Study to Evaluate if the Addition of r-hLH (Luveris®) to... | NCT01071200

NCT01071200

ID	Type	Description	Link
2004-002218-13	EudraCT Number

Status Module

Name	Class
Merck Serono S.P.A., Italy	INDUSTRY

Description Module

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

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
A	Experimental	Subjects treated with r-hFSH and r-hLH (2:1 ratio of r-hFSH:r-hLH)	Drug: Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)
B	Active Comparator	Subjects treated with r-hFSH alone	Drug: r-hFSH

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Recombinant human Follicle Stimulating Hormone (r-hFSH) and Recombinant human Luteinizing Hormone (r-hLH)	Drug	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.

Measure	Description	Time Frame
Total Dose of Follicular Stimulating Hormone (FSH) for Retrieved Oocytes		Baseline (Stimulation day 8 [S8]) until hCG day

Measure	Description	Time Frame
Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose		Baseline (S8) until hCG day
Mean Number of Ovarian Stimulation Days		Baseline (S8) until hCG day

Eligibility Module

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

Name	Affiliation	Role
Salvatore Longobardi	Merck Serono S.P.A., Italy	Study Director

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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).

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	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).
BG001	Follicle-stimulating Hormone (FSH)	FSH injection s.c. administered according to investigator's discretion till r-hCG administration day.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00067 BG00166 BG002133

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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

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.

Posted

Mean

Standard Deviation

Baseline (Stimulation day 8 [S8]) until hCG day

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants	OG00064 OG00164

Title

Denominators

Categories

Baseline (S8)

Title	Measurements
	OG000904.6± 1068.1 OG001703.3± 924.5

Baseline (S8) until hCG day

Title	Measurements
	OG000

Secondary

Mean Total Follicle Stimulating Hormone (FSH) and Recombinant Human Luteinizing Hormone (r-hLH) Dose

mITT population included all randomized participants who entered in the experimental phase at S8.

Posted

Mean

Standard Deviation

Baseline (S8) until hCG day

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants	OG000

Secondary

Mean Number of Ovarian Stimulation Days

mITT population included all randomized participants who entered in the experimental phase at S8.

Posted

Mean

Full Range

Days

Baseline (S8) until hCG day

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Oestradiol (E2) Levels at Human Choriogonadotropin (hCG) Day

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.

Posted

Mean

Standard Deviation

picogram/milliter (pg/mL)

Baseline (S8) and hCG day

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants

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.

mITT population included all randomized participants who entered in the experimental phase at S8.

Posted

Mean

Standard Deviation

oocytes

34-36 hours post-hCG (OPU)

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants

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.

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.

Posted

Mean

Standard Deviation

Metaphase II Oocytes

34-36 hours post-hCG (OPU)

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Secondary

Fertilization Rate

Fertilization rate was measured as the ratio between number of fertilized oocytes and number of inseminated oocytes (maximum 3).

mITT population included all randomized participants who entered in the experimental phase at S8.

Posted

Mean

Standard Deviation

ratio

12-18 day post-hCG and/or Week 7

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants

Secondary

Number of Obtained Embryos

Total number of obtained embryos with maximum 3 inseminated oocytes was calculated.

mITT population included all randomized participants who entered in the experimental phase at S8.

Posted

Number

embryos

Day 3 post-hCG (Embryo transfer [ET])

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants	OG000

Secondary

Number of Transferred Embryos

Embryo transfer is the procedure in which one or more embryos are placed in the uterus or Fallopian tube.

mITT population included all randomized participants who entered in the experimental phase at S8.

Posted

Number

embryos

Day 3 post-hCG (ET)

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants	OG000

Secondary

Percentage of Participants With Pregnancy

mITT population included all randomized participants who entered in the experimental phase at S8.

Posted

Number

percentage of participants

12-18 day post-hCG and/or Week 7

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants	OG000

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.

mITT population included all randomized participants who entered in the experimental phase at S8.

Posted

Number

percentage of participants

12-18 day post-hCG and/or Week 7

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
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.

mITT population included all randomized participants who entered in the experimental phase at S8.

Posted

Number

percentage of participants

12-18 day post-hCG and/or Week 7

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts
Participants

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.

Safety population included all the randomized participants who received at least one dose of the study drug.

Posted

Number

participants

Baseline (S8) until 12-18 day post-hCG and/or Week 7

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts

Secondary

Number of Cycles Cancelled Due to Risk of OHSS

Safety population included all the randomized participants who received at least one dose of the study drug.

Posted

Number

cycles

Baseline (S8) until 12-18 day post-hCG and/or Week 7

ID	Title	Description
OG000	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).
OG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.

Units	Counts

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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).			1	67	2	67
EG001	Follicle-stimulating Hormone (FSH)	FSH injection administered according to investigator's discretion till r-hCG administration day.			2	66	0	66

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Left ectopic pregnancy	General disorders	MedDRA	Non-systematic Assessment	EG0000 affected67 at risk EG0011 affected66 at risk
Cerclage	General disorders	MedDRA	Non-systematic Assessment	EG0001 affected67 at risk EG0010 affected66 at risk
Renal colic	General disorders	MedDRA	Non-systematic Assessment	EG0000 affected67 at risk EG0011 affected66 at risk

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Ovarian Hyper Stimulation Syndrome	General disorders	MedDRA	Non-systematic Assessment		EG0001 affected67 at risk EG0010 affected66 at risk
Urticaria post intake of food (fish)	General disorders	MedDRA	Non-systematic Assessment		EG0001 affected67 at risk EG0010 affected66 at risk

ID	Term
D012919	Social Behavior
D001519	Behavior