Reproductive Techniques, Assisted
Conditions
Keywords
Reproductive Techniques, Assisted, Recombinant human follicle stimulating hormone (r-hFSH), Recombinant leutinizing hormone (r-hLH)
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
Interventions
DRUGRecombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)
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.
DRUGr-hFSH
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.
Sponsors
Merck Serono S.P.A., Italy
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes | Baseline (Stimulation day 8 [S8]) until hCG day |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Ovarian Stimulation Days | Baseline (S8) until hCG day | — |
| Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day | Baseline (S8) and hCG day | — |
| Mean Total Number of Retrieved Oocytes | 34-36 hours post-hCG (OPU) | 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) | 34-36 hours post-hCG (OPU) | 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 | 12-18 day post-hCG and/or Week 7 | Fertilization rate was measured as the ratio between number of fertilized oocytes and number of inseminated oocytes (maximum 3). |
| Number of Obtained Embryos | Day 3 post-hCG (Embryo transfer [ET]) | Total number of obtained embryos with maximum 3 inseminated oocytes was calculated. |
| Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose | Baseline (S8) until hCG day | — |
| Percentage of Participants With Pregnancy | 12-18 day post-hCG and/or Week 7 | — |
| Percentage of Participants With Clinical Pregnancy | 12-18 day post-hCG and/or Week 7 | 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 | 12-18 day post-hCG and/or Week 7 | 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) | Baseline (S8) until 12-18 day post-hCG and/or Week 7 | 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 | Baseline (S8) until 12-18 day post-hCG and/or Week 7 | 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 Transferred Embryos | Day 3 post-hCG (ET) | Embryo transfer is the procedure in which one or more embryos are placed in the uterus or Fallopian tube. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FSH + rhLH Follicle-stimulating hormone (FSH) injection administered according to investigator's discretion till Day 8 of stimulation period (S8) and treatment with recombinant human luteinizing hormone (rhLH, Luveris) injection 150 International Units (IU) subcutaneously (s.c.) daily was started from S8 until recombinant human choriogonadotropin (r-hCG) administration day. r-hLH was administered in a 2:1 ratio (FSH:r-hLH). | 67 |
| Follicle-stimulating Hormone (FSH) FSH injection s.c. administered according to investigator's discretion till r-hCG administration day. | 66 |
| Total | 133 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of ovarian response | 1 | 1 |
| Overall Study | No fertilization | 4 | 0 |
| Overall Study | No oocytes retrieved | 1 | 1 |
| Overall Study | No viable embryos | 0 | 1 |
| Overall Study | Ovarian Hyper Stimulation Syndrome | 1 | 0 |
Baseline characteristics
| Characteristic | FSH + rhLH | Follicle-stimulating Hormone (FSH) | Total |
|---|---|---|---|
| Age, Continuous | 35.6 years STANDARD_DEVIATION 2.9 | 35.0 years STANDARD_DEVIATION 3.8 | 35.3 years STANDARD_DEVIATION 3.4 |
| Sex: Female, Male Female | 67 Participants | 66 Participants | 133 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 67 | 0 / 66 |
| serious Total, serious adverse events | 1 / 67 | 2 / 66 |
Outcome results
Primary
Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes
Time frame: Baseline (Stimulation day 8 [S8]) until hCG day
Population: Modified intention-to-treat (mITT) population included all randomized participants who entered in the experimental phase at S8. Here N represents number of participants analyzed for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FSH + rhLH | Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes | Baseline (S8) | 904.6 IU | Standard Deviation 1068.1 |
| FSH + rhLH | Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes | Baseline (S8) until hCG day | 388.5 IU | Standard Deviation 631.3 |
| Follicle-stimulating Hormone (FSH) | Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes | Baseline (S8) | 703.3 IU | Standard Deviation 924.5 |
| Follicle-stimulating Hormone (FSH) | Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes | Baseline (S8) until hCG day | 318.5 IU | Standard Deviation 534 |
Secondary
Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day
Time frame: Baseline (S8) and hCG day
Population: mITT population included all randomized participants who entered in the experimental phase at S8. Here N represents number of participants analyzed and n represents the number of participants with plasma E2 levels at specified time points for respective treatment groups.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FSH + rhLH | Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day | Baseline (n = 59,59) | 516.1 picogram/milliter (pg/mL) | Standard Deviation 353.6 |
| FSH + rhLH | Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day | Change at hCG day (n = 40,47) | 1391.6 picogram/milliter (pg/mL) | Standard Deviation 743.4 |
| Follicle-stimulating Hormone (FSH) | Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day | Change at hCG day (n = 40,47) | 1179.9 picogram/milliter (pg/mL) | Standard Deviation 746.5 |
| Follicle-stimulating Hormone (FSH) | Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day | Baseline (n = 59,59) | 518.9 picogram/milliter (pg/mL) | Standard Deviation 334.2 |
Comparison: Change at hCG day : Wilcoxon two sample test was used to calculate p-value.p-value: 0.07Wilcoxon two sample test
Secondary
Fertilization Rate
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
Population: mITT population included all randomized participants who entered in the experimental phase at S8.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FSH + rhLH | Fertilization Rate | 0.85 ratio | Standard Deviation 0.29 |
| Follicle-stimulating Hormone (FSH) | Fertilization Rate | 0.89 ratio | Standard Deviation 0.2 |
Secondary
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.
Time frame: 34-36 hours post-hCG (OPU)
Population: mITT population included all randomized participants who entered in the experimental phase at S8. Here N represents those participants undergoing ICSI whose oocytes were assessed for maturity (Metaphase II) using a microscope.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FSH + rhLH | Mean Number of Mature Oocytes (Metaphase II) | 5.1 Metaphase II Oocytes | Standard Deviation 3.7 |
| Follicle-stimulating Hormone (FSH) | Mean Number of Mature Oocytes (Metaphase II) | 5.7 Metaphase II Oocytes | Standard Deviation 3.2 |
Secondary
Mean Number of Ovarian Stimulation Days
Time frame: Baseline (S8) until hCG day
Population: mITT population included all randomized participants who entered in the experimental phase at S8.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| FSH + rhLH | Mean Number of Ovarian Stimulation Days | 4.6 Days |
| Follicle-stimulating Hormone (FSH) | Mean Number of Ovarian Stimulation Days | 4.8 Days |
Secondary
Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose
Time frame: Baseline (S8) until hCG day
Population: mITT population included all randomized participants who entered in the experimental phase at S8.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FSH + rhLH | Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose | Total FSH dose | 1434.0 IU | Standard Deviation 678.1 |
| FSH + rhLH | Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose | Total r-hLH dose | 575.9 IU | Standard Deviation 273 |
| Follicle-stimulating Hormone (FSH) | Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose | Total FSH dose | 1595.0 IU | Standard Deviation 796.4 |
| Follicle-stimulating Hormone (FSH) | Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose | Total r-hLH dose | 0 IU | Standard Deviation 0 |
Secondary
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.
Time frame: 34-36 hours post-hCG (OPU)
Population: mITT population included all randomized participants who entered in the experimental phase at S8.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FSH + rhLH | Mean Total Number of Retrieved Oocytes | 7.0 oocytes | Standard Deviation 4.6 |
| Follicle-stimulating Hormone (FSH) | Mean Total Number of Retrieved Oocytes | 7.8 oocytes | Standard Deviation 3.9 |
Secondary
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.
Time frame: Baseline (S8) until 12-18 day post-hCG and/or Week 7
Population: Safety population included all the randomized participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSH + rhLH | Number of Cycles Cancelled Due to Risk of OHSS | 1 cycles |
| Follicle-stimulating Hormone (FSH) | Number of Cycles Cancelled Due to Risk of OHSS | 0 cycles |
Secondary
Number of Obtained Embryos
Total number of obtained embryos with maximum 3 inseminated oocytes was calculated.
Time frame: Day 3 post-hCG (Embryo transfer [ET])
Population: mITT population included all randomized participants who entered in the experimental phase at S8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSH + rhLH | Number of Obtained Embryos | 142 embryos |
| Follicle-stimulating Hormone (FSH) | Number of Obtained Embryos | 158 embryos |
Secondary
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.
Time frame: Baseline (S8) until 12-18 day post-hCG and/or Week 7
Population: Safety population included all the randomized participants who received at least one dose of the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FSH + rhLH | Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) | Mild OHSS | 0 participants |
| FSH + rhLH | Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) | Moderate OHSS | 1 participants |
| FSH + rhLH | Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) | Severe OHSS | 0 participants |
| Follicle-stimulating Hormone (FSH) | Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) | Mild OHSS | 0 participants |
| Follicle-stimulating Hormone (FSH) | Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) | Moderate OHSS | 0 participants |
| Follicle-stimulating Hormone (FSH) | Number of Participants With Ovarian Hyper Stimulation Syndrome (OHSS) | Severe OHSS | 0 participants |
Secondary
Number of Transferred Embryos
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)
Population: mITT population included all randomized participants who entered in the experimental phase at S8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSH + rhLH | Number of Transferred Embryos | 60 embryos |
| Follicle-stimulating Hormone (FSH) | Number of Transferred Embryos | 63 embryos |
Secondary
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.
Time frame: 12-18 day post-hCG and/or Week 7
Population: mITT population included all randomized participants who entered in the experimental phase at S8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSH + rhLH | Percentage of Participants With Clinical Pregnancy | 23.9 percentage of participants |
| Follicle-stimulating Hormone (FSH) | Percentage of Participants With Clinical Pregnancy | 18.5 percentage of participants |
Secondary
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.
Time frame: 12-18 day post-hCG and/or Week 7
Population: mITT population included all randomized participants who entered in the experimental phase at S8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSH + rhLH | Percentage of Participants With Implantation | 13.38 percentage of participants |
| Follicle-stimulating Hormone (FSH) | Percentage of Participants With Implantation | 11.39 percentage of participants |
Secondary
Percentage of Participants With Pregnancy
Time frame: 12-18 day post-hCG and/or Week 7
Population: mITT population included all randomized participants who entered in the experimental phase at S8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSH + rhLH | Percentage of Participants With Pregnancy | 29.9 percentage of participants |
| Follicle-stimulating Hormone (FSH) | Percentage of Participants With Pregnancy | 30.8 percentage of participants |