AS900672-Enriched in Ovulation Induction

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2, interventional, multi-center, randomized, assessor-blind, active-comparator, dose-finding study to evaluate a new investigational long-acting follicle stimulating hormone (FSH) in oligo-anovulatory women undergoing ovulation induction (OI). This study will compare 4 doses of the investigational drug versus a currently marketed drug follitropin alfa (Gonal-f ®) prefilled pen with regards to ovulation rate.

Detailed Description
-----------------
The study was terminated after Merck Serono had taken the decision not to pursue the development of AS900672-enriched in ovulation induction (OI). This decision was not related to any safety or efficacy concerns over the use of AS900672-Enriched in OI.

Official Title
-----------------
A Phase II, Multicentre, Randomised, Assessor-blinded, Active-comparator, Parallel-group Dose Finding Trial to Evaluate AS900672-enriched Versus Follitropin Alfa (GONAL-f®) in Oligo-anovulatory Infertile Women Undergoing Ovulation Induction (OI)

Conditions
-----------------
Ovulation Induction

Intervention / Treatment
-----------------
* Drug: AS900672-Enriched 10 microgram (mcg)
* Drug: AS900672-Enriched 20 mcg
* Drug: AS900672-Enriched 30 mcg
* Drug: AS900672-Enriched 40 mcg
* Drug: Follitropin alfa 75 international unit (IU)
* Drug: Recombinant human chorionic gonadotropin (r-hCG)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Oligo-anovulation defined by a menstrual period of 35 days to 6 months Spontaneous menses or a positive response to progestin within the prior 6 months or response to clomiphene citrate evidenced by ovulation within the prior 6 months Age between 18 and 36 years, inclusive, at time of informed consent signature Body mass index (BMI) 18 to 30 kilogram per square meter (kg/m^2), inclusive No clinically significant abnormalities in serum thyroid stimulating hormone (TSH), dehydroepiandrosterone (DHEA-S), prolactin, and FSH levels in the early follicular phase. Subjects low TSH level who receive replacement therapy could be enrolled at the discretion of the investigator if local laboratory results (thyroxine [T4]) demonstrated satisfactory thyroid function. Subjects receiving stable dose of dopamine agonists could be enrolled at the discretion of the investigator if local laboratory results demonstrated adequate control of prolactin levels No clinically significant abnormalities in fasting glucose and fasting insulin levels Normal uterine cavity and presence of at least one ovary with ipsilateral patent fallopian tube, as determined by means of hysterosalpingography, laparoscopy, hysteroscopy or combination of these procedures within the prior 3 years Papanicolaou (PAP) smear test without clinically significant abnormalities within 6 months prior to the first screening procedure. If PAP smear is not done, it must be performed as part of screening procedures Negative pregnancy test prior to randomization Male partner with semen analysis demonstrating adequacy for insemination via intercourse and/or intrauterine insemination (IUI) within 6 months prior to the first screening procedure. If semen analysis is not done, it must be performed as part of screening procedures Willing and able to comply with all protocol procedures, including pregnancy and neonatal follow-up Voluntary provision of written informed consent, prior to any trial-related procedure that is 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, including willingness to provide follow-up information on babies born as part of this trial Exclusion Criteria: History of >=2 consecutive gonadotrophin stimulation cycles that did not lead to ovulation History of clomiphene citrate stimulation cycles of which none lead to ovulation Prior excessive response to gonadotrophin stimulation, defined as the development of at least 4 mature follicles (greater than [>]17 mm) or cancellation of the OI cycle due to excessive follicular response after treatment with FSH at a dose of less than 75 IU/day Previous severe ovarian hyperstimulation syndrome (OHSS) Administration of any gonadotrophin, clomiphene citrate, gonadotrophin releasing hormone (GnRH) analogue, tamoxifen or aromatase inhibitors within the prior 30 days Laparoscopic ovarian drilling and/or ovarian cauterization within the prior 6 months Any contraindication to pregnancy and/or to carrying pregnancy to term A clinical pregnancy that ended in a miscarriage within the prior 3 months History of >=3 consecutive miscarriages, due to any cause Abnormal gynecological bleeding of undetermined origin Clinically significant abnormal findings of the uterine cavity evident on a transvaginal pelvic ultrasound performed during screening Presence of endometriosis, Grade III - IV or requiring treatment Ovarian cyst with a mean diameter of >25 mm on the day of randomization History or suspicion of ovarian, uterine or mammary cancer Adrenal congenital hyperplasia, partial or complete enzymatic block Use of metformin or other insulin sensitizing agents related to infertility within the prior 2 months Known allergy or hypersensitivity to human gonadotrophin preparations or to compounds that are structurally similar to any of the other medications administered during the trial Any contra-indication to gonadotrophin therapy Known or suspected infection with human immunodeficiency virus (HIV), Hepatitis B or C in the trial subject or her male partner Any active substance abuse or history of drug, medication or alcohol abuse within 5 years Smoker consuming more than 5 cigarettes per day Serum testosterone (central laboratory) that is suggestive of ovarian tumor Previously randomized in this trial or participation in another investigational drug clinical trial within the prior 3 months Any medical condition, which in the judgment of the investigator may interfere with the absorption, distribution, metabolism or excretion of r-hFSH Clinically significant concurrent disease (including diabetes mellitus and autoimmune diseases) that would compromise subject safety or interfere with the study assessments or clinically significant abnormal laboratory finding

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

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AS900672-Enriched 10 mcg<br> | Drug: AS900672-Enriched 10 microgram (mcg)<br>* Single injection of AS900672-Enriched (hyperglycosylated recombinant human follicle stimulating hormone [r-hFSH]), 10 mcg will be administered subcutaneously on Stimulation Day 1 (S1). Duration of treatment cycle will be up to adequate follicular response received or maximum of 14 days.<br>* Other names: Hyperglycosylated r-hFSH;Drug: Follitropin alfa 75 international unit (IU)<br>* Follitropin alfa (Gonal-f®) 75 IU will be administered subcutaneously once daily from S1 up to Stimulation Day 14 (S14) based upon ovarian response, until recombinant human chorionic gonadotropin (r-hCG) administration day. Subjects who will be receiving AS900672-Enriched 10, 20, 30 and 40 mcg will also receive daily dose of follitropin alfa 75 IU subcutaneously from Stimulation Day 7 (S7) up to S14. Duration of treatment cycle will be up to adequate follicular response received or maximum of 14 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, less than or equal to [=<] 3 follicles with a mean diameter of greater than or equal to [>=] 14 millimeter [mm], and one or two of these follicles with a diameter of >= 17 mm).<br>|
| Experimental: AS900672-Enriched 20 mcg<br> | Drug: AS900672-Enriched 20 mcg<br>* Single injection of AS900672-Enriched (hyperglycosylated r-hFSH), 20 mcg will be administered subcutaneously on S1. Duration of treatment cycle will be up to adequate follicular response received or maximum of 14 days.<br>* Other names: Hyperglycosylated r-hFSH;Drug: Follitropin alfa 75 international unit (IU)<br>* Follitropin alfa (Gonal-f®) 75 IU will be administered subcutaneously once daily from S1 up to Stimulation Day 14 (S14) based upon ovarian response, until recombinant human chorionic gonadotropin (r-hCG) administration day. Subjects who will be receiving AS900672-Enriched 10, 20, 30 and 40 mcg will also receive daily dose of follitropin alfa 75 IU subcutaneously from Stimulation Day 7 (S7) up to S14. Duration of treatment cycle will be up to adequate follicular response received or maximum of 14 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, less than or equal to [=<] 3 follicles with a mean diameter of greater than or equal to [>=] 14 millimeter [mm], and one or two of these follicles with a diameter of >= 17 mm).<br>|
| Experimental: AS900672-Enriched 30 mcg<br> | Drug: AS900672-Enriched 30 mcg<br>* Single injection of AS900672-Enriched (hyperglycosylated r-hFSH), 30 mcg will be administered subcutaneously on S1. Duration of treatment cycle will be up to adequate follicular response received or maximum of 14 days.<br>* Other names: Hyperglycosylated r-hFSH;Drug: Follitropin alfa 75 international unit (IU)<br>* Follitropin alfa (Gonal-f®) 75 IU will be administered subcutaneously once daily from S1 up to Stimulation Day 14 (S14) based upon ovarian response, until recombinant human chorionic gonadotropin (r-hCG) administration day. Subjects who will be receiving AS900672-Enriched 10, 20, 30 and 40 mcg will also receive daily dose of follitropin alfa 75 IU subcutaneously from Stimulation Day 7 (S7) up to S14. Duration of treatment cycle will be up to adequate follicular response received or maximum of 14 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, less than or equal to [=<] 3 follicles with a mean diameter of greater than or equal to [>=] 14 millimeter [mm], and one or two of these follicles with a diameter of >= 17 mm).<br>|
| Experimental: AS900672-Enriched 40 mcg<br> | Drug: AS900672-Enriched 40 mcg<br>* Single injection of AS900672-Enriched (hyperglycosylated r-hFSH), 40 mcg will be administered subcutaneously on S1. Duration of treatment cycle will be up to adequate follicular response received or maximum of 14 days.<br>* Other names: Hyperglycosylated r-hFSH;Drug: Follitropin alfa 75 international unit (IU)<br>* Follitropin alfa (Gonal-f®) 75 IU will be administered subcutaneously once daily from S1 up to Stimulation Day 14 (S14) based upon ovarian response, until recombinant human chorionic gonadotropin (r-hCG) administration day. Subjects who will be receiving AS900672-Enriched 10, 20, 30 and 40 mcg will also receive daily dose of follitropin alfa 75 IU subcutaneously from Stimulation Day 7 (S7) up to S14. Duration of treatment cycle will be up to adequate follicular response received or maximum of 14 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, less than or equal to [=<] 3 follicles with a mean diameter of greater than or equal to [>=] 14 millimeter [mm], and one or two of these follicles with a diameter of >= 17 mm).<br>|
| Active Comparator: Follitropin alfa 75 IU<br> | Drug: Follitropin alfa 75 international unit (IU)<br>* Follitropin alfa (Gonal-f®) 75 IU will be administered subcutaneously once daily from S1 up to Stimulation Day 14 (S14) based upon ovarian response, until recombinant human chorionic gonadotropin (r-hCG) administration day. Subjects who will be receiving AS900672-Enriched 10, 20, 30 and 40 mcg will also receive daily dose of follitropin alfa 75 IU subcutaneously from Stimulation Day 7 (S7) up to S14. Duration of treatment cycle will be up to adequate follicular response received or maximum of 14 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, less than or equal to [=<] 3 follicles with a mean diameter of greater than or equal to [>=] 14 millimeter [mm], and one or two of these follicles with a diameter of >= 17 mm).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Ovulation | Ovulation was defined as a mid-luteal phase progesterone (P4) level >= 30 nanomole per liter (nmol/L) (10 nanogram per milliliter [ng/mL]). In the absence of a positive progesterone response, clinical pregnancy was also considered as evidence of ovulation. | Mid-luteal phase progesterone assessed 5-10 days or clinical pregnancy 35-42 days after recombinant human chorionic gonadotropin (r-hCG) administration day (end of stimulation cycle [approximately 14 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 14 days]) | 
| Duration of Ovarian Stimulation | Ovarian stimulation included from first dose of study drug on S1 until day on which r-hCG was administered (r-hCG day). | Stimulation Day 1 (S1) up to r-hCG administration day (end of stimulation cycle [approximately 14 days]) | 
| Duration of Supplemental Follitropin Alfa Treatment |  | Stimulation Day 7 (S7) up to r-hCG administration day (end of stimulation cycle [approximately 14 days]) | 
| Cumulative Dose of Supplemental Follitropin Alfa Administered |  | Stimulation Day 7 (S7) up to r-hCG administration day (end of stimulation cycle [approximately 14 days]) | 
| Number of Follicles With Mean Diameter Less Than (<) 11 Millimeter (mm) and Greater Than or Equal to (>=) 11 mm |  | Stimulation Day 5 (S5), S7 and r-hCG administration day (end of stimulation cycle [approximately 14 days]) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Infertility, Oligo-anovulation, GONAL-f®, AS900672-Enriched, hyperglycosylated recombinant human follicle stimulating hormone (r-hFSH)