Back to resultsEvidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 2 (ESTHER-2)
Primary Purpose
Infertility
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Follitropin Delta (FE 999049)
Follitropin Alfa (GONAL-F)
Sponsored by
About this trial
This is an interventional treatment trial for Infertility
Eligibility Criteria
Inclusion Criteria:
- Informed Consent Documents signed prior to screening evaluations related to this protocol
- Participation in the pivotal efficacy trial (trial 000004/ESTHER-1)
- Anti-FSH antibody results from baseline and at least one post-dosing assessment in the previous cycle(s) available.
- Having undergone the oocyte retrieval procedure, or having had cycle cancellation prior to oocyte retrieval due to poor ovarian response or excessive ovarian response, in the previous cycle(s).
- Failure to achieve ongoing pregnancy in the previous cycle(s).
Exclusion Criteria:
- Non-compliance to protocol compliance in the previous cycle(s).
- Having undergone any stimulation with gonadotropins since the end-of-trial / end-of-cycle visit in the previous cycle
- One or more follicles ≥10 mm observed on the transvaginal ultrasound prior to start of dosing on stimulation day 1
- Severe OHSS in a previous cycle.
- Any clinically relevant change to any of the eligibility criteria in the previous cycle(s).
- Clinically relevant medical history since the previous cycle which precludes gonadotropin stimulation or is associated with a reduced chance of pregnancy.
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 3
Arm 4
Arm Type
Experimental
Active Comparator
Experimental
Active Comparator
Arm Label
A
B
C
D
Arm Description
Follitropin Delta (FE 999049) (COS cycle 2)
Follitropin Alfa (GONAL-F) (COS cycle 2)
Follitropin Delta (FE 999049) (COS cycle 3)
Follitropin Alfa (GONAL-F) (COS cycle 3)
Outcomes
Primary Outcome Measures
Proportion (Percentage) of Subjects With Treatment-induced Anti-Follicle-Stimulating Hormone (FSH) Antibodies After up to Two Repeated Controlled Ovarian Stimulation Cycles
The proportion (percentage) of participants with at least one treatment-induced anti-FSH antibody response at any time point is presented. The cumulative incidences in COS cycle 2 and COS cycle 3 divided by participants in COS cycle 2 are presented. Participants with observations in both cycles are only counted once.
Secondary Outcome Measures
Proportion (Percentage) of Subjects With Treatment-induced Anti-FSH Antibodies With Neutralising Capacity After up to Two Repeated Controlled Ovarian Stimulation Cycles
The proportion (percentage) of participants with treatment-induced anti-FSH antibodies with neutralising capacity at any time point is presented. The cumulative incidences in COS cycle 2 and COS cycle 3 divided by participants in COS cycle 2 are presented. Participants with observations in both cycles are only counted once.
Proportion (Percentage) of Subjects With Treatment-induced Anti-FSH Antibodies, Overall as Well as With Neutralising Capacity, After One and After Two Repeated Controlled Ovarian Stimulation Cycles
The proportion (percentage) of participants with treatment-induced anti-FSH antibodies, overall as well as with neutralising capacity, after one and after two repeated COS cycles is presented.
Proportion (Percentage) of Subjects With Early Ovarian Hyperstimulation Syndrome (OHSS) (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS for Each Controlled Ovarian Stimulation Cycle
The proportion (percentage) of participants 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 (Percentage) of Subject With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response for Each Controlled Ovarian Stimulation Cycle
Proportion (percentage) of participants with cycle cancellation due to poor ovarian response, excessive ovarian response, and triggering with gonadotropin-releasing hormone (GnRH) agonist are presented.
Vital Pregnancy Rate for Each Controlled Ovarian Stimulation Cycle
Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after blastocyst transfer.
Implantation Rate for Each Controlled Ovarian Stimulation Cycle
Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by number of blastocysts transferred.
Ongoing Pregnancy Rate for Each Controlled Ovarian Stimulation Cycle
Ongoing pregnancy rate was defined as at least one intrauterine viable fetus 10-11 weeks after blastocyst transfer.
Ongoing Implantation Rate for Each Controlled Ovarian Stimulation Cycle
Ongoing implantation rate was defined as the number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred.
Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period for Each Controlled Ovarian Stimulation Cycle
Participants 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 assessment performed is presented.
Proportion (Percentage) of Subjects With Late OHSS (Including OHSS of Moderate/Severe Grade) for Each Controlled Ovarian Stimulation Cycle
Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation.
Technical Malfunctions of the Administration Pen for Each Controlled Ovarian Stimulation Cycle
Incidences of confirmed technical malfunction of administration pen are presented.
Full Information
NCT ID
NCT01956123
First Posted
August 16, 2013
Last Updated
August 9, 2023
Sponsor
Ferring Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT01956123
Brief Title
Evidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 2
Acronym
ESTHER-2
Official Title
A Controlled, Assessor-blind, Parallel Groups, Multicentre, Multinational Trial Evaluating the Immunogenicity of FE 999049 in Repeated Cycles of Controlled Ovarian Stimulation in Women Undergoing an Assisted Reproductive Technology Programme
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
March 26, 2014 (Actual)
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 immunogenicity of FE 999049 in repeated cycles.
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
Non-Randomized
Enrollment
513 (Actual)
8. Arms, Groups, and Interventions
Arm Title
A
Arm Type
Experimental
Arm Description
Follitropin Delta (FE 999049) (COS cycle 2)
Arm Title
B
Arm Type
Active Comparator
Arm Description
Follitropin Alfa (GONAL-F) (COS cycle 2)
Arm Title
C
Arm Type
Experimental
Arm Description
Follitropin Delta (FE 999049) (COS cycle 3)
Arm Title
D
Arm Type
Active Comparator
Arm Description
Follitropin Alfa (GONAL-F) (COS cycle 3)
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
Proportion (Percentage) of Subjects With Treatment-induced Anti-Follicle-Stimulating Hormone (FSH) Antibodies After up to Two Repeated Controlled Ovarian Stimulation Cycles
Description
The proportion (percentage) of participants with at least one treatment-induced anti-FSH antibody response at any time point is presented. The cumulative incidences in COS cycle 2 and COS cycle 3 divided by participants in COS cycle 2 are presented. Participants with observations in both cycles are only counted once.
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
Secondary Outcome Measure Information:
Title
Proportion (Percentage) of Subjects With Treatment-induced Anti-FSH Antibodies With Neutralising Capacity After up to Two Repeated Controlled Ovarian Stimulation Cycles
Description
The proportion (percentage) of participants with treatment-induced anti-FSH antibodies with neutralising capacity at any time point is presented. The cumulative incidences in COS cycle 2 and COS cycle 3 divided by participants in COS cycle 2 are presented. Participants with observations in both cycles are only counted once.
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 (Percentage) of Subjects With Treatment-induced Anti-FSH Antibodies, Overall as Well as With Neutralising Capacity, After One and After Two Repeated Controlled Ovarian Stimulation Cycles
Description
The proportion (percentage) of participants with treatment-induced anti-FSH antibodies, overall as well as with neutralising capacity, after one and after two repeated COS cycles is presented.
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 (Percentage) of Subjects With Early Ovarian Hyperstimulation Syndrome (OHSS) (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS for Each Controlled Ovarian Stimulation Cycle
Description
The proportion (percentage) of participants 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 (Percentage) of Subject With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response for Each Controlled Ovarian Stimulation Cycle
Description
Proportion (percentage) of participants 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
Vital Pregnancy Rate for Each Controlled Ovarian Stimulation Cycle
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 for Each Controlled Ovarian Stimulation Cycle
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
Ongoing Pregnancy Rate for Each Controlled Ovarian Stimulation Cycle
Description
Ongoing pregnancy rate 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 for Each Controlled Ovarian Stimulation Cycle
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
Title
Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period for Each Controlled Ovarian Stimulation Cycle
Description
Participants 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 assessment performed is presented.
Time Frame
End-of-stimulation (up to 20 stimulation days)
Title
Proportion (Percentage) of Subjects With Late OHSS (Including OHSS of Moderate/Severe Grade) for Each Controlled Ovarian Stimulation Cycle
Description
Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation.
Time Frame
>9 days after triggering of final follicular maturation
Title
Technical Malfunctions of the Administration Pen for Each Controlled Ovarian Stimulation Cycle
Description
Incidences of confirmed technical malfunction of administration pen are presented.
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 related to this protocol
Participation in the pivotal efficacy trial (trial 000004/ESTHER-1)
Anti-FSH antibody results from baseline and at least one post-dosing assessment in the previous cycle(s) available.
Having undergone the oocyte retrieval procedure, or having had cycle cancellation prior to oocyte retrieval due to poor ovarian response or excessive ovarian response, in the previous cycle(s).
Failure to achieve ongoing pregnancy in the previous cycle(s).
Exclusion Criteria:
Non-compliance to protocol compliance in the previous cycle(s).
Having undergone any stimulation with gonadotropins since the end-of-trial / end-of-cycle visit in the previous cycle
One or more follicles ≥10 mm observed on the transvaginal ultrasound prior to start of dosing on stimulation day 1
Severe OHSS in a previous cycle.
Any clinically relevant change to any of the eligibility criteria in the previous cycle(s).
Clinically relevant medical history since the previous cycle which precludes gonadotropin stimulation or is associated with a reduced chance of pregnancy.
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
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
37156263
Citation
Fernandez-Sanchez M, Fatemi H, Garcia-Velasco JA, Heiser PW, Daftary GS, Mannaerts B. Incidence and severity of ovarian hyperstimulation syndrome (OHSS) in high responders after gonadotropin-releasing hormone (GnRH) agonist trigger in "freeze-all" approach. Gynecol Endocrinol. 2023 Dec;39(1):2205952. doi: 10.1080/09513590.2023.2205952.
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
Learn more about this trial
Evidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 2
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