Low-dose Gonal-f® in Ovulation Induction

Phase 4

Terminated

Conditions: Infertility
Monofollicular Development

Interventions: Drug: Gonal-f®

Registration Number: NCT01871532

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: This is a prospective, multicenter, open-label, comparative and parallel-group study of ovulation induction evaluating tailoring of Recombinant follicle stimulating hormone (FSH) treatment using the Gonal-f® prefilled pen in World Health Organization (WHO) Type 2 anovulatory subjects who have previously failed to conceive with clomifene treatment.

Detailed Description: Subjects will enter a screening period of up to one month before being randomized at the Baseline Visit, which will occur on Day 1 of the subject's menstrual cycle. Each subject will then receive up to 4 weeks treatment with Gonal-f®. If adequate follicular development (assessed by transvaginal ultrasound) is achieved, the subject will proceed to administration of human chorionic gonadotropin (hCG) within 24-48hrs of last Gonal-f® injection (or according to standard site practice).

Following administration of hCG, subjects will attempt to become pregnant via intercourse or intrauterine insemination. The method of conception will be determined by the subject's requirements and standard practice at the clinic site.

All subjects will be followed up appropriately until confirmation of biochemical pregnancy (hCG + minimum 14 days) and clinical pregnancy (hCG + minimum 42 days, for subjects with positive biochemical pregnancy test).

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 24

Inclusion Criteria

Subjects eligible for ovulation induction treatment, where monofollicular development is the desired treatment outcome and the dose schedule outlined in the protocol is deemed appropriate
Premenopausal female subjects, aged between 18 and 37 years inclusive
Subjects desirous of pregnancy/willing to conceive
Subjects who are infertile due to chronic anovulation demonstrated by cycle duration of greater than 35 days.
Subjects who have been treated with clomifene citrate therapy, according to standard site practice, and have failed to ovulate and/or conceive
Subjects with follicle stimulating hormone (FSH) and prolactin (PRL) serum values within the normal range in the early follicular phase
Subjects with an overall total antral follicle count greater than 10 (of follicle size greater than or equal to 2 millimeter [mm] and less than 11 mm) (that is, total between both ovaries)
Subjects with at least one patent tube, as documented by recent (within 2 years before treatment assignment) hysterosalpingography (HSG) or hysterosalpingo contrast sonography (HyCoSy)
Subjects with normal uterine cavity, as documented by recent (within 2 years before treatment assignment) hysteroscopy, HSG or ultrasound scan
Subjects with body mass index (BMI) greater than 20 and less than or equal to 32 kilogram per square meter (kg/m^2) (BMI is equal to body weight [kilogram {kg}] divided by Height * Height [square meter {m^2}])
Subjects with negative cervical Papanicolaou (PAP) test conducted according to national guidelines and/or standard site practice
Male partners of female subjects with sperm compatible with non-assisted fertilization or availability of donor sperm, as confirmed by the Investigator
Subjects who are willing and able to comply with protocol requirements and have provided written, informed consent

Exclusion Criteria

Subjects with history of hypersensitivity to the investigational medicinal product (IMP) (active substance follitropin alpha, FSH, or to any of the excipients of Gonal-f®) or any other drug used in the trial (that is, Ovitrelle)
Subjects with ovarian enlargement or ovarian cyst unrelated to Polycystic Ovary Syndrome (PCOS), and of unknown origin on ultrasound
Subjects with evidence of diminished ovarian reserve (cycle length less than 26 days; FSH above the upper limit of local serum FSH values, total antral follicle count [AFC] in both ovaries less than 10)
Subjects with uterine pathology/abnormalities, which in the opinion of the Investigator could impair pregnancy evolution
Subjects who have undergone three or more previous miscarriages
Subjects with any previous extrauterine pregnancy
Pregnant or lactating female subjects
Subjects with abnormal gynecological bleeding of unknown etiology.
Subjects with previous history of severe ovarian hyper stimulation syndrome (OHSS) (after clomifene treatment)
Subjects who have evidence of current or previous pelvic inflammatory disease before treatment assignment
Subjects with tumors of the hypothalamus and pituitary gland
Subjects with ovarian, uterine or mammary carcinoma
Subjects treated with clomifene citrate or gonadotropins within 1 month of the screening evaluation
Subjects with any medical condition which, in the opinion of the Investigator, would prevent an effective response, such as primary ovarian failure, or malformations of the reproductive organs incompatible with pregnancy
Subjects with any medical condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug
Subjects with any clinically significant systemic disease (for example, insulin-dependent diabetes) or any contraindication to being pregnant and/or carrying a pregnancy to term
An active substance abuser
Known infection with human immunodeficiency virus (HIV), Hepatitis B or C virus in the trial subject or her male partner
Subjects who are currently participating in another clinical trial
Subjects who are unable to give written informed consent

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Low Dose Gonal-f® Protocol	Gonal-f®	Gonal-f was administered subcutaneously daily at a starting dose of 50 International unit (IU) for Week 1, then dose was gradually increased by 12.5 IU for two weeks, with a final increase of 25 IU, up to maximum dose of 100 IU, until Week 4 for subjects with minimal response. After adequate follicular development was achieved, the subject was administration human chorionic gonadotropin (hCG) within 24-48 hours of last Gonal-f injection as per investigator discretion.
Standard Low Dose Gonal-f® Protocol	Gonal-f®	Gonal-f was administered subcutaneously daily at a starting dose of 50 International Units (IU) for Week 1, then dose was gradually increased by 12.5 IU for two weeks, up to maximum dose of 125 IU, until Week 4 for subjects with minimal response. After adequate follicular development was achieved, the subject was administration human chorionic gonadotropin (hCG) within 24-48 hours of last Gonal-f injection as per investigator discretion.

Primary Outcome Measures

Name	Time	Method
Percentage of Cycles With Monofollicular Development	Baseline up to 4 weeks	The monofollicular development was defined as the number of cycles with monofollicular development only one Follicle Greater Than or Equal (\>= to 17 millimeter (mm) and no other follicles Greater than or equal to 14 mm following up to 4 weeks Gonal-f treatment.

Secondary Outcome Measures

Name	Time	Method
Percentage of Cycles Resulting in Clinical Pregnancy	35-42 days post hCG administration	Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It excludes ectopic pregnancy.
Number of Multiple Pregnancy	35-42 days post hCG administration	Multiple pregnancy is a pregnancy where more than one fetus develops simultaneously in the womb. There are two types of twinning-identical and fraternal. Identical twins represent the splitting of a single fertilized zygote (union of two gametes or male/female sex cells that produce a developing fetus) into two separate individuals.
Number of Miscarriages After Confirmation of Clinical Pregnancy	35-42 days post hCG administration	Miscarriages were calculated per clinical pregnancy, and clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or confirmed by clinical signs of pregnancy. It excludes ectopic pregnancy.
Percentage of Cycles With Bifollicular Development	Baseline up to 4 weeks	The bifollicular development was defined as the number of cycles with bifollicular development of only two follicles greater than or equal to 17 millimeter.
Change From Baseline in Anti-Mullerian Hormone (AMH) Levels at Week 4	Baseline, Week 4
Percentage of Cycles With Multifollicular Development	Baseline up to 4 weeks	The multifollicular development was defined as the number of cycles with multifollicular development of three or more follicles greater than or equal to 14 millimeter
Percentage of Ovulatory Cycles	Baseline up to 42 days post human chorionic gonadotrophin (hCG) administration	Ovulation was defined as a serum progesterone (P4 ) level greater than or equal to 10 nanogram per milliliter (ng/mL) or Clinical Pregnancy. Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It excludes ectopic pregnancy.
Number of Fetuses	35-42 days post hCG administration
Percentage of Cycles Wherein Human Chorionic Gonadotropin (hCG) Was Not Administered	Baseline up to 4 weeks
Number of Subjects With Ovarian Hyper Stimulation Syndrome (OHSS)	up to 42 days post hCG administration	OHSS was defined as an exaggerated systemic response to ovarian stimulation characterized by a wide spectrum of clinical and laboratory manifestations, classified as mild, moderate or severe according to the degree of abdominal distention, ovarian enlargement and respiratory, hemodynamic and metabolic complications.
Total Dose of Recombinant Follicle Stimulating Hormone (r-FSH) Administered Per Cycle	Baseline up to 4 weeks
Testosterone Levels	Baseline
Duration of Recombinant Follicle Stimulating Hormone (rFSH) Stimulation	Baseline up to 4 weeks
Sex Hormone Binding Globulin (SHBG) Levels	Baseline