Clinical trial NCT03738618: Recombinant FSH Investigation in the Treatment of Infertility With Assisted Reproductive Technology (ART) (RITA-2)
Official title: A Randomized, Double-blind, Placebo-controlled, Parallel Groups, Multicenter Trial Investigating the Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Women Aged 35-42 Years Undergoing Assisted Reproductive Technology
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infertility, Female
Lead sponsor: Ferring Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2018-11-13
Enrollment: 588
Sex: FEMALE
Minimum age (years): 35
Maximum age (years): 42
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 placebo.


Eligibility criteria: Inclusion Criteria:

* Informed Consent Documents signed prior to any trial-related procedure.
* In good physical and mental health in the judgement of the investigator.
* Pre-menopausal women between the ages of 35 and 42 years. The participants must be at least 35 years (including the 35th birthday) when they sign the informed consent and no more than 42 years (up to the day before the 42nd birthday) at the time of randomization.
* Body mass index (BMI) between 17.5 and 38.0 kg/m\^2 (both inclusive) at screening.
* Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor.
* Documented history of infertility for at least 6 months before randomization (not applicable in case of tubal or severe male factor infertility, or when the use of donor sperm is indicated).
* Regular menstrual cycles of 24-35 days (both inclusive).
* Hysterosalpingography, hysteroscopy or saline infusion sonography, documenting a uterus consistent with expected normal function (e.g. no evidence of clinically interfering uterine fibroids defined as submucous fibroids of any size 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) at screening or within 1 year prior to screening.
* Transvaginal ultrasound documenting presence and adequate visualization of both ovaries, without evidence of significant abnormality (e.g. enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) at screening. 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 randomization).
* Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests at screening or within 6 months prior to screening.
* Willing to accept the blastocyst transfer policy for the fresh cycle and the cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation using blastocysts obtained in this trial, i.e. transfer of one blastocyst (if a good-quality blastocyst is available) or transfer of one or two blastocysts (if no good-quality blastocyst is available).

Exclusion Criteria:

* More than one previous controlled ovarian stimulation cycle for IVF/ICSI.
* Known endometriosis stage III-IV (defined by the revised ASRM classification, 2012).
* Known history of anovulation.
* One or more follicles greater than or equal to 10 mm (including cysts) observed on the transvaginal ultrasound prior to randomization on stimulation day 1.
* Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy \[excluding ectopic pregnancy\] and before week 24 of pregnancy).
* Known abnormal karyotype of participant or of her partner / sperm donor, as applicable, depending on source of sperm used for insemination in this trial. In case partner sperm will be used and the sperm production is severely impaired (concentration less than 1 million/mL), normal karyotype, including no Y-chromosome microdeletion, must be documented.
* Any known clinically significant systemic disease (e.g. insulin-dependent diabetes).
* Known inherited or acquired thrombophilia.
* Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
* Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) with the exception of pharmacologically controlled sub-clinical hypothyroidism.
* Known tumors of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins.
* Known moderate or severe impairment of renal or hepatic function.
* Any abnormal finding of clinical chemistry, hematology, thyroid-stimulating hormone (TSH) or prolactin, or vital signs at screening, which is judged clinically significant by the investigator.
* Known abnormal cervical cytology of clinical significance observed within three years prior to randomization (unless the clinical significance has been resolved).
* Findings at the gynecological examination at screening which preclude gonadotropin stimulation or are associated with a reduced chance of pregnancy, e.g. congenital uterine abnormalities or retained intrauterine device.
* Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to randomization) or contraindication to pregnancy.
* Known current active pelvic inflammatory disease.
* Use of fertility modifiers during the last menstrual cycle before randomization, including dehydroepiandrosterone (DHEA), metformin or cycle programming with oral contraceptives, progestogen or estrogen preparations.

Primary outcomes:
measure: Cumulative Ongoing Pregnancy Rate After the Fresh Cycle and Cryopreserved Cycles Initiated Within 12 Months From the Start of Controlled Ovarian Stimulation (COS)
timeFrame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
Secondary outcomes:
measure: Ongoing Pregnancy Rate in the Fresh Cycle and in the Cryopreserved Cycles
timeFrame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
measure: Time From Start of COS to Ongoing Pregnancy Across the Fresh and Cryopreserved Cycles, Including Duration
timeFrame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
measure: Time From Start of COS to Ongoing Pregnancy Across the Fresh and Cryopreserved Cycles, Measured in Number of Cycles Before Achieving Ongoing Pregnancy
timeFrame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
measure: Ongoing Implantation Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively
timeFrame: 8-9 weeks after transfer (up to approximately 16 months after start of stimulation)
measure: Clinical Pregnancy Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively
timeFrame: 5-6 weeks after transfer (up to approximately 15 months after start of stimulation)
measure: Vital Pregnancy Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively
timeFrame: 5-6 weeks after transfer (up to approximately 15 months after start of stimulation)
measure: Implantation Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively
timeFrame: 5-6 weeks after transfer (up to approximately 15 months after start of stimulation)
measure: Positive Beta Human Chorionic Gonadotropin (βhCG) Rate in the Fresh Cycle, the Cryopreserved Cycles and Cumulatively
timeFrame: 10-14 days after transfer (up to approximately 14 months after start of stimulation)
measure: Proportion of Subjects in the Fresh Cycle With Triggering of Final Follicular Maturation (With hCG, With GnRH Agonist, and in Total), Cycle Cancellation and Transfer Cancellation
timeFrame: Up to 5 days after oocyte retrieval (up to 27 days after start of stimulation)
measure: Number of Follicles on Stimulation Day 5
timeFrame: On stimulation day 5
measure: Number of Follicles at End-of-stimulation
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Size of Follicles on Stimulation Day 5
timeFrame: On stimulation day 5
measure: Size of Follicles at End-of-stimulation
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Number of Oocytes Retrieved
timeFrame: On day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Proportion of Subjects With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved
timeFrame: On day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Number of Metaphase II Oocytes
timeFrame: On day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Number of Fertilized Oocytes
timeFrame: On day 1 after oocyte retrieval (up to 23 days after start of stimulation)
measure: Fertilization Rate
timeFrame: On day 1 after oocyte retrieval (up to 23 days after start of stimulation)
measure: Number and Quality of Blastocysts on Day 5 After Oocyte Retrieval
timeFrame: On day 5 after oocyte retrieval
measure: Endometrial Thickness on Stimulation Day 5
timeFrame: On stimulation day 5
measure: Endometrial Thickness at End-of-stimulation
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Echogenicity Pattern on Stimulation Day 5
timeFrame: On stimulation day 5
measure: Echogenicity Pattern at End-of-stimulation
timeFrame: At end-of-stimulation (up to 20 stimulation days)
measure: Oocyte Utilization Rate
timeFrame: On day of oocyte retrieval up to 12 months after start of COS
measure: Oocyte Efficiency Index
timeFrame: 8-9 weeks after transfer
measure: Percentage of Blastocysts Surviving Cryopreservation
timeFrame: 0 hour (+0.5 hour) after thawing
measure: Percentage of Blastocysts With Re-expansion After Cryopreservation
timeFrame: 2.5 hour (±0.5 hour) after thawing
measure: Number of Cryopreserved Cycles Initiated Within 12 Months From the Start of COS
timeFrame: Up to 12 months after start of stimulation
measure: Number of Cryopreserved Cycles With Blastocyst Transfer
timeFrame: Up to 12 months after start of stimulation
measure: Circulating Concentrations of Anti-mullerian Hormone (AMH)
timeFrame: From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Circulating Concentrations of Follicle-stimulating Hormone (FSH)
timeFrame: From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Circulating Concentrations of Luteinizing Hormone (LH)
timeFrame: From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Circulating Concentrations of Estradiol
timeFrame: From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Circulating Concentrations of Progesterone
timeFrame: From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Circulating Concentrations of Inhibin A
timeFrame: From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Circulating Concentrations of Inhibin B
timeFrame: From screening to the day of oocyte retrieval (up to 22 days after start of stimulation)
measure: Total Gonadotropin Dose
timeFrame: Up to 20 stimulation days
measure: Number of Stimulation Days
timeFrame: Up to 20 stimulation days
measure: Proportion of Participants With Investigator-requested Gonadotropin Dose Adjustments
timeFrame: Stimulation Day 5
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: From time of signing informed consent until the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Intensity of AEs
timeFrame: From time of signing informed consent until the end-of-cycle visit in the fresh cycle (up to approximately 6 months)
measure: Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Albumin, Protein
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase and Gamma Glutamyl Transferase
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Bicarbonate, Blood Urea Nitrogen, Calcium, Chloride, Cholesterol, Glucose, Phosphate, Potassium and Sodium
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Direct Bilirubin, Total Bilirubin, Creatinine, Urate
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Circulating Levels of Clinical Chemistry Compared to Baseline: Lactate Dehydrogenase
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Haematology Parameters Compared to Baseline: Erythrocytes
timeFrame: From screening to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Haematology Parameters Compared to Baseline: Haemoglobin
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Haematology Parameters Compared to Baseline: Haematocrit
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Haematology Parameters Compared to Baseline: Erythrocyte Mean Corpuscular Volume
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Haematology Parameters Compared to Baseline: Leukocytes and Platelets
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Haematology Parameters Compared to Baseline: Erythrocyte Mean Corpuscular Hemoglobin
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Haematology Parameters Compared to Baseline: Erythrocyte Mean Corpuscular Haemoglobin Concentration
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Changes in Haematology Parameters Compared to Baseline: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Proportion of Subjects With Markedly Abnormal Changes of Clinical Chemistry Parameters: Alanine Aminotransferase, Aspartate Aminotransferase, Bicarbonate, Calcium, Potassium
timeFrame: From screening (baseline) to the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Proportion of Subjects With Markedly Abnormal Changes of Haematology Parameters: Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Neutrophils/Leukocytes
timeFrame: From screening (baseline) to the end-of-stimulation visit and end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Frequency and Intensity 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: Intensity 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: Proportion of Subjects With Treatment-induced Anti-FSH Antibodies, Overall as Well as With Neutralizing Capacity
timeFrame: Up to 28 days after end of the stimulation period
measure: Frequency and Intensity of Immune-related Adverse Events
timeFrame: From time of signing informed consent for participation in the trial until the end-of-cycle visit in the fresh cycle (approximately 6 months)
measure: Proportion of Subjects With Cycle Cancellations Due to an Adverse Event, Including Immune-related Adverse Events, or Due to Technical Malfunctions of the Administration Pen
timeFrame: Up to 20 stimulation days
measure: Proportion of Subjects With OHSS, Overall and by Grade, and Proportion of Subjects With Moderate/Severe OHSS
timeFrame: ≤9 days after triggering of final follicular maturation (early OHSS), >9 days after triggering of final follicular maturation until 21-28 days after last IMP dose or up to ongoing pregnancy 8-9 weeks after transfer in pregnant participants (late OHSS)
measure: Proportion of Subjects Hospitalized Due to OHSS and Proportion of Subjects Undergoing Paracentesis Due to OHSS
timeFrame: ≤9 days after triggering of final follicular maturation (early OHSS), >9 days after triggering of final follicular maturation until 21-28 days after last IMP dose or up to ongoing pregnancy 8-9 weeks after transfer in pregnant participants (late OHSS)
measure: Proportion of Participants With Multi-fetal Gestation in the Fresh Cycle
timeFrame: Up to 8-9 weeks after transfer
measure: Proportion of Cryopreserved Cycles With Multi-fetal Gestation
timeFrame: Up to 8-9 weeks after transfer
measure: Biochemical Pregnancy, Spontaneous Abortion, Ectopic Pregnancy (With and Without Medical/Surgical Intervention) and Vanishing Twins in the Fresh Cycle
timeFrame: Up to 8-9 weeks after transfer
measure: Biochemical Pregnancy, Spontaneous Abortion, Ectopic Pregnancy (With and Without Medical/Surgical Intervention) and Vanishing Twins in the Cryopreserved Cycles
timeFrame: Up to 8-9 weeks after transfer
measure: Proportion of Participants With Technical Malfunctions of the Administration Pen
timeFrame: Up to 20 stimulation days
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Fertility Treatment Center
state: Arizona
city: Encino
country: United States
facility: HRC Fertility
state: California
city: Farmington
country: United States
facility: Center for Advanced Reproductive Services PC
state: Connecticut
city: Newark
country: United States
facility: Reproductive Associates of Delaware
state: Delaware
city: Clearwater
country: United States
facility: Women's Medical Research Group, LLC
state: Florida
city: Winter Park
country: United States
facility: Center for Reproductive Medicine
state: Florida
city: Honolulu
country: United States
facility: Fertility Institute of Hawaii, INC
state: Hawaii
city: Chicago
country: United States
facility: Fertility Centers of Illinois (RH)
state: Illinois
city: Hoffman Estates
country: United States
facility: InVia Fertility
state: Illinois
city: Waltham
country: United States
facility: Boston IVF
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Columbia University Fertility Center
state: New York
city: Charlotte
country: United States
facility: Reproductive Endocrinology Associates of Charlotte (REACH) S. Corporation
state: North Carolina
city: Raleigh
country: United States
facility: Carolina Conceptions
state: North Carolina
city: Cincinnati
country: United States
facility: Institute for Reproductive Health
state: Ohio
city: Abington
country: United States
facility: Abington Reproductive Medicine
state: Pennsylvania
city: Bryn Mawr
country: United States
facility: Main Line Fertility Center
state: Pennsylvania
city: Memphis
country: United States
facility: Fertility Associates of Memphis, PLLC
state: Tennessee
city: Bedford
country: United States
facility: Center for Assisted Reproduction
state: Texas
city: Houston
country: United States
facility: Houston Fertility Institute
state: Texas
city: Webster
country: United States
facility: Center of Reproductive Medicine
state: Texas
city: Pleasant Grove
country: United States
facility: Utah Fertility Center
state: Utah
city: Norfolk
country: United States
facility: Eastern Virginia Medical School | EVMS Obstetrics & Gynecology
state: Virginia
city: Seattle
country: United States
facility: Seattle Reproductive Medicine WA
state: Washington
Study officials:
affiliation: Ferring Pharmaceuticals
name: Global Clinical Compliance
role: STUDY_DIRECTOR
References: