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. (RAINBOW)

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

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.

Study Overview

• Status: Completed
• Conditions: Controlled Ovarian Stimulation
• Intervention / Treatment: Drug: FE 999302 (1 μg) and follitropin delta; Drug: FE 999302 (2 μg) and follitropin delta; Drug: FE 999302 (4 μg) and follitropin delta; Drug: FE 999302 (8 μg) and follitropin delta; Drug: FE 999302 (12 μg) and follitropin delta; Other: Placebo and follitropin delta

• Study Type: Interventional
• Enrollment (Actual): 620
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 42 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo and follitropin delta	Other: Placebo and follitropin delta; Daily dose of placebo; individualized follitropin delta dose.
Experimental: FE 999302 (1 μg) and follitropin delta	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.; Other Names: Choriogonadotropin beta
Experimental: FE 999302 (2 μg) and follitropin delta	Drug: 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.; Other Names: Choriogonadotropin beta
Experimental: FE 999302 (4 μg) and follitropin delta	Drug: 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.; Other Names: Choriogonadotropin beta
Experimental: FE 999302 (8 μg) and follitropin delta	Drug: 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.; Other Names: Choriogonadotropin beta
Experimental: FE 999302 (12 μg) and follitropin delta	Drug: 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 Names: Choriogonadotropin beta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive beta human chorionic gonadotropin (βhCG) rate	Proportion of patients with positive blood βhCG confirmed by a blood test.	13-15 days after blastocyst transfer
Clinical pregnancy rate	Clinical pregnancy was defined as at least one gestational sac, either intrauterine or ectopic.	5-6 weeks after blastocyst transfer
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
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
Number of oocytes retrieved		On the day of oocyte retrieval
Number of metaphase II oocytes		On the day of oocyte retrieval
Number of fertilised 2 pronuclei (2PN) oocytes		On day 1 after insemination
Incidence of cycle cancellation	Cycle cancellation due to poor ovarian response or excessive ovarian response.	At end-of-stimulation (up to 20 stimulation days)
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)
Incidence and intensity of adverse events (AEs)		From screening to end-of-trial (estimated maximum of 4 months from start of stimulation)
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)
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
Incidence of multi-fetal gestation		5 to 6 weeks after transfer
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
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
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
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
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
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
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)
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)
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)
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)
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
Incidence of biochemical pregnancy	Biochemical pregnancy was defined as positive βhCG 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
Incidence of spontaneous abortion (with and without medical/surgical intervention)	Spontaneous abortion was defined as positive βhCG 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
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
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

Collaborators and Investigators

• Sponsor: Ferring Pharmaceuticals
• Investigators: Study Director: Global Clinical Compliance, Ferring Pharmaceuticals

Publications and helpful links

General Publications

• 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/s12958-023-01090-w.

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2018
• Primary Completion (Actual): October 21, 2019
• Study Completion (Actual): January 8, 2020

Study Registration Dates

• First Submitted: May 16, 2018
• First Submitted That Met QC Criteria: June 8, 2018
• First Posted (Actual): June 21, 2018

Study Record Updates

• Last Update Posted (Estimated): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 28, 2023
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Human Chorionic Gonadotropin (hCG); Recombinant Human Chorionic Gonadotropin (rhCG); Controlled Ovarian Stimulation (COS); Assisted Reproductive Technologies (ART)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Reproductive Control Agents; Follicle Stimulating Hormone; Chorionic Gonadotropin
• Other Study ID Numbers: 000289; 2017-003810-13 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No