A Phase 2 Trial to Evaluate if Corifollitropin Alfa (Org 36286), Followed by a Low Daily Dose of hCG or Recombinant FSH Can Induce Monofollicular Growth in Women With WHO Group II Anovulatory Infertility (P05693)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II, Randomized, Controlled, Open-label, Feasibility Trial to Evaluate if a Single or Repeated Dose of Org 36286 (Corifollitropin Alfa) Followed by a Low Daily Dose of Either hCG or Recombinant FSH Can Induce Monofollicular Growth in Women With WHO Group II Anovulatory Infertility

Conditions
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Ovulation Induction

Intervention / Treatment
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* Drug: corifollitropin alfa
* Biological: recombinant Follicle Stimulating Hormone (recFSH)
* Biological: human Chorion Gonadotropin (hCG)
* Biological: hCG Bolus injection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: corifollitropin alfa + recFSH<br>Eligible participants will receive a subcutaneous (SC) injection of corifollitropin alfa (Stage 1a: 15mcg, Stage Ib/II: 30 mcg) the first, second, or third day after onset of a progestagen-induced withdrawal bleeding. If the follicle growth is insufficient, the participant will receive a second or third dose of corifollitropin alfa (Stage 1a: 15 mcg, Stage Ib/II: 20 mcg). As soon as the largest follicle reaches a size of ≥12 mm, the participant will start daily SC injections with FSH (Stage 1A: 50 IU, Stage II: 75 IU) the same day. A bolus injection of hCG (5000 IU) will be administered if at least one follicle is ≥18 mm and in total no more than two follicles ≥15 mm are observed. | Drug: corifollitropin alfa<br>* 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).<br>* Other names: MK-8962;Biological: recombinant Follicle Stimulating Hormone (recFSH)<br>* 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.<br>* Other names: Puregon®;Biological: hCG Bolus injection<br>* 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.<br>* Other names: Pregnyl®;|
| Experimental: corifollitropin alfa + hCG<br>Eligible participants will receive a SC injection of corifollitropin alfa (Stage Ia:15 mcg, Stage Ib/II: 30 mcg) the first, second or third day after onset of a progestagen-induced withdrawal bleeding. If the follicle growth is insufficient the participant will receive a second or third dose of corifollitropin alfa (Stage IA: 15 mcg, stage Ib/II: 20 mcg). As soon as the largest follicle reaches a size of ≥12 mm the participant will start daily SC injections with hCG (Stage Ib/II: 200 IU) the same day. A bolus injection of hCG (5000 IU) will be administered if at least one follicle is ≥18 mm and in total no more than two follicles ≥15 mm are observed. | Drug: corifollitropin alfa<br>* 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).<br>* Other names: MK-8962;Biological: human Chorion Gonadotropin (hCG)<br>* 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.<br>* Other names: Pregnyl®;Biological: hCG Bolus injection<br>* 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.<br>* Other names: Pregnyl®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At day of bolus injection of hCG (up to 20 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 8 days after bolus injection of hCG (up to 28 days) | 
| 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. | 8 days after bolus injection of hCG (up to 28 days) | 
| 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). | Up to 3 weeks after bolus injection of hCG (up to 41 days) | 
| 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. | At least 10 weeks after bolus injection of hCG (up to 13 weeks) | 
| 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. | During In-Treatment Period (up to 14 weeks after first corifollitropin injection) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormones, Pharmacological effects of drugs, Hormone Substitutes and Hormone Antagonists, Pharmacological Actions, Monofollicular growth, Randomized, Open-label, Active-controlled