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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 (Luveris in ART)

Primary Purpose

Reproductive Techniques, Assisted

Status
Terminated
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)
r-hFSH
Sponsored by
Merck KGaA, Darmstadt, Germany
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Reproductive Techniques, Assisted focused on measuring Reproductive Techniques, Assisted, Recombinant human follicle stimulating hormone (r-hFSH), Recombinant leutinizing hormone (r-hLH)

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • 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
  • 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related to the study protocol, which is not part of routine medical care, with the understanding that consent may be withdrawn by the subject at any time, without prejudice on their future medical care

Exclusion Criteria:

  • 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
  • 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

Sites / Locations

  • Merck Serono S.p.A.

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

A

B

Arm Description

Subjects treated with r-hFSH and r-hLH (2:1 ratio of r-hFSH:r-hLH)

Subjects treated with r-hFSH alone

Outcomes

Primary Outcome Measures

Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes

Secondary Outcome Measures

Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose
Mean Number of Ovarian Stimulation Days
Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (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.
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.
Fertilization Rate
Fertilization rate was measured as the ratio between number of fertilized oocytes and number of inseminated oocytes (maximum 3).
Number of Obtained Embryos
Total number of obtained embryos with maximum 3 inseminated oocytes was calculated.
Number of Transferred Embryos
Embryo transfer is the procedure in which one or more embryos are placed in the uterus or Fallopian tube.
Percentage of Participants With Pregnancy
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.
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.
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.
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.

Full Information

First Posted
February 18, 2010
Last Updated
December 2, 2013
Sponsor
Merck KGaA, Darmstadt, Germany
Collaborators
Merck Serono S.P.A., Italy
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1. Study Identification

Unique Protocol Identification Number
NCT01071200
Brief Title
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
Acronym
Luveris in ART
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2013
Overall Recruitment Status
Terminated
Study Start Date
March 2005 (undefined)
Primary Completion Date
April 2009 (Actual)
Study Completion Date
April 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck KGaA, Darmstadt, Germany
Collaborators
Merck Serono S.P.A., Italy

4. Oversight

5. Study Description

Brief 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 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Reproductive Techniques, Assisted
Keywords
Reproductive Techniques, Assisted, Recombinant human follicle stimulating hormone (r-hFSH), Recombinant leutinizing hormone (r-hLH)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
133 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A
Arm Type
Experimental
Arm Description
Subjects treated with r-hFSH and r-hLH (2:1 ratio of r-hFSH:r-hLH)
Arm Title
B
Arm Type
Active Comparator
Arm Description
Subjects treated with r-hFSH alone
Intervention Type
Drug
Intervention Name(s)
Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)
Other Intervention Name(s)
r-hLH, r-hFSH
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
r-hFSH
Intervention Description
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.
Primary Outcome Measure Information:
Title
Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes
Time Frame
Baseline (Stimulation day 8 [S8]) until hCG day
Secondary Outcome Measure Information:
Title
Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose
Time Frame
Baseline (S8) until hCG day
Title
Mean Number of Ovarian Stimulation Days
Time Frame
Baseline (S8) until hCG day
Title
Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day
Time Frame
Baseline (S8) and hCG day
Title
Mean Total Number of Retrieved Oocytes
Description
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.
Time Frame
34-36 hours post-hCG (OPU)
Title
Mean Number of Mature Oocytes (Metaphase II)
Description
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.
Time Frame
34-36 hours post-hCG (OPU)
Title
Fertilization Rate
Description
Fertilization rate was measured as the ratio between number of fertilized oocytes and number of inseminated oocytes (maximum 3).
Time Frame
12-18 day post-hCG and/or Week 7
Title
Number of Obtained Embryos
Description
Total number of obtained embryos with maximum 3 inseminated oocytes was calculated.
Time Frame
Day 3 post-hCG (Embryo transfer [ET])
Title
Number of Transferred Embryos
Description
Embryo transfer is the procedure in which one or more embryos are placed in the uterus or Fallopian tube.
Time Frame
Day 3 post-hCG (ET)
Title
Percentage of Participants With Pregnancy
Time Frame
12-18 day post-hCG and/or Week 7
Title
Percentage of Participants With Clinical Pregnancy
Description
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.
Time Frame
12-18 day post-hCG and/or Week 7
Title
Percentage of Participants With Implantation
Description
Implantation is the attachment and subsequent penetration by the zona-free blastocyst (usually in the endometrium) that starts five to seven days after fertilization.
Time Frame
12-18 day post-hCG and/or Week 7
Title
Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS)
Description
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.
Time Frame
Baseline (S8) until 12-18 day post-hCG and/or Week 7
Title
Number of Cycles Cancelled Due to Risk of OHSS
Description
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.
Time Frame
Baseline (S8) until 12-18 day post-hCG and/or Week 7

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 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 Exclusion Criteria: 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Salvatore Longobardi
Organizational Affiliation
Merck Serono S.P.A., Italy
Official's Role
Study Director
Facility Information:
Facility Name
Merck Serono S.p.A.
City
Roma
Country
Italy

12. IPD Sharing Statement

Learn more about this trial

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

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