).
Information on the delivery outcome for each pregnancy was collected. Information on adverse events was collected during the study period.
OBJECTIVES
The primary objective of the study was:
To determine whether the addition of r-hLH (Luveris) from day 8 of ovarian stimulation reduces the FSH dose needed to obtain/retrieve each oocyte.
The secondary objectives of the study were:
- To determine whether the addition of Luveris to FSH at day 8 of ovarian stimulation improves cycle outcome based on secondary endpoints
- To determine the safety of Luveris in this indication
- Conditions
- Reproductive Techniques, Assisted
- Being tested
- Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH), r-hFSH
- Keywords
- Reproductive Techniques, Assisted, Recombinant human follicle stimulating hormone (r-hFSH), Recombinant leutinizing hormone (r-hLH)
- Medical subject headings
- Helping Behavior
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)Drug
Also called r-hLH, r-hFSH
One r-hFSH and one r-hLH injection subcutaneously (s.c.) once daily during the treatment phase from Day 8 of stimulation until injection of human chorionic gonadotropin (hCG) or cancellation of the treatment cycle.
r-hFSHDrug
One r-hFSH injection s.c. once daily during the treatment phase from Day 8 of stimulation until injection of hCG or cancellation of the treatment cycle.
| Study group | Role | What they receive |
|---|---|---|
| A | Experimental | Subjects treated with r-hFSH and r-hLH (2:1 ratio of r-hFSH:r-hLH) Receives: Drug: Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH) |
| B | Active comparator | Subjects treated with r-hFSH alone Receives: Drug: r-hFSH |
What is being measured
The primary outcome is the main question the study is designed to answer.
Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes
Measured: Baseline (Stimulation day 8 [S8]) until hCG day
Secondary outcomes (13)
Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose
Measured: Baseline (S8) until hCG day
Mean Number of Ovarian Stimulation Days
Measured: Baseline (S8) until hCG day
Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day
Measured: Baseline (S8) and hCG day
Mean Total Number of Retrieved Oocytes
Mean number of oocytes retrieved on the day of ovum pick up (OPU) was counted. 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.
Measured: 34-36 hours post-hCG (OPU)
Mean Number of Mature Oocytes (Metaphase II)
Mean number of metaphase II oocytes was counted for participants undergoing ovum pick up for IntraCytoplasmic Sperm Injection (ICSI). ICSI is a procedure in which a single spermatozoon is injected into the oocyte cytoplasm. Metaphase II stage of the oocyte was classified as the time at which the first polar body was observed microscopically. Metaphase II oocytes are a sub-group of the total number of oocytes.
Measured: 34-36 hours post-hCG (OPU)
Fertilization Rate
Fertilization rate was measured as the ratio between number of fertilized oocytes and number of inseminated oocytes (maximum 3).
Measured: 12-18 day post-hCG and/or Week 7
Number of Obtained Embryos
Total number of obtained embryos with maximum 3 inseminated oocytes was calculated.
Measured: Day 3 post-hCG (Embryo transfer [ET])
Number of Transferred Embryos
Embryo transfer is the procedure in which one or more embryos are placed in the uterus or Fallopian tube.
Measured: Day 3 post-hCG (ET)
Percentage of Participants With Pregnancy
Measured: 12-18 day post-hCG and/or Week 7
Percentage of Participants With Clinical Pregnancy
Clinical pregnancy is defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy.
Measured: 12-18 day post-hCG and/or Week 7
Percentage of Participants With Implantation
Implantation is the attachment and subsequent penetration by the zona-free blastocyst (usually in the endometrium) that starts five to seven days after fertilization.
Measured: 12-18 day post-hCG and/or Week 7
Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS)
OHSS is an exaggerated systemic response to ovarian stimulation characterized by a wide spectrum of clinical and laboratory manifestations. It is classified as mild, moderate or severe according to the degree of abdominal distention, ovarian enlargement and respiratory, haemodynamic and metabolic complications.
Measured: Baseline (S8) until 12-18 day post-hCG and/or Week 7
Number of Cycles Cancelled Due to Risk of OHSS
OHSS is an exaggerated systemic response to ovarian stimulation characterized by a wide spectrum of clinical and laboratory manifestations. It is classified as mild, moderate or severe according to the degree of abdominal distention, ovarian enlargement and respiratory, haemodynamic and metabolic complications.
Measured: Baseline (S8) until 12-18 day post-hCG and/or Week 7
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Feb 2010 (estimated)
- Study startMar 2005
- Primary completionApr 2009
- Study completionApr 2009
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 Reproductive Techniques, AssistedStudies 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 133 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merck KGaA, Darmstadt, Germany
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck Serono S.P.A., Italy
- Responsible party
- Sponsor
- Investigators
- Salvatore Longobardi, Study director, Merck Serono S.P.A., Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01071200
- Sponsor's protocol ID
- IMP25289
- Other IDs
- 2004-002218-13, 2004
- Acronym
- Luveris in ART
- Status last verified
- Dec 2013
- First submitted
- 18 Feb 2010
- Last updated
- 27 Dec 2013
- Results posted
- Yes, on ClinicalTrials.gov
Study at a glance
From the registry record, last updated by the sponsor on 27 Dec 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase III, Multicentric, Randomized, Open, Comparative Study to Evaluate if the Addition of Recombinant Human Luteinising Hormone [r-hLH (Luveris®)] to Follicle Stimulating Hormone (FSH) From Day 8 of Ovarian Stimulation is Able to Decrease Total FSH Dose and to Improve Cycle Outcome in Infertile Women Undergoing Assisted Reproduction Technology (ART), Who Required High FSH Dose in a Previous Cycle
- ClinicalTrials.gov ID
- NCT01071200
- Acronym / sponsor ID
- Luveris in ART / IMP25289
- Conditions
- Reproductive Techniques, Assisted
- Keywords
- Reproductive Techniques, Assisted, Recombinant human follicle stimulating hormone (r-hFSH), Recombinant leutinizing hormone (r-hLH)
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 133 participants (actual)
- Lead sponsor
- Merck KGaA, Darmstadt, GermanyIndustry (pharma, biotech, devices)
- Collaborators
- Merck Serono S.P.A., Italy
- Study start
- Mar 2005
- Primary completion
- Apr 2009 (actual)
- Study completion
- Apr 2009 (actual)
- First posted
- 19 Feb 2010 (estimated)
- Results
- Posted 14 Aug 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The present study was designed to investigate, in hyporesponder subjects, that required in a previous assisted reproductive technologies (ART) cycle follicle stimulating hormone (FSH) >3500 International Unit (IU), the possibility to decrease through recombinant human luteinizing hormone (r-hLH) supplementation, the FSH amount per oocytes retrieved and in the mean time to improve the overall cycle outcome.
Detailed description
Recombinant human follicle stimulating hormone (r-hFSH), which totally lacks LH activity, is widely used to induce multiple follicle development in women under pituitary desensitization, in order to submit them to treatment with assisted reproduction techniques (ART). Clinical experience from hypogonadotropic-hypogonadic women suggests that while FSH alone is sufficient to induce follicle development, LH plays a significant part in final follicle maturation, estrogen synthesis and optimal endometrium growth.
This was a phase III, multicentre, randomized, open-label comparative study to evaluate if the addition of r-hLH (Luveris) in a 2:1 ratio to FSH from day 8 of ovarian stimulation is able to decrease the total FSH dose and to improve cycle outcome in 250 infertile women undergoing ART, who required high FSH dose in a previous cycle (≥ 3500 IU). Subjects who have met all the inclusion criteria, achieved pituitary desensitization and started controlled ovarian hyperstimulation (COH) treatment with FSH, on stimulation day 8 (S8) received an identification number and will be allocated to one of the two following arms:
Arm : FSH + r-hLH (2:1 ratio of FSH:r-hLH), Arm : FSH alone. Treatment with Luveris was commenced on day 8 (S8) and continued until injection of hCG or cancellation of the treatment cycle.
Monitoring of stimulation, FSH dose escalation, criteria for injection of hCG, ovum pick up, embryo transfer and pregnancy confirmation took place according to standard management practice. The in-vitro fertilization (IVF) or intracytosolic sperm injection (ICSI) procedure, including luteal phase support, was performed according to each centres' normal procedures.
The subjects were followed up and the treatment outcome (menstruation or pregnancy) was recorded. The delivery outcome for any pregnant subjects was recorded in the Case Report Form (CRF).
Information on the delivery outcome for each pregnancy was collected. Information on adverse events was collected during the study period.
OBJECTIVES
The primary objective of the study was:
To determine whether the addition of r-hLH (Luveris) from day 8 of ovarian stimulation reduces the FSH dose needed to obtain/retrieve each oocyte.
The secondary objectives of the study were:
- To determine whether the addition of Luveris to FSH at day 8 of ovarian stimulation improves cycle outcome based on secondary endpoints
- To determine the safety of Luveris in this indication
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A | Experimental | Drug: Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)Subjects treated with r-hFSH and r-hLH (2:1 ratio of r-hFSH:r-hLH) |
| B | Active comparator | Drug: r-hFSHSubjects treated with r-hFSH alone |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (12 listed)
- Pre-menopausal infertile woman, aged 18 to 40 years inclusive, who wishes to conceive
- Regular, spontaneous menstrual cycle of 25-35 days
- Body mass index (BMI) ≤ 28
- FSH ≤ 10 IU/L (follicular phase, days 2-5)
- Prolactin (PRL) within the normal ranges
Key exclusion criteria (13 listed)
- Oligo/Anovulatory cycles (World Health Organization [WHO] I and II)
- Male partner azoospermia (assessed within the last 12 months)
- Follicular phase (day 2-5) FSH > 10 IU/L even if only once observed in the medical history
- Abnormal cervical cytology (assessed within the last 12 months)
- History of unexplained gynecologic hemorrhage
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 |
|---|---|---|
| Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)Also: r-hLH, r-hFSHOne r-hFSH and one r-hLH injection subcutaneously (s.c.) once daily during the treatment phase from Day 8 of stimulation until injection of human chorionic gonadotropin (hCG) or cancellation of the treatment cycle. | Drug | A |
| r-hFSHOne r-hFSH injection s.c. once daily during the treatment phase from Day 8 of stimulation until injection of hCG or cancellation of the treatment cycle. | Drug | B |
Primary outcome
Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes
Time frame: Baseline (Stimulation day 8 [S8]) until hCG day
13 secondary outcomes
Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose
Time frame: Baseline (S8) until hCG day
Mean Number of Ovarian Stimulation Days
Time frame: Baseline (S8) until hCG day
Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day
Time frame: Baseline (S8) and hCG day
Mean Total Number of Retrieved Oocytes
Time frame: 34-36 hours post-hCG (OPU)
Mean Number of Mature Oocytes (Metaphase II)
Time frame: 34-36 hours post-hCG (OPU)
Fertilization Rate
Time frame: 12-18 day post-hCG and/or Week 7
Number of Obtained Embryos
Time frame: Day 3 post-hCG (Embryo transfer [ET])
Number of Transferred Embryos
Time frame: Day 3 post-hCG (ET)
Percentage of Participants With Pregnancy
Time frame: 12-18 day post-hCG and/or Week 7
Percentage of Participants With Clinical Pregnancy
Time frame: 12-18 day post-hCG and/or Week 7
Percentage of Participants With Implantation
Time frame: 12-18 day post-hCG and/or Week 7
Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS)
Time frame: Baseline (S8) until 12-18 day post-hCG and/or Week 7
Number of Cycles Cancelled Due to Risk of OHSS
Time frame: Baseline (S8) until 12-18 day post-hCG and/or Week 7
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Dec 2013.
- 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.
Salvatore Longobardi study director
Merck Serono S.P.A., Italy
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH) and r-hFSH in people with Reproductive Techniques, Assisted, run by Merck KGaA, Darmstadt, Germany at 1 site in Italy.
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 12 inclusion and 13 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 Dec 2013. 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 Italy. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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 14 Aug 2012). 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?
Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes (time frame: Baseline (Stimulation day 8 [S8]) until hCG day). 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 Dec 2013.