Clinical trial NCT01956110: Evidence-based Stimulation Trial With Human rFSH in Europe and Rest of World 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infertility
Lead sponsor: Ferring Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2013-10-08
Enrollment: 1329
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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.

Primary outcomes:
measure: Ongoing Pregnancy Rate
timeFrame: 10-11 weeks after blastocyst transfer
measure: Ongoing Implantation Rate
timeFrame: 10-11 weeks after blastocyst transfer
Secondary outcomes:
measure: Vital Pregnancy Rate
timeFrame: 5-6 weeks after blastocyst transfer
measure: Implantation Rate
timeFrame: 5-6 weeks after blastocyst transfer
measure: Proportion of Subjects With Extreme Ovarian Responses, Defined as <4, ≥15 or ≥20 Oocytes Retrieved
timeFrame: Day of oocyte retrieval
measure: Proportion of Subjects With Early OHSS (Ovarian Hyperstimulation Syndrome) and/or Preventive Interventions for Early OHSS
timeFrame: ≤9 days after triggering of final follicular maturation
measure: Proportion of Subjects With Cycle Cancellation Due to Poor Ovarian Response or Excessive Ovarian Response
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Number of Oocytes Retrieved
timeFrame: Day of oocyte retrieval
measure: Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
timeFrame: Day of oocyte retrieval
measure: Percentage of Metaphase II Oocytes (Oocytes Inseminated Using ICSI [Intracytoplasmic Sperm Injection])
timeFrame: Prior to insemination
measure: Fertilisation Rate
timeFrame: Day 1 after insemination
measure: Number and Quality of Embryos on Day 3
timeFrame: On day 3 after oocyte retrieval
measure: Number and Quality of Blastocysts on Day 5
timeFrame: On day 5 after oocyte retrieval
measure: Total Gonadotropin Dose
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Number of Stimulation Days
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Proportion of Subjects With Investigator-requested Gonadotropin Dose Adjustments
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Subject During the Stimulation Period
timeFrame: End-of-stimulation (up to 20 stimulation days)
measure: Abdominal Discomfort Related to Controlled Ovarian Stimulation as Assessed by a Visual Analogue Scale (VAS)
timeFrame: End-of-stimulation and day of blastocyst transfer
measure: Changes in Body Weight
timeFrame: End-of-stimulation and day of blastocyst transfer
measure: Changes in Maximum Abdominal Circumference
timeFrame: End-of-stimulation and day of blastocyst transfer
measure: Proportion of Subjects With Treatment-induced Anti-follicle-stimulating Hormone (FSH) Antibodies
timeFrame: 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
measure: Proportion of Subjects With Late OHSS
timeFrame: >9 days after triggering of final follicular maturation
measure: Technical Malfunctions of the Administration Pen
timeFrame: End-of-stimulation (up to 20 stimulation days)
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: UZ Brussel (there may be other sites in this country)
city: Porto Alegre
country: Brazil
facility: Fertilitat and PUC-RS (there may be other sites in this country)
city: Burnaby
country: Canada
facility: Pacific Centre for Reproductive Medicine
state: British Columbia
city: Vancouver
country: Canada
facility: Olive Fertility Centre
state: British Columbia
city: Ottawa
country: Canada
facility: Ottawa Fertility Centre
state: Ontario
city: Prague
country: Czechia
facility: IVF CUBE SE (there may be other sites in this country)
city: Copenhagen
country: Denmark
facility: Rigshospitalet Fertilitetsklinikken (there may be other sites in this country)
city: Lille
country: France
facility: Department of Endocrine Gynaecology and Reproductive Medicine, Hôpital Jeanne de Flandre (there may be other sites in this country)
city: Milano
country: Italy
facility: Centro Natalità San Raffaele (there may be other sites in this country)
city: Warszawa
country: Poland
facility: The nOvum Clinic (there may be other sites in this country)
city: Moscow
country: Russian Federation
facility: IVF & Reproductive Genetics Center (there may be other sites in this country)
city: Sevilla
country: Spain
facility: IVI Sevilla (there may be other sites in this country)
city: Glasgow
country: United Kingdom
facility: Glasgow Centre for Reproductive Medicine Ltd. (there may be other sites in this country)
Study officials:
affiliation: Ferring Pharmaceuticals
name: Clinical Development Support
role: STUDY_DIRECTOR
References:
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.
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.
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.
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.
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.