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

Infertility Clinical Trial

— CLARA  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04163458
• Other study ID #: 000303
• Status: Completed
• Phase: Phase 3
• Start date: October 25, 2019
• Est. completion date: July 16, 2021

Study information

• Verified date: August 2023
• Source: Ferring Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 405
• Est. completion date: July 16, 2021
• Est. primary completion date: May 28, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 42 Years

Eligibility

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.

Related Conditions & MeSH terms

• Infertility

Intervention

Drug:
• MENOPUR solution for injection in pre-filled pen, 1200 IU/1.92 mL
Solution for injection in pre-filled pen, subcutaneous administration
• MENOPUR powder and solvent for solution for injection, 75 IU
Solution for injection in vials (powder and diluent), subcutaneous administration

Other:
• Placebo (for MENOPUR solution for injection in pre-filled pen)
Solution for injection in pre-filled pen, subcutaneous administration
• Placebo (for MENOPUR powder and solvent for solution for injection)
Solution for injection in vials (powder and diluent); subcutaneous administration

Locations

Country	Name	City	State
United States	Abington Reproductive Medicine	Abington	Pennsylvania
United States	Fertility Answers, LLC	Baton Rouge	Louisiana
United States	Center for Assisted Reproduction	Bedford	Texas
United States	Idaho Center for Reproductive Medicine	Boise	Idaho
United States	Reproductive Endocrinology Associates of Charlotte	Charlotte	North Carolina
United States	Fertility Centers of Illinois	Chicago	Illinois
United States	Institute for Reproductive Health	Cincinnati	Ohio
United States	Center for Advanced Reproductive Services PC	Farmington	Connecticut
United States	InVia Fertility Specialists, SC	Hoffman Estates	Illinois
United States	Houston Fertility Institute	Houston	Texas
United States	SIRM Fertility Center	Las Vegas	Nevada
United States	Fertility Associates of Memphis, PLLC	Memphis	Tennessee
United States	Fertility and IVF Center of Miami	Miami	Florida
United States	Yale Fertility Center	New Haven	Connecticut
United States	OU Physicians Reproductive Medicine	Oklahoma City	Oklahoma
United States	Carolina Conceptions	Raleigh	North Carolina
United States	Fertility Specialists Medical Group - San Diego Center for Reproductive Surgery	San Diego	California
United States	Fertility Treatment Center	Tempe	Arizona
United States	Center of Reproductive Medicine	Webster	Texas
United States	Center for Reproductive Medicine	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Ferring Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Positive Beta Human Chorionic Gonadotropin (ßhCG) Rate	A blood serum ßhCG 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 ßhCG.	10-14 days after blastocyst transfer (up to approximately 6 weeks after start of stimulation)
Secondary	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)
Secondary	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)
Secondary	Early Pregnancy Loss	Number of participants with early pregnancy loss defined as a positive ßhCG tests but no ongoing pregnancy.	8-9 weeks after blastocyst transfer (up to approximately 13 weeks after start of stimulation)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	Number of Stimulation Days	Calculated by start dates and end dates.	Up to 20 stimulation days
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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