A Trial to Investigate the Efficacy and Safety of FE 999302 as add-on Treatment to Follitropin Delta (REKOVELLE) in Women Undergoing Controlled Ovarian Stimulation.

Controlled Ovarian Stimulation Clinical Trial

— RAINBOW  

Official title:

A Randomised, Double-blind, Placebo-controlled, Parallel-group, Dose-range Trial to Investigate the Efficacy and Safety of FE 999302 as add-on Treatment to Follitropin Delta (REKOVELLE) in Women Undergoing Controlled Ovarian Stimulation in a Long GnRH Agonist Protocol

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03564509
• Other study ID #: 000289
• Secondary ID: 2017-003810-13
• Status: Completed
• Phase: Phase 2
• Start date: May 14, 2018
• Est. completion date: January 8, 2020

Study information

• Verified date: January 2020
• Source: Ferring Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this phase 2 dose-ranging trial is to investigate the effects of FE 999302 on parameters influencing pregnancy rates in women undergoing Controlled Ovarian Stimulation (COS) with follitropin delta in a long gonadotropin releasing hormone (GnRH) agonist protocol. Furthermore, the study intends: - To investigate the safety of FE 999302 in women undergoing COS with follitropin delta in a long GnRH agonist protocol. - To investigate the potential immunogenicity of FE 999302 in subjects undergoing COS with follitropin delta in a long GnRH agonist protocol. - To estimate the impact of body weight on FE 999302 exposure in subjects undergoing COS with follitropin delta in a long GnRH agonist protocol.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 620
• Est. completion date: January 8, 2020
• Est. primary completion date: October 21, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 30 Years to 42 Years

Eligibility

Inclusion Criteria:

• Informed consent documents signed prior to screening evaluations.
• In good physical and mental health as judged by the investigator.
• Anti-Müllerian hormone (AMH) levels at screening of 5.0-35.0 pmol/L (as measured by Elecsys® AMH Plus Immunoassay [Roche Diagnostics] at central laboratory).
• Pre-menopausal women between the ages of 30 and 42 years. The subjects must be at least 30 years (including the 30th birthday) and no more than 42 years (up to the day before the 43rd birthday) when they sign the informed consent.
• 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 and/or intracytoplasmic sperm injection using fresh or frozen ejaculated sperm from male partner or sperm donor.
• Infertility for at least 1 year before screening for subjects less than 35 years or for at least 6 months for subjects greater than equal to (=)35 years (not applicable in case of tubal or severe male factor infertility).

Exclusion Criteria:

• Known polycystic ovary syndrome (PCOS) associated with anovulation or known endometriosis stage III-IV (defined by the revised American Society for Reproductive Medicine [ASRM] classification, 1996).
• One or more follicles =10 mm (including cysts) observed on the transvaginal ultrasound after down-regulation prior to randomisation on stimulation day 1 (puncture of cysts is allowed prior to randomisation).
• Pregnancy (negative pregnancy tests must be documented at screening and prior to start of down-regulation) or contraindication to pregnancy.

Related Conditions & MeSH terms

• Controlled Ovarian Stimulation

Intervention

Drug:
• FE 999302 (1 µg) and follitropin delta
Daily dose of 1 µg of FE 999302, a recombinant human chorionic gonadotropin (rhCG) solution for subcutaneous injection; individualized follitropin delta dose.
• FE 999302 (2 µg) and follitropin delta
Daily dose of 2 µg of FE 999302, a rhCG solution for subcutaneous injection; individualized follitropin delta dose.
• FE 999302 (4 µg) and follitropin delta
Daily dose of 4 µg of FE 999302, a rhCG solution for subcutaneous injection; individualized follitropin delta dose.
• FE 999302 (8 µg) and follitropin delta
Daily dose of 8 µg of FE 999302, a rhCG solution for subcutaneous injection; individualized follitropin delta dose.
• FE 999302 (12 µg) and follitropin delta
Daily dose of 12 µg of FE 999302, a rhCG solution for subcutaneous injection; individualized follitropin delta dose.

Other:
• Placebo and follitropin delta
Daily dose of placebo; individualized follitropin delta dose.

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Gent (UZ Gent)	Gent
Belgium	Universitair Ziekenhuis Brussel	Jette
Czechia	Institut fur Reproduktionsmedizin und Genetik	Karlovy Vary
Czechia	Fertimed	Olomouc
Czechia	GYNEM	Praha
Czechia	IVF CUBE	Praha
Denmark	Aalborg University Hospital	Aalborg
Denmark	Rigshospitalet	Copenhagen
Denmark	Dansk Fertilitetsklinik	Frederiksberg
Denmark	Hvidovre Hospital	Hvidovre
Spain	Dexeus Woman's Health	Barcelona
Spain	Instituto Valenciano de Infertilidad (IVI) - Bilbao	Leioa
Spain	GINEFIV - Clinica Belen Location	Madrid
Spain	Instituto Valenciano de Infertilidad (IVI) - Madrid	Madrid
Spain	Instituto Valenciano de Infertilidad (IVI) - Sevilla	Sevilla
Spain	Instituto Valenciano de Infertilidad (IVI) - Valencia	Valencia
United Kingdom	Glasgow Royal Infirmary	Glasgow
United Kingdom	Liverpool Women's Hospital	Liverpool
United Kingdom	Guy's and St Thomas' NHS Trust	London
United Kingdom	Kings College (Assisted Conception Unit)	London

Sponsors (1)

Lead Sponsor	Collaborator
Ferring Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  Czechia,  Denmark,  Spain,  United Kingdom, 

References & Publications (1)

Sanchez MF, Larsson P, Serrano MF, Bosch E, Velasco JAG, Lopez ES, Mannaerts B. Live birth rates following individualized dosing algorithm of follitropin delta in a long GnRH agonist protocol. Reprod Biol Endocrinol. 2023 May 16;21(1):45. doi: 10.1186/s12 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of good-quality blastocysts on Day 5 after oocyte retrieval	Quality of blastocysts was assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cell).	On Day 5 after oocyte retrieval
Secondary	Number of subjects with at least one good-quality blastocyst on Day 5 after oocyte retrieval	Quality of blastocysts was assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cell).	On Day 5 after oocyte retrieval
Secondary	Number of subjects with at least two good-quality blastocysts on Day 5 after oocyte retrieval	Quality of blastocysts was assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cell).	On Day 5 after oocyte retrieval
Secondary	Number and quality of embryos on Day 3 after oocyte retrieval	Embryo quality was assessed by cleavage stage and embryo morphology parameters. The total number of embryos and the number of embryos per quality category were reported.	On Day 3 after oocyte retrieval
Secondary	Number and quality of blastocysts on Day 5 after oocyte retrieval	Blastocyst quality was assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cells).; The total number of blastocysts and the number of blastocysts per quality category will be reported.	On Day 5 after oocyte retrieval
Secondary	Changes in serum hormone levels	Blood samples for analysis of hormone concentrations were drawn at stimulation Day 1, stimulation Day 6, stimulation Day 8, last day of stimulation, and at oocyte retrieval.	Stimulation Day 1 (baseline), stimulation Day 6, stimulation Day 8, end-of-stimulation (up to 20 stimulation days), and oocyte retrieval
Secondary	Number and size of follicles on stimulation Day 6	Number and size of follicles assessed using transvaginal ultrasound. The total number of follicles and the number of follicles per size category were reported.	On stimulation Day 6
Secondary	Number and size of follicles at end-of-stimulation	Number and size of follicles assessed using transvaginal ultrasound. The total number of follicles and the number of follicles per size category were reported.	At end-of-stimulation (up to 20 stimulation days)
Secondary	Positive beta human chorionic gonadotropin (ßhCG) rate	Proportion of patients with positive blood ßhCG confirmed by a blood test.	13-15 days after blastocyst transfer
Secondary	Clinical pregnancy rate	Clinical pregnancy was defined as at least one gestational sac, either intrauterine or ectopic.	5-6 weeks after blastocyst transfer
Secondary	Vital pregnancy rate	Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat, as assessed by transvaginal ultrasound.	5-6 weeks after blastocyst transfer
Secondary	Ongoing pregnancy rate	Ongoing pregnancy was defined as at least one intrauterine viable fetus, assessed using transvaginal or abdominal ultrasound.	10-11 weeks after blastocyst transfer
Secondary	Number of oocytes retrieved		On the day of oocyte retrieval
Secondary	Number of metaphase II oocytes		On the day of oocyte retrieval
Secondary	Number of fertilised 2 pronuclei (2PN) oocytes		On day 1 after insemination
Secondary	Total gonadotropin dose	The daily dose of FE 999302 or placebo, and follitropin delta were recorded.	At end-of-stimulation (up to 20 stimulation days)
Secondary	Total number of stimulation days	The start and end dates of administration of FE 999302 or placebo, and follitropin delta were recorded.	At end-of-stimulation (up to 20 stimulation days)
Secondary	Incidence of cycle cancellation	Cycle cancellation due to poor ovarian response or excessive ovarian response.	At end-of-stimulation (up to 20 stimulation days)
Secondary	Serum concentrations of FE 999302		On stimulation Day 1 (prior to first dose of FE 999302 or placebo), stimulation Day 6, stimulation Day 8, end-of-stimulation (up to 20 stimulation days)
Secondary	Incidence of ovarian hyperstimulation syndrome (OHSS) (early or late, any grade)	Early OHSS was defined as OHSS with onset less than equal to 9 days after triggering of final follicular maturation.; Late OHSS was defined as OHSS with onset greater than 9 days after triggering of final follicular maturation.; All OHSS cases were graded as mild, moderate or severe.	From stimulation Day 1 to end-of-trial (estimated maximum of 4 months from start of stimulation)
Secondary	Incidence and intensity of adverse events (AEs)		From screening to end-of-trial (estimated maximum of 4 months from start of stimulation)
Secondary	Changes in circulating levels of clinical chemistry and haematology parameters		At screening, on stimulation Day 1, end-of-stimulation (up to 20 stimulation days), end-of-trial (estimated maximum of 4 months from start of stimulation)
Secondary	Incidence and intensity of injection site reactions after FE 999302 administration (redness, pain, itching, swelling and bruising) assessed by the subject during the stimulation period		Immediately after injection of FE 999302 or placebo, 30 minutes after injection, and 24 hours after injection
Secondary	Incidence of treatment-induced anti-FE 999302 antibodies, overall as well as with neutralising capacity	The proportion of subjects with treatment-induced anti-FE999302 antibodies as well as the proportion of subjects with treatment-induced anti-FE999302 antibodies with neutralizing capacity were reported.	On stimulation Day 1, end-of-stimulation (up to 20 stimulation days), 19-28 days after the last FE999302 or placebo dose
Secondary	Incidence of multi-fetal gestation		5 to 6 weeks after transfer
Secondary	Incidence of biochemical pregnancy	Biochemical pregnancy was defined as positive ßhCG test but no gestational sac was observed on transvaginal ultrasound conducted later, or menstruation is; was reported.	Up to 5 to 6 weeks after transfer
Secondary	Incidence of spontaneous abortion (with and without medical/surgical intervention)	Spontaneous abortion was defined as positive ßhCG test but all intrauterine gestational sacs without fetal heart beat as documented by ultrasound, or there were no viable fetuses observed by ultrasound.	Up to 10 to 11 weeks after transfer
Secondary	Incidence of ectopic pregnancy (with and without medical/surgical intervention)	Ectopic pregnancy was defined as extrauterine gestational sac with or without fetal heart beat as documented by ultrasound or surgery.	Up to 5 to 6 weeks after transfer
Secondary	Incidence of vanishing twins	Vanishing twin was defined as spontaneous disappearance of an intrauterine gestational sac with or without heart beat in a pregnancy where one viable fetus remained as documented by ultrasound.	Up to 10 to 11 weeks after transfer