A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Three Dosage Strengths of Pulsatile GnRH

Study Overview
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Brief Summary
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This study will be performed in approximately 132 women with anovulatory/oligoovulatory infertility.

Detailed Description
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This multicenter, randomized, double-blind, placebo-controlled study will be performed in approximately 132 women with anovulatory/oligoovulatory infertility. The treatment duration will be approximately 4 weeks with pulsatile GnRH or placebo and 5 days with Clomiphene Citrate or placebo. All subjects will be screened based on inclusion/exclusion criteria, medical/infertility history and general safety assessments. Subjects that complete screening will be dispensed 100 mg of oral progesterone twice a day for 10 days to induce uterine bleeding. On Cycle Day 5 from the start of bleeding the subject will be randomly assigned to 1 of 7 treatment groups. All subjects will be monitored weekly throughout the 4 week treatment period for ovulation and intercourse will be timed. All subjects will be required to return to the study center for a total of 8 visits. In addition, all subjects with a confirmed clinical pregnancy will be monitored until fetal heartbeat is confirmed at approximately 5-6 weeks gestation

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Three Dosage Strengths of Pulsatile GnRH Administered Intravenously or Subcutaneously (Via Portable Infusion Pump) Compared to Oral Treatment With Clomiphene Citrate in Anovulatory or Oligoovulatory Infertile Females

Conditions
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InFertility

Intervention / Treatment
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* Drug: Pulsatile gonadotropin-releasing hormone (GnRH)
* Drug: Clomiphene Citrate
* Drug: Placebo Pulsatile GnRH
* Drug: Placebo Clomiphene Citrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Females between the ages of 18 (or 19 in the State of Alabama) and 40 years. Infertile due to ovulatory dysfunction as described below: Positive progesterone withdrawal test following the screening visit. TSH (thyroid-stimulating hormone) levels within normal limits for the clinical laboratory or considered not clinically significant (eg, secondary to exogenous thyroid medication) by the investigator Normal insulin sensitivity assessed as ratio of fasting blood glucose to fasting insulin > 4.5 at Screening Male partner with recent (within 6 months prior to screening) semen analysis showing normalcy according to the local laboratory normal criteria. If screening semen analysis is borderline, the couple will be accepted into the study only if a second sample obtained prior to screening is adequate. Presence of both ovaries, without evidence of clinically significant abnormality, as detected by transvaginal ultrasound Normal transvaginal ultrasound with respect to uterus and adnexa (eg, no hydrosalpinx) Hysterosalpingography or hysteroscopy or sonohysterogram documenting a uterine cavity consistent with expected normal function and patency of the fallopian tubes within the previous 3 years prior to screening (within 1 year prior to screening there should be no pelvic infection, endometriosis or pelvic surgery). Negative serum pregnancy test (qualitative) prior to the progesterone test Desire to become pregnant Exclusion Criteria Requires donor oocytes or sperm Previous and current use of infertility modifiers, including insulin-sensitizing drugs Primary amenorrhea/hypogonadotropic hypogonadism (eg, isolated gonadotropin deficiency or evidence of primary/premature ovarian failure) Presence of any clinically relevant systemic disease (eg, diabetes mellitus, pituitary tumor, anorexia nervosa). Surgical or medical condition which in the judgment of the Investigator or Sponsor may interfere with absorption, distribution, metabolism, or excretion of the drugs to be used. Any pregnancy within last 3 months prior to Screening. Patients with a body mass index (BMI) >30 at time of Screening Total testosterone and DHEA-S >1.5 times the upper limits of normal laboratory range and prolactin > 20 ng/mL Presence of abnormal uterine bleeding of undetermined origin. Active or prior history of substance abuse History of chemotherapy (except for gestational conditions) or radiotherapy Currently breast feeding, pregnant or contraindication to pregnancy Refusal or inability to comply with the requirements of the Protocol for any reason, including scheduled clinic visits and laboratory tests. Documented intolerance or allergy to any of the medications used including the study medication Participation in any experimental drug study within 60 days prior to Screening

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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Accepts Healthy Volunteers

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 |
| --- | --- |
| Experimental: Lutrepulse® 5mcg IV<br>5.0 mcg Pulsatile GnRH (Lutrepulse®) administered intravenously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks and oral placebo clomiphene citrate for 5 days | Drug: Pulsatile gonadotropin-releasing hormone (GnRH)<br>* Dosages as specified, administered either subcutaneously (SC) or intraveneously (IV) as specified, via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks<br>* Other names: Lutrepulse®;Drug: Placebo Clomiphene Citrate<br>* oral placebo clomiphene citrate for 5 days<br>|
| Experimental: Lutrepulse® 10 mcg IV<br>10.0 mcg Pulsatile GnRH (Lutrepulse®) administered intravenously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks and oral placebo clomiphene citrate for 5 days | Drug: Pulsatile gonadotropin-releasing hormone (GnRH)<br>* Dosages as specified, administered either subcutaneously (SC) or intraveneously (IV) as specified, via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks<br>* Other names: Lutrepulse®;Drug: Placebo Clomiphene Citrate<br>* oral placebo clomiphene citrate for 5 days<br>|
| Experimental: Lutrepulse® 20 mcg SC<br>20.0 mcg Pulsatile GnRH (Lutrepulse®) administered subcutaneously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks and oral placebo clomiphene citrate for 5 days | Drug: Pulsatile gonadotropin-releasing hormone (GnRH)<br>* Dosages as specified, administered either subcutaneously (SC) or intraveneously (IV) as specified, via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks<br>* Other names: Lutrepulse®;Drug: Placebo Clomiphene Citrate<br>* oral placebo clomiphene citrate for 5 days<br>|
| Placebo Comparator: Placebo IV<br>Placebo Pulsatile GnRH (Lutrepulse®) administered intravenously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks and oral placebo clomiphene citrate for 5 days | Drug: Placebo Pulsatile GnRH<br>* Administered either intravenously or subcutaneously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks<br>Drug: Placebo Clomiphene Citrate<br>* oral placebo clomiphene citrate for 5 days<br>|
| Placebo Comparator: Placebo SC<br>Placebo Pulsatile GnRH (Lutrepulse®) administered subcutaneously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks and oral placebo clomiphene citrate for 5 days | Drug: Placebo Pulsatile GnRH<br>* Administered either intravenously or subcutaneously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks<br>Drug: Placebo Clomiphene Citrate<br>* oral placebo clomiphene citrate for 5 days<br>|
| Active Comparator: Clomiphene Citrate/Placebo IV<br>Oral clomiphene citrate (over encapsulated) for 5 days and Placebo Pulsatile GnRH (Lutrepulse®) administered intravenously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks | Drug: Clomiphene Citrate<br>* Oral clomiphene citrate (over encapsulated) for 5 days<br>* Other names: Clomid;Drug: Placebo Pulsatile GnRH<br>* Administered either intravenously or subcutaneously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks<br>|
| Active Comparator: Clomiphene Citrate / Placebo SC<br>Oral clomiphene citrate (over encapsulated) for 5 days and Placebo Pulsatile GnRH (Lutrepulse®) administered subcutaneously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks | Drug: Clomiphene Citrate<br>* Oral clomiphene citrate (over encapsulated) for 5 days<br>* Other names: Clomid;Drug: Placebo Pulsatile GnRH<br>* Administered either intravenously or subcutaneously via portable infusion pump in a pulsatile fashion (every 90 minutes) for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pregnancy rate |  | Day 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events, including ovarian hyperstimulation syndrome (OHSS) |  | Day 1 to week 5 |