Clinical trial NCT00505752: Investigation of a Long-Acting Follicle Stimulating Hormone in Infertile Women Undergoing Assisted Reproductive Technology (ART)
Official title: A Phase II, Multicenter, Randomized, Assessor-blinded, Active-comparator, Dose-finding Study to Evaluate AS900672 Enriched Versus Follitropin Alfa (Gonal-f®) in Stimulating Multiple Follicular Development in Infertile Women Undergoing Assisted Reproductive Technology (ART)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infertility
Keywords: Assisted reproductive technology, follicle stimulating hormone
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2007-07-23
Enrollment: 520
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 36
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 2, interventional, prospective, multi-center, randomized, assessor-blind, active-comparator, dose-finding study to evaluate a new investigational long-acting follicle stimulating hormone (FSH) in infertile women who are undergoing an assisted reproductive technology (ART) procedure (In vitro fertilization/Intra cytoplasmic sperm injection \[IVF/ICSI\]). This study will compare 3 doses of the investigational drug versus a currently marketed drug follitropin alfa (Gonal-f® revised formulation female \[RFF\] Pen) in regards to the number of fertilized oocytes.

Detailed description: Infertile women who are candidates for ART will be prospectively screened for enrollment at 24 clinical trial sites in the United States and Argentina. Enrolled subjects will start treatment using oral contraceptives (OCP) and will then receive a Gonadotropin releasing hormone (GnRH)-agonist (leuprolide acetate) for pituitary desensitization. Once down-regulation is achieved, the subjects will be randomized in a 1:1:1:1 ratio to begin ovarian stimulation with one of 3 doses of AS900672-Enriched or with follitropin alfa (Gonal-f®) daily injections. Subjects will be recruited to the four study arms in parallel. Beginning on S1, the subjects will receive either a single injection of AS900672-Enriched or start daily injections of follitropin alfa. The subjects' response to treatment will be monitored by ovarian ultrasound and E2 levels. On S6, subjects randomized to AS900672-Enriched may begin receiving supplemental follitropin alfa 150 IU, according to the each subject's ovarian response, and subjects randomized to follitropin alfa 150 IU daily injections will continue treatment at the same dose. Recombinant human chorionic gonadotropin (r-hCG, Ovidrel®) will be administered to subjects meeting response criteria and who are not at risk for ovarian hyperstimulation syndrome (OHSS). Oocyte retrieval will occur within 34-38 hours after r-hCG administration and subjects will begin luteal phase support using vaginal progesterone (Crinone® 8 percent or Prochieve® 8 percent) the following day. Fertilization will be done by conventional IVF or ICSI. Embryo transfer will occur in accordance with the specific requirements of each subject and the clinical trial site's standard practice, with the exception that a maximum of two embryos at the cleavage or blastocyst stage may be transferred. Subjects who undergo embryo transfer will be assessed for pregnancy and a follow-up visit will be performed 15-20 days post r-hCG administration. Subjects with a positive pregnancy test will undergo a confirmatory ultrasound evaluation at Day 35 - 42 post r-hCG. Additionally, all subjects recruited at certain trial centers will participate in a pharmacokinetic (PK) sub-study.

Eligibility criteria: Inclusion Criteria :

* Infertility and desire to conceive, justifying ART treatment
* Age between 18 and 36 years, inclusive, at time of informed consent
* Body mass index (BMI) 18 to 30 kilogram per square meter (kg/m\^2), inclusive
* Regular spontaneous menstrual cycles of 21 to 35 days
* Presence of both ovaries
* Transvaginal ultrasound within 6 weeks and hysterosalpingogram, hysterosonogram or hysteroscopy within 2 years prior to beginning OCP treatment, showing no clinically significant uterine abnormality, which, in the Investigator's opinion, could impair embryo implantation or pregnancy continuation
* Normal early follicular phase (Day 2-4) serum FSH level, according to the local laboratory
* Normal serum thyroid stimulating hormone (TSH) level, according to the local laboratory
* Papanicolaou (PAP) smear test without clinically significant abnormalities within the last 6 months prior to beginning oral contraceptive therapy,
* Negative pregnancy test prior to beginning GnRH-agonist therapy
* Male partner with semen analysis which is at least adequate for ICSI within last 6 months prior to beginning GnRH agonist therapy, according to local laboratory
* Willing and able to comply with the protocol
* Voluntary provision of written informed consent, prior to any study-related procedure that was not part of normal medical care, with the understanding that the subject could withdraw consent at any time without prejudice to her future medical care, and
* Willingness to provide follow-up information on babies born as part of this study
* For subjects recruited at PK sub-study centers, voluntary provision of written informed consent to participate in the PK sub-study

Exclusion Criteria:

* Subject who require a starting dose of FSH greater than (\>) 150 international unit per day (IU/day), in the opinion of the Investigator
* Screening ultrasound demonstrating more than 12 follicles less than (\<) 11 mm mean diameter in either ovary
* Two or more previous ART cycles (consecutive or not) with poor response to gonadotrophin, defined as less than or equal to (=\<)3 oocytes retrieved
* Three or more previous consecutive ART cycles without a biochemical or clinical pregnancy
* Previous failure of fertilization with ICSI
* A previous ART attempt in which there were no adequate or motile sperm before or after the processing of ejaculated sperm
* Previous severe OHSS
* History or presence of tumors of the hypothalamus or pituitary gland
* History or presence of ovarian, uterine or mammary cancer
* History or presence of ovarian enlargement or cyst of unknown etiology, or presence of ovarian cyst \>25 mm on the day of randomization
* Presence of endometriosis Grade III - IV
* Presence of uni- or bilateral hydrosalpinx
* Abnormal gynecological bleeding of undetermined origin
* Contraindication to being pregnant and/or carrying a pregnancy to term
* History of \>= 3 clinical or preclinical (absence of gestational sac) miscarriages due to any cause
* Extra-uterine pregnancy within the 3 months prior to randomization
* Clinically significant concurrent disease that would have compromised subject safety or interfered with the study assessments
* Known infection with human immunodeficiency virus (HIV), hepatitis B or C virus in the female or male partner
* Known allergy or hypersensitivity to human gonadotrophin preparations or to compounds that are structurally similar to any of the other medications administered during the study
* Any medical condition, which in the judgment of the Investigator may have interfere with the absorption, distribution, metabolism or excretion of r-hFSH
* Any active substance abuse or history of drug, medication or alcohol abuse within 5 years before screening
* ART cycle and/or ovarian stimulation within 30 days prior to informed consent
* Entered previously into this study or simultaneous participation in another clinical trial
* Subject is a smoker consuming more than 5 cigarettes per day
* In the opinion of the Investigator, either assisted hatching or pre-implantation genetic diagnosis is indicated for the subject
* Planning to undergo experimental procedures such as blastomere biopsy, or
* Any known autoimmune disease

Primary outcomes:
measure: Number of Fertilized Oocytes (2 Pronuclei [PN])
timeFrame: Ovum pick-up (OPU) day (34-38 hours post r-hCG administration day [end of stimulation cycle {approximately 21 days}])
Secondary outcomes:
measure: Percentage of Participants With Clinical Pregnancy
timeFrame: Day 35-42 post r-hCG administration day (end of stimulation cycle [approximately 21 days])
Other outcomes:
Locations:
city: Rockland
country: United States
facility: Local US Medical Information Office
state: Massachusetts
Study officials:
affiliation: EMD Serono
name: Zourab Bebia, MD
role: STUDY_DIRECTOR
References: