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

• ClinicalTrials.gov Identifier: NCT01956110
• Recruitment Status: Completed
• First Posted: October 8, 2013
• Results First Posted: September 25, 2018
• Last Update Posted: January 13, 2022
• Sponsor: Ferring Pharmaceuticals
• Information provided by (Responsible Party): Ferring Pharmaceuticals

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Infertility	Drug: Follitropin Delta (FE 999049); Drug: Follitropin Alfa (GONAL-F)	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1329 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Study Start Date: October 2013
• Actual Primary Completion Date: May 2015
• Actual Study Completion Date: January 3, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: A; Follitropin Delta (FE 999049)	Drug: Follitropin Delta (FE 999049)
Active Comparator: B; Follitropin Alfa (GONAL-F)	Drug: Follitropin Alfa (GONAL-F)

Outcome Measures

Primary Outcome Measures :

1. Ongoing Pregnancy Rate [ Time Frame: 10-11 weeks after blastocyst transfer ]
   Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer.
2. Ongoing Implantation Rate [ Time Frame: 10-11 weeks after blastocyst transfer ]
   Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred.

Secondary Outcome Measures :

1. Vital Pregnancy Rate [ Time Frame: 5-6 weeks after blastocyst transfer ]
   Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer.
2. Implantation Rate [ Time Frame: 5-6 weeks after blastocyst transfer ]
   Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred.
3. Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved [ Time Frame: Day of oocyte retrieval ]
4. Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS [ Time Frame: ≤9 days after triggering of final follicular maturation ]
   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.
5. Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
   Proportion of subjects with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with gonadotropin-releasing hormone (GnRH) agonist are presented.
6. Number of Oocytes Retrieved [ Time Frame: Day of oocyte retrieval ]
7. Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved [ Time Frame: Day of oocyte retrieval ]
8. Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection]) [ Time Frame: Prior to insemination ]
   Number of oocytes in metaphase II prior to ICSI insemination is presented.
9. Fertilisation Rate [ Time Frame: Day 1 after insemination ]
   Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
10. Number and Quality of Embryos on Day 3 [ Time Frame: On day 3 after oocyte retrieval ]
    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.
11. Number and Quality of Blastocysts on Day 5 [ Time Frame: On day 5 after oocyte retrieval ]
    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.
12. Total Gonadotropin Dose [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    The total gonadotropin dose was recorded.
13. Number of Stimulation Days [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
14. Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
15. Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    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.
16. Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS) [ Time Frame: End-of-stimulation and day of blastocyst transfer ]
    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).
17. Changes in Body Weight [ Time Frame: End-of-stimulation and day of blastocyst transfer ]
    Change in body weight from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
18. Changes in Maximum Abdominal Circumference [ Time Frame: End-of-stimulation and day of blastocyst transfer ]
    Change in maximum abdominal circumference from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
19. Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies [ Time Frame: 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 ]
    The proportion of subjects with at least one treatment-induced anti-FSH antibody response at any time point.
20. Proportion of Subjects With Late OHSS [ Time Frame: >9 days after triggering of final follicular maturation ]
    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.
21. Technical Malfunctions of the Administration Pen [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    Confirmed technical malfunction of administration pen.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Belgium

UZ Brussel (there may be other sites in this country)

Brussels, Belgium

Brazil

Fertilitat and PUC-RS (there may be other sites in this country)

Porto Alegre, Brazil

Canada, British Columbia

Pacific Centre for Reproductive Medicine

Burnaby, British Columbia, Canada

Olive Fertility Centre

Vancouver, British Columbia, Canada

Canada, Ontario

Ottawa Fertility Centre

Ottawa, Ontario, Canada

Czechia

IVF CUBE SE (there may be other sites in this country)

Prague, Czechia

Denmark

Rigshospitalet Fertilitetsklinikken (there may be other sites in this country)

Copenhagen, Denmark

France

Department of Endocrine Gynaecology and Reproductive Medicine, Hôpital Jeanne de Flandre (there may be other sites in this country)

Lille, France

Italy

Centro Natalità San Raffaele (there may be other sites in this country)

Milano, Italy

Poland

The nOvum Clinic (there may be other sites in this country)

Warszawa, Poland

Russian Federation

IVF & Reproductive Genetics Center (there may be other sites in this country)

Moscow, Russian Federation

Spain

IVI Sevilla (there may be other sites in this country)

Sevilla, Spain

United Kingdom

Glasgow Centre for Reproductive Medicine Ltd. (there may be other sites in this country)

Glasgow, United Kingdom

Sponsors and Collaborators

Ferring Pharmaceuticals

Investigators

• Study Director: Clinical Development Support; Ferring Pharmaceuticals

More Information

Publications of Results:

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.

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 Oct;38(10):2651-2661. doi: 10.1007/s10815-021-02271-5. Epub 2021 Jul 13.

Ishihara O, Nelson SM, Arce JC. Comparison of ovarian response to follitropin delta in Japanese and White IVF/ICSI patients. Reprod Biomed Online. 2022 Jan;44(1):177-184. doi: 10.1016/j.rbmo.2021.09.014. Epub 2021 Sep 23.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nelson SM, Larsson P, Mannaerts BMJL, Nyboe Andersen A, Fauser BCJM. Anti-Müllerian hormone variability and its implications for the number of oocytes retrieved following individualized dosing with follitropin delta. Clin Endocrinol (Oxf). 2019 May;90(5):719-726. doi: 10.1111/cen.13956. Epub 2019 Mar 18.

Nyboe Andersen A, Nelson SM, Fauser BC, García-Velasco JA, Klein BM, Arce JC; ESTHER-1 study group. Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial. Fertil Steril. 2017 Feb;107(2):387-396.e4. doi: 10.1016/j.fertnstert.2016.10.033. Epub 2016 Nov 29.

• Responsible Party: Ferring Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01956110
• Other Study ID Numbers: 000004; 2013-001669-17 ( EudraCT Number ); U1111-1147-6826 ( Other Identifier: WHO )
• First Posted: October 8, 2013
• Results First Posted: September 25, 2018
• Last Update Posted: January 13, 2022
• Last Verified: September 2018

Additional relevant MeSH terms:

Infertility; Follicle Stimulating Hormone; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs