Recombinant Follicle Stimulating Hormone (FSH) (Gonal-f®): Use in Ovulation Induction

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01081626
• Collaborator: Merck Serono Middle East FZ-LLC, United Arab Emirates, an affiliate of Merck KGaA, Darmstadt, Germany (Other)
• Enrollment: 310
• Locations: 3
• Arms: 2
• Duration (Months): 24
• Patients Per Site: 103.3
• Patients Per Site Per Month: 4.3

Study Details

Study Description

Brief Summary

This is an open-label, prospective, randomized, controlled, multicentric, multinational, phase IV study to evaluate the use of Gonal-f in inducing ovulation in female subjects with chronic anovulation. It has been observed that conventional high dose set up regimen of gonadotropin and human chorionic gonadotropin (hCG) is effective in anovulatory subjects in terms of overall pregnancy rates. However, development of multiple follicles leading to multiple pregnancy and/or ovarian hyperstimulation syndrome (OHSS) is the major complications associated with this high dose set up. Chronic low-dose (CLD) protocols of follicle stimulating hormone (FSH), aimed at finding the threshold amount of FSH necessary to promote monofolliculogenesis, have been found to be successful in reducing the rate of OHSS almost to nil and the rate of multiple pregnancies to a minimum. This post-marketing study will investigate tailoring of recombinant follicle stimulating hormone (r-FSH) in a large population (N=310) of subjects from a region (North Africa/Middle East) that has not been included in previous studies of ovulation induction in subjects with chronic anovulation. The study aims to increase current knowledge of the efficacy and safety of Gonal-f, and provide fertility physicians with experience in Gonal-f treatment in anovulatory infertility, thereby contributing to the development of FSH dosing guidelines for ovulation induction by defining the optimal CLD and Low dose (LD) regimens.

Condition or Disease	Intervention/Treatment	Phase
Ovulation Induction	Drug: Recombinant FSH (follitropin alpha)	Phase 4

Detailed Description

Gonal-f is a recombinant form of human FSH (r-hFSH), an endogenous gonadotropin which is being produced in genetically engineered chinese hamster ovary cells and is indicated for induction of ovulation and pregnancy in anovulatory infertile women in whom the cause of infertility is functional and not due to primary ovarian failure. It is also indicated for the development of multiple follicles in ovulatory women participating in an assisted reproductive technology (ART) programme, such as in in vitro fertilization (IVF). The primary cause of infertility in women is an abnormality of ovulation. Most of these anovulatory subjects fall into the World Health Organization (WHO) Group II category, characterized by asynchronous gonadotropin and oestrogen production and normal levels of prolactin (PRL). These subjects present with a variety of menstrual disorders, most commonly polycystic ovarian syndrome (PCOS).

Gonal-f is administered as a course of daily injections, subcutaneously into the anterior abdominal wall. A commonly used regimen commences at 75-150 IU FSH daily and is increased preferably by 37.5 IU, or 75 IU at 7 or preferably 14 day intervals if necessary, to obtain an adequate but not excessive response. A single injection of 5,000 IU urinary hCG (u-hCG) (or 250 microgram [mcg] r-hCG) should be administered after the last dose of Gonal-f and when the leading follicle has reached 17 mm in diameter. The subject is later recommended to have coitus on the day of, and the day following, hCG administration. The efficacy of Gonal-f in the treatment of WHO Group II anovulatory infertile women has been confirmed by 2 randomized, open-label, multicentric, phase III non-inferiority studies that compared Gonal-f with Metrodin® (urinary FSH) for ovulation induction. The possible serious adverse events (SAEs) associated with Gonal-f include OHSS and its possible complications, multiple pregnancies, pregnancy wastage, ectopic pregnancies and the possible risk of ovarian cancer and reproductive system neoplasms (e.g. endometrial, breast carcinoma).

OBJECTIVES

Primary objective:

• To investigate tailoring of recombinant FSH treatment in subjects with chronic anovulation

Secondary objectives:

• To evaluate commonly used ovulation induction regimens and treatments

• To establish local experience with the Gonal-f pen and investigate ease of use

The study will enroll 310 eligible subjects, randomized in a 1:1 ratio to either Group I or II at the baseline visit prior to the first dose of FSH (pre-stimulation). Each subject will be refrained from the use of gonadotropins or any other ovulation stimulation therapy during the period from screening to the start of stimulation treatment. During the stimulation period, Gonal-f will be administered as a course of once daily (OD) injections, s.c. into the anterior abdominal wall through Gonal-f pen, according to either one of the following 2 step-up, low-dose regimens:

Group I: CLD regimen which recommends a starting dose of 75 IU and a first adjustment on Day 14 of stimulation, if no ovarian response is observed.

Group II: LD regimen which recommends a starting dose of 75 IU and a first adjustment on Day 7 of stimulation, if no ovarian response is observed.

For both groups, when at least 1 follicle reaches 10 to 12 mm in diameter, the Gonal-f administration will be maintained at that dose until the leading follicle reaches 17 mm or more in diameter and no more than 2 follicles have reached 14 mm in diameter. A single injection of hCG (5,000 IU u-hCG or 250 mcg r-hCG) will be administered intramuscularly or subcutaneously after the last Gonal-f injection, to trigger ovulation. Subjects will also be advised to have coitus on the day of, and the day following hCG administration. The total length of the stimulation treatment will not exceed 35 days unless an ultrasound assessment suggests imminent follicular growth and maturation and each subject will undergo one cycle of stimulation treatment only. Subjects will also be followed for a post stimulation period of up to 20 days after the triggering of ovulation by hCG injection, or cancellation of the cycle.

Study Design

• Study Type: Interventional
• Actual Enrollment: 310 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IV, Open-label, Post Marketing, Prospective, Randomized, Controlled, Multicentre, Multinational Study to Investigate Tailoring of Recombinant FSH Use in Ovulation Stimulation Treatment in Chronic Anovulatory Subjects (WHO Group II)
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group I: Chronic Low dose Protocol Gonal-f will be injected on the second or third day of a spontaneous or progestogen-induced menstrual cycle (Day 0), with a daily dose of 75 International Units (IU) for 7 days. Ovarian response will be assessed on Day 7 of stimulation by ultrasound scan. If no follicle has reached at least 10 to 12 millimeter (mm) diameter, stimulation will be continued with the same dose for further 7 days. On Day 14 of stimulation, if no ovarian response is seen, the dose will be increased by 37.5 IU (total 112.5 IU) and administered for the next 7 days. Subsequent increments of 37.5 IU, at intervals of 7 days up to Day 35 of stimulation would be made, depending on ovarian response.	Drug: Recombinant FSH (follitropin alpha); A starting dose of 75 IU and a first adjustment on Day 14 or Day 7 of stimulation in Group I and II respectively, if no ovarian response is observed.; Other Names: Gonal-f® Follitropin alpha
Experimental: Group II: Low dose Protocol Gonal-f will be administered on the second or third day of a spontaneous or progestogen-induced menstrual cycle (Day 0), with a daily dose of 75 IU for 7 days. Ovarian response will be assessed on Day 7 of stimulation by ultrasound scan. If no follicle has reached at least 10 to 12 mm diameter, the dose will be increased by 37.5 IU (total 112.5 IU) and administered for the next 7 days. Subsequent increments of 37.5 IU, at intervals of 7 days up to Day 35 of stimulation will be made, depending on ovarian response.	Drug: Recombinant FSH (follitropin alpha); A starting dose of 75 IU and a first adjustment on Day 14 or Day 7 of stimulation in Group I and II respectively, if no ovarian response is observed.; Other Names: Gonal-f® Follitropin alpha

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a Mono-follicular Development [Day 0 (first dose) up to Days 35-42 post human chorionic gonadotropin [hCG] administration (end of stimulation cycle {less than or equal to [<=] 35 days})]

   Mono-follicular development was defined as the development of only 1 follicle of greater than or equal to (>=) 17 millimeter (mm) diameter and no more than 2 other follicles larger than 14 mm in diameter at or before Days 35-42 of stimulation period assessed by means of a transvaginal ultrasound scan.

Secondary Outcome Measures

1. Number of Participants With Multi-follicular Development [Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})]

   Multi-follicular development was defined as the development of more than 3 follicles >= 15 mm in diameter at or before Days 35-42 of stimulation period assessed by means of a transvaginal ultrasound scan.

2. Number of Participants With Adverse Events (AEs) [Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})]

   AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug.

3. Number of Participants With Multiple Pregnancies [Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})]

   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.

4. Number of Participants With Injection Tolerability [Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})]

   Participants who did not show any injection site reactions such as pain, redness, bruises, swelling and irritation were considered to have injection tolerability.

5. Number of Participants Who Received Human Chorionic Gonadotropin (hCG) [End of stimulation cycle (less than or equal to [<=] 35 days)]

6. Number of Participants With Cancelled Cycles [End of stimulation cycle (less than or equal to [<=] 35 days)]

   Participants with cancelled cycles were those who did not achieve adequate follicular formation (at least 17 mm) for hCG administration.

7. Number of Participants With Clinical Pregnancies [Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})]

   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.

8. Duration of Follicle Stimulating Hormone (FSH) [End of stimulation cycle (less than or equal to [<=] 35 days)]

9. Total Follicle Stimulating Hormone (FSH) Dose [End of stimulation cycle (less than or equal to [<=] 35 days]

10. Number of Participants Who Answered Ease of Use of Gonal-f® Pen Questionnaire [On hCG administration day (end of stimulation cycle {less than or equal to [<=] 35 days})]

    Ease of use of Gonal-f® pen was assessed through a questionnaire consisting of 23 questions and the number of participants who responded to the questionnaire was recorded.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 37 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Premenopausal female subjects, aged between 18 and 37 years inclusive

• Subjects willing to conceive

• Subjects who are infertile due to chronic anovulation demonstrated by a cycle duration of > 35 days, or regular cycles with progesterone (P4) levels < 1 nanomole/milliliter (nmol/mL) during luteal phase (Day 25)

• Subjects who have experienced spontaneous menses, menses induced by clomiphene citrate therapy, or a positive progestin-induced withdrawal within the previous year

• Subjects with FSH and PRL serum values within the normal range in the early follicular phase

• Subjects with total antral follicle count (AFC) > 10 (of follicle size ≥ 2 mm and < 11 mm) in both ovaries

• Subjects with at least 1 patent tube, as documented by recent (within 2 years before treatment assignment) hysterosalpingography (HSG)

• 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) >20 and ≤32 kilogram square per meter (kg/m^2)

• Subjects with negative cervical Papanicolaou (PAP) test within the 6 months prior to screening

• Male partners of female subjects with sperm compatible with non assisted fertilization

• Subjects who are willing and able to participate in the study and have provided written, informed consent

Exclusion Criteria:

• Subjects with history of hypersensitivity to the active substance follitropin alpha, FSH, or to any of the excipients of Gonal-f

• Subjects with ovarian enlargement or ovarian cyst unrelated to PCOS, and of unknown origin on ultrasound

• Subjects with evidence of diminished ovarian reserve (cycle length < 26 days; FSH above the upper limit of local serum FSH values, total AFC in both ovaries < 10)

• Subjects with myomatous uterus, which in the opinion of the investigator could impair pregnancy evolution

• Subjects who have undergone 3 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 OHSS

• Subjects who have undergone operative pelvic surgery which could induce mechanical infertility (e.g tubes blockage) or pelvic inflammatory disease (PID) before treatment assignment excluding curettage and hysteroscopy

• Subjects with tumors of the hypothalamus and pituitary gland

• Subjects with ovarian, uterine or mammary carcinoma

• Subjects treated with clomiphene 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 (e.g. insulin-dependent diabetes) or any contraindication to being pregnant and/or carrying a pregnancy to term; also including subjects with non insulin dependent diabetes mellitus (NIDDM)

• An active substance abuser

• Subjects with known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus in the trial subject or her male partner

• Subjects who have simultaneously participated in another clinical trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New Mowasat Hospital	Salmiya	P.O.Box 6661	Kuwait	22077
2	Mount Lebanon Hospital	Hazmieh	P.O.Box 470	Lebanon
3	King Abdel Aziz University Hospital	Jeddah	P.O.Box 80215	Saudi Arabia	21589

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany
• Merck Serono Middle East FZ-LLC, United Arab Emirates, an affiliate of Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Khaled Esmat, MD, Merck Serono Middle East FZ-LLC, United Arab Emirates, an affiliate of Merck KGaA, Darmstadt, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01081626
• Other Study ID Numbers: EMR 700623-501
• First Posted: Mar 5, 2010
• Last Update Posted: Feb 13, 2014
• Last Verified: Jan 1, 2014

• Keywords provided by Merck KGaA, Darmstadt, Germany: Infertility; Ovulation induction; Gonal-f; Follitropin alpha; Polycystic ovarian syndrome; Anovulatory infertility
• Additional relevant MeSH terms: Follicle Stimulating Hormone

Study Results

Participant Flow

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Period Title: Overall Study
STARTED	155	155
Assessed for Efficacy	122	125
COMPLETED	95	94
NOT COMPLETED	60	61

Baseline Characteristics

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol	Total
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Total of all reporting groups
Overall Participants	122	125	247
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.51 (4.42)	27.88 (4.33)	27.70 (4.37)
Sex: Female, Male (Count of Participants)
Female	122 100%	125 100%	247 100%
Male	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Mono-follicular Development
Description	Mono-follicular development was defined as the development of only 1 follicle of greater than or equal to (>=) 17 millimeter (mm) diameter and no more than 2 other follicles larger than 14 mm in diameter at or before Days 35-42 of stimulation period assessed by means of a transvaginal ultrasound scan.
Time Frame	Day 0 (first dose) up to Days 35-42 post human chorionic gonadotropin [hCG] administration (end of stimulation cycle {less than or equal to [<=] 35 days})

Outcome Measure Data

Analysis Population Description

The Intention-To-Treat (ITT) population included all the participants who received at least 1 dose of study medication, had 1 efficacy assessment and did not have any protocol criteria violations or did not receive a wrong treatment.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	122	125
Number [percentage of participants]	56.55 46.4%	55.20 44.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronic Low Dose (CLD) Protocol, Low Dose (LD) Protocol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9560
	Comments
	Method	Chi-squared, Corrected
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0135
	Confidence Interval	(2-Sided) 95%; -0.1325 to 0.1637
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Multi-follicular Development
Description	Multi-follicular development was defined as the development of more than 3 follicles >= 15 mm in diameter at or before Days 35-42 of stimulation period assessed by means of a transvaginal ultrasound scan.
Time Frame	Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})

Outcome Measure Data

Analysis Population Description

The ITT population included all the participants who received at least 1 dose of study medication, had 1 efficacy assessment and did not have any protocol criteria violations or did not receive a wrong treatment.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	122	125
Number [participants]	17 13.9%	15 12%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronic Low Dose (CLD) Protocol, Low Dose (LD) Protocol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7924
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.088
	Confidence Interval	(2-Sided) 95%; 0.7642 to 1.5490
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug.
Time Frame	Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})

Outcome Measure Data

Analysis Population Description

The safety population included all the participants who received at least 1 dose of study medication and had 1 follow-up visit.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	155	155
Number [participants]	30 24.6%	31 24.8%

4. Secondary Outcome

Title	Number of Participants With Multiple Pregnancies
Description	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.
Time Frame	Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})

Outcome Measure Data

Analysis Population Description

The ITT population included all the participants who received at least 1 dose of study medication, had 1 efficacy assessment and did not have any protocol criteria violations or did not receive a wrong treatment. Number of participants analyzed (N) included participants who were evaluated for this particular measure.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	94	91
Number [participants]	3 2.5%	1 0.8%

5. Secondary Outcome

Title	Number of Participants With Injection Tolerability
Description	Participants who did not show any injection site reactions such as pain, redness, bruises, swelling and irritation were considered to have injection tolerability.
Time Frame	Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})

Outcome Measure Data

Analysis Population Description

The safety population included all the participants who received at least 1 dose of study medication and had 1 follow-up visit. Number of participants analyzed (N) included participants who were evaluated for this particular measure.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	73	77
Number [participants]	54 44.3%	54 43.2%

6. Secondary Outcome

Title	Number of Participants Who Received Human Chorionic Gonadotropin (hCG)
Time Frame	End of stimulation cycle (less than or equal to [<=] 35 days)

Outcome Measure Data

Analysis Population Description

The ITT population included all the participants who received at least 1 dose of study medication, had 1 efficacy assessment and did not have any protocol criteria violations or did not receive a wrong treatment.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	122	125
Number [participants]	94 77%	91 72.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronic Low Dose (CLD) Protocol, Low Dose (LD) Protocol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5331
	Comments
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Number of Participants With Cancelled Cycles
Description	Participants with cancelled cycles were those who did not achieve adequate follicular formation (at least 17 mm) for hCG administration.
Time Frame	End of stimulation cycle (less than or equal to [<=] 35 days)

Outcome Measure Data

Analysis Population Description

The ITT population included all the participants who received at least 1 dose of study medication, had 1 efficacy assessment and did not have any protocol criteria violations or did not receive a wrong treatment.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	122	125
Number [participants]	19 15.6%	19 15.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Chronic Low Dose (CLD) Protocol, Low Dose (LD) Protocol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9351
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.015
	Confidence Interval	(2-Sided) 95%; 0.7175 to 1.4350
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Participants With Clinical Pregnancies
Description	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.
Time Frame	Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days})

Outcome Measure Data

Analysis Population Description

The ITT population included all the participants who received at least 1 dose of study medication, had 1 efficacy assessment and did not have any protocol criteria violations or did not receive a wrong treatment. Number of participants analyzed (N) included participants who were evaluated for this particular measure.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	94	91
Number [participants]	19 15.6%	18 14.4%

9. Secondary Outcome

Title	Duration of Follicle Stimulating Hormone (FSH)
Time Frame	End of stimulation cycle (less than or equal to [<=] 35 days)

Outcome Measure Data

Analysis Population Description

The ITT population included all the participants who received at least 1 dose of study medication, had 1 efficacy assessment and did not have any protocol criteria violations or did not receive a wrong treatment. Number of participants analyzed (N) included participants who were evaluated for this particular measure.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	94	91
Mean (Standard Deviation) [Days]	13.68 (6.33)	12.85 (5.58)

10. Secondary Outcome

Title	Total Follicle Stimulating Hormone (FSH) Dose
Time Frame	End of stimulation cycle (less than or equal to [<=] 35 days

Outcome Measure Data

Analysis Population Description

The ITT population included all the participants who received at least 1 dose of study medication, had 1 efficacy assessment and did not have any protocol criteria violations or did not receive a wrong treatment. Number of participants analyzed (N) included participants who were evaluated for this particular measure.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	94	91
Mean (Standard Deviation) [IU]	1119.41 (690.04)	1155.47 (730.45)

11. Secondary Outcome

Title	Number of Participants Who Answered Ease of Use of Gonal-f® Pen Questionnaire
Description	Ease of use of Gonal-f® pen was assessed through a questionnaire consisting of 23 questions and the number of participants who responded to the questionnaire was recorded.
Time Frame	On hCG administration day (end of stimulation cycle {less than or equal to [<=] 35 days})

Outcome Measure Data

Analysis Population Description

The ITT population included all the participants who received at least 1 dose of study medication, had 1 efficacy assessment and did not have any protocol criteria violations or did not receive a wrong treatment.

Arm/Group Title	Chronic Low Dose (CLD) Protocol	Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.	Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
Measure Participants	122	125
Number [participants]	58 47.5%	75 60%

Adverse Events

Time Frame	AEs were collected on an ongoing basis from day of written informed consent. All new AEs were recorded until the post-treatment safety, on day 35-42 post-hCG administration.
Adverse Event Reporting Description	Pre-Treatment:Medical conditions present at the initial study visit that did not worsen in severity or frequency during the study;Treatment-Emergent: If the onset date of the AE was on or after the first dose date of the study medication; Post-Treatment: If the onset date of the AE was post-hCG Days 35- 42 for participants who completed the study.
Arm/Group Title	Chronic Low Dose (CLD) Protocol		Low Dose (LD) Protocol
Arm/Group Description	Gonal-f® (follitropin alpha) injection 75 International Units (IU) subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 14 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.		Gonal-f® (follitropin alpha) injection 75 IU subcutaneously administered for 7 days. Dose increased by 37.5 IU on Day 7 of stimulation period, at intervals of 7 days up to Day 35 of stimulation period or until ovarian response observed.
All Cause Mortality
	Chronic Low Dose (CLD) Protocol		Low Dose (LD) Protocol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Chronic Low Dose (CLD) Protocol		Low Dose (LD) Protocol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/155 (0%)		1/155 (0.6%)
Reproductive system and breast disorders
Ectopic pregnancy	0/155 (0%)		1/155 (0.6%)
Other (Not Including Serious) Adverse Events
	Chronic Low Dose (CLD) Protocol		Low Dose (LD) Protocol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/155 (19.4%)		30/155 (19.4%)
Cardiac disorders
Dizziness	1/155 (0.6%)		5/155 (3.2%)
Gastrointestinal disorders
Burning pain of the stomach	0/155 (0%)		1/155 (0.6%)
Abdominal colic pain	0/155 (0%)		2/155 (1.3%)
Abdominal pain	12/155 (7.7%)		7/155 (4.5%)
Gums swelling	0/155 (0%)		1/155 (0.6%)
Heart burn	0/155 (0%)		1/155 (0.6%)
In abdomen	0/155 (0%)		1/155 (0.6%)
Lower abdominal pain	2/155 (1.3%)		1/155 (0.6%)
Nausea	5/155 (3.2%)		5/155 (3.2%)
Pain in stomach	0/155 (0%)		4/155 (2.6%)
Vomiting	0/155 (0%)		1/155 (0.6%)
Abdominal bloating	1/155 (0.6%)		0/155 (0%)
General disorders
Burning	1/155 (0.6%)		0/155 (0%)
Fever	2/155 (1.3%)		0/155 (0%)
Generalized fatigability	1/155 (0.6%)		0/155 (0%)
Pain	2/155 (1.3%)		0/155 (0%)
Spasm and pain	1/155 (0.6%)		0/155 (0%)
Chest pain	0/155 (0%)		3/155 (1.9%)
Fatigue	0/155 (0%)		1/155 (0.6%)
Hot flash	0/155 (0%)		1/155 (0.6%)
Body pain	0/155 (0%)		1/155 (0.6%)
Blood	0/155 (0%)		1/155 (0.6%)
Car accident (spotting)	1/155 (0.6%)		0/155 (0%)
Immune system disorders
Allergic rhinitis	1/155 (0.6%)		0/155 (0%)
Musculoskeletal and connective tissue disorders
Back pain	3/155 (1.9%)		3/155 (1.9%)
Joint pain	0/155 (0%)		1/155 (0.6%)
Pain in the foot	1/155 (0.6%)		0/155 (0%)
Pain in the right loin	1/155 (0.6%)		0/155 (0%)
Legs pain	0/155 (0%)		1/155 (0.6%)
Lower back pain	0/155 (0%)		2/155 (1.3%)
Weakness Generalized	0/155 (0%)		1/155 (0.6%)
Nervous system disorders
Headache	10/155 (6.5%)		14/155 (9%)
Psychiatric disorders
Drowsiness	2/155 (1.3%)		0/155 (0%)
Insomnia	1/155 (0.6%)		1/155 (0.6%)
Nervousness	1/155 (0.6%)		0/155 (0%)
Anxiety	0/155 (0%)		1/155 (0.6%)
Lethargy	0/155 (0%)		1/155 (0.6%)
Reproductive system and breast disorders
Breast pain	0/155 (0%)		1/155 (0.6%)
Ectopic pregnancy	0/155 (0%)		1/155 (0.6%)
Ovarian Hyper Stimulation Syndrome	1/155 (0.6%)		0/155 (0%)
Respiratory, thoracic and mediastinal disorders
Cold	1/155 (0.6%)		1/155 (0.6%)
Skin and subcutaneous tissue disorders
Itching in upper and lower limb and abdomen	1/155 (0.6%)		0/155 (0%)
Insect bite	0/155 (0%)		1/155 (0.6%)
Itching	0/155 (0%)		1/155 (0.6%)
Itching and burning	0/155 (0%)		1/155 (0.6%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.