Clinical Outcomes in WHO Type I Anovulatory Women Using r-hFSH+r-hLH in a 2:1 Ratio or hMG-HP

Study Overview
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Brief Summary
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The aim of the study is to compare the efficacy and safety of r-hFSH+r-hLH in a 2:1 ratio with human Menopausal Gonadotropin Highly Purified (hMG-HP), in WHO type I anovulation, HH women. This open-label monocentric, randomized comparative trial, to receive the two different standard clinical practice treatments: 1 vial of Pergoveris: (vial/powder 150 International unit (IU) r-hFSH+ 75IU r-hLH) 2 vials of Menopur: (vials/powder hMG 75IU). Follicular development were monitored until the protocol hCG requirement is met and a single injection of hCG was administered. Main Outcome Measures were follicular development i.e. follicle ≥ 17 millimeters (mm), pre-ovulatory E2 ≥ 400 picomole/Liter (pmol/L) and mid-luteal phase Progesterone (P4) ≥ 25 nanomole/Liter (nmol/L).

Detailed Description
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World Health Organization (WHO) type I hypogonadotropic anovulation (hypogonadotropic hypogonadism, HH) is a rare alteration of the reproductive system with absent or decreased function of the gonads, caused by congenital, including genetic, or acquired reduced hypothalamic or pituitary activity. This results in abnormally low serum levels of Follicular Stimulation Hormone (FSH) and Luteinizing Hormone (LH) and negligible oestrogen (E2) activity. The most convenient treatment is daily injections of exogenous gonadotropins that has been proven to be effective. Patients lacking an effective hypothalamic-pituitary activity (WHO type I anovulation) do not produce sufficient threshold levels of endogenous LH, which is required to obtain optimal follicular development and steroidogenesis when treated with FSH alone. Therefore a combination therapy with adequate doses of both FSH and LH in an optimal ratio is required in order to restore fertility. The LH activity could be produced by LH itself or by human Chorionic Gonadotropin (hCG) and the two gonadotropins are available to be used in the WHO type I patients in two different formulations both in indication for this type of patients. It would be worth of interest to assess if these two different formulations could elicit the same clinical outcomes in standard clinical practice or not. The aim of the study is to compare the efficacy and safety of recombinant human FSH and recombinant human LH (r-hFSH+r-hLH) in a 2:1 ratio with human Menopausal Gonadotropin Highly Purified (hMG-HP), containing LH-like activity, in women with severe LH and FSH deficiency (WHO type I anovulation, HH). All patients were diagnosed with HH according to a negative progesterone (P4) challenge test, serum LH<1.2 IU/L and FSH <5 IU/L, a transvaginal ultrasound showing a uterus with a midline echo, no ovarian tumor or cyst and ≤ 13 small follicles (mean diameter ≤ 10millimeters (mm)) on the largest section through each ovary, a Body Mass Index (BMI) between 18 and 32 Kilograms for square meters(Kg/m2), and no systemic diseases. In this open-label monocentric, randomized comparative trial, patients was randomized in two arms in 1:1 ratio, to receive the two different standard clinical practice treatments: 1 vial of Pergoveris: (vial/powder 150 International Units (IU) r-hFSH+ 75IU r-hLH)stimulation day 1 until required hCG level is met. The dose can be adjusted at stimulation Day 6 according to subject ovarian response and standard clinical practice 2 vials of Menopur: (vial/powder hMG containing 75IU FSH + 75IU LH-like activity). stimulation day 1 until required hCG level is met. The dose can be adjusted at stimulation Day 6 according to subject ovarian response and standard clinical practice Follicular development were monitored according clinical practice by ultrasound (US) and/or estradiol (E2) levels, until the protocol hCG requirement is met (i.e., at least one follicle greater than or equal to 17 mm). After this, a single injection of hCG was administered in order to induce final oocyte maturation. Main Outcome Measures were ovulation induction as measured by follicular development i.e. follicle ≥ 17 mm, pre-ovulatory E2 ≥ 400 picomole/Liter (pmol/L) and mid-luteal phase Progesterone ≥ 25 nanomole/Liter (nmol/L). Secondary efficacy endpoints included estradiol levels/follicle at mid-cycle, number of follicles at mid-cycle and pregnancy rate (PR). Drug safety was assessed by monitoring adverse events and the incidence of local reactions after drug injection at local site. Ovarian hyperstimulation syndrome (OHSS) was assessed and recorded according to Golan classification According to this protocol, patients were initially treated for one cycle. If consenting, patients who did not become pregnant during the first cycle were treated for a further optional one or two series of cycles with the same criteria of randomization, i.e. maintaining the same treatment as the previous cycle.

Official Title
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Prospective Randomized Open Label Study to Compare the Efficacy and Safety of Ovarian Stimulation With Pergoveris® and Menopur® in Women With Severe Luteinizing Hormone (LH) and Follicular Stimulating Hormone (FSH) Deficiency.

Conditions
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Hypogonadotropic Hypogonadism

Intervention / Treatment
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* Drug: Pergoveris: 150IU r-hFSH + 75IU r-hLH
* Drug: Menopur: HMG-HP (150 IU)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: WHO Type I HH Women Serum LH <1.2 IU/L Serum FSH <5 IU/L Age 25-36 years No ovarian tumor No cyst ≤ 13 small follicles (mean diameter ≤ 10mm) BMI between 18 - 32 Kg/m2 no systemic diseases Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 36 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: Pergoveris: 150IU r-hFSH+ 75IU r-hLH<br>This is a prospective randomized study using two in-label treatments for the patient disease: Pergoveris and Menopur. Pergoveris arms can be considered as experimental for the aim of the study, anyway it is standard routine practice for HH women. | Drug: Pergoveris: 150IU r-hFSH + 75IU r-hLH<br>* Fixed formulation of two recombinant gonadotropins<br>* Other names: Pergoveris;|
| Experimental: Menopur: hMG-HP (150IU)<br>This is a prospective randomized study using two in-label treatments for the patient disease: Pergoveris and Menopur. Menopur can be considered as experimental for the aim of the study, anyway it is standard routine practice for HH women | Drug: Menopur: HMG-HP (150 IU)<br>* Human Menopausal Gonadotropin is an urinary estract from menopausal women containing 150IU of FSH and 150 IU of LH-like activity (HCG)<br>* Other names: Menopur;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| E2 in pmol/L | Evaluate the patients steroidogenesis | Day after the protocol hCG requirement is met (at least one follicle of 17mm is monitored by ultrasound) | 
| Number of Follicles > 17mm | To evaluate the efficacy of the stimulation and maturity of follicles | last US day before hCG administration | 
| P4 in nmol/L | Progesteron level to evaluate the endometrial receptivity | Day after the protocol hCG requirement is met (at least one follicle of 17mm by US) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endometrial thickness | Evaluation of endometrial development and receptivity | Day 5 and Day 10 of stimulation treatment | 
| Total number of Follicles | To evaluate the overall efficacy of stimulation treatment, also including follicles < 17mm | Last US day before hCG administration | 
| Clinical Pregnancy rate | Evaluate the ratio between primary end points and final stimulation outcome | days 35-42 post hCG | 
| Occurence of any adverse events (early or late ovarian hyperstimulation syndrome) |  | Days 15-20 post hCG | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Luteinizing Hormone, Hypogonadotropic Hypogonadism, Ovulation Induction, Chorionic Gonadotropin