Luveris® (Lutropin Alfa for Injection) in Women With Hypogonadotropic Hypogonadism (Luteinizing Hormone [LH] Less Than [<] 1.2 International Unit Per Liter [IU/L])

Study Overview
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Brief Summary
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Sponsor has decided to discontinue Luveris® in the United States (US) due to level of customer demand for this product, and not due to any efficacy or safety concerns.

Detailed Description
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To confirm the efficacy of the 75 IU dose of Luveris® compared to placebo when administered concomitantly with follitropin alfa for induction of clinical pregnancy in women with hypogonadotropic hypogonadism and profound LH deficiency (LH <1.2 IU/L), and to study the efficacy of a lower dose (25 IU) of Luveris® compared to placebo when administered concomitantly with follitropin alfa for induction of follicular development in women with hypogonadotropic hypogonadism and profound LH deficiency (LH <1.2 IU/L).

Official Title
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A Phase IV, Multicenter, Randomized, Double-blinded, Clinical Trial to Confirm the Efficacy of the 75 IU Dose of Luveris® vs. Placebo When Administered With Follitropin Alfa for Induction of Follicular Development and Pregnancy in Hypogonadotropic Hypogonadal Women With Profound LH Deficiency, as Defined by a Baseline LH Level <1.2 IU/L

Conditions
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Hypogonadotropic Hypogonadism

Intervention / Treatment
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* Drug: Luveris® 75 IU
* Drug: Luveris® 25 IU
* Drug: Placebo
* Drug: Recombinant human follicle stimulating hormone (r-hFSH)
* Drug: Recombinant human chorionic gonadotropin (r-hCG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be premenopausal, between 18 and 40 years of age inclusive on the day of consent Have a clinical history of hypogonadotropic hypogonadism (World health organization [WHO] Group I type of anovulation) on the basis of congenital or acquired hypothalamic or pituitary endocrine dysfunction in the presence of qualifying screening laboratories Have no prior treatment cycles with gonadotropins or gonadotropin releasing hormone (GnRH) (gonadotropin naïve) Have discontinued estrogen-progesterone replacement therapy at least one month before the screening procedure Have primary or secondary amenorrhea Have a negative progestin challenge test performed during Screening Have the following hormonal values in a centrally analyzed fasting blood sample, drawn within 6 weeks before initiation of treatment: Follicle-Stimulating Hormone (FSH): less than (<)5 international unit per liter (IU/L) Leutinizing hormone (LH): <1.2 IU/L (a second Baseline serum LH level will be repeated two weeks after the initial LH draw) Prolactin: < 43.3 nanogram per milliliter (ng/mL) (<1040 milli-international unit per liter [mIU/L]) Thyroid Stimulating Hormone (TSH): <6.5 micro-international units per milliliter (mcIU/mL) Free Thyroxin (T4): 0.8-1.8 nanogram per deciliter (ng/dL) (11-24 picomole per liter [pmol/L]) Testosterone: <1.0 ng/mL (<3.5 nanomole per liter [nmol/L]) Have an endovaginal pelvic ultrasound scan showing (i) no clinically significant uterine abnormality, (ii) no ovarian tumor or cyst, and (iii) less than or equal to (=<)13 small follicles (mean diameter =<10 milliliter [mm]) on the largest section through each ovary Have a normal cervical pap smear within 6 months of the initial visit Where indicated, have a normal or unchanged computed tomography (CT) scan or nuclear magnetic resonance (NMR) scan of the hypothalamic pituitary region on file Have a body mass index (BMI) between 18.4 and 31.4 kilogram per square meter (kg/m^2) Be willing and able to comply with the protocol for the duration of the study Have given written informed consent prior to any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to her future medical care Exclusion Criteria: Any medical condition which in the judgment of the investigator may interfere with the absorption, distribution, metabolism or excretion of the drug Any pre-existing medical condition which would compromise the subject's ability to conceive in vivo or to successfully complete a pregnancy Ongoing pregnancy Clinically important systemic disease (example: insulin-dependent diabetes mellitus, epilepsy, serious migraine, intermittent purpura, hepatic, renal or cardiovascular disease, serious corticoid-dependent asthma) Known infection with human immunodeficiency virus (HIV), Hepatitis B or C Ovarian enlargement or cyst of unknown etiology Abnormal gynecological bleeding of undetermined origin Previous or current hormone dependent tumor Known active substance abuse or eating disorder Known central nervous system (CNS) Lesions: In cases where hypogonadotropic hypogonadism (HH) is secondary to a CNS lesion or its treatment Exercise program exceeding 10 hours per week Is planning to undergo in vitro fertilization, intracytoplasmic sperm injection or another assisted reproductive technology (ART) procedure, other than intrauterine insemination, in the course of a study treatment cycle Currently undergoing treatment with psychotropic medication or with any other medication known to interfere with normal reproductive function (example: neuroleptics, dopamine antagonists)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Luveris® 75 IU<br> | Drug: Luveris® 75 IU<br>* Recombinant human luteinizing hormone (r-hLH, lutropin alfa, Luveris®), 75 IU will be administered subcutaneously once daily. Duration of treatment cycle will be up to 14 days, or maximum of 21 days (if follicular maturation is imminent, based upon follicular growth and estradiol [E2] levels). Total duration will be of 3 treatment cycles.<br>* Other names: Recombinant human luteinizing hormone (r-hLH);Drug: Recombinant human follicle stimulating hormone (r-hFSH)<br>* Fixed dose of recombinant human follicle stimulating hormone (r-hFSH, follitropin alfa) 75 to 150 IU will be administered subcutaneously for 7 days. After 7 days of treatment, if the subject response will suboptimal, based on follicular growth and serum E2 levels, follitropin alfa dose adjusted to maximal dose of 225 IU. Duration of treatment cycle will be up to 14 days, or maximum of 21 days (if follicular maturation is imminent, based upon follicular growth and E2 levels). Total duration will be of 3 treatment cycles.<br>* Other names: Follitropin alfa;Drug: Recombinant human chorionic gonadotropin (r-hCG)<br>* When the follicular response will adequate, ovulation will be triggered by a single 250 microgram subcutaneous injection of recombinant human chorionic gonadotropin (r-hCG, choriogonadotropin alfa). Duration of treatment cycle will be up to 14 days, or maximum of 21 days (if follicular maturation is imminent, based upon follicular growth and E2 levels). Total duration will be of 3 treatment cycles.<br>* Other names: Choriogonadotropin alfa;|
| Active Comparator: Luveris® 25 IU<br> | Drug: Luveris® 25 IU<br>* Recombinant human luteinizing hormone (r-hLH, lutropin alfa, Luveris®), 25 IU will be administered subcutaneously once daily. Duration of treatment cycle will be up to 14 days, or maximum of 21 days (if follicular maturation is imminent, based upon follicular growth and E2 levels). Total duration will be of 3 treatment cycles.<br>* Other names: Recombinant human luteinizing hormone (r-hLH);Drug: Recombinant human follicle stimulating hormone (r-hFSH)<br>* Fixed dose of recombinant human follicle stimulating hormone (r-hFSH, follitropin alfa) 75 to 150 IU will be administered subcutaneously for 7 days. After 7 days of treatment, if the subject response will suboptimal, based on follicular growth and serum E2 levels, follitropin alfa dose adjusted to maximal dose of 225 IU. Duration of treatment cycle will be up to 14 days, or maximum of 21 days (if follicular maturation is imminent, based upon follicular growth and E2 levels). Total duration will be of 3 treatment cycles.<br>* Other names: Follitropin alfa;Drug: Recombinant human chorionic gonadotropin (r-hCG)<br>* When the follicular response will adequate, ovulation will be triggered by a single 250 microgram subcutaneous injection of recombinant human chorionic gonadotropin (r-hCG, choriogonadotropin alfa). Duration of treatment cycle will be up to 14 days, or maximum of 21 days (if follicular maturation is imminent, based upon follicular growth and E2 levels). Total duration will be of 3 treatment cycles.<br>* Other names: Choriogonadotropin alfa;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo will be administered subcutaneously once daily. Duration of treatment cycle will be up to 14 days, or maximum of 21 days (if follicular maturation is imminent, based upon follicular growth and E2 levels). Total duration will be of 3 treatment cycles.<br>Drug: Recombinant human follicle stimulating hormone (r-hFSH)<br>* Fixed dose of recombinant human follicle stimulating hormone (r-hFSH, follitropin alfa) 75 to 150 IU will be administered subcutaneously for 7 days. After 7 days of treatment, if the subject response will suboptimal, based on follicular growth and serum E2 levels, follitropin alfa dose adjusted to maximal dose of 225 IU. Duration of treatment cycle will be up to 14 days, or maximum of 21 days (if follicular maturation is imminent, based upon follicular growth and E2 levels). Total duration will be of 3 treatment cycles.<br>* Other names: Follitropin alfa;Drug: Recombinant human chorionic gonadotropin (r-hCG)<br>* When the follicular response will adequate, ovulation will be triggered by a single 250 microgram subcutaneous injection of recombinant human chorionic gonadotropin (r-hCG, choriogonadotropin alfa). Duration of treatment cycle will be up to 14 days, or maximum of 21 days (if follicular maturation is imminent, based upon follicular growth and E2 levels). Total duration will be of 3 treatment cycles.<br>* Other names: Choriogonadotropin alfa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Clinical Pregnancy | Clinical pregnancy was defined as the presence of one or more fetal sac with fetal heart activity on the Day 35-42 post r-hCG ultrasound examination. | Stimulation Day 1 up to clinical pregnancy (Day 35-42 post r-hCG administration day [end of stimulation cycle {approximately 21 days}]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Cumulative Clinical Pregnancy | Clinical pregnancy was defined as the presence of one or more fetal sac with fetal heart activity on the Day 35-42 post r-hCG ultrasound examination. Cumulative clinical pregnancy referred to all clinical pregnancy that occurred during all the 3 treatment cycles. | Day 35-42 post r-hCG administration day (end of stimulation cycle [approximately 21 days]) | 
| Percentage of Participants With Cumulative Ovulation | Ovulation was defined as a mid-luteal phase progesterone (P4) level greater than or equal to (>=) 10 nanogram per milliliter (ng/mL). Cumulative ovulation referred to all ovulations that occurred during all the 3 treatment cycles. | Recombinant human chorionic gonadotropin (r-hCG) administration day (end of stimulation cycle [approximately 21 days]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypogonadotropic Hypogonadism (LH <1.2 IU/L), Placebo, Luveris® 75 IU, Luveris® 25 IU, Recombinant human chorionic gonadotropin (r-hCG)