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

Primary Purpose

Infertility

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Follitropin Delta (FE 999049)
Follitropin Alfa (GONAL-F)
Sponsored by
Ferring Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infertility

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • UZ Brussel (there may be other sites in this country)
  • Fertilitat and PUC-RS (there may be other sites in this country)
  • Pacific Centre for Reproductive Medicine
  • Olive Fertility Centre
  • Ottawa Fertility Centre
  • IVF CUBE SE (there may be other sites in this country)
  • Rigshospitalet Fertilitetsklinikken (there may be other sites in this country)
  • Department of Endocrine Gynaecology and Reproductive Medicine, Hôpital Jeanne de Flandre (there may be other sites in this country)
  • Centro Natalità San Raffaele (there may be other sites in this country)
  • The nOvum Clinic (there may be other sites in this country)
  • IVF & Reproductive Genetics Center (there may be other sites in this country)
  • IVI Sevilla (there may be other sites in this country)
  • Glasgow Centre for Reproductive Medicine Ltd. (there may be other sites in this country)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

A

B

Arm Description

Follitropin Delta (FE 999049)

Follitropin Alfa (GONAL-F)

Outcomes

Primary Outcome Measures

Ongoing Pregnancy Rate
Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer.
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.

Secondary Outcome Measures

Vital Pregnancy Rate
Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer.
Implantation Rate
Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred.
Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved
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.
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.
Number of Oocytes Retrieved
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection])
Number of oocytes in metaphase II prior to ICSI insemination is presented.
Fertilisation Rate
Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
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.
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.
Total Gonadotropin Dose
The total gonadotropin dose was recorded.
Number of Stimulation Days
Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments
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.
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).
Changes in Body Weight
Change in body weight from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
Changes in Maximum Abdominal Circumference
Change in maximum abdominal circumference from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
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.
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.
Technical Malfunctions of the Administration Pen
Confirmed technical malfunction of administration pen.

Full Information

First Posted
August 16, 2013
Last Updated
January 4, 2022
Sponsor
Ferring Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01956110
Brief Title
Evidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 1
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
October 2013 (undefined)
Primary Completion Date
May 2015 (Actual)
Study Completion Date
January 3, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ferring Pharmaceuticals

4. Oversight

Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infertility

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
1329 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A
Arm Type
Experimental
Arm Description
Follitropin Delta (FE 999049)
Arm Title
B
Arm Type
Active Comparator
Arm Description
Follitropin Alfa (GONAL-F)
Intervention Type
Drug
Intervention Name(s)
Follitropin Delta (FE 999049)
Intervention Type
Drug
Intervention Name(s)
Follitropin Alfa (GONAL-F)
Primary Outcome Measure Information:
Title
Ongoing Pregnancy Rate
Description
Ongoing pregnancy was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer.
Time Frame
10-11 weeks after blastocyst transfer
Title
Ongoing Implantation Rate
Description
Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred.
Time Frame
10-11 weeks after blastocyst transfer
Secondary Outcome Measure Information:
Title
Vital Pregnancy Rate
Description
Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer.
Time Frame
5-6 weeks after blastocyst transfer
Title
Implantation Rate
Description
Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred.
Time Frame
5-6 weeks after blastocyst transfer
Title
Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved
Time Frame
Day of oocyte retrieval
Title
Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS
Description
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.
Time Frame
≤9 days after triggering of final follicular maturation
Title
Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response
Description
Proportion of subjects with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with gonadotropin-releasing hormone (GnRH) agonist are presented.
Time Frame
End-of-stimulation (up to 20 stimulation days)
Title
Number of Oocytes Retrieved
Time Frame
Day of oocyte retrieval
Title
Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
Time Frame
Day of oocyte retrieval
Title
Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection])
Description
Number of oocytes in metaphase II prior to ICSI insemination is presented.
Time Frame
Prior to insemination
Title
Fertilisation Rate
Description
Fertilisation rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
Time Frame
Day 1 after insemination
Title
Number and Quality of Embryos on Day 3
Description
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.
Time Frame
On day 3 after oocyte retrieval
Title
Number and Quality of Blastocysts on Day 5
Description
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.
Time Frame
On day 5 after oocyte retrieval
Title
Total Gonadotropin Dose
Description
The total gonadotropin dose was recorded.
Time Frame
End-of-stimulation (up to 20 stimulation days)
Title
Number of Stimulation Days
Time Frame
End-of-stimulation (up to 20 stimulation days)
Title
Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments
Time Frame
End-of-stimulation (up to 20 stimulation days)
Title
Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period
Description
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.
Time Frame
End-of-stimulation (up to 20 stimulation days)
Title
Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS)
Description
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).
Time Frame
End-of-stimulation and day of blastocyst transfer
Title
Changes in Body Weight
Description
Change in body weight from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
Time Frame
End-of-stimulation and day of blastocyst transfer
Title
Changes in Maximum Abdominal Circumference
Description
Change in maximum abdominal circumference from baseline to end-of-stimulation and from baseline to day of blastocyst transfer.
Time Frame
End-of-stimulation and day of blastocyst transfer
Title
Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies
Description
The proportion of subjects with at least one treatment-induced anti-FSH antibody response at any time point.
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
Title
Proportion of Subjects With Late OHSS
Description
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.
Time Frame
>9 days after triggering of final follicular maturation
Title
Technical Malfunctions of the Administration Pen
Description
Confirmed technical malfunction of administration pen.
Time Frame
End-of-stimulation (up to 20 stimulation days)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Development Support
Organizational Affiliation
Ferring Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
UZ Brussel (there may be other sites in this country)
City
Brussels
Country
Belgium
Facility Name
Fertilitat and PUC-RS (there may be other sites in this country)
City
Porto Alegre
Country
Brazil
Facility Name
Pacific Centre for Reproductive Medicine
City
Burnaby
State/Province
British Columbia
Country
Canada
Facility Name
Olive Fertility Centre
City
Vancouver
State/Province
British Columbia
Country
Canada
Facility Name
Ottawa Fertility Centre
City
Ottawa
State/Province
Ontario
Country
Canada
Facility Name
IVF CUBE SE (there may be other sites in this country)
City
Prague
Country
Czechia
Facility Name
Rigshospitalet Fertilitetsklinikken (there may be other sites in this country)
City
Copenhagen
Country
Denmark
Facility Name
Department of Endocrine Gynaecology and Reproductive Medicine, Hôpital Jeanne de Flandre (there may be other sites in this country)
City
Lille
Country
France
Facility Name
Centro Natalità San Raffaele (there may be other sites in this country)
City
Milano
Country
Italy
Facility Name
The nOvum Clinic (there may be other sites in this country)
City
Warszawa
Country
Poland
Facility Name
IVF & Reproductive Genetics Center (there may be other sites in this country)
City
Moscow
Country
Russian Federation
Facility Name
IVI Sevilla (there may be other sites in this country)
City
Sevilla
Country
Spain
Facility Name
Glasgow Centre for Reproductive Medicine Ltd. (there may be other sites in this country)
City
Glasgow
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
32819842
Citation
Arce JC, Larsson P, Garcia-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.
Results Reference
result
PubMed Identifier
34254211
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 Oct;38(10):2651-2661. doi: 10.1007/s10815-021-02271-5. Epub 2021 Jul 13.
Results Reference
result
PubMed Identifier
34799275
Citation
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.
Results Reference
result
PubMed Identifier
30801744
Citation
Nelson SM, Larsson P, Mannaerts BMJL, Nyboe Andersen A, Fauser BCJM. Anti-Mullerian 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.
Results Reference
derived
PubMed Identifier
27912901
Citation
Nyboe Andersen A, Nelson SM, Fauser BC, Garcia-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.
Results Reference
derived

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

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