Safety and Efficacy of Pre-defined, Fixed Dose of Gonal-f Pen Based on Subject Baseline Characteristics in Subjects Undergoing in Vitro Fertilization (IVF)

A Phase IIIB/IV, Open Label Study to Assess the Efficacy and Safety of a Pre-defined, Fixed Dose of Gonal-f® (Filled-by-Mass in a Prefilled Pen) Based on Subject Baseline Characteristics, for Ovarian Stimulation in Subjects Undergoing in Vitro Fertilization (IVF)

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00249834

Acronym

CONSORT

Enrollment

166

Registered

2005-11-07

Start date

2004-09-22

Completion date

2006-01-16

Last updated

2018-03-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Infertility

Keywords

Assisted Reproductive Technology (ART), Infertility, Ovarian stimulation

Brief summary

Clinical validation of the assisted reproductive technology (ART) treatment guidelines, which determine the optimal dose of recombinant human follicle stimulating hormone (r-hFSH) based on subject baseline characteristics/predictors of ovarian response.

Interventions

DRUGGonal-f

GONAL-f (follitropin alfa) will be administered subcutaneously based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle.

DRUGRecombinant human chorionic gonadotrophin (r-hCG)

When at least 1 follicle greater than or equal to (\>=) 18 millimeter (mm) and 2 follicles \>=16 mm in diameter develop, 250 microgram (mcg) of recombinant human chorionic gonadotrophin (r-hCG) will be administered.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 34 Years

Healthy volunteers

Inclusion criteria

* Be an infertile subject justifying an in-vitro fertilization/embryo transfer (IVF/ET) treatment. * Have a male partner with semen analysis within the past six months prior to study entry considered adequate to proceed with regular insemination or intracytoplasmic sperm injection (ICSI) according to the center's standard practice. If these criteria are not met, the subject can only be entered if donor sperm will be used. * Be between her 18th and 35th birthday (35 not included). * Have a regular spontaneous ovulatory menstrual cycle between 21 and 35 days in length. * Have early follicular phase (Day 2-4) serum levels within the last 3 months prior to study entry of: * Follicle stimulating hormone (FSH) greater than or equal to (\>=) 12 International units per liter (IU/L), and * Oestradiol (E2) within center's local normal laboratory range values. * Presence of both ovaries. * Have a uterine cavity without abnormalities, which, in the investigator's opinion, could impair embryo implantation or pregnancy evolution as assessed within the last 3 years using ultrasound (US), hysteroscopy (HSC), or hysterosalpingography (HSG). * Have a negative cervical papanicolaou (PAP) test within the last 6 months prior to study entry. * Have at least one wash-out cycle (defined as \>= 30 days since the last dose of clomiphene citrate or gonadotrophin treatment) since the last ART cycle and/or clomiphene citrate or gonadotrophin treatment prior to starting gonadotrophin releasing hormone (GnRH) agonist therapy. * Have a negative pregnancy test prior to beginning GnRH agonist therapy. * Be willing and able to comply with the protocol for the duration of the study. Have given written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to her future medical care.

Exclusion criteria

* Had 2 previous ART cycles with a poor response to gonadotrophin stimulation, defined as less than or equal to (\<=) 5 mature follicles and/or \<=3 oocytes collected in any previous IVF cycle or hyper response, defined as \>=25 oocytes retrieved. * Any medical condition, which in the judgement of the investigator may interfere with the absorption, distribution, metabolism or excretion of the drug. In case of doubt, the subject in question should be discussed with Serono's Therapeutic Director. * Had previous severe ovarian hyperstimulation syndrome (OHSS). * A body mass index (BMI) greater than (\>) 30 kilogram per square meter (kg/m\^2) * Any contraindication to being pregnant and/or carrying a pregnancy to term. * Extra-uterine pregnancy within the last 3 months. * History of 3 or more miscarriages (early or late miscarriages) due to any cause. * Tumours of the hypothalamus and pituitary gland. * Ovarian enlargement or cyst of unknown aetiology. * Ovarian, uterine or mammary cancer. * A clinically significant systemic disease. * Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus. * Abnormal gynaecological bleeding of undetermined origin. * Known allergy or hypersensitivity to human gonadotrophin preparations. * Any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years. * Entered previously into this study or simultaneous participation in another clinical trial

Design outcomes

Primary

Measure	Time frame	Description
Number of Oocytes Retrieved	Ovum pick up day (34 to 38 hours post r-hCG administration)	Mean number of oocytes retrieved on the day of ovum pick up (OPU) was calculated. Oocyte retrieval was a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.

Secondary

Measure	Time frame	Description
Mean Number of Ovarian Stimulation Days	up to end of stimulation cycle (approximately 31 days)	The mean number of stimulation days were determined based on the treatment administration information collected in the case report form. Ovarian stimulation included time from first r-hFSH injection (stimulation Day) until day on which r-hCG was administered (r-hCG day). As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.
Percentage of Cycles Cancelled Due to Excessive or Inadequate Response to r-hFSH	up to end of stimulation cycle (approximately 31 days)	As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.
Number of Subjects Needing Dose Adjustment	6 days post r-hFSH treatment	Number of subjects needing increase in dose, decrease in dose or increase and decrease both in dose were reported. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.
Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH)	up to end of stimulation cycle (approximately 31 days)	As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.
Embryo Implantation Rate	35-42 days post r-hCG administration	Embryo implantation rate was measured as the number of gestational sacs observed divided by the number of embryos transferred multiplied by 100. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.
Overall Pregnancy Rate, Clinical Rate and Multiple Pregnancy Rate	35-42 days post r-hCG administration	Overall pregnancy rate was defined as the percentage of subjects with serum beta-hCG levels greater than 10 IU/L. Clinical pregnancy rate was defined as the percentage of subjects with at least 1 ultrasound confirmed gestational sac, with or without foetal heart activity. Multiple pregnancy rate was defined as the percentage of subjects with more than 1 ultrasound confirmed gestational sac in the uterus with fetal heart activity. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.
Mean Daily Recombinant Human Follicle Stimulating Hormone (r-hFSH) Dose	up to end of stimulation cycle (approximately 31 days)	As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.

Countries

France

Participant flow

Pre-assignment details

A total of 166 subjects received at least 1 dose of recombinant human follicle stimulating hormone (r-hFSH). Of these, 161 subjects received r-hFSH in a dose group of 5 or more subjects. As per statistical analysis plan, only dose groups having 5 or more subjects were to be analyzed for efficacy and safety analysis in this study.

Participants by arm

Arm	Count
Gonal-f 37.5 IU GONAL-f (follitropin alfa) administered subcutaneously, at a dose of 37.5 IU/day based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle. When at least 1 follicle \>=18 mm and 2 follicles \>=16 mm in diameter were developed, a single injection of 250 mcg of r-hCG was administered.	1
Gonal-f 75 IU GONAL-f (follitropin alfa) administered subcutaneously, at a dose of 75 IU/day based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle. When at least 1 follicle \>=18 mm and 2 follicles \>=16 mm in diameter were developed, a single injection of 250 mcg of r-hCG was administered.	48
Gonal-f 112.5 IU GONAL-f (follitropin alfa) administered subcutaneously, at a dose of 112.5 IU/day based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle. When at least 1 follicle \>=18 mm and 2 follicles \>=16 mm in diameter were developed, a single injection of 250 mcg of r-hCG was administered.	45
Gonal-f 150 IU GONAL-f (follitropin alfa) administered subcutaneously, at a dose of 150 IU/day based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle. When at least 1 follicle \>=18 mm and 2 follicles \>=16 mm in diameter were developed, a single injection of 250 mcg of r-hCG was administered.	34
Gonal-f 187.5 IU GONAL-f (follitropin alfa) administered subcutaneously, at a dose of 187.5 IU/day based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle. When at least 1 follicle \>=18 mm and 2 follicles \>=16 mm in diameter were developed, a single injection of 250 mcg of r-hCG was administered.	24
Gonal-f 225 IU GONAL-f (follitropin alfa) administered subcutaneously, at a dose of 225 IU/day based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle. When at least 1 follicle \>=18 mm and 2 follicles \>=16 mm in diameter were developed, a single injection of 250 mcg of r-hCG was administered.	10
Gonal-f 262.5 IU GONAL-f (follitropin alfa) administered subcutaneously, at a dose of 262.5 IU/day based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle. When at least 1 follicle \>=18 mm and 2 follicles \>=16 mm in diameter were developed, a single injection of 250 mcg of r-hCG was administered.	2
Gonal-f 300 IU GONAL-f (follitropin alfa) administered subcutaneously, at a dose of 300 IU/day based on ART treatment guidelines, which determined the optimal dose of r-hFSH based on subject baseline characteristics/predictors of ovarian response throughout stimulation cycle. When at least 1 follicle \>=18 mm and 2 follicles \>=16 mm in diameter were developed, a single injection of 250 mcg of r-hCG was administered.	2
Total	166

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006
Overall Study	Failure of down-regulation	0	0	0	0	0	0	1
Overall Study	Ovarian stimulation failed	1	0	0	0	0	0	0
Overall Study	Protocol Violation	0	19	14	8	5	2	0

Baseline characteristics

Characteristic	Gonal-f 37.5 IU	Gonal-f 75 IU	Gonal-f 112.5 IU	Gonal-f 150 IU	Gonal-f 187.5 IU	Gonal-f 225 IU	Gonal-f 262.5 IU	Gonal-f 300 IU	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	1 Participants	48 Participants	45 Participants	34 Participants	24 Participants	10 Participants	2 Participants	2 Participants	166 Participants
Sex: Female, Male Female	1 Participants	48 Participants	45 Participants	34 Participants	24 Participants	10 Participants	2 Participants	2 Participants	166 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	11 / 48	15 / 45	5 / 34	10 / 24	3 / 10
serious Total, serious adverse events	3 / 48	3 / 45	1 / 34	1 / 24	0 / 10

Outcome results

Primary

Number of Oocytes Retrieved

Mean number of oocytes retrieved on the day of ovum pick up (OPU) was calculated. Oocyte retrieval was a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.

Time frame: Ovum pick up day (34 to 38 hours post r-hCG administration)

Population: Intention-To-Treat (ITT) population included all 161 treated subjects who received at least 1 injection of r-hFSH, and were allocated to a dosage group that contained at least 5 subjects. Here overall number of subjects analyzed signifies those subjects who were evaluable for this outcome measure.

Arm	Measure	Value (MEAN)	Dispersion
Gonal-f 75 IU	Number of Oocytes Retrieved	8.3 Oocytes	Standard Deviation 4.5
Gonal-f 112.5 IU	Number of Oocytes Retrieved	9.6 Oocytes	Standard Deviation 6.5
Gonal-f 150 IU	Number of Oocytes Retrieved	12.1 Oocytes	Standard Deviation 6.4
Gonal-f 187.5 IU	Number of Oocytes Retrieved	12.7 Oocytes	Standard Deviation 4.3
Gonal-f 225 IU	Number of Oocytes Retrieved	8.3 Oocytes	Standard Deviation 3.8

Secondary

Embryo Implantation Rate

Embryo implantation rate was measured as the number of gestational sacs observed divided by the number of embryos transferred multiplied by 100. As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.

Time frame: 35-42 days post r-hCG administration

Population: ITT population included all 161 treated subjects who received at least 1 injection of r-hFSH, and were allocated to a dosage group that contained at least 5 subjects. Here overall number of subjects analyzed signifies those subjects who were evaluable for this outcome measure.

Arm	Measure	Value (MEAN)	Dispersion
Gonal-f 75 IU	Embryo Implantation Rate	36.5 Percent sacs per embryo	Standard Deviation 42.8
Gonal-f 112.5 IU	Embryo Implantation Rate	24.3 Percent sacs per embryo	Standard Deviation 35
Gonal-f 150 IU	Embryo Implantation Rate	28.2 Percent sacs per embryo	Standard Deviation 38.9
Gonal-f 187.5 IU	Embryo Implantation Rate	37.1 Percent sacs per embryo	Standard Deviation 40.5
Gonal-f 225 IU	Embryo Implantation Rate	11.9 Percent sacs per embryo	Standard Deviation 20.9

Secondary

Mean Daily Recombinant Human Follicle Stimulating Hormone (r-hFSH) Dose

As per statistical analysis plan, efficacy analysis were performed for only those dose groups (Gonal-f 75 IU, Gonal-f 112.5 IU, Gonal-f 150 IU, Gonal-f 187.5 IU and Gonal-f 225 IU) which included more than 5 subjects.

Time frame: up to end of stimulation cycle (approximately 31 days)