Progesterone Serum Levels in Subfertile Female Patients Undergoing in Vitro Fertilisation (IVF)

Study Overview
=================
Brief Summary
-----------------
This study is aimed to demonstrate that highly purified Menotrophin produces significant lower progesterone serum levels during the follicular phase in comparison to Follitropin alpha in the treatment of subfertile females undergoing an in vitro fertilisation (IVF) and to investigate if the progesterone serum levels might be a useful predictor for the success rate of the ongoing pregnancy rates

Official Title
-----------------
Effect of Highly Purified Menotrophin and Recombinant Follicle Stimulating (rFSH, Follitrophin Alpha) in Subfertile Female Patients Undergoing IVF on Progesterone Serum Levels During the Follicular Phase and Their Possible Use as Predictors for the Success Rate of Ongoing Pregnancies

Conditions
-----------------
Infertility

Intervention / Treatment
-----------------
* Drug: Menotrophin
* Drug: Follitrophin alpha
* Drug: Cetrorelix
* Drug: Choriongonadotropin
* Drug: Progesterone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent Subfertile premenopausal female patients eligible for in vitro fertilisation (IVF) treatment Aged ≥34 and ≤42 years Body mass index of >18 and <28 kg/m^2 Normal pelvic ultrasound at Screening No more than two previous gonadotrophin stimulated cycles of IVF or intracytoplasmic sperm injection (ICSI) in the history of infertility treatment (gonadotrophin stimulated cycles not used for IVF or ICSI do not count; Clomifen cycles are no exclusion criterion) At least 3 consecutive ovulatory menstrual cycles of 24-35 days No fertility stimulating drugs at all Sperm of partner classified as normal according to World Health Organisation (WHO) 2010 criteria Clinically normal baseline haematology, clinical chemistry, and urinalysis values Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests within the last 6 months prior to Screening Endocrine test results within the clinically normal limits at Screening Exclusion Criteria: Presence of any clinically relevant systemic disease (e.g., insulin-dependent diabetes mellitus) A history of or current endocrine disease (excluding treated hypothyreosis), including polycystic ovary syndrome (PCOS) and hyperprolactinaemia A history of coagulation disorders Persistent ovarian cysts (>3 months) A history of hypersensitivity to any of the constituents of the study medication or related compounds Diagnosed poor (<3 oocytes) responders to prior gonadotrophin stimulated ART-cycle History of severe ovarian hyperstimulation syndrome in former gonadotrophin stimulated assisted reproductive technology (ART)-cycle

Ages Eligible for Study
-----------------
Minimum Age: 34 Years
Maximum Age: 42 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Menotrophin<br>Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met. Pituitary down-regulation (cetrorelix), ovulation induction (choriongonadotropin), and luteal phase support (intravaginal progesterone) are administered the same way in both treatment arms. | Drug: Menotrophin<br>* Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met.<br>* Other names: Menogon® HP;Drug: Cetrorelix<br>* Participants self-inject subcutaneously Cetrorelix in the morning at a daily dose of 0.25 mg/day from Day 5 of gonadotrophin administration on and continue throughout the period of gonadotrophin treatment up to day 12 as a maximum. The last dose of Cetrorelix is given on the day of ovulation induction.<br>* Other names: GnRH antagonist;Drug: Choriongonadotropin<br>* 10,000 IU administered by the Investigator or designated personnel in the evening of the day on which the hCG criterion is met (no later than Day 13). The criterion for hCG administration is three follicles >+17 mm diameter as shown by pelvic ultrasound examination.<br>* Other names: human chorionic gonadotropin (hCG);Drug: Progesterone<br>* Vaginal gel progesterone is used once daily at a dose of 90 mg for a period of 30 days starting on the day of oocyte retrieval (approximately Day 14).<br>* Other names: intravaginal progesterone;|
| Active Comparator: Follitrophin Alpha<br>Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met. Pituitary down-regulation (cetrorelix), ovulation induction (choriongonadotropin), and luteal phase support (intravaginal progesterone) are administered the same way in both treatment arms. | Drug: Follitrophin alpha<br>* Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met.<br>* Other names: Gonal-f®;Drug: Cetrorelix<br>* Participants self-inject subcutaneously Cetrorelix in the morning at a daily dose of 0.25 mg/day from Day 5 of gonadotrophin administration on and continue throughout the period of gonadotrophin treatment up to day 12 as a maximum. The last dose of Cetrorelix is given on the day of ovulation induction.<br>* Other names: GnRH antagonist;Drug: Choriongonadotropin<br>* 10,000 IU administered by the Investigator or designated personnel in the evening of the day on which the hCG criterion is met (no later than Day 13). The criterion for hCG administration is three follicles >+17 mm diameter as shown by pelvic ultrasound examination.<br>* Other names: human chorionic gonadotropin (hCG);Drug: Progesterone<br>* Vaginal gel progesterone is used once daily at a dose of 90 mg for a period of 30 days starting on the day of oocyte retrieval (approximately Day 14).<br>* Other names: intravaginal progesterone;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Progesterone (P4) Level in the Morning of the Day of Human Chorionic Gonadotrophin (hCG) Administration | Ovulation induction was performed by administration of hCG once three follicles >=17 mm diameter as shown by pelvic ultrasound examination. This outcome compares the serum progesterone level the morning prior to hCG administration across treatment arm, and also by age stratum (<39 years and >=39 years). | approximately day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Receiver Operating Characteristic (ROC) Analysis of Progesterone as Predictor for Ongoing Pregnancy Rate at Day 7 and Day of hCG Administration | The influence of the progesterone level on the ongoing pregnancy rate (in relation to all randomized patients) was determined by means of the receiver operating characteristic (ROC) curve. Youden's Index (sensitivity + specificity -1) has a range of 0-1, with 0.5 indicating a random effect. | Day 7, approximately Day 10 (hCG Administration) | 
| Percentage of Participants With Ongoing Pregnancy | Ongoing pregnancy is defined as having a positive foetal heart action nine or more weeks after the first positive pregnancy test. | approximately 3.5 months from study start (at least 9 weeks after first positive pregnancy test) | 
| Number of Follicles at hCG Administration | Number of follicles >=17 mm diameter detected by pelvic ultrasound examination at day of hCG administration. | approximately day 10 | 
| Average Follicle Diameter at hCG Administration |  | approximately day 10 | 
| Number of Cumulus-oocyte Complexes Retrieved | Cumulus-oocyte complexes are oocytes with surrounding cumulus cells. | approximately day 12 after study start | 
| Number of Pronuclear Oocytes | Pronuclear oocytes are fertilized oocytes. | approximately day 13 after study start | 
| Number of Participants With Pronuclear Stage Oocytes at Each Quality Grade | The count of participants with different quality grades of pronuclear stage oocytes is offered. Pronuclear stage oocytes are categorized into seven grades (0A, 0B, 1-5) representing different patterns of pronuclear morphology, according to the German Pronuclear Morphology Study Group. 0A is the highest quality oocyte and grade 5 is the lowest quality. Participants can have pronuclear stage oocytes of different grades and therefore are counted more than once. | approximately day 13 | 
| Number of Embryos Transferred | Mean number of embryos transferred 2-3 days following oocyte retrieval. | approximately day 14 | 
| Best Quality of an Embryo Transferred | Embryo quality was measured by the following grades: Grade 1: Evenly sized cells, regular cleavage, no fragmentation Grade 2: Regular or slightly irregular cleavage, <=20% fragmentation Grade 2.5: Regular or slightly irregular cleavage, >20%and <=50% fragmentation Grade 3: Irregular cleavage, >50% fragmentation, >1 intact cell Grade 4: Extensive fragmentation, only 1 cell intact Grade 5: Totally fragmented, no viable cells. Grade 1 represents the healthiest embryos and Grade 5 embryos are not viable. | approximately day 14 | 
| Number of Frozen Oocytes at Pronuclear Stage | No more than three normally developed embryos were transferred 2-3 days after oocyte retrieval. Other normally developed embryos were frozen. | approximately day 14 | 
| Endometrial Thickness on Day of hCG Administration | Endometrial thickness was assessed by pelvic ultrasound on the day of hCG administration. | approximately day 10 | 
| Estradiol (E2) Levels on Day of hCG Administration |  | approximately day 10 | 
| Percentage of Participants With Successful Embryo Transfer |  | approximately day 18 | 
| Number of Days Stimulated With Gonadotrophins | Number of days in which gonadotrophins were administered until hCG criteria were met. If hCG criteria were not met by day 13, the participant was withdrawn from the study. | Day 1 up to Day 12 | 
| Number of Ampoules of Gonadotrophins Used | Number of ampoules of gonadotrophins used with the goal of reaching hCG criteria. Each ampoule contained 75 IU of either menotrophin or follitrophin alpha. | Day 1 up to Day 12 | 
| Percentage of Participants With Clinical Pregnancy 6 Weeks After the First Positive Pregnancy Test | A pelvic ultrasound scan was performed approximately 6 weeks after the first positive pregnancy test and the presence of an active foetal heart action indicated a clinical pregnancy. | approximately 2.5 months from start of study, 6 weeks after first positive pregnancy test | 
| Summary of Pregnancy Outcome | Pregnancy outcomes were reported at the optional long-term follow up visit. | up to 10 months |