FSH in GnRH-AntagoniST Controlled Ovarian Hyperstimulation Cycles (FAST)

• Sponsor: IBSA Institut Biochimique SA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01969201
• Collaborator: (none)
• Enrollment: 710
• Locations: 16
• Arms: 2
• Actual Duration (Months): 43
• Patients Per Site: 44.4
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The purpose of the non-inferiority study is to evaluate the clinical efficacy and the safety of two different subcutaneous FSH preparations (Fostimon versus Gonal-F) for controlled ovarian hyperstimulation in a GnRH-antagonist cycle.

Condition or Disease	Intervention/Treatment	Phase
Infertility	Drug: Urofollitrophin; Drug: Follitrophin alpha	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 710 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Official Title: Randomised Clinical Trial Comparing Highly Purified FSH Formulation (Fostimon®) and Recombinant FSH (Gonal-F®) in GnRH-antagonist Controlled Ovarian Hyperstimulation Cycles.
• Actual Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fostimon® 75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA)	Drug: Urofollitrophin; Other Names: human derived follicle stimulation hormone
Active Comparator: Gonal-F® 75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono)	Drug: Follitrophin alpha; Other Names: Recombinant follicle stimulation hormone

Outcome Measures

Primary Outcome Measures

1. Clinical Pregnancy Rate [8 weeks]

   A clinical pregnancy is defined as a pregnancy showing ultrasound embryonic heart activity at 8 weeks of gestation;

Secondary Outcome Measures

1. Number of Follicles >16 mm on the Day of hCG Injection [10-15 days after starting FSH stimulation]

2. Total Number of Oocytes Retrieved [end of treatment period, approximately 2 - 3 weeks.]

3. Fertilization Rate [end of treatment period, approximately 2 - 3 weeks]

4. Embryo Quality (Number of Top Quality Embryos Transferred Per Patient) [On culture day 3]

   The embryo quality evaluation will be performed on culture day 3, just before embryo transfer and will consist in the assessment of blastomeres number and 2 embryo morphology parameters: degree of fragmentation and cell division aspect.

5. Positive Serum Pregnancy Test Rate [2 weeks after embryo transfer]

   Two weeks after embryo transfer, a serum pregnancy test will be performed.

6. Delivery Rate [9 months]

7. Cumulative Pregnancy Rate [2 years]

   Patients who will not get pregnant during the study, will be allowed to perform a frozen embryo transfer. Cumulative pregnancy rate will include also pregnancies achieved after a frozen embryo transfer.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 38 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age: 18-38 years old;

• BMI: 18-28 kg/m2;

• Less than 3 previously completed IVF cycles;

• Basal FSH <10 IU/L and E2 <80 pg/ml;

• TSH < 2.5 mIU/L

• 10 and <30 antral follicles 2-10 mm in size for both ovaries combined

• AMH: >1 ng/ml (7.15 pmol/l) and <5.6 ng/ml (40.0 pmol/l)

• Presence and adequate visualization of both ovaries;

• Within 12 months of the beginning of the study, uterine cavity consistent with expected normal function as assessed through transvaginal ultrasound, hysterosalpingogram, sonohysterogram or hysteroscopic examination;

Exclusion Criteria:

• Primary ovarian failure or women known as poor responders;

• PCO and PCOS;

• Severe OHSS in a previous COH cycle;

• Uterine malformation that may impair the possibility to get pregnant;

• Ovarian cysts >10 mm;

• Hydrosalpinx that have not been surgically removed or ligated;

• Endometriosis stage 3 or 4;

• Oocyte donation;

• Severe male factor;

• Pathologies associated with any contraindication of being pregnant;

• History of recurrent miscarriage (more than 3 previous miscarriages);

• Hypersensitivity to the study medication;

• Abnormal bleeding of undetermined origin;

• Uncontrolled thyroid or adrenal dysfunction;

• Neoplasias;

• Severe impairment of renal and/or hepatic function.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCL- Cliniques Universitaires Saint Luc	Brussels		Belgium
2	Universitair Ziekenhuis Brussel	Brussels		Belgium
3	Spedali Civili di Brescia	Brescia		Italy
4	Fondazione Ca'Granda, Osp Maggiore Policlinico	Milan		Italy
5	IRCCS San Raffaele	Milan		Italy
6	Università degli Studi di Napoli 'Federico II'	Naples		Italy
7	Azienda Ospedaliera Di Reggio Emilia	Reggio Emilia		Italy
8	Clinica IVI Alicante	Alicante		Spain	03015
9	Institut Universitari Dexeus	Barcelona		Spain	8028
10	Ginefiv Clínica de Fertilidad	Madrid		Spain
11	Instituto Valenciano de Infertilidad (IVI)	Sevilla		Spain	40011
12	Universitätsklinik für Frauenheilkunde	Bern	Be	Switzerland
13	Universitäts-Frauenklinik	Basel	BS	Switzerland
14	Prof. Bülent Urman	Istanbul		Turkey
15	Ege University	Izmir		Turkey
16	Midland Fertility Services	Aldridge		United Kingdom

Sponsors and Collaborators

• IBSA Institut Biochimique SA

Investigators

• Study Chair: Pedro Barri, MD, Institut Universitari Dexeus, Barcelona, Spain
• Study Chair: Christophe Blockeel, MD, Universitair Ziekenhuis Brussel, Belgium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: IBSA Institut Biochimique SA
• ClinicalTrials.gov Identifier: NCT01969201
• Other Study ID Numbers: 13EU/FSH01
• First Posted: Oct 25, 2013
• Last Update Posted: Oct 9, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by IBSA Institut Biochimique SA: In vitro fertilization (IVF); Assisted reproduction technologies (ART); GnRH-antagonist; Follicle stimulating hormone (FSH)
• Additional relevant MeSH terms: Infertility; Hormones

Study Results

Participant Flow

Arm/Group Title	Fostimon®	Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
Period Title: Overall Study
STARTED	352	358
COMPLETED	307	313
NOT COMPLETED	45	45

Baseline Characteristics

Arm/Group Title	Fostimon®	Gonal-F®	Total
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha	Total of all reporting groups
Overall Participants	352	358	710
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.39 (3.83)	32.68 (3.52)	32.53 (3.5)
Sex: Female, Male (Count of Participants)
Female	352 100%	358 100%	710 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	336 95.5%	339 94.7%	675 95.1%
Black	2 0.6%	5 1.4%	7 1%
Asian	13 3.7%	14 3.9%	27 3.8%
American Indian or Alaska native	1 0.3%	0 0%	1 0.1%
Region of Enrollment (participants) [Number]
Turkey	55 15.6%	59 16.5%	114 16.1%
Belgium	39 11.1%	41 11.5%	80 11.3%
United Kingdom	44 12.5%	44 12.3%	88 12.4%
Italy	91 25.9%	88 24.6%	179 25.2%
Switzerland	24 6.8%	25 7%	49 6.9%
Spain	99 28.1%	101 28.2%	200 28.2%

Outcome Measures

1. Primary Outcome

Title	Clinical Pregnancy Rate
Description	A clinical pregnancy is defined as a pregnancy showing ultrasound embryonic heart activity at 8 weeks of gestation;
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fostimon®	Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
Measure Participants	352	358
Number [percentage of participants]	36.93 10.5%	39.66 11.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fostimon®, Gonal-F®
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority was evaluated by calculating the 95% CI for the differences in pregnancy rates between the two treatment groups. If the lower bound of the 95% CI of the difference between the two proportions was greater than -0.10 (i.e. 10%), then Fostimon was to be considered not inferior to the control treatment.
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.73
	Confidence Interval	(2-Sided) 95%; -9.88 to 4.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Follicles >16 mm on the Day of hCG Injection
Time Frame	10-15 days after starting FSH stimulation

Outcome Measure Data

Analysis Population Description

Subject with available data.

Arm/Group Title	Fostimon®	Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
Measure Participants	347	350
Mean (Standard Deviation) [follicles >16 mm]	4.10 (2.47)	4.47 (2.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fostimon®, Gonal-F®
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Total Number of Oocytes Retrieved
Time Frame	end of treatment period, approximately 2 - 3 weeks.

Outcome Measure Data

Analysis Population Description

subjects who underwent oocytes retrieval

Arm/Group Title	Fostimon®	Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
Measure Participants	337	346
Mean (Standard Deviation) [oocytes]	8.45 (4.72)	9.33 (4.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fostimon®, Gonal-F®
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Fertilization Rate
Time Frame	end of treatment period, approximately 2 - 3 weeks

Outcome Measure Data

Analysis Population Description

subjects with at least one oocyte inseminated.

Arm/Group Title	Fostimon®	Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
Measure Participants	331	338
Mean (Standard Deviation) [percentage of oocytes]	73.98 (26.44)	75.85 (21.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fostimon®, Gonal-F®
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Embryo Quality (Number of Top Quality Embryos Transferred Per Patient)
Description	The embryo quality evaluation will be performed on culture day 3, just before embryo transfer and will consist in the assessment of blastomeres number and 2 embryo morphology parameters: degree of fragmentation and cell division aspect.
Time Frame	On culture day 3

Outcome Measure Data

Analysis Population Description

Subject with at least one embryo transferred, with embryo scoring available.

Arm/Group Title	Fostimon®	Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
Measure Participants	304	314
Mean (Standard Deviation) [Top embryos]	0.47 (0.64)	0.48 (0.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fostimon®, Gonal-F®
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	ANOVA
	Comments

6. Secondary Outcome

Title	Positive Serum Pregnancy Test Rate
Description	Two weeks after embryo transfer, a serum pregnancy test will be performed.
Time Frame	2 weeks after embryo transfer

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fostimon®	Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
Measure Participants	352	358
Number [percentage of participants]	47.2 13.4%	49.7 13.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fostimon®, Gonal-F®
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5
	Comments
	Method	Fisher Exact
	Comments

7. Secondary Outcome

Title	Delivery Rate
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

For 4 patients, 3 allocated to the Fostimon® group and 1 allocated to the Gonal-F® group this information was not available because of lost to follow-up.

Arm/Group Title	Fostimon®	Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
Measure Participants	349	357
Number [percentage of participants]	34.4 9.8%	36.7 10.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fostimon®, Gonal-F®
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Cumulative Pregnancy Rate
Description	Patients who will not get pregnant during the study, will be allowed to perform a frozen embryo transfer. Cumulative pregnancy rate will include also pregnancies achieved after a frozen embryo transfer.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fostimon®	Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin	75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
Measure Participants	352	358
Number [percentage of participants]	45.2 12.8%	52.0 14.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fostimon®, Gonal-F®
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Adverse events were recorded from the signature of the informed consent to the end-of-trial (i.e. up to 9 months in case of a positive pregnancy).
Arm/Group Title	Fostimon®		Gonal-F®
Arm/Group Description	75 IU/vial, powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone,IBSA Institut Biochimique SA) Urofollitrophin		75 IU/vial powder and solvent for solution for subcutaneous injection (Follicle Stimulating Hormone; Merck Serono) Follitrophin alpha
All Cause Mortality
	Fostimon®		Gonal-F®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/352 (0%)		0/358 (0%)
Serious Adverse Events
	Fostimon®		Gonal-F®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/352 (6.8%)		31/358 (8.7%)
Gastrointestinal disorders
abdominal pain lower	1/352 (0.3%)	1	0/358 (0%)	0
intra abdominal haemorrage	0/352 (0%)	0	1/358 (0.3%)	1
peritoneal haemorrage	0/352 (0%)	0	1/358 (0.3%)	1
Infections and infestations
infection	1/352 (0.3%)	1	0/358 (0%)	0
Injury, poisoning and procedural complications
Road traffic accident	0/352 (0%)	0	1/358 (0.3%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/352 (0%)	0	1/358 (0.3%)	1
Nervous system disorders
seizure	0/352 (0%)	0	1/358 (0.3%)	1
Pregnancy, puerperium and perinatal conditions
Abortion early	1/352 (0.3%)	1	1/358 (0.3%)	1
Abortion incomplete	0/352 (0%)	0	1/358 (0.3%)	1
abortion missed	1/352 (0.3%)	1	0/358 (0%)	0
abortion spontaneous	3/352 (0.9%)	3	3/358 (0.8%)	3
Cervical incompetence	2/352 (0.6%)	2	0/358 (0%)	0
ectopic pregnancy	3/352 (0.9%)	3	1/358 (0.3%)	1
gestational diabetes	0/352 (0%)	0	1/358 (0.3%)	1
Hyperemesis gravidarum	1/352 (0.3%)	1	2/358 (0.6%)	2
imminent abortion	2/352 (0.6%)	2	2/358 (0.6%)	2
Multiple pregnancy	0/352 (0%)	0	1/358 (0.3%)	1
Oligohydramniosis	1/352 (0.3%)	1	1/358 (0.3%)	1
Placenta praevia haemorrage	0/352 (0%)	0	1/358 (0.3%)	1
Postpartum haemorrage	0/352 (0%)	0	1/358 (0.3%)	1
Pre-eclampsia	1/352 (0.3%)	1	2/358 (0.6%)	2
premature delivery	3/352 (0.9%)	3	7/358 (2%)	7
premature labour	1/352 (0.3%)	1	1/358 (0.3%)	1
premature rupture of membranes	2/352 (0.6%)	2	0/358 (0%)	0
Threatened labour	1/352 (0.3%)	1	2/358 (0.6%)	2
Vomiting in pregnancy	1/352 (0.3%)	1	0/358 (0%)	0
Reproductive system and breast disorders
Adnexal torsion	0/352 (0%)	0	1/358 (0.3%)	1
Ovarian cyst	1/352 (0.3%)	1	0/358 (0%)	0
Ovarian hyperstimulation syndrome	2/352 (0.6%)	2	4/358 (1.1%)	4
pelvic pain	1/352 (0.3%)	1	0/358 (0%)	0
Uterine polyp	1/352 (0.3%)	1	0/358 (0%)	0
Vaginal haemorrage	0/352 (0%)	0	2/358 (0.6%)	2
Surgical and medical procedures
Abortion induced	1/352 (0.3%)	1	0/358 (0%)	0
Other (Not Including Serious) Adverse Events
	Fostimon®		Gonal-F®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/352 (10.2%)		42/358 (11.7%)
Injury, poisoning and procedural complications
Procedural pain	7/352 (2%)	7	8/358 (2.2%)	8
Nervous system disorders
Headache	7/352 (2%)	7	11/358 (3.1%)	15
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	15/352 (4.3%)	15	15/358 (4.2%)	15
Reproductive system and breast disorders
Vaginal haemorrage	7/352 (2%)	8	8/358 (2.2%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.