Clinical trial NCT01297465: PERgoveriS In Stratified Treatment for Assisted Reproductive Technique
Official title: A Phase IIIB, Multicentre, Multinational, Randomized, Open-label Trial to Compare the Efficacy and Safety of Ovarian Stimulation With GONAL-f® Day 1 to Day 5 Followed by Pergoveris® Starting Day 6 to Pergoveris® Starting Day 1 in Women Between 36 and 40 Years of Age Undergoing Assisted Reproductive Technique (ART)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Assisted Reproductive Techniques
Reproductive Technology, Assisted
Keywords: Ovulation Induction
Ovarian Stimulation
Reproductive Technique, Assisted
Assisted Reproductive Technics
Assisted Reproductive Technique
Reproductive Technology, Assisted
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
Collaborators: name: Merck Serono S.A., Geneva
name: Merck A/S, Denmark
name: Merck OY, Finland
name: Merck Serono S.A.S, France
name: Merck Serono GmbH, Germany
name: Merck A.E., Greece
name: Merck B.V., Netherlands
name: Merck SP. Z.O.O., Poland
name: Merck Serono S.P.A., Italy
name: Merck Services U.K. Ltd, UK
name: LLC Merck, Russia
name: Merck spol. s r.o., Slovakia
name: Merck Pharma, K.S., Slovakia
First posted: 2011-02-16
Enrollment: 202
Sex: FEMALE
Minimum age (years): 36
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, multi-national, randomized, open-label comparative trial. After screening, the subjects will start down-regulation treatment on Day 21-22 of the cycle. Down-regulation treatment will start within 2 months following the screening visit. The routine long luteal phase protocol for gonadotropin-releasing hormone (GnRH) agonist treatment will be followed. Once down-regulation has been confirmed, a pregnancy test will be performed just before randomization and 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 international unit \[IU\] of per day) stimulation Day 1-5 followed by Pergoveris® (vial/powder, 300 IU per day) from stimulation Day 6 and until required recombinant human chorionic hormone (r-hCG) criterion 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.
* Pergoveris®: (vial/powder, 300 IU per day) from stimulation Day 1 and until required r-hCG criterion 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. Follicular development will be monitored according to the center's standard practice by ultrasound (US) and/or estradiol (E2) levels, until the protocol r-hCG requirement is met (i.e., at least one follicle greater than or equal to \[\>=\] 18 millimeter \[mm\] and two follicles \>=16 mm). After this, a single injection of r-hCG 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 2-5 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.

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


Eligibility criteria: Inclusion Criteria:

* Be a female subject justifying an in vitro fertilization and embryo transfer (IVF/ET) treatment
* Be between her 36th and 40th birthday (both included) at the time of the randomization visit
* Have early follicular phase (Day 2-4) serum level of basal follicle stimulating hormone (FSH less than or equal to (=\<)12 IU/L) measured in the center's local laboratory during the screening period (that is within 2 months prior to down-regulation start)
* A body mass index (BMI) less than (\<) 30 kilogram per square meter (kg/m\^2)
* Have a regular spontaneous ovulatory menstrual cycle between 21 and 35 days in length
* 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 intracytoplasmic sperm injection (ICSI) according to the center's standard practice. If these criteria are not met, the subject can only be entered if donor sperm will be used
* Other protocol specified inclusion criteria could also apply.

Exclusion Criteria:

* Had \>= 2 previous ART cycles with a poor response to gonadotrophin stimulation defined as =\< 6 mature follicles and/or =\<4 oocytes collected in any previous IVF cycle or previous cycles with a hyper response defined as \>= 25 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
* Any contraindication to being pregnant and/or carrying a pregnancy to term
* History of 3 or more miscarriages (early or late miscarriages) due to any cause
* 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
* Known allergy or hypersensitivity to human gonadotrophin preparations
* 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
* Other protocol specified inclusion criteria could also apply.

Primary outcomes:
measure: Total Number of Oocytes Retrieved
timeFrame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 11 days}])
Secondary outcomes:
measure: Total Dose and Mean Daily Dose of Follicle Stimulating Hormone (FSH)
timeFrame: Day 1 up to r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Total Number of Stimulation Treatment Days
timeFrame: Day 1 up to r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Implantation Rate
timeFrame: Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Number of Fetal Sacs With Activity
timeFrame: Days 35-42 post r-hCG day [end of stimulation cycle {approximately 11 days}])
measure: Number of Fetal Hearts With Activity
timeFrame: Days 35-42 post r-hCG day [end of stimulation cycle {approximately 11 days}])
measure: Clinical Pregnancy Rate
timeFrame: Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Number of Participants With Cancelled Cycles Due to Excessive or Insufficient Ovarian Response to Treatment
timeFrame: S1 until Day 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Biochemical Pregnancies Rate
timeFrame: Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Number of Participants With Multiple Pregnancies
timeFrame: Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Number of Participants With Early and Late Ovarian Hyper Stimulation Syndrome (OHSS)
timeFrame: Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Number of Participants With Treatment-emergent Adverse Events
timeFrame: Day 1 up to days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Systolic and Diastolic Arterial Blood Pressure Assessments
timeFrame: Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])
measure: Heart Rate Assessments
timeFrame: Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days])
Other outcomes:
Locations:
city: Dronninglund
country: Denmark
facility: Research Site
city: Fredericia
country: Denmark
facility: Research Site
city: Helsinki
country: Finland
facility: Research Site
city: Bondy CEDEX
country: France
facility: Research Site
city: Bruges
country: France
facility: Research Site
city: Clamart CEDEX
country: France
facility: Research Site
city: Tenon
country: France
facility: Research Site
city: Villeurbanne
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Halle
country: Germany
facility: Research Site
city: Heraklion
country: Greece
facility: Research Site
state: Crete
city: Pylaia
country: Greece
facility: Research Site
state: Thessaloniki
city: Athen
country: Greece
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Zwolle
country: Netherlands
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Samara
country: Russian Federation
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Swansea
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Merck Serono S.P.A., Italy
name: Salvatore Longobardi, MD
role: STUDY_DIRECTOR
References:
citation: H Behre, C Howles, S Longobardi. Luteinizing hormone supplementation from Day 1 versus 6 of ovarian stimulation in women aged 36-40 years: results from an open-label, randomized, multicentre, multinational trial. Human Reproduction. 2013;28(suppl 1)
citation: Behre HM, Howles CM, Longobardi S; PERSIST Study Investigators. Randomized trial comparing luteinizing hormone supplementation timing strategies in older women undergoing ovarian stimulation. Reprod Biomed Online. 2015 Sep;31(3):339-46. doi: 10.1016/j.rbmo.2015.06.002. Epub 2015 Jun 15.