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Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese Women

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ClinicalTrials.gov Identifier: NCT03228680
Recruitment Status : Completed
First Posted : July 25, 2017
Results First Posted : March 24, 2021
Last Update Posted : January 14, 2022
Sponsor:
Information provided by (Responsible Party):
Ferring Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE July 13, 2017
First Posted Date  ICMJE July 25, 2017
Results First Submitted Date  ICMJE January 20, 2021
Results First Posted Date  ICMJE March 24, 2021
Last Update Posted Date January 14, 2022
Actual Study Start Date  ICMJE July 29, 2017
Actual Primary Completion Date June 10, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 1, 2021)
Number of Oocytes Retrieved [ Time Frame: 36h (± 2h) after triggering of final follicular maturation (On day of oocyte retrieval) ]
The number of oocytes retrieved was recorded at the oocyte retrieval visit.
Original Primary Outcome Measures  ICMJE
 (submitted: July 21, 2017)
Number of oocytes retrieved [ Time Frame: 36h (± 2h) after triggering of final follicular maturation ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 1, 2021)
  • Clinical Pregnancy Rate [ Time Frame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) ]
    Clinical pregnancy was defined as at least one gestational sac 5-6 weeks after transfer.
  • Positive Beta Unit of Human Chorionic Gonadotropin (Beta-hCG) Rate [ Time Frame: 13-15 days after transfer (up to approximately 1.5 months after start of stimulation) ]
    Defined as positive serum beta-hCG test 13-15 days after transfer.
  • Vital Pregnancy Rate [ Time Frame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) ]
    Vital pregnancy was defined as at least one intrauterine gestational sac with fetal heart beat 5-6 weeks after transfer.
  • Implantation Rate [ Time Frame: 5-6 weeks after transfer (up to approximately 3 months after start of stimulation) ]
    Implantation rate was defined as the number of gestational sacs 5-6 weeks after transfer divided by the number of blastocysts transferred.
  • Proportion of Participants With Cycle Cancellation Due to Poor or Excessive Ovarian Response [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
  • Proportion of Participants With Blastocyst Transfer Cancellation Due to Excessive Ovarian Response / OHSS Risk [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
  • Proportion of Participants With <4, 4-7, 8-14, 15-19 and ≥20 Oocytes Retrieved [ Time Frame: On the day of oocyte retrieval (up to 22 days after start of stimulation) ]
    Defined as proportion of participants grouped according to the number of oocytes retrieved. The proportion of participants with <4 oocytes (low response), 4-7 oocytes (moderate response), 8-14 oocytes (targeted response), 15-19 oocytes (hyperresponse) and ≥20 oocytes (severe hyperresponse) are presented.
  • Proportion of Participants With Extreme Ovarian Responses (Defined as <4, ≥15 or ≥20 Oocytes Retrieved) in Risk Population [ Time Frame: On the day of oocyte retrieval (up to 22 days after start of stimulation) ]
  • Proportion of Participants With Preventive Interventions for Early Ovarian Hyperstimulation Syndrome (OHSS) [ Time Frame: ≤9 days after triggering of final follicular maturation ]
  • Proportions of Participants With Early OHSS (Including OHSS of Moderate/Severe Grade) and/or Preventive Interventions for Early OHSS [ Time Frame: Up to 9 days after triggering of final follicular maturation ]
    Defined as proportion 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.
  • Proportions of Participants With Late OHSS (Including OHSS of Moderate/Severe Grade) [ Time Frame: >9 days after triggering of final follicular maturation ]
    Defined as proportions of participants with late OHSS (including OHSS of moderate/severe grade). Late OHSS was defined as OHSS with onset >9 days after triggering of final follicular maturation. The proportion of participants with late OHSS, and late OHSS of moderate or severe grade are presented. All OHSS cases were graded as mild, moderate, or severe.
  • Number of Follicles on Stimulation Day 6 [ Time Frame: At Day 6 of stimulation ]
    Defined as the number of follicles observed in both ovaries at the last transvaginal ultrasound (TVUS) in the stimulation phase (on stimulation Day 6).
  • Number of Follicles at End-of-stimulation [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    Defined as the number of follicles observed in both ovaries at the last TVUS in the stimulation phase (end-of-stimulation).
  • Size of Follicles on Stimulation Day 6 [ Time Frame: At Day 6 of stimulation ]
    Defined as size characteristics of follicles on stimulation Day 6. Average size of 3 largest follicles has been presented in this endpoint.
  • Size of Follicles at End-of-Stimulation [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    Defined as size characteristics of follicles at end-of-stimulation. Average size of 3 largest follicles has been presented in this endpoint.
  • Fertilization Rate [ Time Frame: Day 1 after oocyte retrieval (up to approximately 22 days after start of stimulation) ]
    The fertilization rate was defined as the number of oocytes with 2 pronuclei divided by the number of oocytes retrieved.
  • Number and Quality of Embryos [ Time Frame: Day 3 after oocyte retrieval (up to approximately 24 days after start of stimulation) ]
    Number of embryos (total and good-quality) on Day 3 are presented. A good-quality embryo was defined as an embryo with ≥6 blastomeres and fragmentation ≤20% on Day 3.
  • Number and Quality of Blastocysts [ Time Frame: Day 5 after oocyte retrieval (up to approximately 26 days after start of stimulation) ]
    Number of embryos (total and good-quality) on Day 5 are presented. The quality evaluation of blastocysts consisted of assessment of three parameters, as per the Gardner & Schoolcraft system: blastocyst expansion and hatching status (graded: 1-6), inner cell mass (graded: A-D) and trophectoderm (graded: A-D). A good-quality blastocyst was defined as a blastocyst of grade 3BB or higher.
  • Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) on Stimulation Day 6 [ Time Frame: At Day 6 of stimulation ]
    The median and inter-quartile range (IQR) of FSH and LH levels on stimulation Day 6 are presented.
  • Circulating Levels of Endocrine Parameters (Follicle-stimulating Hormone [FSH], Luteinising Hormone [LH]) at End-of-stimulation [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    The median and IQR of FSH and LH levels at end-of-stimulation are presented.
  • Circulating Levels of Endocrine Parameter (Estradiol) on Stimulation Day 6 [ Time Frame: At Day 6 of stimulation ]
    The median and IQR of estradiol levels on stimulation Day 6 are presented.
  • Circulating Levels of Endocrine Parameter (Estradiol) at End-of-stimulation [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    The median and IQR of estradiol levels at end-of-stimulation are presented.
  • Circulating Levels of Endocrine Parameter (Progesterone) on Stimulation Day 6 [ Time Frame: At Day 6 of stimulation ]
    The median and IQR of progesterone levels on stimulation Day 6 are presented.
  • Circulating Levels of Endocrine Parameter (Progesterone) at End-of-stimulation [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    The median and IQR of progesterone levels at end-of-stimulation are presented.
  • Circulating Levels of Endocrine Parameters (Inhibin A) on Stimulation Day 6 [ Time Frame: At Day 6 of stimulation ]
    The median and IQR of Inhibin A levels on stimulation Day 6 are presented.
  • Circulating Levels of Endocrine Parameters (Inhibin A) at End-of-stimulation [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    The median and IQR of Inhibin A levels at end-of-stimulation are presented.
  • Circulating Levels of Endocrine Parameters (Inhibin B) on Stimulation Day 6 [ Time Frame: At Day 6 of stimulation ]
    The median and IQR of inhibin B levels on stimulation Day 6 are presented.
  • Circulating Levels of Endocrine Parameters (Inhibin B) at End-of-stimulation [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    The median and IQR of inhibin B levels at end-of-stimulation are presented.
  • Number of Stimulation Days [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
  • Total Gonadotropin Dose of FE 999049 [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
  • Total Gonadotropin Dose of FOLLISTIM [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
  • Number of Participants With Adverse Events (AEs) Stratified by Intensity [ Time Frame: From signed informed consent up to 5-6 weeks after transfer ]
    The frequency of participants with total AEs and AEs by categories of intensity (mild, moderate, severe) are presented. An AE was any untoward medical occurrence in a participants participating in clinical trial. The intensity of AE was classified using the following 3-point scale: mild = awareness of signs or symptoms, but no disruption of usual activity); moderate = event sufficient to affect usual activity (disturbing); or severe = inability to work or perform usual activities (unacceptable).
  • Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-stimulation [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
  • Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-stimulation [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
  • Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Clinical Chemistry Parameters at End-of-trial [ Time Frame: Up to 5-6 weeks after transfer ]
    Defined as number of participants with at least one markedly abnormal finding in clinical chemistry parameters (as assessed by investigator) were reported. The clinical chemistry parameters included: alanine transaminase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bicarbonate, bilirubin direct, bilirubin total, blood urea nitrogen, calcium, chloride, cholesterol total, creatinine, gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, phosphorus, potassium, sodium, total protein, uric acid.
  • Proportion of Participants Who Had Markedly Abnormal Value Changes From Baseline in Hematology Parameters at End-of-trial [ Time Frame: Up to 5-6 weeks after transfer ]
    Defined as number of participants with at least one markedly abnormal changes in hematology parameters (as assessed by investigator) were reported. Hematology parameters included: red blood cells, white blood cells, red blood cells morphology, white blood cells morphology, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelets.
  • Frequency and Intensity of Injection Site Reactions [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
    The presence of of injection site reactions (redness, itching, pain, swelling and bruising) immediately, 30 minutes and 24 hours after the injection are presented. The injection site reactions were assessed as none, mild, moderate and severe. The number of injection site reactions (mild, moderate or severe) based on all assessments performed is presented.
  • Technical Malfunctions of the Administration Pens [ Time Frame: End-of-stimulation (up to 20 stimulation days) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: July 21, 2017)
  • Clinical pregnancy rate [ Time Frame: 5-6 weeks after transfer ]
    Pregnancy defined as at least one gestational sac
  • Positive βhCG rate [ Time Frame: 13-15 days after transfer ]
    Measured by positive serum βhCG test
  • Vital pregnancy [ Time Frame: 5-6 weeks after transfer ]
    Rated as at least one intrauterine gestational sac with fetal heart beat
  • Implantation rate [ Time Frame: 5-6 weeks after transfer ]
    Number of gestational sacs divided by number of blastocysts transferred
  • Proportion of subjects with cycle cancellation due to poor or excessive ovarian response or blastocyst transfer cancellation due to excessive ovarian response / OHSS risk [ Time Frame: End of stimulations visit or transfer visit =up to 4 weeks ]
    For each subject, the reason for each cycle cancellation will be recorded
  • Proportion of subjects with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved [ Time Frame: On the day of oocyte retrieval ]
    Grouped according to number of oocytes
  • Proportion of subjects with extreme ovarian responses [ Time Frame: On the day of oocyte retrieval ]
    Defined as <4, ≥15 or ≥20 oocytes retrieved
  • Proportion of subjects with preventive interventions for early ovarian hyperstimulation syndrome (OHSS) [ Time Frame: Up to 20 stimulation days ]
    Measured as cycle cancellation due to excessive ovarian response or GnRH agonist triggering
  • Proportions of subjects with early OHSS (including OHSS of moderate/severe grade) and/or preventive interventions for early OHSS [ Time Frame: Up to 9 days after triggering of final follicular maturation ]
    Measured as mild, moderate or severe
  • Proportions of subjects with late OHSS (including OHSS of moderate/severe grade) [ Time Frame: >9 days after triggering of final follicular maturation ]
    Measured as mild, moderate or severe
  • Number of follicles [ Time Frame: Up to 20 stimulation days ]
    Counted for the right and left ovary via ultrasound
  • Size of follicles [ Time Frame: Up to 20 stimulation days ]
    Measured for the right and left ovary via ultrasound
  • Fertilisation rate [ Time Frame: Day 1 after oocyte retrieval ]
    Measured by number of pronuclei
  • Number and quality of embryos [ Time Frame: Day 3 after oocyte retrieval ]
    Combined assesment of number of blastomeres/compaction status and embryo morphology parameters
  • Number and quality of blastocysts [ Time Frame: Day 5 after oocyte retrieval ]
    Assessed as a score combining three parameters (blastocyst expansion and hatching status, inner cell mass and trophectoderm)
  • Circulating levels of endocrine parameters [ Time Frame: At stimulation day 6 and end-of-stimulation (up to 20 stimulation days) ]
    Measured by follicle-stimulating hormone (FSH), luteinising hormone (LH), estradiol, progesterone, inhibin A and inhibin B
  • Total gonadotropin dose [ Time Frame: Up to 20 stimulation days ]
    Calculated by start dates, end dates and daily dose of investigational medicinal product (IMP)
  • Number of stimulation days [ Time Frame: Up to 20 stimulation days ]
    Calculated by start dates, end dates and daily dose of IMP
  • Frequency of adverse events [ Time Frame: From signed informed consent up to 5-6 weeks after transfer ]
    Recorded for FE 999049 and FOLLISTIM
  • Intensity of adverse events [ Time Frame: From signed informed consent up to 5-6 weeks after transfer ]
    Recorded for FE 999049 and FOLLISTIM
  • Changes in circulating levels of clinical chemistry compared to baseline [ Time Frame: End-of-stimulation and up to 5-6 weeks after transfer ]
    Measured by CHEM-20
  • Changes in haematology parameters compared to baseline [ Time Frame: End-of-stimulation and up to 5-6 weeks after transfer ]
    Measured by complete blood count
  • Frequency of injection site reactions [ Time Frame: Up to 20 stimulation days ]
    Assessed by subjects during the stimulation period
  • Intensity of injection site reactions [ Time Frame: Up to 20 stimulation days ]
    Assessed by subjects during the stimulation period
  • Technical malfunctions [ Time Frame: Up to 20 stimulation days ]
    Of the administration pens
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese Women
Official Title  ICMJE A Randomised, Controlled, Assessor-blind, Parallel Groups, Multicentre Trial Assessing the Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Japanese Women Undergoing an Assisted Reproductive Technology Programme
Brief Summary To demonstrate non-inferiority of FE 999049 compared to FOLLISTIM with respect to number of oocytes retrieved in Japanese IVF/ICSI patients undergoing controlled ovarian stimulation.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Infertility
Intervention  ICMJE
  • Drug: Follitropin delta
    Single daily subcutaneous administration through pre-filled injection pen
    Other Names:
    • FE 999049
    • REKOVELLE
  • Drug: Follitropin beta
    Single daily subcutaneous injection in the abdomen
    Other Name: FOLLISTIM
Study Arms  ICMJE
  • Experimental: Follitropin delta
    FE 999049 was administered as single daily subcutaneous injections in the abdomen. Participants randomized to FE 999049 had their individual dose determined on the basis of their anti-Müllerian hormone (AMH) level at screening and their body weight at randomization. The daily FE 999049 dose was fixed throughout the stimulation period. The minimum allowed daily FE 999049 dose was 6 μg and maximum allowed daily dose was 12 μg. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
    Intervention: Drug: Follitropin delta
  • Active Comparator: Follitropin beta
    FOLLISTIM was administered as single daily subcutaneous injections in the abdomen. The starting dose of FOLLISTIM was 150 IU and fixed for the first five stimulation days, after which it could be adjusted by 75 IU based on the individual response. The maximum allowed daily dose was 375 IU. Dosing continued until the criterion for triggering of final follicular maturation was met. Participants could be treated for a maximum of 20 days.
    Intervention: Drug: Follitropin beta
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 1, 2021)
373
Original Estimated Enrollment  ICMJE
 (submitted: July 21, 2017)
328
Actual Study Completion Date  ICMJE July 8, 2019
Actual Primary Completion Date June 10, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Informed Consent Documents signed prior to any trial-related procedures.
  • In good physical and mental health.
  • Japanese females between the ages of 20 and 40 years.
  • Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II (defined by the revised American Society for Reproductive Medicine (ASRM) classification) or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) treatment using ejaculated sperm from male partner.
  • Infertility for at least 1 year before randomization (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 screening. This also includes women who have been diagnosed with any of the above medical conditions but have had them surgically corrected within 1 year prior to screening.
  • Transvaginal ultrasound documenting presence and adequate visualization 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 fallopian tubes and surrounding tissue without evidence of significant abnormality (e.g. no hydrosalpinx) within 1 year prior to screening. Both ovaries must be accessible for oocyte retrieval.
  • Early follicular phase (cycle day 2-4) serum levels of follicle stimulating hormone (FSH) between 1 and 15 IU/L (results obtained within 3 months prior to screening).
  • Body mass index (BMI) between 17.5 and 32.0 kg/m^2 (both inclusive) at screening.

Exclusion Criteria:

  • Known endometriosis stage III-IV (defined by the revised ASRM classification).
  • One or more follicles >10 mm (including cysts) observed on the transvaginal ultrasound prior to start of stimulation on stimulation day 1 (puncture of cysts prior randomization is allowed).
  • 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. In case the sperm production is severely impaired (concentration <1 million/mL), normal karyotype, including no Y chromosome microdeletion, must be documented.
  • Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 20 Years to 40 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03228680
Other Study ID Numbers  ICMJE 000273
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Ferring Pharmaceuticals
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Ferring Pharmaceuticals
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Global Clinical Compliance Ferring Pharmaceuticals
PRS Account Ferring Pharmaceuticals
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP