Infertility
Conditions
Keywords
Reproductive Techniques, Assisted, Follicle Stimulating Hormone, Human, Fertilization In Vitro
Brief summary
The purpose of this study is to show that a single injection of SCH 900962/MK-8962 is non-inferior to daily injections of recombinant follicle-stimulating hormone (recFSH) during the first week of ovarian stimulation in terms of the number of vital pregnancies (ie, presence of at least one fetus with heart activity as assessed by ultrasound at least 35 days after embryo transfer) in women aged 35 to 42 years undergoing controlled ovarian stimulation (COS) prior to in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).
Interventions
BIOLOGICALSCH 900962 / Corifollitropin alfa / Org 36286
SCH 900962 will be provided as ready-for-use prefilled syringes containing 150 μg corifollitropin alfa per 0.5 mL. On day 2 or 3 of the menstrual cycle, a single dose of 150 μg corifollitropin alfa will be administered by subcutaneous injection in the abdominal wall in the morning.
BIOLOGICALRecFSH / follitropin beta
RecFSH will be provided as a ready-for-use solution in 900 IU cartridges for subcutaneous injection with the Follistim Pen. Starting on day 2 or 3 of the menstrual cycle (=Stimulation Day 1), administration of recFSH will be done in the morning by daily injections in the abdominal wall. A starting dose of 300 IU will be administered and fixed for at least 7 days.
DRUGPlacebo for SCH 900962
Supplied as a pre-filled syringe containing an identical solution when compared to SCH 900962, however without the active ingredient corifollitropin alfa. On Day 2 or 3 of the menstrual cycle (=Stimulation Day 1), a single dose of placebo SCH 900962 is to be administered in the morning by subcutaneous injection in the abdominal wall.
DRUGPlacebo for recFSH
Supplied as identical ready-for-use solution, but without the active ingredient, in cartridges for subcutaneous injection with the Follistim Pen. Starting on day 2 or 3 of the menstrual cycle (=Stimulation Day 1), administration of placebo-recFSH will be done by daily injections in the abdominal wall in the morning for a period of 7 days.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
35 Years to 42 Years
Healthy volunteers
No
Inclusion criteria
* Willing and able to provide written informed consent for trial P06029 as well as for the Frozen-Thawed Embryo Transfer (FTET) follow-up trial P06031, and for the pharmacogenetic analysis (if applicable). * Female and \>=35 to \<=42 years of age with indication for COS and IVF/ICSI. * Body weight ≥50.0 kg, body mass index (BMI) \>=18.0 to \<=32.0 kg/m2. * Regular spontaneous menstrual cycle with variation not outside the 24-35 days. * Ejaculatory sperm must be available (donated and/or cryopreserved sperm is allowed). * Results of clinical laboratory tests, cervical smear, physical examination within normal limits or clinically acceptable to the investigator. * Adhere to trial schedule.
Exclusion criteria
* A recent history of/or any current endocrine abnormality. * A history of ovarian hyper-response or ovarian hyperstimulation syndrome (OHSS). * A history of/or current polycystic ovary syndrome. * More than 20 basal antral follicles \<11 mm (both ovaries combined) in the early follicular phase. * Less than 2 ovaries or any other ovarian abnormality. * Unilateral or bilateral hydrosalpinx. * Intrauterine fibroids ≥5 cm or any clinically relevant pathology, which could impair embryo implantation or pregnancy continuation. * More than three unsuccessful COS cycles for IVF/ICSI since the last established ongoing pregnancy (if applicable). * A history of non- or low ovarian response to FSH/human menopausal gonadotropin (hMG) treatment. * A history of recurrent miscarriage. * FSH \>15.0 IU/L or luteinizing hormone (LH) \>12.0 IU/L during the early follicular phase. * Positive for human immunodeficiency virus (HIV) or Hepatitis B. * Contraindications for the use of gonadotropins or gonadotropin releasing hormone (GnRH) antagonists. * A recent history of/or current epilepsy, thrombophilia, diabetes, cardiovascular, gastro-intestinal, hepatic, renal or pulmonary or auto-immune disease requiring regular treatment. * Smoking or recently stopped smoking (ie, within the last 3 months prior to signing informed consent). * A recent history or presence of alcohol or drug abuse. * The participant or the sperm donor has known gene defects, genetic abnormalities, or abnormal karyotyping, relevant for the current indication or for the health of the offspring. * Prior or concomitant medications disallowed by protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Vital Pregnancy | Vital pregnancy will be assessed by ultrasound at least 35 days after embryo transfer (with a timeframe of 35-42 days). Time from start of study treatment to embryo transfer is maximally 24 days. | Vital pregnancy was defined as the presence of at least 1 fetus with heart activity at least 35 days (≥5 weeks) after embryo transfer in the controlled ovarian stimulation (COS) treatment cycle |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Oocytes Retrieved Per Attempt | Maximally 21 days after the start of study treatment. | The number of cumulus oocyte-complexes retrieved was summarized per treatment group and per attempt (= per started COS cycle). |
| Live Birth Rate | Approximately nine months after embryo transfer | The live-birth rate is the percentage of participants with at least 1 live born infant after an ongoing pregnancy in the controlled ovarian stimulation (COS)treatment cycle relative to the number of participants treated. |
| Number of Participants With Moderate or Severe Ovarian Hyperstimulation Syndrome (OHSS) | Up to approximately 1 month after oocyte pick-up | Grade II (moderate OHSS) is characterized by distinct ovarian cysts (ovary size 8-10 cm), accompanied by abdominal pain and tension, nausea, vomiting, diarrhea. Grade III (severe OHSS) is characterized by enlarged cystic ovaries (ovary size \>10 cm), accompanied by ascites and occasionally hydrothorax. Abdominal tension and pain may be severe. Pronounced hydrothorax together with an abdominal cavity filled with cysts and fluid elevating the diaphragm, may cause severe breathing difficulties. Large quantities of fluid inside the cysts and in the peritoneal and pleural cavities cause hemoconcentration and increased blood viscosity. In rare cases, the syndrome may further be complicated by the occurrence of thromboembolic phenomena. |
| Number of Participants Who Cancelled the Cycle Due to a (Serious) Adverse Event | Up to time of embryo transfer (maximum of 24 days after start of study drug) | The number of participants who started stimulation but did not undergo embryo transfer due to (S)AEs will be compared between the treatment groups. |
Participant flow
Recruitment details
Women, aged between 35 and 42 years, with an indication for controlled ovarian stimulation and in vitro fertilization/intracytoplasmic sperm injection without a history of previous hyper or low ovarian response to follicle-stimulating hormone/human menopausal gonadotropins, ovarian hyperstimulation syndrome (OHSS), or polycystic ovary syndrome.
Pre-assignment details
1424 participants were originally enrolled in the study. All data for 1 participant, who was incorrectly randomized and did not receive study medication and for all 33 participants at 1 clinical site were excluded from all analyses, including disposition, prior to unblinding. Only women who became pregnant continued into Pregnancy Follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| Single Injection of 150 µg SCH 900962/MK-8962 Participants received a single injection of 150 ug SCH 900962 (MK-8962) on Stimulation Day 1 and 7 injections with placebo-recFSH from Stimulation Days 1-7 | 694 |
| Daily 300 IU recFSH Participants received a single injection of placebo SCH 900962 (MK-8962) on Stimulation Day 1 and 7 injections of 300 IU recFSH from Stimulation Days 1-7 | 696 |
| Total | 1,390 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention Period | Adverse Event | 5 | 6 |
| Intervention Period | Insufficient ovarian response | 11 | 17 |
| Intervention Period | No or abnormal fertilization | 25 | 10 |
| Intervention Period | No/too few/bad oocytes | 7 | 5 |
| Intervention Period | No/too few/bad quality embryos | 3 | 3 |
| Intervention Period | Other | 7 | 5 |
| Intervention Period | Risk of OHSS | 0 | 1 |
| Intervention Period | Too high ovarian response | 4 | 2 |
Baseline characteristics
| Characteristic | Single Injection of 150 µg SCH 900962/MK-8962 | Daily 300 IU recFSH | Total |
|---|---|---|---|
| Age, Continuous | 38.0 years STANDARD_DEVIATION 2.2 | 38.0 years STANDARD_DEVIATION 2.2 | 38.0 years STANDARD_DEVIATION 2.2 |
| Sex: Female, Male Female | 694 Participants | 696 Participants | 1390 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 267 / 692 | 262 / 698 | 94 / 154 | 105 / 167 |
| serious Total, serious adverse events | 4 / 692 | 19 / 698 | 110 / 154 | 112 / 167 |
Outcome results
Primary
Percentage of Participants With a Vital Pregnancy
Vital pregnancy was defined as the presence of at least 1 fetus with heart activity at least 35 days (≥5 weeks) after embryo transfer in the controlled ovarian stimulation (COS) treatment cycle
Time frame: Vital pregnancy will be assessed by ultrasound at least 35 days after embryo transfer (with a timeframe of 35-42 days). Time from start of study treatment to embryo transfer is maximally 24 days.
Population: Intent-To-Treat Group: all randomized participants who received 1 or more dose(s) of SCH 900962 or recFSH. Participants were grouped according to the treatment they were randomized to. Participants who did not have embryo transfer or who were lost to follow-up before the ultrasound assessment to confirm vital pregnancy were counted as non-pregnant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Injection of 150 µg SCH 900962/MK-8962 | Percentage of Participants With a Vital Pregnancy | 23.9 percentage of participants |
| Daily 300 IU recFSH | Percentage of Participants With a Vital Pregnancy | 26.9 percentage of participants |
95% CI: [-7.4, 1.4]generalized linear model
Secondary
Live Birth Rate
The live-birth rate is the percentage of participants with at least 1 live born infant after an ongoing pregnancy in the controlled ovarian stimulation (COS)treatment cycle relative to the number of participants treated.
Time frame: Approximately nine months after embryo transfer
Population: Intent-To-Treat Group: all randomized participants who received 1 or more dose(s) of SCH 900962 or recFSH. Participants were grouped according to the treatment they were randomized to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Injection of 150 µg SCH 900962/MK-8962 | Live Birth Rate | 21.3 Percentage of participants |
| Daily 300 IU recFSH | Live Birth Rate | 23.4 Percentage of participants |
95% CI: [-6.5, 1.9]generalized linear model
Secondary
Number of Oocytes Retrieved Per Attempt
The number of cumulus oocyte-complexes retrieved was summarized per treatment group and per attempt (= per started COS cycle).
Time frame: Maximally 21 days after the start of study treatment.
Population: Intent-To-Treat (ITT) Group, defined as all randomized participants who received one or more dose(s) of SCH 900962 or recFSH. Participants were grouped according to the treatment they were randomized to. The number of oocytes retrieved were set to zero for participants who did not have oocyte retrieval.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Injection of 150 µg SCH 900962/MK-8962 | Number of Oocytes Retrieved Per Attempt | 10.7 Number of oocytes | Standard Deviation 7.2 |
| Daily 300 IU recFSH | Number of Oocytes Retrieved Per Attempt | 10.3 Number of oocytes | Standard Deviation 6.8 |
95% CI: [-0.2, 1.2]ANOVA
Secondary
Number of Participants Who Cancelled the Cycle Due to a (Serious) Adverse Event
The number of participants who started stimulation but did not undergo embryo transfer due to (S)AEs will be compared between the treatment groups.
Time frame: Up to time of embryo transfer (maximum of 24 days after start of study drug)
Population: All-Subjects-Treated (AST) Group, defined as all participants who received 1 or more dose(s) of SCH 900962 or recFSH. Participants were grouped according to the active treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Injection of 150 µg SCH 900962/MK-8962 | Number of Participants Who Cancelled the Cycle Due to a (Serious) Adverse Event | 5 participants |
| Daily 300 IU recFSH | Number of Participants Who Cancelled the Cycle Due to a (Serious) Adverse Event | 6 participants |
p-value: >0.999Fisher Exact
Secondary
Number of Participants With Moderate or Severe Ovarian Hyperstimulation Syndrome (OHSS)
Grade II (moderate OHSS) is characterized by distinct ovarian cysts (ovary size 8-10 cm), accompanied by abdominal pain and tension, nausea, vomiting, diarrhea. Grade III (severe OHSS) is characterized by enlarged cystic ovaries (ovary size \>10 cm), accompanied by ascites and occasionally hydrothorax. Abdominal tension and pain may be severe. Pronounced hydrothorax together with an abdominal cavity filled with cysts and fluid elevating the diaphragm, may cause severe breathing difficulties. Large quantities of fluid inside the cysts and in the peritoneal and pleural cavities cause hemoconcentration and increased blood viscosity. In rare cases, the syndrome may further be complicated by the occurrence of thromboembolic phenomena.
Time frame: Up to approximately 1 month after oocyte pick-up
Population: All-Subjects-Treated (AST) Group, defined as all participants who received 1 or more dose(s) of SCH 900962 or recFSH. Participants were grouped according to the active treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Injection of 150 µg SCH 900962/MK-8962 | Number of Participants With Moderate or Severe Ovarian Hyperstimulation Syndrome (OHSS) | 5 participants |
| Daily 300 IU recFSH | Number of Participants With Moderate or Severe Ovarian Hyperstimulation Syndrome (OHSS) | 10 participants |
p-value: 0.3Fisher Exact