Anovulation, Oligo-ovulation, Hypothalamic-pituitary Dysfunction, Polycystic Ovarian Syndrome
Conditions
Keywords
Japanese
Brief summary
This is an open-label, parallel-group, randomized, multicenter Phase III trial to compare the efficacy and safety of a single 250 microgram (mcg) subcutaneous dose of MSJ-0011 to a single 5,000 international units (IU) intramuscular dose of urinary human chorionic gonadotropin (hCG) in inducing ovulation in Japanese women diagnosed with anovulation or oligo-ovulation. Ovulation induction therapy will be undertaken with follitropin alfa. The primary objective is to show that MSJ-0011 is non-inferior to urinary hCG, as assessed by the ovulation rate.
Interventions
DRUGMSJ-0011
Subjects who underwent ovarian stimulation with follitropin alfa according to a low-dose step-up protocol for maximum of 28 days will receive a single dose of 250 microgram (mcg) MSJ-0011 (choriogonadotropin alfa \[recombinant human Chorionic Gonadotropin, r-hCG\]) subcutaneously (SC) within 32 hours after the last dose of follitropin alfa administration unless dominant follicle reached a mean diameter of greater than or equal to (\>=) 18 millimeter (mm); not more than 3 follicles each with a mean diameter of \>=16 mm and serum Estradiol (E2) level within an acceptable range for the number of follicle present, and not more than 2,000 picogram per milliliter (pg/mL).
DRUGurinary hCG (u-hCG)
Subjects who underwent ovarian stimulation with follitropin alfa according to a low-dose step-up protocol for maximum of 28 days will receive a single dose of 5,000 IU u-hCG intramuscularly dose within 32 hours after the last dose of follitropin alfa administration unless dominant follicle reached a mean diameter of \>=18 mm; not more than 3 follicles each with a mean diameter of \>=16 mm and serum E2 level within an acceptable range for the number of follicle present, and not more than 2,000 pg/mL.
Low-dose step-up protocol involves starting dose of follitropin alfa as 75 International Units (IU) subcutaneously per day ,increments by 37.5 IU every 7 days (Day 8, 15, 28) will be done if no ovarian response will be observed for maximum of 28 days.
Sponsors
Merck Serono Co., Ltd., Japan
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 39 Years
Healthy volunteers
No
Inclusion criteria
* Premenopausal women aged between 20 to 39 years inclusive and wishing to conceive * Body Mass Index (BMI) of 17.0 to 29.0 kilogram per square meter (kg/m\^2) inclusive (value up to first decimal place) * No clinically significant abnormalities in serum thyroid stimulating hormone (TSH), dehydroepiandrosterone sulfate (DHEA-S), 17-hydroxyProgesterone (17-OHP), prolactin (PRL) and follicle-stimulating hormone (FSH) levels in the early follicular phase * Anovulation or oligo-ovulation * Any one of the following: spontaneous menstruation (at least twice per year) or a positive response to progestin as evidenced by menstruation. * Eligible for ovarian stimulation with gonadotropins (e.g. documented failure to ovulate or achieve pregnancy with anti-estrogenic therapy such as clomiphene citrate) * Male partner with normal semen analysis, as defined by World Health Organization (WHO) standards, within 12 months prior to date of informed consent * Normal cervical smear results (Papanicolaou \[PAP\] score less than or equal to \[\<=\] II) taken within 12 months prior to date of informed consent; if not available a cervical smear will be performed as part of screening * Full comprehension of the trial and voluntary consent obtained in writing prior to participation in this trial
Exclusion criteria
* Infertility involving gynecological factors other than anovulation or oligo-ovulation secondary to hypothalamic-pituitary dysfunction (Grade 1 Amenorrhea, Oligomenorrhea or Anovulatory Cycles) or polycystic ovarian syndrome (PCOS) and for whom ovulation induction (OI) therapy is contraindicated * Subjects with known surgical/histological diagnosis of endometriosis greater than Stage II (American Fertility Society classification), or endometriosis requiring treatment * Infertility secondary to amenorrhea of uterine cause * Infertility secondary to primary or premature ovarian failure * Infertility secondary to known adrenal or thyroid dysfunction, or hyperprolactinemia * Failure of ovulation in 2 or more consecutive previous cycles with any gonadotropins * Subjects in whom pregnancy is contraindicated, e.g. malformations of sexual organs or fibroid tumors of the uterus incompatible with pregnancy * Extrauterine pregnancy in the previous 3 months * History or presence of intracranial tumor (e.g. hypothalamic or pituitary tumor) * Presence of or suspected gonadotropin- or estrogen-dependent malignancy (e.g. ovarian, uterine or mammary carcinoma) * Untreated endometrial hyperplasia * Abnormal hemorrhage of the reproductive tract of unknown origin * History of severe ovarian hyper stimulation syndrome (OHSS) (Classification of OHSS Severity, Japan Reproductive/Endocrine Working Group) * Clinically significant systemic disease (e.g. insulin-dependent diabetes, epilepsy, severe migraine, intermittent porphyria, hepatic, renal or cardiovascular disease, severe corticosteroid-dependent asthma) * Participation in another clinical trial within 3 months prior to date of informed consent or simultaneous participation in another clinical trial * Gonadotropin treatment within 2 months prior to date of informed consent * Legal incapacity or limited legal capacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Ovulation Mid-luteal Serum Progesterone (P4) Level of Greater Than or Equal (>=) 5 Nanogram Per Milliliter (ng/mL) or Clinical Pregnancy | Mid-luteal phase progesterone assessed (Day 5 to 10) or clinical pregnancy (Day 35 to 42) post hCG treatment | Ovulation was defined as mid-luteal serum progesterone level of \>= 5 ng/mL or clinical pregnancy. Clinical pregnancy was defined as the presence of at least a fetal sac on transvaginal ultrasound (TVUS). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Ovulation Mid-Luteal Serum Progesterone (P4) Level of Greater Than or Equal (>=) 9.4 Nanogram Per Milliliter (ng/mL) or Clinical Pregnancy | Mid-luteal phase progesterone assessed (Day 5 to 10) or clinical pregnancy (Day 35 to 42) post hCG treatment | Ovulation was defined as mid-luteal serum progesterone level of \>= 9.4 ng/mL or clinical pregnancy. Clinical pregnancy was defined as the presence of at least a fetal sac on TVUS. |
| Mid-luteal Endometrial Thickness | Day 5 to 7 post hCG treatment | Endometrial thickness was measured using TVUS. |
| Percentage of Participants With Biochemical Pregnancy | Day 35 to 42 post hCG treatment | Percentage of subjects with biochemical pregnancy was assessed. Biochemical pregnancy was defined as any miscarriage without any evidence of a fetal sac on TVUS on the Day 35 to 42 post hCG treatment, but with a positive serum β-hCG pregnancy test on Day 15 to 20 post hCG treatment (Beta-hCG level greater than \[\>\] 10 IU/Liter) |
| Percentage of Participants With Clinical Pregnancy | Day 35 to 42 post hCG treatment | Percentage of subjects with clinical pregnancy was assessed. Clinical pregnancy was defined as the presence of at least a fetal sac on TVUS. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MSJ-0011 Subjects who underwent ovarian stimulation with follitropin alfa according to a low-dose step-up protocol (starting dose of follitropin alfa as 75 International Units (IU) subcutaneously per day ,increments by 37.5 IU every 7 days was done if no ovarian response was observed) for maximum of 28 days received a single dose of 250 microgram (mcg) MSJ-0011 subcutaneously (SC) within 32 hours after the last dose of follitropin alfa administration unless dominant follicle reached a mean diameter of greater than or equal to (\>=) 18 millimeter (mm); not more than 3 follicles each with a mean diameter of \>=16 mm and serum Estradiol (E2) level within an acceptable range for the number of follicle present, and not more than 2,000 picogram per milliliter (pg/mL). | 54 |
| Urinary Human Chorionic Gonadotropin (u-hCG) Subjects who underwent ovarian stimulation with follitropin alfa according to a low-dose step-up protocol (starting dose of follitropin alfa as 75 IIU subcutaneously per day ,increments by 37.5 IU every 7 days was done if no ovarian response was observed) for maximum of 28 days received a single dose of 5,000 IU u-hCG intramuscularly dose within 32 hours after the last dose of follitropin alfa administration unless dominant follicle reached a mean diameter of \>=18 mm; not more than 3 follicles each with a mean diameter of \>=16 mm and serum E2 level within an acceptable range for the number of follicle present, and not more than 2,000 pg/mL. | 27 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Investigator discretion | 3 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | MSJ-0011 | Urinary Human Chorionic Gonadotropin (u-hCG) | Total |
|---|---|---|---|
| Age, Continuous | 32.61 years STANDARD_DEVIATION 3.303 | 30.67 years STANDARD_DEVIATION 3.603 | 31.96 years STANDARD_DEVIATION 3.506 |
| Sex: Female, Male Female | 54 Participants | 27 Participants | 81 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 54 | 11 / 27 |
| serious Total, serious adverse events | 1 / 54 | 0 / 27 |
Outcome results
Primary
Percentage of Subjects With Ovulation Mid-luteal Serum Progesterone (P4) Level of Greater Than or Equal (>=) 5 Nanogram Per Milliliter (ng/mL) or Clinical Pregnancy
Ovulation was defined as mid-luteal serum progesterone level of \>= 5 ng/mL or clinical pregnancy. Clinical pregnancy was defined as the presence of at least a fetal sac on transvaginal ultrasound (TVUS).
Time frame: Mid-luteal phase progesterone assessed (Day 5 to 10) or clinical pregnancy (Day 35 to 42) post hCG treatment
Population: The modified intent to treat (Mod ITT) population was defined as all subjects randomized to IMP (MSJ-0011 or u-hCG) and who completed the primary efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MSJ-0011 | Percentage of Subjects With Ovulation Mid-luteal Serum Progesterone (P4) Level of Greater Than or Equal (>=) 5 Nanogram Per Milliliter (ng/mL) or Clinical Pregnancy | 100 percentage of subjects |
| u-hCG | Percentage of Subjects With Ovulation Mid-luteal Serum Progesterone (P4) Level of Greater Than or Equal (>=) 5 Nanogram Per Milliliter (ng/mL) or Clinical Pregnancy | 100 percentage of subjects |
Secondary
Mid-luteal Endometrial Thickness
Endometrial thickness was measured using TVUS.
Time frame: Day 5 to 7 post hCG treatment
Population: The Mod ITT population was defined as all subjects randomized to IMP (MSJ-0011 or u-hCG) and who completed the primary efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MSJ-0011 | Mid-luteal Endometrial Thickness | 11.6 millimeter | Standard Deviation 2.64 |
| u-hCG | Mid-luteal Endometrial Thickness | 12.4 millimeter | Standard Deviation 2.58 |
Secondary
Percentage of Participants With Biochemical Pregnancy
Percentage of subjects with biochemical pregnancy was assessed. Biochemical pregnancy was defined as any miscarriage without any evidence of a fetal sac on TVUS on the Day 35 to 42 post hCG treatment, but with a positive serum β-hCG pregnancy test on Day 15 to 20 post hCG treatment (Beta-hCG level greater than \[\>\] 10 IU/Liter)
Time frame: Day 35 to 42 post hCG treatment
Population: The Mod ITT population was defined as all subjects randomized to IMP (MSJ-0011 or u-hCG) and who completed the primary efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MSJ-0011 | Percentage of Participants With Biochemical Pregnancy | 3.7 percentage of subjects |
| u-hCG | Percentage of Participants With Biochemical Pregnancy | 3.7 percentage of subjects |
Secondary
Percentage of Participants With Clinical Pregnancy
Percentage of subjects with clinical pregnancy was assessed. Clinical pregnancy was defined as the presence of at least a fetal sac on TVUS.
Time frame: Day 35 to 42 post hCG treatment
Population: The Mod ITT population was defined as all subjects randomized to IMP (MSJ-0011 or u-hCG) and who completed the primary efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MSJ-0011 | Percentage of Participants With Clinical Pregnancy | 29.6 percentage of subjects |
| u-hCG | Percentage of Participants With Clinical Pregnancy | 33.3 percentage of subjects |
Secondary
Percentage of Subjects With Ovulation Mid-Luteal Serum Progesterone (P4) Level of Greater Than or Equal (>=) 9.4 Nanogram Per Milliliter (ng/mL) or Clinical Pregnancy
Ovulation was defined as mid-luteal serum progesterone level of \>= 9.4 ng/mL or clinical pregnancy. Clinical pregnancy was defined as the presence of at least a fetal sac on TVUS.
Time frame: Mid-luteal phase progesterone assessed (Day 5 to 10) or clinical pregnancy (Day 35 to 42) post hCG treatment
Population: The Mod ITT population was defined as all subjects randomized to IMP (MSJ-0011 or u-hCG) and who completed the primary efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MSJ-0011 | Percentage of Subjects With Ovulation Mid-Luteal Serum Progesterone (P4) Level of Greater Than or Equal (>=) 9.4 Nanogram Per Milliliter (ng/mL) or Clinical Pregnancy | 96.3 percentage of subjects |
| u-hCG | Percentage of Subjects With Ovulation Mid-Luteal Serum Progesterone (P4) Level of Greater Than or Equal (>=) 9.4 Nanogram Per Milliliter (ng/mL) or Clinical Pregnancy | 88.9 percentage of subjects |