Ovulation Induction
Conditions
Keywords
Pharmacological effects of drugs, Hormones, Hormone Substitutes and Hormone Antagonists, Pharmacological Actions, Monofollicular growth, Randomized, Open-label, Active-controlled
Brief summary
The primary objective of this trial is to evaluate whether a corifollitropin alfa (Org 36286) regimen applying a single or repeated dose of corifollitropin alfa followed by a low daily dose of Human Chorion Gonadotropin (hCG) or recombinant Follicular Stimulating Hormone (recFSH) can induce monofollicular growth (one follicle ≥18 mm and no other follicle ≥15 mm at day of bolus injection of hCG) in women with WHO group II anovulatory infertility.
Detailed description
This trial will include two separate stages (Ia+Ib and II). Stage Ia will be open-label and uncontrolled in a small cohort of women (n=5) to explore whether the intended dosing regimen of corifollitropin alfa followed by daily low dose recFSH provide an appropriate response in eligible participants meeting all inclusion and none of the exclusion criteria. Stage Ib will be open-label and uncontrolled in a small cohort of women (n=5) to explore whether the intended dosing regimen of corifollitropin alfa followed by daily low dose hCG provide an appropriate response in eligible participants meeting all inclusion and none of the exclusion criteria. Stage II is open-label and randomized (n=40) to evaluate whether the intended dosing regimen of corifollitropin alfa followed by low dose FSH (n=20) or hCG (n=20) provide an appropriate response in eligible participants meeting all inclusion and none of the exclusion criteria.
Interventions
DRUGcorifollitropin alfa
SC corifollitropin alfa on the 1st, 2nd or 3rd day after onset of a progestagen-induced withdrawal bleeding (Stage 1a: 15mcg, Stage Ib/II: 30 mcg).
Daily injections of SC recFSH (50 IU/75 IU) administered as soon as the largest follicle reaches a size ≥12 mm 4 days after a corifollitropin alfa injection on stimulation day 5, 9 or 13.
BIOLOGICALhuman Chorion Gonadotropin (hCG)
Daily injections of SC hCG (200 IU) administered as soon as the largest follicle reaches a size ≥12 mm 4 days after a corifollitropin alfa injection on stimulation day 5, 9 or 13.
BIOLOGICALhCG Bolus injection
Bolus injection of SC hCG was administered to induce final oocyte maturation if at least one follicle is ≥18 mm and no more than two follicles ≥15 mm are observed.
Sponsors
Organon and Co
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 39 Years
Healthy volunteers
No
Inclusion criteria
* Oligomenorrhea (average cycle length ≥35 days and \<6 months) * Amenorrhea (average cycle length ≥6 months) * Body Mass Index ≥18 and ≤30 kg/m\^2 * Normal serum FSH levels and normal estradiol levels at screening * Progestagen induced withdrawal bleeding * Age ≥18 years and ≤39 years at the time of signing informed consent * Willing and able to sign informed consent
Exclusion criteria
* History of or current ovarian cysts or enlarged ovaries not related to polycystic ovarian syndrome (PCOS) * History of or current tumors of the ovary, breast, uterus, pituitary or hypothalamus * Less than 2 ovaries * Undiagnosed vaginal bleeding * Any ovarian and/or abdominal abnormality interfering with ultrasound examination * Malformations of the sexual organs incompatible with pregnancy * Pregnancy or lactation * Abnormal serum endocrinology levels based on screening sample * Any clinically relevant abnormal laboratory value based on screening sample * Alcohol or drug abuse within the 12 months preceding signing of informed consent * Hypersensitivity to any of the substances in corifollitropin alfa * Hypersensitivity to hCG/ Puregon® or any of its components * Previous use of corifollitropin alfa * Use of any investigational drug during 90 days before screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Monofollicular Response (Monofollicular Rate) | At day of bolus injection of hCG (up to 20 days) | The monofollicular rate was defined as the number of participants with monofollicular response (one follicle ≥18 mm and no other follicle ≥15 mm on the day of the bolus injection of hCG) divided by the number of the treated participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Ovulation (Ovulation Rate) | 8 days after bolus injection of hCG (up to 28 days) | Ovulation rate was defined as the number of participants with confirmed ovulation (≥15 nmol/l serum progesterone eight days after the bolus injection of hCG) divided by the number of treated participants. Ovulation was also considered confirmed for participants who became pregnant, had an ectopic pregnancy or had a miscarriage. |
| Percentage of Participants With Monofollicular Ovulation (Monofollicular Ovulation Rate) | 8 days after bolus injection of hCG (up to 28 days) | Monofollicular ovulation rate was defined as the number of participants with monofollicular response (one follicle ≥18 mm and no other follicle ≥15 mm on the day of the bolus injection of hCG) and confirmed ovulation (≥15 nmol/l serum progesterone eight days after the bolus injection of hCG) divided by the number of treated participants. Ovulation was also considered confirmed for participants who became pregnant, had an ectopic pregnancy or had a miscarriage. |
| Percentage of Participants Who Cancelled Treatment (Cancellation Rate) | Up to 3 weeks after bolus injection of hCG (up to 41 days) | Treatment was considered cancelled if no bolus injection of hCG was administrated. Reasons of treatment failure included Adverse Event (AE)/ Serious Adverse Event (SAE), insufficient ovarian response on stimulation day 13 (no follicle ≥12 mm), insufficient ovarian response after 7 days of hCG/recFSH treatment (no follicle ≥18 mm), and multifollicular growth (≥3 follicles ≥15 mm). |
| Number of Participants With Pregnancy | At least 10 weeks after bolus injection of hCG (up to 13 weeks) | A pregnancy test (serum or urinary hCG) was performed two to three weeks after bolus injection of hCG. In case of a positive pregnancy test vaginal and/or abdominal ultrasound scan was performed to confirm the pregnancy at 5 to 6 weeks after bolus injection of hCG and ≥10 weeks after bolus injection of hCG to confirm ongoing pregnancy. |
| Number of Participants With AEs of Ovarian Hyperstimulation Syndrome (OHSS) | During In-Treatment Period (up to 14 weeks after first corifollitropin injection) | OHSS was classified on study based on a slightly modified WHO Scientific Group (1973) classification: Grade I (mild) = characterized by excessive steroid secretion and ovarian enlargement (5-7 cm). Abdominal discomfort, including abdominal pain, is present. Grade II (moderate) = characterized by distinct ovarian cysts (ovary size 8-10 cm), accompanied by abdominal pain and tension, nausea, vomiting, diarrhea. Grade III (severe) = 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 haemoconcentration and increased blood viscosity. In rare cases, the syndrome may further be complicated by the occurrence of thromboembolic phenomena. |
Participant flow
Pre-assignment details
5 participants were enrolled in Stage 1a to receive corifollitropin alfa + recombinant Follicular Stimulating Hormone (recFSH), and 3 participants were enrolled in Stage 1b to receive corifollitropin alfa + Human Chorion Gonadotropin (hCG).
Participants by arm
| Arm | Count |
|---|---|
| Corifollitropin Alfa + recFSH Eligible participants in Stage 1a received a subcutaneous (SC) injection of corifollitropin alfa (15 mcg) the first, second, or third day after onset of a progestagen-induced withdrawal bleeding. If the follicle growth was insufficient, the participant received a second or third dose of corifollitropin alfa (15 mcg). As soon as the largest follicle reached a size of ≥12 mm, the participant started daily SC injections with recFSH (50 IU) the same day. A bolus injection of hCG (5000 IU) was administered if at least one follicle was ≥18 mm and in total no more than two follicles ≥15 mm were observed. | 5 |
| Corifollitropin Alfa + hCG Eligible participants in Stage 1b received a SC injection of corifollitropin alfa (30 mcg) the first, second or third day after onset of a progestagen-induced withdrawal bleeding. If the follicle growth was insufficient the participant received a second or third dose of corifollitropin alfa (20 mcg). As soon as the largest follicle reached a size of ≥12 mm the participant started daily SC injections with hCG (200 IU) the same day. A bolus injection of hCG (5000 IU) was administered if at least one follicle was ≥18 mm and in total no more than two follicles ≥15 mm were observed. | 3 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Stage 1a | Insufficient ovarian response | 1 | 0 |
| Stage 1a | Multifollicular growth | 1 | 0 |
| Stage 1a | Not growing of dominant follicle | 1 | 0 |
| Stage 1b | Insufficient ovarian response | 0 | 1 |
| Stage 1b | Not growing of dominant follicle | 0 | 1 |
Baseline characteristics
| Characteristic | Corifollitropin Alfa + recFSH | Corifollitropin Alfa + hCG | Total |
|---|---|---|---|
| Age, Continuous | 30.8 years STANDARD_DEVIATION 5.9 | 28.7 years STANDARD_DEVIATION 2.5 | 30.0 years STANDARD_DEVIATION 4.8 |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 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 | 2 / 5 | 2 / 3 |
| serious Total, serious adverse events | 0 / 5 | 0 / 3 |
Outcome results
Primary
Percentage of Participants With Monofollicular Response (Monofollicular Rate)
The monofollicular rate was defined as the number of participants with monofollicular response (one follicle ≥18 mm and no other follicle ≥15 mm on the day of the bolus injection of hCG) divided by the number of the treated participants.
Time frame: At day of bolus injection of hCG (up to 20 days)
Population: Intent-to-Treat group (ITT) consisted of all treated participants (5 participants in Stage Ia and 3 participants in Stage Ib).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corifollitropin Alfa + recFSH | Percentage of Participants With Monofollicular Response (Monofollicular Rate) | 0 percentage of participants |
| Corifollitropin Alfa + hCG | Percentage of Participants With Monofollicular Response (Monofollicular Rate) | 0 percentage of participants |
Secondary
Number of Participants With AEs of Ovarian Hyperstimulation Syndrome (OHSS)
OHSS was classified on study based on a slightly modified WHO Scientific Group (1973) classification: Grade I (mild) = characterized by excessive steroid secretion and ovarian enlargement (5-7 cm). Abdominal discomfort, including abdominal pain, is present. Grade II (moderate) = characterized by distinct ovarian cysts (ovary size 8-10 cm), accompanied by abdominal pain and tension, nausea, vomiting, diarrhea. Grade III (severe) = 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 haemoconcentration and increased blood viscosity. In rare cases, the syndrome may further be complicated by the occurrence of thromboembolic phenomena.
Time frame: During In-Treatment Period (up to 14 weeks after first corifollitropin injection)
Population: The All-Participants-Treated (APT) group consisted of all participants who received corifollitropin alfa. Participants were grouped according to the stage of the trial and the active treatment group (recFSH Stage Ia, hCG Stage Ib) they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corifollitropin Alfa + recFSH | Number of Participants With AEs of Ovarian Hyperstimulation Syndrome (OHSS) | 0 participants |
| Corifollitropin Alfa + hCG | Number of Participants With AEs of Ovarian Hyperstimulation Syndrome (OHSS) | 0 participants |
Secondary
Number of Participants With Pregnancy
A pregnancy test (serum or urinary hCG) was performed two to three weeks after bolus injection of hCG. In case of a positive pregnancy test vaginal and/or abdominal ultrasound scan was performed to confirm the pregnancy at 5 to 6 weeks after bolus injection of hCG and ≥10 weeks after bolus injection of hCG to confirm ongoing pregnancy.
Time frame: At least 10 weeks after bolus injection of hCG (up to 13 weeks)
Population: Intent-to-Treat group (ITT) consisted of all treated participants (5 participants in Stage Ia and 3 participants in Stage Ib).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corifollitropin Alfa + recFSH | Number of Participants With Pregnancy | 0 participants |
| Corifollitropin Alfa + hCG | Number of Participants With Pregnancy | 1 participants |
Secondary
Percentage of Participants Who Cancelled Treatment (Cancellation Rate)
Treatment was considered cancelled if no bolus injection of hCG was administrated. Reasons of treatment failure included Adverse Event (AE)/ Serious Adverse Event (SAE), insufficient ovarian response on stimulation day 13 (no follicle ≥12 mm), insufficient ovarian response after 7 days of hCG/recFSH treatment (no follicle ≥18 mm), and multifollicular growth (≥3 follicles ≥15 mm).
Time frame: Up to 3 weeks after bolus injection of hCG (up to 41 days)
Population: Intent-to-Treat group (ITT) consisted of all treated participants (5 participants in Stage Ia and 3 participants in Stage Ib).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Corifollitropin Alfa + recFSH | Percentage of Participants Who Cancelled Treatment (Cancellation Rate) | Insufficient ovarian response | 20.0 percentage of participants |
| Corifollitropin Alfa + recFSH | Percentage of Participants Who Cancelled Treatment (Cancellation Rate) | Multifollicular growth | 20.0 percentage of participants |
| Corifollitropin Alfa + recFSH | Percentage of Participants Who Cancelled Treatment (Cancellation Rate) | Not growing of dominant follicle | 20.0 percentage of participants |
| Corifollitropin Alfa + hCG | Percentage of Participants Who Cancelled Treatment (Cancellation Rate) | Insufficient ovarian response | 33.3 percentage of participants |
| Corifollitropin Alfa + hCG | Percentage of Participants Who Cancelled Treatment (Cancellation Rate) | Multifollicular growth | 0 percentage of participants |
| Corifollitropin Alfa + hCG | Percentage of Participants Who Cancelled Treatment (Cancellation Rate) | Not growing of dominant follicle | 33.3 percentage of participants |
Secondary
Percentage of Participants With Monofollicular Ovulation (Monofollicular Ovulation Rate)
Monofollicular ovulation rate was defined as the number of participants with monofollicular response (one follicle ≥18 mm and no other follicle ≥15 mm on the day of the bolus injection of hCG) and confirmed ovulation (≥15 nmol/l serum progesterone eight days after the bolus injection of hCG) divided by the number of treated participants. Ovulation was also considered confirmed for participants who became pregnant, had an ectopic pregnancy or had a miscarriage.
Time frame: 8 days after bolus injection of hCG (up to 28 days)
Population: Intent-to-Treat group (ITT) consisted of all treated participants (5 participants in Stage Ia and 3 participants in Stage Ib).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corifollitropin Alfa + recFSH | Percentage of Participants With Monofollicular Ovulation (Monofollicular Ovulation Rate) | 0 percentage of participants |
| Corifollitropin Alfa + hCG | Percentage of Participants With Monofollicular Ovulation (Monofollicular Ovulation Rate) | 0 percentage of participants |
Secondary
Percentage of Participants With Ovulation (Ovulation Rate)
Ovulation rate was defined as the number of participants with confirmed ovulation (≥15 nmol/l serum progesterone eight days after the bolus injection of hCG) divided by the number of treated participants. Ovulation was also considered confirmed for participants who became pregnant, had an ectopic pregnancy or had a miscarriage.
Time frame: 8 days after bolus injection of hCG (up to 28 days)
Population: Intent-to-Treat group (ITT) consisted of all treated participants (5 participants in Stage Ia and 3 participants in Stage Ib).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Corifollitropin Alfa + recFSH | Percentage of Participants With Ovulation (Ovulation Rate) | 40.0 percentage of participants |
| Corifollitropin Alfa + hCG | Percentage of Participants With Ovulation (Ovulation Rate) | 33.3 percentage of participants |