Multi-centre Study to Compare Efficacy and Safety of AFOLIA and Gonal-f in Women for Assisted Reproductive Treatment

• Sponsor: Finox AG (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01121666
• Collaborator: (none)
• Enrollment: 460
• Locations: 16
• Arms: 2
• Duration (Months): 33
• Patients Per Site: 28.8
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Ther purpose of this study is to show equivalence between AFOLIA and Gonal-f® with regard to the number of oocytes retrieved in women for assisted reproductive treatment.

Condition or Disease	Intervention/Treatment	Phase
Infertility	Drug: Follitropin alfa	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 460 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III Assessor-blinded Randomized Parallel Group Multi-centre Study to Compare Efficacy and Safety of Two r-hFSH Formulations (AFOLIA Versus Gonal-f) in Women for Assisted Reproductive Treatment
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Gonal-f® (Follitropin alfa)	Drug: Follitropin alfa; 150IU per day subcutaneously for a maximum of 16 days
Experimental: AFOLIA-150 (Follitropin alfa)	Drug: Follitropin alfa; 150IU per day subcutaneously for a maximum of 16 days

Outcome Measures

Primary Outcome Measures

1. Number of Oocytes Retrieved (Per Protocol Population) [34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment]

   As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes

2. Number of Oocytes Retrieved (Intention-to-treat Population) [34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment]

   As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes

Secondary Outcome Measures

1. Number and Size of Follicles ≥ 12 mm at Day 8 of Stimulation [Day 8 of stimulation]

   The number and size of follicles 12 mm or over in diameter at day 8 of stimulation were evaluated as secondary end-point.

2. E2 Concentration at Day 8 and at Day of hCG Administration [Day 8 of stimulation and at the day of hCG administration (after max. 16 days of r-FSH treatment)]

   The serum concentration of oestradiol was assessed at day 8 and the day of hCG administration.

3. Total Dose of r-hFSH Administered [Day of hCG administration (after maximum 16 days of r-hFSH treatment)]

   Total dose of r-hFSH required was assessed.

4. Quality of Oocytes Retrieved [34-36 hours after hCG administration]

   Number of patients with ovum pick-up

5. Fertilisation Rate of Oocytes [1 day after ovum pick-up]

   Fertilisation rate was assessed

6. Embryo Quality: Mean Number of Blastomeres [Day 2 of OPU/fertilisation]

   Main embryo quality parameter "mean number of blastomeres"

7. Number of Participants With Cryopreserved 2PNs, Embryos/Blastocysts [Day 1, 2, 3 and 5 of OPU/fertilisation]

8. Number of Days of r-hFSH Stimulation [At the day of hCG administration, up to 16 days]

   Mean duration of stimulation was assessed.

9. Number of Patients With Cycle Cancellation [Until child birth/miscarriage, up to the end of the study]

   Number of patients with cycle cancellation was assessed.

10. Number of Patients With Good Response [Until child birth/miscarriage, up to the end of the study]

    Good response was defined as "patients with an oocyte retrieval of four or more oocytes"

11. Implantation Rate [Five to six weeks after oocyte retrieval]

    Defined as fetal sac per embryo transferred.

12. Clinical Pregnancy Rate [Five to six weeks after oocyte retrieval]

    Presence of at least one intrauterine gestational sac.

13. Ongoing Pregnancy [Ten weeks after embryo transfer]

    Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer.

14. Live Birth Rate [After childbirth with questionnaire]

    Patients with liveborn children

15. Embryo Quality: Absence of Multinucleation [Day 3]

    Main embryo quality parameter "absence of multinucleation" observed.

16. Quality of Oocytes Retrieved [At day 4 and 5]

    Number of patients with transferred blastocysts

17. Quality of Oocytes Retrieved [Day of embryo transfer, either 2, 3 or 5 days after oocyte retrieval]

    Number of embryos per blastocysts transferred

18. Clinical Pregnancy Rate (Second Treatment Cycle) [Five to six weeks after oocyte retrieval]

    Presence of at least one intrauterine gestational sac.

19. Ongoing Pregnancy (Second Treatment Cycle) [10 weeks after embryo transfer]

    Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer.

20. Quality of Oocytes Retrieved [After oocyte retrieval, 34 to 36 hours after hCG administration]

    The maturity of the cumulus oophorus was assessed.

21. Quality of Oocytes Retrieved [After oocyte retrieval, 34 to 36 hours after hCG administration]

    The nuclear maturity was assessed (Germinal vesicle, Metaphase I, Metaphase II).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 38 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age between 20 and 38 years with regular menstrual cycles of 25-35 days

• First or second cycle in the present series of ART

• BMI ≥ 18 ≤ 30 kg/m2

• Basal FSH < 10 IU/L (cycle day 2-5)

• E2 levels < 50pg/mL (< 0.18 nmol/L) at the day of FSH administration

• Antral follicle count (AFC) ≥ 10 to ≤ 25 follicles (sum of both ovaries)

• Infertility due to any of the following factors: tubal factor, mild endometriosis (ASRM stage 1-2), male factor, unexplained infertility

• Presence of both ovaries and normal uterine cavity (confirmed by transvaginal ultrasound within 6 months before randomisation)

• Willingness to participate in the study and to comply with the study protocol

• Informed consent

Exclusion Criteria:

• Presence of pregnancy

• History of ≥2 succeeding ART cycles (IVF and/or ICSI) before the study cycle without clinical pregnancy

• Presence of clinically significant systemic disease

• Presence of chronic cardiovascular, hepatic, renal or pulmonary disease

• Presence of uncontrolled endocrine disorder

• Previous history or presence of severe ovarian hyperstimulation syndrome

• Presence of polycystic ovaries (PCO)

• Presence of severe endometriosis (ASRM stage 3 or stage 4) and hydrosalpinx

• Neoplasia, including tumors of the hypothalamus and pituitary gland

• Abnormal bleeding of undetermined origin

• History of poor response to gonadotropin treatment (defined as fewer than 5 oocytes retrieved in a previous attempt)

• Male infertility without mobile spermatozoa in the ejaculate, that need testicular of epididymal sperm retrieval (MESA/TESE/TESA)

• Endocrine abnormality such as TSH or prolactin level elevations outside the reference range if clinically relevant at screening

• Any hormonal treatment within 1 month before the start of the FSH treatment (with the exception of levothyroxin)

• History of drug, nicotine or alcohol abuse within the last 12 months (> 10 cigarettes/day)

• Administration of other investigational products within the last month

• Clinically abnormal findings at Visit 1

• Planned PGS/PGD/PBB or assisted hatching

• Concomitant participation in an other study protocol

• History of extrauterine pregnancy in the previous 3 months

• Known allergy or hypersensitivity to progesterone or to any of the excipients (including peanut oil) of the additional study medication (GnRH agonist, vitrelle®, and Utrogestan®)

• Presence or history of thrombophlebitis or thromboembolic disorders

• Presence or history of cerebral haemorrhage

• Presence or history of porphyria

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kinderwunsch Institut Schenk GmbH	Graz		Austria
2	Landes-Frauenklinik und Kinderklinik Linz	Linz		Austria
3	AKH Vienna	Vienna		Austria	1090
4	IVF Zentrum Döbling	Vienna		Austria	11920
5	Privatspital Goldenes Kreuz	Wien		Austria
6	Fertility Clinic	Copenhagen		Denmark	2100
7	Copenhagen Fertility Center	Copenhagen		Denmark	2400
8	Dansk Fertilitetsklinik	Frederiksberg		Denmark	2000
9	Universitätsklinikum Bonn	Bonn		Germany	53105
10	Universitäts-Frauenklinik	Heidelberg		Germany
11	Institut Universitari Dexeus	Barcelona		Spain	08028
12	IVI Madrid	Madrid		Spain	28023
13	University Hospital of Zurich	Zurich		Switzerland	8091
14	Guy's and St Thomas' NHS Foundation Trust	London		United Kingdom	SE1 9RT
15	Kings College Hospital	London		United Kingdom
16	St Barthlomew's Hospital	London		United Kingdom

Sponsors and Collaborators

• Finox AG

Investigators

• Principal Investigator: Bruno Imthurn, University of Zurich

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Finox AG
• ClinicalTrials.gov Identifier: NCT01121666
• Other Study ID Numbers: FIN3001; 2010-019287-37
• First Posted: May 12, 2010
• Last Update Posted: Apr 15, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Finox AG: Assisted reproductive treatment; Superovulation; Follitropin alfa; r-hFSH; AFOLIA
• Additional relevant MeSH terms: Infertility; Follicle Stimulating Hormone

Study Results

Participant Flow

Recruitment Details	Subjects were screened and enrolled at 15 centers in six European countries from July 2010 until April 2012.
Pre-assignment Detail	Of 460 participants in this trial 88 were reported as screening failures prior the group assignment.

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Period Title: Overall Study
STARTED	249	123
COMPLETED	220	113
NOT COMPLETED	29	10

Baseline Characteristics

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)	Total
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Total of all reporting groups
Overall Participants	249	123	372
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.8 (4.02)	32.1 (3.76)	31.95 (3.90)
Sex: Female, Male (Count of Participants)
Female	249 100%	123 100%	372 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	12 4.8%	3 2.4%	15 4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 0.8%	1 0.8%	3 0.8%
White	229 92%	117 95.1%	346 93%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	6 2.4%	2 1.6%	8 2.2%
Region of Enrollment (participants) [Number]
Austria	88 35.3%	43 35%	131 35.2%
Denmark	75 30.1%	37 30.1%	112 30.1%
Spain	33 13.3%	19 15.4%	52 14%
Germany	24 9.6%	11 8.9%	35 9.4%
United Kingdom	21 8.4%	10 8.1%	31 8.3%
Switzerland	8 3.2%	3 2.4%	11 3%
FSH baseline concentration ((IU/L)) [Mean (Full Range) ]
Mean (Full Range) [(IU/L)]	6.9	6.9	6.9
Antral follicle count (Antral follicle count) [Mean (Full Range) ]
Mean (Full Range) [Antral follicle count]	15.1	15.3	15.2
Body Mass Index (kilogramm/ square meter) [Mean (Full Range) ]
Mean (Full Range) [kilogramm/ square meter]	22.7	22.4	22.6
GnRH-agonist duration (days) [Mean (Full Range) ]
Mean (Full Range) [days]	23.5	22.7	23.1
AMH less than 24 pmol/L (Number of participants) [Number]
Number [Number of participants]	106 42.6%	47 38.2%	153 41.1%

Outcome Measures

1. Primary Outcome

Title	Number of Oocytes Retrieved (Per Protocol Population)
Description	As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes
Time Frame	34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment

Outcome Measure Data

Analysis Population Description

Per protocol population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	220	113
Mean (Standard Deviation) [Number of retrieved oocytes]	10.8 (5.11)	10.6 (6.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AFOLIA-150 (Follitropin Alfa), Gonal-f® (Follitropin Alfa)
	Comments	This study was powered to test equivalence using a two one-sided test (TOST) of the number of oocytes retrieved.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This study was powered to test equivalence using a two one-sided test (TOST) of the number of oocytes retrieved with a power of 90%, an alpha error of 2.5% and a pre-determined clinical equivalence margin of +/-2.9 oocytes for the relevant population.
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	This study was powered to test equivalence using a two one-sided test (TOST) with a power of 90%, an alpha error of 2.5% and a pre-determined clinical equivalence margin of +/-2.9 oocytes for the relevant population.
	Method	Shuirmann's TOST
	Comments

2. Secondary Outcome

Title	Number and Size of Follicles ≥ 12 mm at Day 8 of Stimulation
Description	The number and size of follicles 12 mm or over in diameter at day 8 of stimulation were evaluated as secondary end-point.
Time Frame	Day 8 of stimulation

Outcome Measure Data

Analysis Population Description

All participants were analyzed.

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
≥ 12 mm	11.8 (4.73)	11.1 (4.23)
≥ 15 mm	8.3 (3.81)	7.7 (3.60)
≥ 17 mm	4.9 (3.29)	4.5 (2.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AFOLIA-150 (Follitropin Alfa), Gonal-f® (Follitropin Alfa)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2357
	Comments	Follicles of 12 mm
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AFOLIA-150 (Follitropin Alfa), Gonal-f® (Follitropin Alfa)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1395
	Comments	Follicles of 15 mm
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	AFOLIA-150 (Follitropin Alfa), Gonal-f® (Follitropin Alfa)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3992
	Comments	Follicles of 17 mm
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	E2 Concentration at Day 8 and at Day of hCG Administration
Description	The serum concentration of oestradiol was assessed at day 8 and the day of hCG administration.
Time Frame	Day 8 of stimulation and at the day of hCG administration (after max. 16 days of r-FSH treatment)

Outcome Measure Data

Analysis Population Description

All participants were analyzed.

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Day of hCG administration	8982.3 (6535.3)	7704.2 (5345.8)
Day 8	3958.9 (3699.4)	3234.0 (2428.1)

4. Secondary Outcome

Title	Total Dose of r-hFSH Administered
Description	Total dose of r-hFSH required was assessed.
Time Frame	Day of hCG administration (after maximum 16 days of r-hFSH treatment)

Outcome Measure Data

Analysis Population Description

All participants were analyzed.

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Mean (Standard Deviation) [IU]	1555.7 (293.00)	1569.2 (259.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AFOLIA-150 (Follitropin Alfa), Gonal-f® (Follitropin Alfa)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9638
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Quality of Oocytes Retrieved
Description	Number of patients with ovum pick-up
Time Frame	34-36 hours after hCG administration

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
day 2	82 32.9%	36 29.3%
day 3	53 21.3%	28 22.8%

6. Secondary Outcome

Title	Fertilisation Rate of Oocytes
Description	Fertilisation rate was assessed
Time Frame	1 day after ovum pick-up

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Mean (Standard Deviation) [percentage of oocytes]	66.1 (24.84)	64.0 (24.76)

7. Secondary Outcome

Title	Embryo Quality: Mean Number of Blastomeres
Description	Main embryo quality parameter "mean number of blastomeres"
Time Frame	Day 2 of OPU/fertilisation

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Mean (Standard Deviation) [Number of blastomeres at day 3]	6.6 (2.41)	6.4 (2.49)

8. Secondary Outcome

Title	Number of Participants With Cryopreserved 2PNs, Embryos/Blastocysts
Time Frame	Day 1, 2, 3 and 5 of OPU/fertilisation

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Number [Patients with cryopreservation]	103	55

9. Secondary Outcome

Title	Number of Days of r-hFSH Stimulation
Description	Mean duration of stimulation was assessed.
Time Frame	At the day of hCG administration, up to 16 days

Outcome Measure Data

Analysis Population Description

All participants were analyzed.

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Mean (Standard Deviation) [days]	10.6 (1.91)	10.7 (1.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AFOLIA-150 (Follitropin Alfa), Gonal-f® (Follitropin Alfa)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8926
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Number of Patients With Cycle Cancellation
Description	Number of patients with cycle cancellation was assessed.
Time Frame	Until child birth/miscarriage, up to the end of the study

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Number [Number of patients]	13	5

11. Secondary Outcome

Title	Number of Patients With Good Response
Description	Good response was defined as "patients with an oocyte retrieval of four or more oocytes"
Time Frame	Until child birth/miscarriage, up to the end of the study

Outcome Measure Data

Analysis Population Description

Intention to treat population.

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Number [Participants]	217 87.1%	107 87%

12. Secondary Outcome

Title	Implantation Rate
Description	Defined as fetal sac per embryo transferred.
Time Frame	Five to six weeks after oocyte retrieval

Outcome Measure Data

Analysis Population Description

Intention to treat population.

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Number [Percentage of implantations]	31.8	36.7

13. Secondary Outcome

Title	Clinical Pregnancy Rate
Description	Presence of at least one intrauterine gestational sac.
Time Frame	Five to six weeks after oocyte retrieval

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Number [Clinical pregnancies]	90	55

14. Secondary Outcome

Title	Ongoing Pregnancy
Description	Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer.
Time Frame	Ten weeks after embryo transfer

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Number [Ongoing pregnancies]	84	51

15. Secondary Outcome

Title	Live Birth Rate
Description	Patients with liveborn children
Time Frame	After childbirth with questionnaire

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Number [Patients with liveborn children]	80	51

16. Primary Outcome

Title	Number of Oocytes Retrieved (Intention-to-treat Population)
Description	As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes
Time Frame	34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment

Outcome Measure Data

Analysis Population Description

Intention-to-treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Mean (Standard Deviation) [Number of retrieved oocytes]	10.7 (5.62)	10.4 (6.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AFOLIA-150 (Follitropin Alfa), Gonal-f® (Follitropin Alfa)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This study was powered to test equivalence using a two one-sided test (TOST) of the number of oocytes retrieved with a power of 90%, an alpha error of 2.5% and a pre-determined clinical equivalence margin of +/-2.9 oocytes for the relevant population.
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Shuirmann's TOST
	Comments

17. Secondary Outcome

Title	Embryo Quality: Absence of Multinucleation
Description	Main embryo quality parameter "absence of multinucleation" observed.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Number [Percentage of absent multinucleation]	93.6	93.9

18. Secondary Outcome

Title	Quality of Oocytes Retrieved
Description	Number of patients with transferred blastocysts
Time Frame	At day 4 and 5

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
day 4	10 4%	2 1.6%
day 5	76 30.5%	46 37.4%

19. Secondary Outcome

Title	Quality of Oocytes Retrieved
Description	Number of embryos per blastocysts transferred
Time Frame	Day of embryo transfer, either 2, 3 or 5 days after oocyte retrieval

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Mean (Standard Deviation) [embryos per blastocysts transferred]	1.5 (0.52)	1.6 (0.53)

20. Secondary Outcome

Title	Clinical Pregnancy Rate (Second Treatment Cycle)
Description	Presence of at least one intrauterine gestational sac.
Time Frame	Five to six weeks after oocyte retrieval

Outcome Measure Data

Analysis Population Description

Population with a second treatment cycle

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	72	38
Number [Clinical pregnancies]	25	10

21. Secondary Outcome

Title	Ongoing Pregnancy (Second Treatment Cycle)
Description	Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer.
Time Frame	10 weeks after embryo transfer

Outcome Measure Data

Analysis Population Description

Population with a second treatment cycle

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	72	38
Number [Ongoing pregnancies]	22	9

22. Secondary Outcome

Title	Quality of Oocytes Retrieved
Description	The maturity of the cumulus oophorus was assessed.
Time Frame	After oocyte retrieval, 34 to 36 hours after hCG administration

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
very mature	9.1	9.4
mature	75.7	75.3
immature	14.5	14.2

23. Secondary Outcome

Title	Quality of Oocytes Retrieved
Description	The nuclear maturity was assessed (Germinal vesicle, Metaphase I, Metaphase II).
Time Frame	After oocyte retrieval, 34 to 36 hours after hCG administration

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	AFOLIA-150 (Follitropin Alfa)	Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
Measure Participants	249	123
Germinal vesicle	9.5	9.1
Metaphase I	7.2	7.7
Metaphase II	83.4	83.3

Adverse Events

Time Frame	Study period + 30 days
Arm/Group Title	AFOLIA-150 (Follitropin Alfa)		Gonal-f® (Follitropin Alfa)
Arm/Group Description	Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days		Follitropin alfa: 150IU per day subcutaneously for a maximum of 16 days
All Cause Mortality
	AFOLIA-150 (Follitropin Alfa)		Gonal-f® (Follitropin Alfa)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	AFOLIA-150 (Follitropin Alfa)		Gonal-f® (Follitropin Alfa)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/249 (4.8%)		3/123 (2.4%)
Gastrointestinal disorders
Abdominal pain	2/249 (0.8%)		0/123 (0%)
Hepatobiliary disorders
Biliary colic	1/249 (0.4%)		0/123 (0%)
Investigations
Body temparature increased	1/249 (0.4%)		0/123 (0%)
Nervous system disorders
Syncope	0/249 (0%)		1/123 (0.8%)
Reproductive system and breast disorders
Ovarian haemorrhage	1/249 (0.4%)		0/123 (0%)
Ovarian hyperstimulation syndrome	7/249 (2.8%)		2/123 (1.6%)
Other (Not Including Serious) Adverse Events
	AFOLIA-150 (Follitropin Alfa)		Gonal-f® (Follitropin Alfa)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	182/249 (73.1%)		83/123 (67.5%)
Gastrointestinal disorders
Nausea	23/249 (9.2%)		6/123 (4.9%)
Abdominal distension	14/249 (5.6%)		6/123 (4.9%)
Abdominal pain	13/249 (5.2%)		6/123 (4.9%)
Abdominal pain upper	7/249 (2.8%)		7/123 (5.7%)
General disorders
Injection site erythema	68/249 (27.3%)		44/123 (35.8%)
Injection site haematoma	60/249 (24.1%)		19/123 (15.4%)
Injection site pain	39/249 (15.7%)		21/123 (17.1%)
Injection site swelling	15/249 (6%)		10/123 (8.1%)
Fatigue	13/249 (5.2%)		4/123 (3.3%)
Nervous system disorders
Headache	55/249 (22.1%)		25/123 (20.3%)
Reproductive system and breast disorders
Ovarian hyperstimulation syndrome	55/249 (22.1%)		16/123 (13%)

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.