PERgoveriS In Stratified Treatment for Assisted Reproductive Technique (PERSIST)

This study has been completed.
Sponsor:
Collaborators:
Merck Serono S.A., Geneva
Merck A/S, Denmark
Merck OY, Finland
Merck Serono S.A.S, France
Merck Serono GmbH, Germany
Merck A.E., Greece
Merck B.V., Netherlands
Merck SP. Z.O.O., Poland
Merck Serono S.P.A., Italy
Merck Services U.K. Ltd, UK
LLC Merck, Russia
Merck spol. s r.o., Slovakia
Merck Pharma, K.S., Slovakia
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01297465
First received: February 15, 2011
Last updated: January 10, 2014
Last verified: January 2014
  Purpose

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).


Condition Intervention Phase
Assisted Reproductive Techniques
Reproductive Technology, Assisted
Drug: Gonal-f®
Drug: Pergoveris®
Drug: Recombinant human chorionic gonadotropin (r-hCG)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Total Number of Oocytes Retrieved [ Time Frame: OPU day (34-38 hours post r-hCG day [end of stimulation cycle {approximately 11 days}]) ] [ Designated as safety issue: No ]
    The total number of oocytes retrieved per reporting group on the day of ovum pick-up (OPU) (34-38 hours post r-hCG day) was calculated. Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocytes from the ovary of the female participant, enabling fertilization outside the body.


Secondary Outcome Measures:
  • Total Dose and Mean Daily Dose of Follicle Stimulating Hormone (FSH) [ Time Frame: Day 1 up to r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: No ]
  • Total Number of Stimulation Treatment Days [ Time Frame: Day 1 up to r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: No ]
  • Implantation Rate [ Time Frame: Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: No ]
    Implantation rate per reporting group was measured as the number of fetal sacs observed, divided by the number of embryos transferred multiplied by 100.

  • Number of Fetal Sacs With Activity [ Time Frame: Days 35-42 post r-hCG day [end of stimulation cycle {approximately 11 days}]) ] [ Designated as safety issue: No ]
    Number of fetal sacs with activity was evaluated by ultrasound scan

  • Number of Fetal Hearts With Activity [ Time Frame: Days 35-42 post r-hCG day [end of stimulation cycle {approximately 11 days}]) ] [ Designated as safety issue: No ]
    Number of fetal hearts with activity was evaluated by ultrasound scan

  • Clinical Pregnancy Rate [ Time Frame: Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: No ]
    Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy. Clinical pregnancy rate was reported as total clinical pregnancy rate, clinical pregnancy rate per cycle started and per embryo transfer [ET]).

  • Number of Participants With Cancelled Cycles Due to Excessive or Insufficient Ovarian Response to Treatment [ Time Frame: S1 until Day 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: No ]
    An excessive ovarian response: greater than or equal to 25 oocytes which could put the participant at risk of OHSS; An insufficient ovarian response: defined as 3 or less follicles of greater than or equal to 12 millimeter developing following at least 7 days of treatment.

  • Biochemical Pregnancies Rate [ Time Frame: Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: No ]
    Biochemical pregnancy was defined as the pregnancy diagnosed only by the detection of human chorionic gonadotropin (hCG) in serum or urine and that does not develop into a clinical pregnancy. Participants with beta- hCG concentration greater than 10 international units per liter (IU/L) were considered as biochemical pregnant.

  • Number of Participants With Multiple Pregnancies [ Time Frame: Days 35-42 post r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: No ]
    Multiple pregnancy was defined as the existence of more than one fetal sac with fetal heart activity.

  • Number of Participants With Early and Late Ovarian Hyper Stimulation Syndrome (OHSS) [ Time Frame: Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: Yes ]
    Ovarian Hyper Stimulation Syndrome (OHSS) is a syndrome which can manifest with enlarged ovaries, advanced ascites with increased vascular permeability, pleural fluid accumulation, hemoconcentration, and increased blood clotting. Early OHSS was defined as the onset of OHSS occurring within 9 days after oocyte retrieval and late OHSS was defined as the onset of OHSS occurring on or after day 10 from oocyte retrieval.

  • Number of Participants With Treatment-emergent Adverse Events [ Time Frame: Day 1 up to days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: Yes ]
    An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.

  • Systolic and Diastolic Arterial Blood Pressure Assessments [ Time Frame: Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: Yes ]
  • Heart Rate Assessments [ Time Frame: Days 15-20 post r-hCG day (end of stimulation cycle [approximately 11 days]) ] [ Designated as safety issue: Yes ]

Enrollment: 202
Study Start Date: May 2011
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Gonal-f® Plus Pergoveris® Drug: Gonal-f®
Gonal-f® (follitropin alfa) 300 International Unit (IU) will be administered subcutaneously once daily from stimulation day 1 (S1) to stimulation day 5 (S5).
Other Name: Follitropin alfa
Drug: Pergoveris®
Pergoveris® (follitropin alfa and lutropin alfa) 300 IU will be administered subcutaneously starting from S6 until recombinant human chorionic gonadotropin (r-hCG) administration day (at least 1 follicles >= 18 mm). The dose of Pergoveris® was adjusted based upon the participant's ovarian response and according to the site's standard practice.
Drug: Recombinant human chorionic gonadotropin (r-hCG)
250 microgram of r-hCG will be administered once subcutaneously on r-hCG day (at least 1 follicles >= 18 mm).
Other Names:
  • Ovidrel®
  • Ovitrelle®
Experimental: Pergoveris® Drug: Pergoveris®
Pergoveris® (follitropin alfa and lutropin alfa) 300 IU will be administered subcutaneously once daily from S1 until r-hCG administration day (at least 1 follicles >= 18 mm). The dose of Pergoveris® was adjusted starting from S6 based upon the participant's ovarian response and according to the site's standard practice.
Drug: Recombinant human chorionic gonadotropin (r-hCG)
250 microgram of r-hCG will be administered once subcutaneously on r-hCG day (at least 1 follicles >= 18 mm).
Other Names:
  • Ovidrel®
  • Ovitrelle®

  Eligibility

Ages Eligible for Study:   36 Years to 40 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01297465

Locations
Denmark
Merck Serono Research Site
Dronninglund, Denmark
Merck Serono Research Site
Fredericia, Denmark
Finland
Merck Serono Research Site
Helsinki, Finland
France
Merck Serono Research Site
Bondy CEDEX, France
Merck Serono Research Site
Bruges, France
Merck Serono Research Site
Clamart CEDEX, France
Merck Serono Research Site
Tenon, France
Merck Serono Research Site
Villeurbanne, France
Germany
Merck Serono Research Site
Berlin, Germany
Merck Serono Research Site
Halle, Germany
Greece
Merck Serono Research Site
Heraklion, Crete, Greece
Merck Serono Research Site
Pylaia, Thessaloniki, Greece
Merck Serono Research Site
Athen, Greece
Italy
Merck Serono Research Site
Bologna, Italy
Merck Serono Research Site
Firenze, Italy
Merck Serono Research Site
Torino, Italy
Netherlands
Merck Serono Research Site
Zwolle, Netherlands
Poland
Merck Serono Research Site
Warszawa, Poland
Russian Federation
Merck Serono Research Site
Moscow, Russian Federation
Merck Serono Research Site
Samara, Russian Federation
Slovakia
Merck Serono Research Site
Bratislava, Slovakia
United Kingdom
Merck Serono Research Site
London, United Kingdom
Merck Serono Research Site
Swansea, United Kingdom
Sponsors and Collaborators
Merck KGaA
Merck Serono S.A., Geneva
Merck A/S, Denmark
Merck OY, Finland
Merck Serono S.A.S, France
Merck Serono GmbH, Germany
Merck A.E., Greece
Merck B.V., Netherlands
Merck SP. Z.O.O., Poland
Merck Serono S.P.A., Italy
Merck Services U.K. Ltd, UK
LLC Merck, Russia
Merck spol. s r.o., Slovakia
Merck Pharma, K.S., Slovakia
Investigators
Study Director: Salvatore Longobardi, MD Merck Serono S.P.A., Italy
  More Information

Additional Information:
No publications provided

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01297465     History of Changes
Other Study ID Numbers: EMR 200061-504, 2010-023534-23
Study First Received: February 15, 2011
Results First Received: October 23, 2013
Last Updated: January 10, 2014
Health Authority: Denmark: Danish Medicines Agency
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: National Organization of Medicines
Italy: The Italian Medicines Agency
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Slovakia: State Institute for Drug Control
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Russia: Ministry of Health of the Russian Federation

Keywords provided by Merck KGaA:
Ovulation Induction
Ovarian Stimulation
Reproductive Technique, Assisted
Assisted Reproductive Technics
Assisted Reproductive Technique
Reproductive Technology, Assisted

Additional relevant MeSH terms:
Chorionic Gonadotropin
Follicle Stimulating Hormone
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on April 17, 2014