Polycystic Ovarian Syndrome
Conditions
Keywords
Cetrorelix acetate; follitropin alfa; human chorionic-gonadotropin alfa; follicular maturation; pregnancy; ovarian stimulation
Brief summary
This is a randomized open-label study to compare between in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes of the two regimen of Cetrotide® (Cetrorelix acetate) which are 0.25 milligram (mg) used from Day 1 or Day 7 of the menstrual cycle (Day 0 or Day 6 of stimulation) in polycystic ovarian (PCO) women in assisted reproductive technology (ART).
Detailed description
Polycystic ovarian syndrome population is an androgenic syndrome characterized by a wide spectrum of clinical manifestations such as obesity, hirsutism, insulin resistance, diabetes and presence of specific ultrasonic features. Cetrotide®, cetrorelix acetate, is an antagonist of luteinizing-hormone-releasing hormone (LHRH). Cetrotide® is registered in 70 countries (including France) for the prevention of premature ovulation in subjects undergoing a controlled ovarian stimulation, followed by oocyte pick-up and ARTs. Ovitrelle®, active ingredient human chorionic-gonadotropin alfa, is administered to trigger final follicular maturation and luteinization after stimulation of follicular growth. OBJECTIVES Primary objective: * To compare the hormonal level of plasmatic estradiol on the releasing day (day of r-hCG administration) induced by Cetrotide® 0.25 mg/day started on Day 1 (Group A: Day 1) or on Day 7 (Group B: Day 7) of the menstrual cycle (Day 0 (S0) or Day 6 (S6) of stimulation) in PCO subjects undergoing IVF/ICSI procedures. Secondary objectives: * To compare the hormonal changes during the stimulation induced by Cetrotide® in A and B Groups * To assess by ultrasound scans (US) the follicular development induced by Cetrotide® in A and B Groups * To assess biological and clinical outcomes induced by Cetrotide® in A and B Groups * To monitor safety of Cetrotide in A and B Groups The trial will be conducted on an outpatient basis. Once each subject has met all eligibility criteria, they will be randomly assigned in one of the two treatment groups.
Interventions
Cetrotide® 0.25 mg will be administered subcutaneously once daily from Day 1 (Day 0 of stimulation period \[S0\]) until r-hCG day (at least 2 follicles \>=17 mm)
The r-hCG will be administered subcutaneously as a single dose of 250 microgram (mcg) on r-hCG day
Recombinant human follicle stimulating hormone (r-hFSH) will be administered subcutaneously at a dose between 75 and 187.5 international unit (IU) once daily from Day 2 (Day 1 of stimulation period \[S1\]) until r-hCG day
Sponsors
Merck Serono S.A.S, France
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
* Female subjects with PCO or Polycystic ovary syndrome (PCOS) according to the revised 2003 Rotterdam Consensus * Female subjects suitable for IVF/ICSI, undergoing first or second attempt * 18-35 years old, Body Mass Index (BMI) less than or equal to 32, non-smoking at least from Visit 0 (V0) * Normal FSH value (less than 10 international unit per liter \[IU/L\]) on Day 3 of spontaneous cycle within 12 months prior to the trial * Anti Mullerian Hormone (AMH) value (greater than 1.5 nanogram per milliliter \[ng/mL\]) of a spontaneous cycle within 12 months prior to the trial or at least at V0 * No history of active genito-urinary infection * Normal thyroid function (or adequate substitution for at least 3 months) * Negative cervical papanicolaou test within the last 12 months prior to study entry * No gonadotropins, for at least one month prior to the trial * No metformin therapy for at least one month prior to Visit 1 (V1) * Subject who is able to participate in the trial and has provided written, informed consent.
Exclusion criteria
* Ongoing pregnancy, any pregnancy within 3 months prior to study entry, or any contraindication to pregnancy or carrying pregnancy to term * Drilling 3 months prior to V0 * Uterine malformation, diethylstilbestrol syndrome, synechia * Female subjects with World Health Organization (WHO) Type I or III anovulation * Female subjects with hyperprolactinemia * Female subjects with more than 2 recurrent miscarriages (early or late, and for any reasons) * Known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus, for subject or partner * Abnormal gynecological bleeding of undetermined origin * History of major thromboembolic disease * Endometriosis (Grade III or IV) * Presence or history of malignant tumors and related treatment * Known case of tumors of the hypothalamus or pituitary gland * Clinically significant systemic disease or clinically significant abnormal hematology, chemistry, or urinalysis results at screening * Known allergic reaction or hypersensitivity to Cetrotide® or Ovitrelle® * Any active substance abuse or history of drug, medication or alcohol abuse in the past 5 years * Participation in another clinical trial within 3 months prior to study entry.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Estradiol (E2) Levels on r-hCG Day | r-hCG day (end of stimulation cycle [approximately 15 days]) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Estradiol (E2) Levels | Day 1 | — |
| Serum Progesterone (P4) Levels | Day 1 | — |
| Anti Mullerian Hormone (AMH) Levels | Day 0 | — |
| Number of Follicles Greater Than or Equal (>=) to 17 mm (For Day 1 Protocol) or 19 mm (For Day 7 Protocol) on r-hCG Day | r-hCG day (end of stimulation cycle [approximately 15 days]) | — |
| Number and Quality of Oocytes Retrieved | Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocytes from the ovary of the female participant, enabling fertilization outside the body. Oocytes were classified into 4 different categories based on their quality: mature, fractured, immature and inseminated oocytes. |
| Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH) | Day 1 up to r-hCG day (end of stimulation cycle [approximately 15 days]) | — |
| Serum Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Levels | Day 1 | — |
| Number of Embryos | Day 2-3 post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | Embryo is defined as the product of the zygote, two or three days after fertilization of the oocytes. |
| Number of Blastocysts | Day 5-6 post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | Blastocyst is an embryo, five or six days after fertilization, with an inner cell mass, outer layer of trophectoderm and a fluid-filled blastocoele cavity. |
| Number of Transferred Embryos | Day 2-3 post Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | Embryo transfer is the procedure in which one or more embryos are placed in the uterus. |
| Implantation Rate | 5 weeks post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | Implantation rate per reporting group was measured as the number of gestational sacs observed, divided by the number of embryos transferred multiplied by 100. |
| Percentage of Participants With Clinical Pregnancy | 10 weeks post r-hCG day (end of stimulation cycle [approximately 15 days]) | Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It excludes ectopic pregnancy. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 up to end of study (15 days post last administration of study drug) | An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. To avoid the participant/event combination double-count AEs and SAEs are reported separately. |
| Percentage of Fertilized Oocytes Retrieved | Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}]) | Oocytes were fertilized using Intra-cytoplasmic Sperm Injection (ICSI) technique which is an IVF procedure in which a single sperm is injected directly into an egg under a microscope. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Day 1 Protocol Cetrotide® 0.25 milligram (mg) was administered subcutaneously once daily from Day 1 (Day 0 of stimulation period \[S0\]) along with Recombinant human follicle stimulating hormone (r-hFSH) at a dose between 75 and 187.5 international unit (IU) subcutaneously once daily from Day 2 (Day 1 of stimulation period \[S1\]) until recombinant human chorionic gonadotropin (r-hCG) administration day (at least 2 follicles greater than or equal to (\>=) 17 millimeter \[mm\]). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. | 65 |
| Day 7 Protocol Cetrotide® 0.25 mg was administered subcutaneously once daily from Day 7 (Day 6 of stimulation period \[S6\]) along with r-hFSH at a dose between 75 and 187.5 IU subcutaneously once daily from Day 2 (S1) until r-hCG administration day (at least 2 follicles \>= 19 mm). On r-hCG day, 250 microgram of r-hCG was administered once subcutaneously. | 65 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ectopic pregnancy | 0 | 1 |
| Overall Study | Lack of ovarian response | 5 | 1 |
| Overall Study | Ovarian hyperstimulation syndrome risk | 5 | 3 |
| Overall Study | Randomized but not treated | 3 | 3 |
Baseline characteristics
| Characteristic | Day 1 Protocol | Day 7 Protocol | Total |
|---|---|---|---|
| Age, Continuous | 29.7 years STANDARD_DEVIATION 2.9 | 29.7 years STANDARD_DEVIATION 3.3 | 29.7 years STANDARD_DEVIATION 3.1 |
| Sex: Female, Male Female | 65 Participants | 65 Participants | 130 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 | 9 / 65 | 14 / 65 |
| serious Total, serious adverse events | 2 / 65 | 4 / 65 |
Outcome results
Primary
Estradiol (E2) Levels on r-hCG Day
Time frame: r-hCG day (end of stimulation cycle [approximately 15 days])
Population: Intent to treat (ITT) population included all randomized participants who had received at least 1 dose of the study medication. N (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Estradiol (E2) Levels on r-hCG Day | 1668.86 picogram/milliliter (pg/mL) | Standard Deviation 862.62 |
| Day 7 Protocol | Estradiol (E2) Levels on r-hCG Day | 1672.80 picogram/milliliter (pg/mL) | Standard Deviation 835.49 |
Secondary
Anti Mullerian Hormone (AMH) Levels
Time frame: Day 0
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Anti Mullerian Hormone (AMH) Levels | 6.27 nanogram/milliliter (ng/mL) | Standard Deviation 4.4 |
| Day 7 Protocol | Anti Mullerian Hormone (AMH) Levels | 7.18 nanogram/milliliter (ng/mL) | Standard Deviation 4.11 |
Secondary
Implantation Rate
Implantation rate per reporting group was measured as the number of gestational sacs observed, divided by the number of embryos transferred multiplied by 100.
Time frame: 5 weeks post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Day 1 Protocol | Implantation Rate | 36.90 percent sacs per embryo |
| Day 7 Protocol | Implantation Rate | 32.25 percent sacs per embryo |
Secondary
Number and Quality of Oocytes Retrieved
Oocyte retrieval is a technique used in in-vitro fertilization (IVF) in order to remove oocytes from the ovary of the female participant, enabling fertilization outside the body. Oocytes were classified into 4 different categories based on their quality: mature, fractured, immature and inseminated oocytes.
Time frame: Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Day 1 Protocol | Number and Quality of Oocytes Retrieved | Mature oocytes | 2.52 oocytes | Standard Deviation 4.07 |
| Day 1 Protocol | Number and Quality of Oocytes Retrieved | Immature oocytes | 0.98 oocytes | Standard Deviation 2.29 |
| Day 1 Protocol | Number and Quality of Oocytes Retrieved | Fractured oocytes | 0.09 oocytes | Standard Deviation 0.34 |
| Day 1 Protocol | Number and Quality of Oocytes Retrieved | Inseminated oocytes | 3.06 oocytes | Standard Deviation 4.14 |
| Day 1 Protocol | Number and Quality of Oocytes Retrieved | Total number of oocytes | 7.48 oocytes | Standard Deviation 5.21 |
| Day 7 Protocol | Number and Quality of Oocytes Retrieved | Inseminated oocytes | 4.52 oocytes | Standard Deviation 4.66 |
| Day 7 Protocol | Number and Quality of Oocytes Retrieved | Total number of oocytes | 8.11 oocytes | Standard Deviation 5.55 |
| Day 7 Protocol | Number and Quality of Oocytes Retrieved | Mature oocytes | 3.72 oocytes | Standard Deviation 4.43 |
| Day 7 Protocol | Number and Quality of Oocytes Retrieved | Fractured oocytes | 0.11 oocytes | Standard Deviation 0.44 |
| Day 7 Protocol | Number and Quality of Oocytes Retrieved | Immature oocytes | 1.38 oocytes | Standard Deviation 2.55 |
Secondary
Number of Blastocysts
Blastocyst is an embryo, five or six days after fertilization, with an inner cell mass, outer layer of trophectoderm and a fluid-filled blastocoele cavity.
Time frame: Day 5-6 post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Number of Blastocysts | 0.26 blastocysts | Standard Deviation 1.05 |
| Day 7 Protocol | Number of Blastocysts | 0.20 blastocysts | Standard Deviation 0.9 |
Secondary
Number of Embryos
Embryo is defined as the product of the zygote, two or three days after fertilization of the oocytes.
Time frame: Day 2-3 post oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Number of Embryos | 3.18 embryos | Standard Deviation 3.18 |
| Day 7 Protocol | Number of Embryos | 3.60 embryos | Standard Deviation 3.27 |
Secondary
Number of Follicles Greater Than or Equal (>=) to 17 mm (For Day 1 Protocol) or 19 mm (For Day 7 Protocol) on r-hCG Day
Time frame: r-hCG day (end of stimulation cycle [approximately 15 days])
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Number of Follicles Greater Than or Equal (>=) to 17 mm (For Day 1 Protocol) or 19 mm (For Day 7 Protocol) on r-hCG Day | 3.55 follicles | Standard Deviation 2.2 |
| Day 7 Protocol | Number of Follicles Greater Than or Equal (>=) to 17 mm (For Day 1 Protocol) or 19 mm (For Day 7 Protocol) on r-hCG Day | 2.49 follicles | Standard Deviation 1.99 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. To avoid the participant/event combination double-count AEs and SAEs are reported separately.
Time frame: Day 1 up to end of study (15 days post last administration of study drug)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Day 1 Protocol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 11 participants |
| Day 1 Protocol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| Day 7 Protocol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 18 participants |
| Day 7 Protocol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 participants |
Secondary
Number of Transferred Embryos
Embryo transfer is the procedure in which one or more embryos are placed in the uterus.
Time frame: Day 2-3 post Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Number of Transferred Embryos | 0.95 transferred embryos | Standard Deviation 0.74 |
| Day 7 Protocol | Number of Transferred Embryos | 1.02 transferred embryos | Standard Deviation 0.74 |
Secondary
Percentage of Fertilized Oocytes Retrieved
Oocytes were fertilized using Intra-cytoplasmic Sperm Injection (ICSI) technique which is an IVF procedure in which a single sperm is injected directly into an egg under a microscope.
Time frame: Oocytes retrieval day (36 +/- 2 hours post r-hCG day [end of stimulation cycle {approximately 15 days}])
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Percentage of Fertilized Oocytes Retrieved | 46.22 percent fertilized oocytes | Standard Deviation 30.66 |
| Day 7 Protocol | Percentage of Fertilized Oocytes Retrieved | 46.86 percent fertilized oocytes | Standard Deviation 30.54 |
Secondary
Percentage of Participants With Clinical Pregnancy
Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It excludes ectopic pregnancy.
Time frame: 10 weeks post r-hCG day (end of stimulation cycle [approximately 15 days])
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Day 1 Protocol | Percentage of Participants With Clinical Pregnancy | 20 percentage of participants |
| Day 7 Protocol | Percentage of Participants With Clinical Pregnancy | 20 percentage of participants |
Secondary
Serum Estradiol (E2) Levels
Time frame: Day 1
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Serum Estradiol (E2) Levels | 30.42 pg/mL | Standard Deviation 14.06 |
| Day 7 Protocol | Serum Estradiol (E2) Levels | 68.79 pg/mL | Standard Deviation 116.09 |
Secondary
Serum Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Levels
Time frame: Day 1
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication. N (number of participants analyzed) signifies those participants who were evaluable for this measure. Here n signifies those participants who were evaluated for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Day 1 Protocol | Serum Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Levels | FSH levels (n=57, 59) | 4.98 International unit/liter (IU/L) | Standard Deviation 1.54 |
| Day 1 Protocol | Serum Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Levels | LH levels (n=58, 62) | 4.87 International unit/liter (IU/L) | Standard Deviation 4.62 |
| Day 7 Protocol | Serum Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Levels | LH levels (n=58, 62) | 6.84 International unit/liter (IU/L) | Standard Deviation 3.99 |
| Day 7 Protocol | Serum Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Levels | FSH levels (n=57, 59) | 6.69 International unit/liter (IU/L) | Standard Deviation 10.29 |
Secondary
Serum Progesterone (P4) Levels
Time frame: Day 1
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Serum Progesterone (P4) Levels | 0.83 nanomolar/liter (nmol/L) | Standard Deviation 0.72 |
| Day 7 Protocol | Serum Progesterone (P4) Levels | 0.97 nanomolar/liter (nmol/L) | Standard Deviation 1.82 |
Secondary
Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH)
Time frame: Day 1 up to r-hCG day (end of stimulation cycle [approximately 15 days])
Population: ITT population included all randomized participants who had received at least 1 dose of the study medication. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Day 1 Protocol | Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH) | 1462.50 international unit (IU) | Standard Deviation 537.85 |
| Day 7 Protocol | Total Dose of Recombinant Human Follicle Stimulating Hormone (r-hFSH) | 1221.35 international unit (IU) | Standard Deviation 478.31 |