Investigation of a Long-Acting Follicle Stimulating Hormone in Infertile Women Undergoing Assisted Reproductive Technology (ART)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Infertility

Intervention / Treatment
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* Drug: AS900672-Enriched 50 microgram (mcg)
* Drug: AS900672-Enriched 100 mcg
* Drug: AS900672-Enriched 150 mcg
* Drug: Follitropin alfa 150 international unit (IU)
* Drug: Recombinant human chorionic gonadotropin (r-hCG)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 36 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AS900672-Enriched 50 mcg<br> | Drug: AS900672-Enriched 50 microgram (mcg)<br>* Single injection of AS900672-Enriched (hyperglycosylated recombinant human follicle stimulating hormone [r-hFSH]), 50 mcg will be administered subcutaneously on Stimulation Day 1 (S1). Duration of treatment cycle will be up to adequate follicular response or maximum of 21 days.<br>* Other names: Hyperglycosylated r-hFSH;Drug: Follitropin alfa 150 international unit (IU)<br>* Follitropin alfa (Gonal-f®) 150 IU will be administered subcutaneously once daily from S1 up to Stimulation Day 21 (S21) based upon ovarian response, until recombinant human chorionic gonadotropin (r-hCG) administration day. Subjects who will be receiving AS900672-Enriched 50, 100 and 150 mcg will also receive daily dose of follitropin alfa 150 IU subcutaneously from Stimulation Day 6 (S6) up to S21. Duration of treatment cycle will be up to adequate follicular response or maximum of 21 days.<br>* Other names: Follicle stimulating hormone (FSH);Drug: Recombinant human chorionic gonadotropin (r-hCG)<br>* Recombinant human chorionic gonadotropin (r-hCG) will be administered as a single dose of 250 mcg subcutaneously, when follicular response is adequate (that is, at least 1 follicle with a diameter of greater than or equal to [>=] 18 millimeter [mm], two or more additional follicles with a diameter of >= 16 mm, and Estradiol [E2] levels will approximately 150 picogram per milliliter [pg/mL] per mature follicle).<br>* Other names: Choriogonadotropin alfa;|
| Experimental: AS900672-Enriched 100 mcg<br> | Drug: AS900672-Enriched 100 mcg<br>* Single injection of AS900672-Enriched (hyperglycosylated r-hFSH), 100 mcg will be administered subcutaneously on S1. Duration of treatment cycle will up to adequate follicular response or maximum of 21 days.<br>* Other names: Hyperglycosylated r-hFSH;Drug: Follitropin alfa 150 international unit (IU)<br>* Follitropin alfa (Gonal-f®) 150 IU will be administered subcutaneously once daily from S1 up to Stimulation Day 21 (S21) based upon ovarian response, until recombinant human chorionic gonadotropin (r-hCG) administration day. Subjects who will be receiving AS900672-Enriched 50, 100 and 150 mcg will also receive daily dose of follitropin alfa 150 IU subcutaneously from Stimulation Day 6 (S6) up to S21. Duration of treatment cycle will be up to adequate follicular response or maximum of 21 days.<br>* Other names: Follicle stimulating hormone (FSH);Drug: Recombinant human chorionic gonadotropin (r-hCG)<br>* Recombinant human chorionic gonadotropin (r-hCG) will be administered as a single dose of 250 mcg subcutaneously, when follicular response is adequate (that is, at least 1 follicle with a diameter of greater than or equal to [>=] 18 millimeter [mm], two or more additional follicles with a diameter of >= 16 mm, and Estradiol [E2] levels will approximately 150 picogram per milliliter [pg/mL] per mature follicle).<br>* Other names: Choriogonadotropin alfa;|
| Experimental: AS900672-Enriched 150 mcg<br> | Drug: AS900672-Enriched 150 mcg<br>* Single injection of AS900672-Enriched (hyperglycosylated r-hFSH), 150 mcg will be administered subcutaneously on S1. Duration of treatment cycle will up to adequate follicular response or maximum of 21 days.<br>* Other names: Hyperglycosylated r-hFSH;Drug: Follitropin alfa 150 international unit (IU)<br>* Follitropin alfa (Gonal-f®) 150 IU will be administered subcutaneously once daily from S1 up to Stimulation Day 21 (S21) based upon ovarian response, until recombinant human chorionic gonadotropin (r-hCG) administration day. Subjects who will be receiving AS900672-Enriched 50, 100 and 150 mcg will also receive daily dose of follitropin alfa 150 IU subcutaneously from Stimulation Day 6 (S6) up to S21. Duration of treatment cycle will be up to adequate follicular response or maximum of 21 days.<br>* Other names: Follicle stimulating hormone (FSH);Drug: Recombinant human chorionic gonadotropin (r-hCG)<br>* Recombinant human chorionic gonadotropin (r-hCG) will be administered as a single dose of 250 mcg subcutaneously, when follicular response is adequate (that is, at least 1 follicle with a diameter of greater than or equal to [>=] 18 millimeter [mm], two or more additional follicles with a diameter of >= 16 mm, and Estradiol [E2] levels will approximately 150 picogram per milliliter [pg/mL] per mature follicle).<br>* Other names: Choriogonadotropin alfa;|
| Active Comparator: Follitropin alfa 150 IU<br> | Drug: Follitropin alfa 150 international unit (IU)<br>* Follitropin alfa (Gonal-f®) 150 IU will be administered subcutaneously once daily from S1 up to Stimulation Day 21 (S21) based upon ovarian response, until recombinant human chorionic gonadotropin (r-hCG) administration day. Subjects who will be receiving AS900672-Enriched 50, 100 and 150 mcg will also receive daily dose of follitropin alfa 150 IU subcutaneously from Stimulation Day 6 (S6) up to S21. Duration of treatment cycle will be up to adequate follicular response or maximum of 21 days.<br>* Other names: Follicle stimulating hormone (FSH);Drug: Recombinant human chorionic gonadotropin (r-hCG)<br>* Recombinant human chorionic gonadotropin (r-hCG) will be administered as a single dose of 250 mcg subcutaneously, when follicular response is adequate (that is, at least 1 follicle with a diameter of greater than or equal to [>=] 18 millimeter [mm], two or more additional follicles with a diameter of >= 16 mm, and Estradiol [E2] levels will approximately 150 picogram per milliliter [pg/mL] per mature follicle).<br>* Other names: Choriogonadotropin alfa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Fertilized Oocytes (2 Pronuclei [PN]) | Oocytes were fertilized using Intra-cytoplasmic Sperm Injection (ICSI) technique which is an in-vitro fertilization procedure in which a single sperm is injected directly into an egg under a microscope. The appearance of 2PN is the first sign of successful fertilization as observed during in vitro fertilization, and is usually observed after ICSI. The zygote is then termed 2PN. | Ovum pick-up (OPU) day (34-38 hours post r-hCG administration day [end of stimulation cycle {approximately 21 days}]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Pregnancy | Clinical pregnancy was defined as the presence of one or more fetal sacs with fetal heart activity on the Day 35-42 post r-hCG ultrasound examination. | Day 35-42 post r-hCG administration day (end of stimulation cycle [approximately 21 days]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Assisted reproductive technology, follicle stimulating hormone