Evidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 1

Infertility Clinical Trial

— ESTHER-1  

Official title:

A Randomised, Controlled, Assessor-blind, Parallel Groups, Multicentre, Multinational Trial Comparing the Efficacy and Safety of FE 999049 With Follitropin Alfa (GONAL-F) in Controlled Ovarian Stimulation in Women Undergoing an Assisted Reproductive Technology Programme

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01956110
• Other study ID #: 000004
• Secondary ID: 2013-001669-17U1
• Status: Completed
• Phase: Phase 3
• Start date: October 2013
• Est. completion date: January 3, 2017

Study information

• Verified date: September 2018
• Source: Ferring Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial investigates the effects of FE 999049 compared to GONAL-F.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1329
• Est. completion date: January 3, 2017
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

Inclusion Criteria:

• Informed Consent Documents signed prior to screening evaluations
• In good physical and mental health
• Pre-menopausal females between the ages of 18 and 40 years
• Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilisation (IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor
• Infertility for at least one year before randomisation for subjects =37 years or for at least 6 months for subjects =38 years (not applicable in case of tubal or severe male factor infertility)
• The trial cycle will be the subject's first controlled ovarian stimulation cycle for IVF/ICSI
• Hysterosalpingography, hysteroscopy, saline infusion sonography, or transvaginal ultrasound documenting a uterus consistent with expected normal function (e.g. no evidence of clinically interfering uterine fibroids defined as submucous or intramural fibroids larger than 3 cm in diameter, no polyps and no congenital structural abnormalities which are associated with a reduced chance of pregnancy) within 1 year prior to randomisation
• Transvaginal ultrasound documenting presence and adequate visualisation of both ovaries, without evidence of significant abnormality (e.g. no endometrioma greater than 3 cm or enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) within 1 year prior to randomisation. Both ovaries must be accessible for oocyte retrieval.
• Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results obtained within 3 months prior to randomisation)
• Body mass index (BMI) between 17.5 and 32.0 kg/m2 (both inclusive) at screening

Exclusion Criteria:

• Known endometriosis stage III-IV
• One or more follicles =10 mm observed on the transvaginal ultrasound prior to randomisation on stimulation day 1
• Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy (excl. ectopic pregnancy) and before week 24 of pregnancy)
• Known abnormal karyotype of subject or of her partner/sperm donor, as applicable, depending on source of sperm used for insemination in this trial.
• Any known clinically significant systemic disease (e.g. insulin-dependent diabetes)
• Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) which can compromise participation in the trial with the exception of controlled thyroid function disease
• Known tumours of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins.

Related Conditions & MeSH terms

• Infertility

Intervention

Drug:
• Follitropin Delta (FE 999049)

• Follitropin Alfa (GONAL-F)

Locations

Country	Name	City	State
Belgium	UZ Brussel (there may be other sites in this country)	Brussels
Brazil	Fertilitat and PUC-RS (there may be other sites in this country)	Porto Alegre
Canada	Pacific Centre for Reproductive Medicine	Burnaby	British Columbia
Canada	Ottawa Fertility Centre	Ottawa	Ontario
Canada	Olive Fertility Centre	Vancouver	British Columbia
Czechia	IVF CUBE SE (there may be other sites in this country)	Prague
Denmark	Rigshospitalet Fertilitetsklinikken (there may be other sites in this country)	Copenhagen
France	Department of Endocrine Gynaecology and Reproductive Medicine, Hôpital Jeanne de Flandre (there may be other sites in this country)	Lille
Italy	Centro Natalità San Raffaele (there may be other sites in this country)	Milano
Poland	The nOvum Clinic (there may be other sites in this country)	Warszawa
Russian Federation	IVF & Reproductive Genetics Center (there may be other sites in this country)	Moscow
Spain	IVI Sevilla (there may be other sites in this country)	Sevilla
United Kingdom	Glasgow Centre for Reproductive Medicine Ltd. (there may be other sites in this country)	Glasgow

Sponsors (1)

Lead Sponsor	Collaborator
Ferring Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  Brazil,  Canada,  Czechia,  Denmark,  France,  Italy,  Poland,  Russian Federation,  Spain,  United Kingdom, 

References & Publications (3)

Arce JC, Larsson P, García-Velasco JA. Establishing the follitropin delta dose that provides a comparable ovarian response to 150 IU/day follitropin alfa. Reprod Biomed Online. 2020 Oct;41(4):616-622. doi: 10.1016/j.rbmo.2020.07.006. Epub 2020 Jul 15. — View Citation

Havelock J, Aaris Henningsen AK, Mannaerts B, Arce JC; ESTHER-1 and ESTHER-2 Trial Groups. Pregnancy and neonatal outcomes in fresh and frozen cycles using blastocysts derived from ovarian stimulation with follitropin delta. J Assist Reprod Genet. 2021 Oc — View Citation

Ishihara O, Nelson SM, Arce JC. Comparison of ovarian response to follitropin delta in Japanese and White IVF/ICSI patients. Reprod Biomed Online. 2021 Sep 23. pii: S1472-6483(21)00473-9. doi: 10.1016/j.rbmo.2021.09.014. [Epub ahead of print] — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ongoing Pregnancy Rate	Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer.	10-11 weeks after blastocyst transfer
Primary	Ongoing Implantation Rate	Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred.	10-11 weeks after blastocyst transfer
Secondary	Vital Pregnancy Rate	Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer.	5-6 weeks after blastocyst transfer
Secondary	Implantation Rate	Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred.	5-6 weeks after blastocyst transfer
Secondary	Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, =15 or =20 Oocytes Retrieved		Day of oocyte retrieval
Secondary	Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS	The proportion of subjects with early OHSS, early OHSS of moderate or severe grade, preventive interventions for early OHSS, early OHSS and/or preventive interventions for early OHSS, and early OHSS of moderate or severe grade and/or preventive interventions for early OHSS are presented.	=9 days after triggering of final follicular maturation
Secondary	Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response	Proportion of subjects with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with gonadotropin-releasing hormone (GnRH) agonist are presented.	End-of-stimulation (up to 20 stimulation days)
Secondary	Number of Oocytes Retrieved		Day of oocyte retrieval
Secondary	Proportion of Subjects With <4, 4-7, 8-14, 15-19 and =20 Oocytes Retrieved		Day of oocyte retrieval
Secondary	Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection])	Number of oocytes in metaphase II prior to ICSI insemination is presented.	Prior to insemination
Secondary	Fertilisation Rate	Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.	Day 1 after insemination
Secondary	Number and Quality of Embryos on Day 3	Number of embryos (total and good-quality) on Day 3 are presented. A good-quality embryo was defined as an embryo with =6 blastomeres and fragmentation =20% on Day 3.	On day 3 after oocyte retrieval
Secondary	Number and Quality of Blastocysts on Day 5	Number of blastocysts (total and good-quality) on Day 5 are presented. A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.	On day 5 after oocyte retrieval
Secondary	Total Gonadotropin Dose	The total gonadotropin dose was recorded.	End-of-stimulation (up to 20 stimulation days)
Secondary	Number of Stimulation Days		End-of-stimulation (up to 20 stimulation days)
Secondary	Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments		End-of-stimulation (up to 20 stimulation days)
Secondary	Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period	Subjects self-assessed injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after each injection. The injection site reactions were assessed as none, mild, moderate and severe. The frequency of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.	End-of-stimulation (up to 20 stimulation days)
Secondary	Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS)	The subject self-assessed abdominal discomfort related to controlled ovarian stimulation using a VAS going from 0 mm (no abdominal discomfort) to 100 mm (worst imaginable abdominal discomfort).	End-of-stimulation and day of blastocyst transfer
Secondary	Changes in Body Weight	Change in body weight from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.	End-of-stimulation and day of blastocyst transfer
Secondary	Changes in Maximum Abdominal Circumference	Change in maximum abdominal circumference from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.	End-of-stimulation and day of blastocyst transfer
Secondary	Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies	The proportion of subjects with at least one treatment-induced anti-FSH antibody response at any time point.	Stimulation day 1, 7-10 days after last FE 999049 or GONAL-F dose and 21-28 days after last FE 999049 or GONAL-F dose
Secondary	Proportion of Subjects With Late OHSS	Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation.The proportion of subjects with late OHSS, and late OHSS of moderate or severe grade are presented.	>9 days after triggering of final follicular maturation
Secondary	Technical Malfunctions of the Administration Pen	Confirmed technical malfunction of administration pen.	End-of-stimulation (up to 20 stimulation days)