Comparison of MENOPUR Liquid and Powder in Women Undergoing Assisted Reproductive Technology (ART)

Study Overview
=================
Brief Summary
-----------------
Development of multiple follicles and pregnancy in ovulatory women undergoing controlled ovarian stimulation as part of an assisted reproductive technology (ART) cycle.

Official Title
-----------------
A Randomized, Double-blind Double-dummy Trial Comparing MENOPUR Solution for Injection in a Pre-filled Pen and MENOPUR Powder and Solvent for Solution for Injection (Menotropins for Injection) in a GnRH Agonist Cycle in Women Aged 18-42 Years Undergoing an Assisted Reproductive Technology Program

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

Intervention / Treatment
-----------------
* Drug: MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL
* Drug: MENOPUR powder and solvent for solution for injection, 75 IU
* Other: Placebo (for MENOPUR solution for injection in pre-filled pen)
* Other: Placebo (for MENOPUR powder and solvent for solution for injection)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consents, prior to any trial-related procedure. Females between the ages of 18 and 42 years. The participants must be at least 18 years (including the 18th birthday) when they sign the informed consent and no more than 42 years (up to the day before the 43rd birthday) at the time of randomization who desire pregnancy. Body mass index (BMI) between 17.5 and 38.0 kg/m^2 (both inclusive) at screening. Regular menstrual cycles of 24 to 35 days, presumed to be ovulatory. Documented history of infertility for at least 12 months before randomization for women ≤35 years or for at least 6 months for women ≥36 years. Women with documented bilateral tubal occlusion or male factor infertility requiring the use of donor sperm established as a cause of infertility are eligible at diagnosis. Early follicular phase (cycle day 2-4) serum FSH level between 1 and 12 IU/L (results obtained within 3 months prior to randomization). Male partner with semen analysis that is at least adequate for intracytoplasmic sperm injection (ICSI) at screening or within 6 months prior to the screening date. Partners with severe male factors requiring invasive or surgical sperm retrieval may not be used. Use of donor sperm is allowed. At least 1 cycle with no fertility medication immediately prior to screening. Hysterosalpingography, hysteroscopy, or saline hysterosonogram documenting uterine anatomy appropriate for ART at screening or within 12 months prior to screening. Transvaginal ultrasound documenting presence and adequate visualization of both ovaries, without evidence of clinically significant abnormality (e.g., endometrioma ≥3 cm, no dermoid cysts) and normal adnexa (e.g., no hydrosalpinx) at screening. Both ovaries must be accessible for oocyte retrieval. Exclusion Criteria: More than two previous controlled ovarian stimulation cycles for in vitro fertilization (IVF)/ICSI Known stage III-IV endometriosis (American Society for Reproductive Medicine, 2012). Oocyte donor or embryo recipient; gestational or surrogate carrier. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy [excluding ectopic pregnancy] and before week 24 of pregnancy). Participant's male partner, with obvious leukospermia (>2 million white blood cells/mL) or signs of infection in semen sample within 6 months of the participant's screening. If either of these conditions exists, the male should be treated with antibiotics and retested prior to the participant's randomization. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events. Any known endocrine (total testosterone, prolactin and TSH) or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) with the exception of controlled thyroid function disease. Known tumors of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotrophins. Any abnormal finding of clinical chemistry, hematology and vital signs at screening, which is judged clinically significant by the investigator. Pregnancy (negative urine pregnancy test must be documented at screening and prior to the first investigational medicinal product [IMP] administration), or contraindication to pregnancy. Hypersensitivity to any active ingredient or excipients in the medicinal products used in this trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MENOPUR liquid<br>MENOPUR liquid (including placebo to MENOPUR powder) initiated at a fixed dose of 225 international units (IU) for first five stimulation days. From stimulation Day 6, dosing could be adjusted as needed every second day by 75 IU per adjustment based on the participant's follicular response. The maximum dose was 450 IU/day and the minimum dose was 75 IU/day. The dosing could continue for a maximum of 20 days. | Drug: MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL<br>* Solution for injection in pre-filled pen, subcutaneous administration<br>* Other names: Highly purified menotropin;Other: Placebo (for MENOPUR powder and solvent for solution for injection)<br>* Solution for injection in vials (powder and diluent); subcutaneous administration<br>|
| Active Comparator: MENOPUR powder<br>MENOPUR powder (including placebo to MENOPUR liquid) initiated at a fixed dose of 225 IU for first five stimulation days. From stimulation Day 6, dosing could be adjusted as needed every second day by 75 IU per adjustment based on the participant's follicular response. The maximum dose was 450 IU/day and the minimum dose was 75 IU/day. The dosing could continue for a maximum of 20 days. | Drug: MENOPUR powder and solvent for solution for injection, 75 IU<br>* Solution for injection in vials (powder and diluent), subcutaneous administration<br>* Other names: Highly purified menotropin;Other: Placebo (for MENOPUR solution for injection in pre-filled pen)<br>* Solution for injection in pre-filled pen, subcutaneous administration<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Fertilized (2 Pronuclei [2PN]) Oocytes | Fertilized oocytes with 2PN were regarded as correctly fertilized. | On Day 1 after oocyte retrieval (up to 23 days after start of stimulation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive Beta Human Chorionic Gonadotropin (βhCG) Rate | A blood serum βhCG test was obtained 10-14 days after blastocyst transfer. If the test was positive according to the local laboratory's reference ranges, this confirmed a positive βhCG. | 10-14 days after blastocyst transfer (up to approximately 6 weeks after start of stimulation) | 
| Clinical Pregnancy Rate | Clinical pregnancy was based on detection of at least 1 intrauterine gestational sac with fetal heart beat on transvaginal ultrasound. | 5-6 weeks after blastocyst transfer (up to approximately 10 weeks after start of stimulation) | 
| Ongoing Pregnancy Rate | Ongoing pregnancy was based on detection of at least 1 intrauterine viable fetus by transvaginal or abdominal ultrasound | 8-9 weeks after blastocyst transfer (up to approximately 13 weeks after start of stimulation) | 
| Early Pregnancy Loss | Number of participants with early pregnancy loss defined as a positive βhCG tests but no ongoing pregnancy. | 8-9 weeks after blastocyst transfer (up to approximately 13 weeks after start of stimulation) | 
| Follicular Development on Stimulation Day 6 | The total number of follicles and the number of follicles per size category were reported. | At stimulation Day 6 | 
| Follicular Development on Last Day of Stimulation | The total number of follicles and the number of follicles per size category were reported. | At last day of stimulation (up to 20 stimulation days) | 
| Serum Follicle-stimulating Hormone (FSH) Concentration | The concentration of serum FSH was measured. The median and IQR of FSH levels on stimulation day 6, End of stimulation and Oocyte Retrieval visit are presented. | At Day 6, last day of stimulation (up to 20 stimulation days) and at oocyte retrieval (up to 22 days after start of stimulation) | 
| Serum Anti-Müllerian Hormone (AMH) Concentration | The concentration of serum AMH was measured. The median and IQR of AMH levels on End of stimulation and End of Trial are presented. | At the last day of stimulation (up to 20 stimulation days) and at end-of-trial (up to approximately 6 months from the start of screening) | 
| Human Chorionic Gonadotropin (hCG) Concentration | The concentration of hCG was measured. The median and IQR of hCG levels on stimulation day 6 and End of stimulation are presented. | At Day 6 and last day of stimulation (up to 20 stimulation days) | 
| Luteinizing Hormone (LH) Concentration | The concentration of LH was measured. The median and IQR of LH levels on stimulation day 6 and End of stimulation are presented. | At Day 6 and last day of stimulation (up to 20 stimulation days) | 
| Progesterone (P4) Concentration | The concentration of P4 was measured. The median and IQR of P4 levels on stimulation day 6 and End of stimulation are presented. | At Day 6 and last day of stimulation (up to 20 stimulation days) | 
| Estradiol (E2) Concentration | The concentration of E2 was measured. The median and IQR of E2 levels on stimulation day 6 and End of stimulation are presented. | At stimulation Day 6 and last day of stimulation (up to 20 stimulation days) | 
| Number of Oocytes Retrieved | The number of oocytes retrieved was recorded at the oocyte retrieval visit. | On day of oocyte retrieval (up to 22 days after start of stimulation) | 
| Number of Metaphase II (MII) Oocytes | Maturity stage was assessed prior to undergoing ICSI. Maturity stage was categorized as germinal vesicle, metaphase I, metaphase II, degenerated or other. | On day of oocyte retrieval (up to 22 days after start of stimulation) | 
| Fertilization Rate | Fertilization rate(%) is the number of 2PN oocytes divided by the number of oocytes retrieved. | On Day 1 after oocyte retrieval (up to 23 days after start of stimulation) | 
| Number of Blastocysts and Number of Good-Quality Blastocysts 5 Days After Oocyte Retrieval | The number of blastocysts (total and good-quality) was reported. Blastocyst quality was assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring was based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cells) | On Day 5 after oocyte retrieval (up to 27 days after start of stimulation) | 
| Total Gonadotropin Dose | The gonadotropin starting dose was 225 IU for the first 5 days, followed by individual adjustments according to the participant's follicular response. Dose adjustment should be 75 IU per adjustment. Gonadotropin was to be initiated within 3 days of confirmed downregulation. | Up to 20 stimulation days | 
| Number of Stimulation Days | Calculated by start dates and end dates. | Up to 20 stimulation days | 
| Proportion of Participants With Ovarian Hyperstimulation Syndrome (OHSS) | OHSS was defined as the total of early OHSS with onset ≤9 days after triggering of final follicular maturation, and late OHSS with onset >9 days after triggering of final follicular maturation. | ≤9 days after triggering of final follicular maturation (early OHSS), >9 days after triggering of final follicular maturation until 21-28 days after last IMP dose or up to ongoing pregnancy 8-9 weeks after transfer in pregnant participants (late OHSS) | 
| Frequency of Adverse Events (AEs) | Any AE occurring after start of IMP and before the end-of-trial visit, or a pre-treatment AE or pre-existing medical condition that worsens in intensity after start of IMP and before the end-of-trial visit was considered treatment-emergent, and is presented for this endpoint. | From the time of signed informed consent for participation in the trial until the end-of-trial visit (up to approximately 6 months) | 
| Intensity of AEs | The intensity of an AE was classified using the following 3-point scale: Mild = Awareness of signs or symptoms, but no disruption of usual activity. Moderate = Event sufficient to affect usual activity (disturbing). Severe = Inability to work or perform usual activities (unacceptable). | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Alanine Aminotransferase | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Aspartate Aminotransferase | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Blood Urea Nitrogen | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Calcium | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Chloride | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Creatinine | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Gamma Glutamyl Transferase | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Glucose | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Potassium | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Sodium | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Egfr African American | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters Compared to Baseline: Egfr Non-afr. American | Blood samples were collected for the analysis of clinical chemistry parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Erythrocytes | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Leukocytes | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Hemoglobin | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Hematocrit | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Platelets | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Basophils | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Basophils/Leukocytes | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Eosinophils | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Eosinophils/Leukocytes | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Lymphocytes | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Lymphocytes/Leukocytes | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Monocytes | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Monocytes/Leukocytes | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Neutrophils | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Changes in Circulating Levels of Haematology Parameters Compared to Baseline: Neutrophils/Leukocytes | Blood samples were collected for the analysis of haematology parameters. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Proportion of Subjects With Markedly Abnormal Changes of Clinical Parameters and Haematology Parameters | The table represents the percentage of participants in each group with normal baseline values and markedly abnormal end-of-stimulation or end-of-trial visit values. It is only parameters with markedly abnormal values at end of stimulation or end of trial visit which are represented. Parameters with normal baseline values and normal end of stimulation and end of trial values are not represented. | From the start of screening until the end-of-trial (up to approximately 6 months) | 
| Frequency of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Participant During the Stimulation Period | Assessed by the participant during the stimulation period. Participants assessed the injection site reactions (redness, pain, itching, swelling and bruising) three times daily: immediately after the injection, 30 minutes after the injection and 24 hours after the injection. Total Number of events include all categories None, Mild, Moderate and Severe. Percentage of events with injection site reactions as a sum of the categories Mild, Moderate and Severe is presented. | Up to 20 stimulation days | 
| Intensity of Injection Site Reactions (Redness, Pain, Itching, Swelling and Bruising) Assessed by the Participant During the Stimulation Period | Assessed by the participant during the stimulation period as mild, moderate or severe. Participants assessed the injection site reactions (redness, pain, itching, swelling and bruising) three times daily: immediately after the injection, 30 minutes after the injection and 24 hours after the injection. | Up to 20 stimulation days | 
| Proportion of Participants With Treatment-induced Anti-MENOPUR Antibodies. Overall as Well as With Neutralizing Capacity | Measured by presence of anti-MENOPUR antibodies. 95% Clopper-Pearson confidence interval has been reported in this endpoint. | Up to 28 days after end of the stimulation period (simulation period up to 20 days) | 
| Number of Participants With Potential Technical Malfunctions of the Administration Pen | Number of participants With Potential Technical malfunctions of the Administration Pen were recorded. | Up to 20 stimulation days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Controlled Ovarian Stimulation, Assisted Reproductive Technology