Evidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 2

Study Overview
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Brief Summary
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This trial investigates the immunogenicity of FE 999049 in repeated cycles.

Official Title
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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

Conditions
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Infertility

Intervention / Treatment
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* Drug: Follitropin Delta (FE 999049)
* Drug: Follitropin Alfa (GONAL-F)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Follitropin Delta (FE 999049) (COS cycle 2) | Drug: Follitropin Delta (FE 999049)<br> <br> |
| Active Comparator: B<br>Follitropin Alfa (GONAL-F) (COS cycle 2) | Drug: Follitropin Alfa (GONAL-F)<br> <br> |
| Experimental: C<br>Follitropin Delta (FE 999049) (COS cycle 3) | Drug: Follitropin Delta (FE 999049)<br> <br> |
| Active Comparator: D<br>Follitropin Alfa (GONAL-F) (COS cycle 3) | Drug: Follitropin Alfa (GONAL-F)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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. | ≤9 days after triggering of final follicular maturation. | 
| 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. | End-of-stimulation (up to 20 stimulation days) | 
| 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. | 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. | 5-6 weeks after blastocyst transfer | 
| 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. | 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. | 10-11 weeks after blastocyst transfer | 
| 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. | End-of-stimulation (up to 20 stimulation days) | 
| 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. | >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. | End-of-stimulation (up to 20 stimulation days) |