Luteal Hormone Supplementation
Conditions
Brief summary
The purposes of the study are to verify sufficient supplementation of luteal hormone after administrating FE999913 Vaginal Tablet twice a day (BID) or three times a day (TID) and to determine the efficacy and safety of FE999913 Vaginal Tablet in Japanese women undergoing fertility treatment with IVF-ET (a fresh embryo transfer).
Interventions
DRUGFE 999913 vaginal tablet
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 42 Years
Healthy volunteers
No
Inclusion criteria
* Pre-menopausal adult women between the ages of 20 and 42 years. * Early follicular phase (day 2-4) follicle stimulating hormone (FSH) ≤12 IU/L and Estradiol \<100 pg/mL. * Luteinizing hormone (LH), prolactin (PRL), and thyroid-stimulating hormone (TSH), within the normal limits for the clinical laboratory tests, or considered not clinically significant by the investigator within 6 months prior to screening. * Documented history of infertility \[e.g., unable to conceive for at least one year (or for 6 months for women ≥38 years of age) or bilateral tubal occlusion or absence\]. * Transvaginal ultrasound at screening (or within 14 days prior to screening) consistent with findings adequate for Assisted Reproduction Technology (ART) with respect to uterus and adnexa (peripheral reproductive organs). * At least one cycle with no fertility medication prior to screening. * Hysterosalpingography, hysteroscopy, sonohysterogram, or transvaginal ultrasound documenting a normal uterine cavity. * Consent to contraception during the cycle in which pituitary down regulation is performed (prior to start of controlled ovarian stimulation). * Signed informed consent to fertility treatment using FE999913 Vaginal Tablet after the subject and her husband have thoroughly understood the content.
Exclusion criteria
* Donor oocyte or embryo recipient; gestational or surrogate carrier. * Undergoing blastomer biopsy and other experimental ART procedures. * Severe hepatic dysfunction or disease. * Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events. * Porphyria. * Presence of any clinically relevant systemic disease (eg, insulin-dependent diabetes mellitus). * Past or current surgical or medical condition which in the judgment of the Principal Investigator (or Sub-investigator) may interfere with absorption, distribution, metabolism, or excretion of the study drug. * Subjects with a body mass index (BMI) of \>34 at time of Screening. * Previous IVF or ART failure due to a poor response to gonadotropins\*. \* Defined as development of ≤2 mature follicles or history of 2 previous cycle cancellations prior to oocyte retrieval due to poor response. * Presence of abnormal uterine bleeding of undetermined origin. * Current or recent (within the past 12 months) substance abuse, including alcohol. * Known or suspected breast or genital tract cancer. * History of chemotherapy or radiotherapy for malignant disorder (chorionic disease). * Currently breast feeding, pregnant or contraindication to pregnancy. * Refusal or inability to comply with the requirements of the Protocol for any reason, including scheduled visits and clinical laboratory tests. * Documented intolerance or allergy to any of the medications to be used in the study including the investigational medicinal product. * Participation in any experimental drug study within 60 days prior to Screening. * Use of any of the following medications during the pretreatment and treatment phase: hormonal drug products (use of oral contraceptives prior to start of controlled ovarian stimulation is allowed), other progesterone drug products, hydrocortisone and other steroid drug products, and fertility modifiers such as insulin sensitizers. * History of recurrent pregnancy loss defined as 3 or more spontaneous miscarriages.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Subjects With Blood Progesterone Concentration Not Less Than 10 ng/ml | Day 5 of treatment | — |
| Ongoing Pregnancy Rate | Week 5 of study | Defined as identification of fetal survival and fetal heart movements on transvaginal ultrasound |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Positive βeta Human Chorionic Gonadotrophin (βhCG) | Week 2 of study | — |
| Clinical Pregnancy Rate | Week 4 of study | Defined as presence of a gestational sac on transvaginal ultrasound |
| Blood Progesterone Concentration | Weeks 2, 4, 5, 8, and end of study | — |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FE 999913 100 mg BID FE 999913 100 mg vaginal tablet BID | 46 |
| FE 999913 100 mg TID FE 999913 100 mg vaginal tablet TID | 48 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 7 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | FE 999913 100 mg TID | Total | FE 999913 100 mg BID |
|---|---|---|---|
| Age, Continuous | 34.5 years STANDARD_DEVIATION 4.25 | 34.7 years STANDARD_DEVIATION 3.93 | 34.9 years STANDARD_DEVIATION 3.6 |
| Age, Customized 35-37 years | 14 participants | 31 participants | 17 participants |
| Age, Customized <35 years | 21 participants | 38 participants | 17 participants |
| Age, Customized 38-40 years | 8 participants | 19 participants | 11 participants |
| Age, Customized 41-42 years | 5 participants | 6 participants | 1 participants |
| Day of transfer Day 3 | 45 participants | 83 participants | 38 participants |
| Day of transfer Day 5 | 2 participants | 7 participants | 5 participants |
| Embryos transferred | 1.11 embryos STANDARD_DEVIATION 0.312 | 1.1 embryos STANDARD_DEVIATION 0.302 | 1.09 embryos STANDARD_DEVIATION 0.294 |
| Method of insemination Intracytoplasmic Sperm Injection (ICSI) | 26 participants | 50 participants | 24 participants |
| Method of insemination IVF | 21 participants | 40 participants | 19 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 48 Participants | 94 Participants | 46 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 48 Participants | 94 Participants | 46 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Subjects with embryo transferred 1 embryo | 42 participants | 81 participants | 39 participants |
| Subjects with embryo transferred 2 embryos | 5 participants | 9 participants | 4 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 54 | 22 / 54 | 37 / 108 |
| serious Total, serious adverse events | 0 / 54 | 1 / 54 | 1 / 108 |
Outcome results
Primary
Ongoing Pregnancy Rate
Defined as identification of fetal survival and fetal heart movements on transvaginal ultrasound
Time frame: Week 5 of study
Population: FAS with ET population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE999913 000072 (BID/TID) | Ongoing Pregnancy Rate | 14.0 percentage of participants |
| FE 999913 100 mg TID | Ongoing Pregnancy Rate | 29.8 percentage of participants |
| FE 999913 Total | Ongoing Pregnancy Rate | 22.2 percentage of participants |
Primary
The Proportion of Subjects With Blood Progesterone Concentration Not Less Than 10 ng/ml
Time frame: Day 5 of treatment
Population: FAS population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE999913 000072 (BID/TID) | The Proportion of Subjects With Blood Progesterone Concentration Not Less Than 10 ng/ml | 98.9 percentage of subjects |
Comparison: To verify sufficient supplementation of luteal hormone, the proportion of subjects with blood progesterone concentration ≥ 10 ng/mL on Day 5 was compared to the result from a historical control, trial CS08 (NCT number: 00884221). The corresponding proportion of subjects in trial CS08 was 99.8% (95%CI: 99.1;100.0, 631/632 subjects). The non-inferiority hypothesis tested for this primary endpoint was: H0: P(000072)-P(CS08) ≤ -10.0% against the alternative Ha: P(000072)-P(CS08) \> -10.0%.95% CI: [-3.6, 1.8]
Secondary
Blood Progesterone Concentration
Time frame: Weeks 2, 4, 5, 8, and end of study
Population: FAS population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FE999913 000072 (BID/TID) | Blood Progesterone Concentration | Baseline; n=46, 48, 94 | 0.626 ng/mL | Standard Deviation 0.379 |
| FE999913 000072 (BID/TID) | Blood Progesterone Concentration | End of study; n=38, 46, 84 | 10.8 ng/mL | Standard Deviation 16.3 |
| FE999913 000072 (BID/TID) | Blood Progesterone Concentration | Week 4; n=6, 14, 20 | 32.5 ng/mL | Standard Deviation 23.1 |
| FE999913 000072 (BID/TID) | Blood Progesterone Concentration | Week 2; n=32, 42,74 | 11.4 ng/mL | Standard Deviation 12 |
| FE999913 000072 (BID/TID) | Blood Progesterone Concentration | Week 8; n=5, 12, 17 | 41.4 ng/mL | Standard Deviation 15.7 |
| FE999913 000072 (BID/TID) | Blood Progesterone Concentration | Week 5; n=6, 14,20 | 32.3 ng/mL | Standard Deviation 17 |
| FE 999913 100 mg TID | Blood Progesterone Concentration | Week 4; n=6, 14, 20 | 77.9 ng/mL | Standard Deviation 41.3 |
| FE 999913 100 mg TID | Blood Progesterone Concentration | Week 5; n=6, 14,20 | 67.7 ng/mL | Standard Deviation 35.7 |
| FE 999913 100 mg TID | Blood Progesterone Concentration | Week 8; n=5, 12, 17 | 53.3 ng/mL | Standard Deviation 23.5 |
| FE 999913 100 mg TID | Blood Progesterone Concentration | Baseline; n=46, 48, 94 | 0.704 ng/mL | Standard Deviation 0.364 |
| FE 999913 100 mg TID | Blood Progesterone Concentration | Week 2; n=32, 42,74 | 30.7 ng/mL | Standard Deviation 37.9 |
| FE 999913 100 mg TID | Blood Progesterone Concentration | End of study; n=38, 46, 84 | 21.9 ng/mL | Standard Deviation 26.4 |
| FE 999913 Total | Blood Progesterone Concentration | Baseline; n=46, 48, 94 | 0.666 ng/mL | Standard Deviation 0.371 |
| FE 999913 Total | Blood Progesterone Concentration | Week 5; n=6, 14,20 | 57.1 ng/mL | Standard Deviation 35 |
| FE 999913 Total | Blood Progesterone Concentration | Week 8; n=5, 12, 17 | 49.8 ng/mL | Standard Deviation 21.7 |
| FE 999913 Total | Blood Progesterone Concentration | Week 4; n=6, 14, 20 | 64.2 ng/mL | Standard Deviation 42 |
| FE 999913 Total | Blood Progesterone Concentration | End of study; n=38, 46, 84 | 16.9 ng/mL | Standard Deviation 23 |
| FE 999913 Total | Blood Progesterone Concentration | Week 2; n=32, 42,74 | 22.3 ng/mL | Standard Deviation 31 |
Secondary
Clinical Pregnancy Rate
Defined as presence of a gestational sac on transvaginal ultrasound
Time frame: Week 4 of study
Population: FAS with ET population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE999913 000072 (BID/TID) | Clinical Pregnancy Rate | 14.0 percentage of participants |
| FE 999913 100 mg TID | Clinical Pregnancy Rate | 29.8 percentage of participants |
| FE 999913 Total | Clinical Pregnancy Rate | 22.2 percentage of participants |
Secondary
Rate of Positive βeta Human Chorionic Gonadotrophin (βhCG)
Time frame: Week 2 of study
Population: FAS with ET population In the TID group 13 subjects had a positive beta-hCG assessment while 14 subjects had a positive clinical pregnancy at Week 4. This is because one subject had a negative beta-hCG at Week 2, but she had a positive local serum hCG on the same day and continued the trial. Then clinical and ongoing pregnancy were confirmed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FE999913 000072 (BID/TID) | Rate of Positive βeta Human Chorionic Gonadotrophin (βhCG) | 16.3 percentage of participants |
| FE 999913 100 mg TID | Rate of Positive βeta Human Chorionic Gonadotrophin (βhCG) | 27.7 percentage of participants |
| FE 999913 Total | Rate of Positive βeta Human Chorionic Gonadotrophin (βhCG) | 22.2 percentage of participants |