A Trial to Compare the Efficacy and Safety of Ovarian Stimulation With GONAL-f® and Luveris® Starting on Day 1 Versus Day 6 in Women Undergoing Assisted Reproductive Technique

Phase 3

Terminated

Conditions: Fertility
Infertility
Follicle Stimulating Hormone Deficiency

Interventions: Drug: GONAL-f®
Drug: Luveris®
Biological: Recombinant human chorionic gonadotropin (r-hCG)

Registration Number: NCT01497197

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: This is a phase IIIb, interventional, multicenter, multinational, randomised, open-label, comparative trial which primary objective is to generate data on the ovarian stimulation profile obtained when Luveris® is started either on Day 1 or Day 6 in women in advanced reproductive age (36-42) undergoing Assisted Reproductive Technique (ART).

Detailed Description: The subjects who complete the screening assessments and fulfil all the eligibility criteria will start down-regulation treatment on day 21-22 of the cycle.

Down-regulation treatment must start within 2 months following the screening visit. The routine long luteal phase protocol for Gonadotrophin-releasing hormone (GnRH) agonist treatment will be followed.

Once down-regulation has been confirmed, a pregnancy test will be performed within 1 week prior to start of Recombinant human follicle stimulating hormone (r-hFSH) treatment to rule out any pre-existing pregnancy. If the result is negative, the subject will be randomly assigned to one of the two treatment arms of the trial:

* GONAL-f® (Liquid Pen; 300 IU of per day) stimulation day 1-5 then followed by Luveris® (vial/powder, 150 IU per day) from stimulation Day 1 and until required r-hCG level is met. The dose can be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.

* GONAL-f® (Liquid Pen; 300 IU per day) stimulation Day 1-5 then add Luveris® (vial/powder, 150 IU per day) from stimulation Day 6 and until required recombinant Human chorionic gonadotrophin (r-hCG) level is met. The dose can be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.

Randomization across the two treatment arms will be kept balanced in a 1:1 ratio. Subjects will be provided with a subject diary (including r-hCG and Crinone® administration and safety information) to record daily dosing information for GONAL-f® and Luveris®.

Follicular development will be monitored according to the center's standard practice by US and/or Oestradiol (E2) levels, until the protocol r-hCG requirement is met (i.e., at least 1 follicle greater or equal to 18 mm and 2 follicles greater or equal to 16 millimeter \[mm\]). After this, a single injection of 250 microgram (mcg) of r-hCG (Ovidrel®/Ovitrelle®), will be administered in order to induce final oocyte maturation.

At a time of 34-38 hours after r-hCG administration, oocytes will be recovered vaginally under US monitoring. Oocytes will then be fertilized in vitro and embryos replaced 2-3 days after oocyte recovery. Ovum pick up (OPU), in vitro fertilization (IVF), Embryo Transfer (ET) and luteal support will be performed as per center's standard practice. In addition, Crinone® 8% (progesterone gel) will be administered once daily.

A post-treatment safety visit will be performed for all subjects who received r-hCG (pregnant and non-pregnant) on post r-hCG Day 15-20. For subjects who have withdrawn from treatment (i.e. after starting Luveris® or GONAL f® but before r-hCG is given) this visit will take place 20-30 days after their first Luveris® or GONAL-f® treatment injection (excluding pregnancy testing).

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 174

Inclusion Criteria

Should be a female subject justifying an In Vitro Fertilization/Embryo transfer (IVF)/ET treatment
Should be between 36th and 42nd birthday (both included) at the time of the randomization visit
Have early follicular phase (day 2-4) serum level of basal FSH <= 12 IU/L measured in the center's local laboratory during the screening period (i.e. within 2 months prior to down regulation start)
Have a regular spontaneous ovulatory menstrual cycle between 21 and 35 days in length
Presence of both ovaries
Normal uterine cavity, which in the investigator's opinion is compatible with Pregnancy
Have a negative cervical Papanicolaou (PAP or smear) test within the last 6 months prior to randomization
Have at least one wash-out cycle (defined as >=30 days since the last dose of clomiphene citrate or gonadotrophin treatment) since the last ART cycle and/or clomiphene citrate or gonadotrophin treatment prior to starting GnRH agonist therapy
Be willing and able to comply with the protocol for the duration of the trial
Have given written informed consent, prior to any trial-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to her future medical care
Have a male partner with semen analysis within the past 6 months prior to randomization considered adequate to proceed with regular insemination or intra-cytoplasmic sperm injection (ICSI) according to the center's standard practice

Exclusion Criteria

Had 2 (or more) previous ART cycles with a poor response to gonadotrophin stimulation defined as 6 (or less) mature follicles and/or 4 (or less) oocytes collected in any previous IVF cycle or previous cycles with a hyper response defined as 25 (or more) oocytes retrieved
Any medical condition, which in the judgment of the investigator may interfere with the absorption, distribution, metabolism or excretion of the drug. In case of doubt, the subject in question should be discussed with Merck Serono's Medical responsible
Had previous severe ovarian hyperstimulation syndrome (OHSS)
Polycystic ovary syndrome (PCOS; Rotterdam criteria) to reduce the risk of the occurrence of OHSS
Presence of endometriosis requiring treatment
Uterine myoma requiring treatment
Any contraindication to being pregnant and/or carrying a pregnancy to term
Extra-uterine pregnancy within the last 3 months prior to screening
History of 3 or more miscarriages (early or late miscarriages) due to any cause
Tumours of the hypothalamus and pituitary gland
Ovarian enlargement or cyst of unknown etiology
Ovarian, uterine or mammary cancer
A clinically significant systemic disease
Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus in the trial subject or her male partner
Abnormal gynecological bleeding of undetermined origin
Known allergy or hypersensitivity to human gonadotrophin preparations
Any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years prior to the screening visit
Entered previously into this trial or simultaneous participation in another clinical trial
Pregnancy and lactation period
Participation in another clinical trial within the past 30 days

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Gonal-f® Followed by Luveris®	Luveris®	GONAL-f® 300 IU per day as subcutaneous injection using liquid pen from stimulation Day 1-5 followed by Luveris® 150 IU per day lyophilized powder for subcutaneous injection from stimulation Day 6 until required r-hCG level is met. The dose will be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.
Gonal-f®+Luveris®	Recombinant human chorionic gonadotropin (r-hCG)	GONAL f® 300 international units \[IU\] per day as subcutaneous injection using liquid pen from stimulation Day 1-5 followed by Luveris® 150 IU per day lyophilized powder for subcutaneous injection from stimulation Day 1 until required recombinant human chorionic gonadotropin (r-hCG) level is met. The dose will be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.
Gonal-f®+Luveris®	GONAL-f®	GONAL f® 300 international units \[IU\] per day as subcutaneous injection using liquid pen from stimulation Day 1-5 followed by Luveris® 150 IU per day lyophilized powder for subcutaneous injection from stimulation Day 1 until required recombinant human chorionic gonadotropin (r-hCG) level is met. The dose will be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.
Gonal-f®+Luveris®	Luveris®	GONAL f® 300 international units \[IU\] per day as subcutaneous injection using liquid pen from stimulation Day 1-5 followed by Luveris® 150 IU per day lyophilized powder for subcutaneous injection from stimulation Day 1 until required recombinant human chorionic gonadotropin (r-hCG) level is met. The dose will be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.
Gonal-f® Followed by Luveris®	GONAL-f®	GONAL-f® 300 IU per day as subcutaneous injection using liquid pen from stimulation Day 1-5 followed by Luveris® 150 IU per day lyophilized powder for subcutaneous injection from stimulation Day 6 until required r-hCG level is met. The dose will be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.
Gonal-f® Followed by Luveris®	Recombinant human chorionic gonadotropin (r-hCG)	GONAL-f® 300 IU per day as subcutaneous injection using liquid pen from stimulation Day 1-5 followed by Luveris® 150 IU per day lyophilized powder for subcutaneous injection from stimulation Day 6 until required r-hCG level is met. The dose will be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.

Primary Outcome Measures

Name	Time	Method
Total Number of Oocytes Retrieved Per Subject Following Ovarian Stimulation	34-38 hours post r-hCG administration	Ovarian stimulation was performed using in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). The total number of oocytes collected per subject following stimulation was reported.

Secondary Outcome Measures

Name	Time	Method
Total Dose and Mean Daily Dose of Follicle Stimulating Hormone (FSH)	Screening	Mean daily dose of FSH was to be determined by dividing the total daily dose by the number of stimulation days.
Total Number of Stimulation Treatment Days	6 days post stimulation (Number of stimulation days+6 days)	The total number of stimulation treatment days for each subject was determined based on the treatment administration information collected in the case report form.
Total Pregnancy Rate and Clinical Pregnancy Rate	35-42 days post r-hCG administration	The subject was considered to have a positive pregnancy result if beta-hCG \>10 international units per liter (IU/L) and the subject had not menstruated between post-r-hCG Days 15-20. Clinical pregnancy was defined as the existence of at least an US confirmed gestational sac in the uterus with fetal heart activity post-r-hCG Days 35-42.
Implantation Rate	35-42 days post r-hCG administration	The implantation rate was determined as number of fetal sacs divided by the number of embryos transferred post r-hCG administration.
Number of Fetal Sacs With Activity	35-42 days post r-hCG administration	Number of fetal sacs with activity was evaluated by ultrasound scan (US) on Days 35-42 post r-hCG to confirm clinical pregnancy.
Number of Fetal Sacs With Detectable Heart Beats	35-42 days post r-hCG administration	Number of fetal sacs with detectable heart beats was evaluated by US on Days 35-42 post r-hCG to confirm clinical pregnancy
Cycle Cancellation Rate Prior to r-hCG	Up to 85 days	If the subject was not administered with r-hCG and withdrew prematurely from the trial, it was considered as cycle cancellation.
Number of Subjects With Biochemical Pregnancies	35 to 42 days post r-hCG administration	Biochemical pregnancy was defined as the pregnancy diagnosed only by the detection of hCG in serum or urine and that does not develop into a clinical pregnancy. Subjects with beta-hCG concentration greater than 10 IU/L were considered as biochemical pregnant.
Number of Subjects With Multiple Pregnancies	35 to 42 days post r-hCG administration	Multiple pregnancy was defined as the existence of more than one ultrasound confirmed gestational sac in the uterus with fetal heart activity at post-r-hCG Days 35-42.
Number of Subjects With Any Adverse Events (AEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation	Baseline up to 15-20 days post r-hCG administration	An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious AE is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.