Luteal Hormone Supplementation in In-vitro Fertilization, Embryo Transfer
Conditions
Keywords
Infertility, COL-1620, progesterone gel, Fertilization in Vitro, Embryo Transfer
Brief summary
The primary objective of this trial is to demonstrate the non-inferiority of the clinical pregnancy rate per embryo transfer to the historical standard value in in-vitro fertilization (IVF)/embryo transfer (ET) cycles in Japan (Japan Society of Obstetrics and Gynecology \[JSOG\] 2009 registry data: 24.3 percent \[%\]). The secondary objectives of this trial are to assess the biochemical pregnancy rate per ET, pharmacokinetics, and safety of COL-1620.
Interventions
DRUGCOL-1620
The subjects will be administered with COL-1620 vaginal progesterone gel (1.125 grams of progesterone gel containing 90 milligram that is 8 percent \[%\] gel) vaginally once daily, from the day of ovum pick-up (OPU) until Week 12.
DRUGGonadotropin-releasing hormone (GnRH) analogue
Subjects will undergo conventional controlled ovarian stimulation (COS) therapy for in-vitro Fertilization and Embryo Transfer (IVF/ET) according to the Investigator's discretion using GnRH analogue (agonist or antagonist) preparation.
Subjects will undergo conventional COS therapy for IVF/ET according to the Investigator's discretion using FSH containing preparation.
Subjects will undergo conventional COS therapy for IVF/ET according to the Investigator's discretion using hCG preparation.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Japanese race * Woman with a history of infertility and in whom In-vitro fertilization and embryo transfer (IVF/ET) is indicated * The controlled ovarian stimulation (COS) therapy is gonadotropin-releasing hormone (GnRH) analogue (agonist or antagonist) in combination with a follicle-stimulating hormone (FSH) containing preparation * Healthy premenopausal woman aged between 20 and 45 years (inclusive) and wishing to conceive * Body mass index (BMI) of 17.0 to 25.0 kilogram per square meter (kg/m\^2) (inclusive) * A negative pregnancy test (urinary beta-human chorionic gonadotropin \[hCG\]) prior to starting COS * Normal cervical smear result (Papanicolaou \[PAP\] test: Negative for Intraepithelial Lesion or Malignancy \[NILM\] or \[Atypical Squamous Cells of Undetermined Significance {ASC-US} and Human Papillomavirus {HPV} negative\]) within 12 months prior to the date of informed consent. If not available, a cervical smear and HPV test will be performed as part of Screening * No clinically significant abnormal findings in the screening hematology, biochemistry and urinalysis parameters * Full comprehension of the study and voluntary written informed consent obtained in writing prior to any trial-related activities
Exclusion criteria
* History of recurrent pregnancy loss (defined as 3 or more previous spontaneous abortions) * History of 3 or more consecutive cancelled or failed (no clinical pregnancy) IVF/ET cycles * Abnormal hemorrhage of the reproductive tract of undetermined origin * Any contraindication to being pregnant and/or carrying a pregnancy to term (for example, malformations of sexual organs or fibroid tumors of the uterus incompatible with pregnancy) * Uterine myoma requiring treatment * Extra-uterine pregnancy within the last 3 months prior to the date of informed consent * History or presence of intracranial tumor (for example, hypothalamic or pituitary tumor) * Presence of or suspected gonadotropin- or estrogen-dependent malignancy (for example, ovarian, uterine or mammary carcinoma) * Ovarian enlargement or cyst of unknown etiology * Breast-feeding or lactation * History of severe Ovarian Hyperstimulation Syndrome (OHSS) (Classification of OHSS Severity, as per Japan Reproductive/Endocrine Working Group) * Known Human Immunodeficiency Virus (HIV)-positive status, or a history of or current active infection with Hepatitis B or C * Known allergy or hypersensitivity to progesterone preparations or gonadotropin preparations and/or their excipients, or any contraindication to receive medication for controlled ovarian stimulation (for example, gonadotropin, GnRH analogues, combined oral contraceptive pill, as appropriate) * History of or suspected alcohol or substance abuse within 5 years prior to the date of informed consent * Clinically significant systemic disease (for example, insulin-dependent diabetes, epilepsy, severe migraine, acute porphyria, hepatic, renal or cardiovascular disease, severe corticosteroid-dependent asthma) * Active thrombophlebitis, thromboembolic disorder or cerebral apoplexy, or a history of such conditions * Other significant disease that in the Investigator's or Sub-Investigator's opinion would exclude the subject from the trial * Participation in another clinical trial within 3 months prior to the date of informed consent or simultaneous participation in another clinical trial * Legal incapacity or limited legal capacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Pregnancy Rate Per Embryo Transfer | Week 5 post embryo transfer (2-6 days after Ovum Pick-up [OPU]) | Clinical pregnancy was defined as the presence of a fetal sac on transvaginal ultrasound (TVUS) during Week 5 or the presence of an extra-uterine pregnancy (as confirmed during surgery or by 2 positive serum beta-human chorionic gonadotropin (beta-hCG) results from Week 5). The clinical pregnancy rate was calculated as number of subjects who were clinically pregnant divided by the number of subjects who had at least 1 embryo transferred. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical Pregnancy Rate Per Embryo Transfer | Week 5 post embryo transfer (2-6 days after Ovum Pick-up [OPU]) | Biochemical pregnancy was defined as any miscarriage without any evidence of a fetal sac on TVUS during Visit 6 (Week 5), but with a positive serum beta-hCG pregnancy test result at Visit 5 (Day 14+/-3). Biochemical pregnancy rate was calculated as the number of subjects who had no fetal sac observed during Visit 6 (Week 5) TVUS assessment or subjects who had a positive serum pregnancy test at Visit 5 (Day 14+/-3) and no data recorded at Visit 6 (Week 5) divided by the number of subjects who has at least 1 embryo transferred. |
| Serum Progesterone Level | Visit 2-2 (Prior to hCG administration) and Visit 5 (Day 14+/-3) | Two pharmacokinetic (PK) samples were collected per subject for the measurement of serum progesterone concentrations; 1st sample at Visit 2-2 (prior to hCG administration) and second sample during Visit 5 (Day 14+/-3, 7 hours after the morning of investigational medicinal product administration). |
Countries
Japan
Participant flow
Recruitment details
First subject/Last subject (signed informed consent form \[ICF\]): 22 Jul 2013/02 Jun 2014; Study completed: 14 Oct 2014; Data base lock: 12 Nov 2014.
Pre-assignment details
A total of 195 subjects were screened and 178 subjects were enrolled in the trial; 169 subjects started controlled ovarian stimulation (COS) treatment and 149 subjects received at least 1 dose of investigational medicinal product (IMP), 123 subjects have undergone in-vitro fertilization/ embryo transfer (IVF/ET).
Participants by arm
| Arm | Count |
|---|---|
| COL-1620 The subjects were administered with COL-1620 vaginal progesterone gel (1.125 grams of progesterone gel containing 90 milligram that is 8% gel) vaginally once daily, from the day of ovum pick-up (OPU) until Week 12 or until the confirmation of miscarriage or extra-uterine pregnancy, or a negative pregnancy test whichever was earlier.
Subjects had undergone conventional controlled ovarian stimulation (COS) therapy for in-vitro fertilization and embryo transfer (IVF/ET) according to the Investigator's discretion using GnRH analogue (agonist or antagonist) preparation, follicle-stimulating hormone (FSH) or human chorionic gonadotropin (hCG). | 149 |
| Total | 149 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 17 |
| Overall Study | Did not undergo IVF/ET | 14 |
| Overall Study | Other | 6 |
| Overall Study | Risk of OHSS | 17 |
| Overall Study | Spontaneous pregnancy | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | COL-1620 |
|---|---|
| Age, Continuous | 34.41 Years STANDARD_DEVIATION 3.71 |
| Sex: Female, Male Female | 149 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 92 / 149 |
| serious Total, serious adverse events | 5 / 149 |
Outcome results
Primary
Clinical Pregnancy Rate Per Embryo Transfer
Clinical pregnancy was defined as the presence of a fetal sac on transvaginal ultrasound (TVUS) during Week 5 or the presence of an extra-uterine pregnancy (as confirmed during surgery or by 2 positive serum beta-human chorionic gonadotropin (beta-hCG) results from Week 5). The clinical pregnancy rate was calculated as number of subjects who were clinically pregnant divided by the number of subjects who had at least 1 embryo transferred.
Time frame: Week 5 post embryo transfer (2-6 days after Ovum Pick-up [OPU])
Population: The intention-to-treat subjects included all the subjects who underwent IVF/ET.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| COL-1620 | Clinical Pregnancy Rate Per Embryo Transfer | 28.5 Percentage of pregnancy/embryo transfer |
Secondary
Biochemical Pregnancy Rate Per Embryo Transfer
Biochemical pregnancy was defined as any miscarriage without any evidence of a fetal sac on TVUS during Visit 6 (Week 5), but with a positive serum beta-hCG pregnancy test result at Visit 5 (Day 14+/-3). Biochemical pregnancy rate was calculated as the number of subjects who had no fetal sac observed during Visit 6 (Week 5) TVUS assessment or subjects who had a positive serum pregnancy test at Visit 5 (Day 14+/-3) and no data recorded at Visit 6 (Week 5) divided by the number of subjects who has at least 1 embryo transferred.
Time frame: Week 5 post embryo transfer (2-6 days after Ovum Pick-up [OPU])
Population: The intention-to-treat subjects included all the subjects who underwent IVF/ET.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| COL-1620 | Biochemical Pregnancy Rate Per Embryo Transfer | 7.3 Percentage of pregnancy/embryo transfer |
Secondary
Serum Progesterone Level
Two pharmacokinetic (PK) samples were collected per subject for the measurement of serum progesterone concentrations; 1st sample at Visit 2-2 (prior to hCG administration) and second sample during Visit 5 (Day 14+/-3, 7 hours after the morning of investigational medicinal product administration).
Time frame: Visit 2-2 (Prior to hCG administration) and Visit 5 (Day 14+/-3)
Population: The PK analysis set included all subjects who had serum beta-hCG pregnancy test performed at Visit 5 (Day 14+/-3), who had two progesterone concentrations at Visit 2-2 and Visit 5, and who had no relevant problems for compliance of administration until Visit 5. n signifies the number of subjects who were evaluable in each category, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| COL-1620 | Serum Progesterone Level | Subjects with +ve serum beta-hCG: Visit 2-2 (n=44) | 1.023 nanogram per milliliter (ng/mL) | Standard Deviation 0.414 |
| COL-1620 | Serum Progesterone Level | Subjects with +ve serum beta-hCG: Visit 5 (n=44) | 61.508 nanogram per milliliter (ng/mL) | Standard Deviation 76.206 |
| COL-1620 | Serum Progesterone Level | Subjects with -ve serum beta-hCG: Visit 2-2 (n=77) | 0.988 nanogram per milliliter (ng/mL) | Standard Deviation 0.471 |
| COL-1620 | Serum Progesterone Level | Subjects with -ve serum beta-hCG: Visit 5 (n=77) | 7.765 nanogram per milliliter (ng/mL) | Standard Deviation 3.202 |