Infertility
Conditions
Keywords
Assisted Reproductive Technology
Brief summary
The objective of this study was to compare the fertilization rate between the combination of Menopur and Bravelle mixed in the same syringe and Menopur alone, both administered subcutaneously (SC), in subjects undergoing Assisted Reproductive Technology (ART). Additionally the study assessed subjects' ability to mix and store the combination of Menopur and Bravelle and to assess safety of the Menopur and Bravelle combination.
Sponsors
Ferring Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 42 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Infertile pre-menopausal female subjects * Documented history of infertility (eg., unable to conceive for at least 1 year, or 6 months for women ≥36 years of age, or women with bilateral tubal occlusion or absence, or subjects who require donor sperm). * Subject's male partner with semen analysis that was at least adequate for intracytoplasmic sperm injection (ICSI) within 6 months prior to the subjects beginning down-regulation with gonadotropin-releasing hormone (GnRH)-agonist. Partners with severe male factor requiring invasive or surgical sperm retrieval or donor sperm could have been used. * Anti-mullerian hormone (AMH) \> 1 ng/mL and \< 3 ng/mL at screening. * Eligible for in-vitro fertilisation (IVF) or ICSI treatment. Main
Exclusion criteria
* Oocyte donor or embryo recipient; gestational or surrogate carrier * Previous IVF or assisted reproductive technology (ART) failure due to a poor response to gonadotropins. Poor response was defined as development of ≤ 2 mature follicles or history of 2 previous failed cycle cancellations prior to oocyte retrieval due to poor response. * Inadequate number of oocytes, defined as fewer than 5 oocytes retrieved in previous ART attempts. * Subject's male partners with obvious leukospermia (\>2 million white blood cells \[WBC\]/mL) or signs of infection in semen sample within 2 months of the start of subject's pituitary down-regulation. If either of these conditions existed, the male was to be treated with antibiotics and retested prior to subject's pituitary down-regulation. * Undergoing blastomere biopsy and other experimental ART procedures. * Body mass index (BMI) of ≤18 and ≥32 kg/m\^2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fertilization Rate | approximately day 13 (16-20 hours post insemination by in vitro fertilization (IVF) insemination or intracytoplasmic sperm injection (ICSI)) | The fertilization rate was defined for each participant and calculated as the number of 2 pronuclei (fertilized) (2PN) oocytes divided by the total number of oocytes retrieved multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of the Subject Comprehension Questionnaire (SCQ) on Day 1 | Day 1 | Subject comprehension questionnaires were completed on Day 1 only by participants assigned to the Menopur and Bravelle treatment arm. On Day 1, the participant read the Mixing Instructions Guide on how to mix and administer the medications at home. The participant was given enough time to read and understand the instructions and ask any questions. The participant then completed the SCQ which consists of 7 questions with YES/NO answers, to self-gauge their understanding of drug administration procedures. Reported data represent the number of participants who answered the question YES. Gonadotropins are referred to as investigational medicinal product (IMP). |
| Summary of the Subject Comprehension Questionnaire (SCQ) on Day 6 | Day 6 | Subject comprehension questionnaires were repeated on Day 6 after 5 days of combination therapy by participants assigned to the Menopur and Bravelle treatment arm. The SCQ consists of 7 questions with YES/NO answers to self-gauge participants' understanding of drug administration procedures. Reported data represent the number of participants who answered the question YES. Gonadotropins are referred to as investigational medicinal product (IMP). |
| Summary of Assessor Questionnaire on Day 1 | Day 1 | Participants assigned to the Menopur and Bravelle treatment arm read the Mixing Instructions Guide on how to mix and administer the medications at home. Participants were given enough time to read and understand the instructions and ask any questions. After completing the SCQ, participants prepared and self-administered her assigned first daily dose in the presence of the study coordinator or designee assessor. The assessor then completed a 7 question questionnaire with YES or NO answers to document their assessment of participant understanding of drug administration procedures. Reported data represent the number of participants for whom the assessor answered the question YES. Gonadotropins are referred to as investigational medicinal product (IMP). |
| Summary of Assessor Questionnaire on Day 6 | Day 6 | Participants assigned to the Menopur and Bravelle treatment arm prepared and self-administered her daily dose on Day 6 in the presence of the study coordinator or designee assessor. The assessor then completed a 7 question questionnaire with YES or NO answers to document their assessment of participant understanding of drug administration procedures. Reported data represent the number of participants for whom the assessor answered the question YES. Gonadotropins are referred to as investigational medicinal product (IMP). |
| Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Day 1 up to Day 20 | A treatment-emergent AE was any AE occurring after start of investigational medicinal product (IMP) and within the time of residual drug effect, or a pretreatment AE or pre-existing medical condition that worsened in intensity after start of IMP and within the time of residual drug effect. The time of residual drug effect was the estimated period of time after the last dose of the IMP, where the effect of the product was still considered to be present based on pharmacokinetic, pharmacodynamic, or other IMP characteristics. |
Countries
United States
Participant flow
Pre-assignment details
A total of 122 subjects (60 Menopur/Bravelle, 62 Menopur) entered pituitary down-regulation and were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Menopur and Bravelle Combination The initial daily dose consisted of 225 IU of gonadotropins, mixed in the same syringe and administered by subcutaneous (SC) injection for 5 days. The initial daily dose, based on the Investigator's judgment, consisted of either 150 IU of Menopur and 75 IU of Bravelle or 150 IU of Bravelle and 75 IU of Menopur. Dosing adjustments were allowed as of day 6. Dose could vary between 150-450 IU daily and was always to include at least 75 IU of Menopur and 75 IU of Bravelle. Treatment could not continue beyond day 20. | 60 |
| Menopur Alone The initial daily dose consisted of 225 IU of Menopur and administered by subcutaneous (SC) injection for 5 days. Dosing adjustments were allowed as of day 6. Dose could vary between 150-450 IU daily and treatment could not continue beyond day 20. | 62 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No embryos for transfer | 0 | 1 |
| Overall Study | No transfer due to elevated progesterone | 1 | 0 |
| Overall Study | No transfer due to risk of OHSS | 1 | 0 |
| Overall Study | Stimulation failure | 1 | 0 |
Baseline characteristics
| Characteristic | Menopur and Bravelle Combination | Menopur Alone | Total |
|---|---|---|---|
| Age, Customized 35 to 37 years | 13 participants | 15 participants | 28 participants |
| Age, Customized <35 years | 35 participants | 40 participants | 75 participants |
| Age, Customized 38 to 40 years | 9 participants | 6 participants | 15 participants |
| Age, Customized >40 years | 3 participants | 1 participants | 4 participants |
| Body Mass Index 18 to <=25 kg/m^2 | 33 participants | 29 participants | 62 participants |
| Body Mass Index >25 to <=30 kg/m^2 | 19 participants | 23 participants | 42 participants |
| Body Mass Index >30 to <=35 kg/m^2 | 8 participants | 10 participants | 18 participants |
| Current Drinkers No | 15 participants | 11 participants | 26 participants |
| Current Drinkers Yes | 45 participants | 51 participants | 96 participants |
| Current Smokers No | 56 participants | 57 participants | 113 participants |
| Current Smokers Yes | 4 participants | 5 participants | 9 participants |
| Ever Smoked? No | 52 participants | 56 participants | 108 participants |
| Ever Smoked? Yes | 8 participants | 6 participants | 14 participants |
| Race/Ethnicity, Customized Asian | 9 participants | 4 participants | 13 participants |
| Race/Ethnicity, Customized Black or African American | 9 participants | 11 participants | 20 participants |
| Race/Ethnicity, Customized Hispanic | 6 participants | 3 participants | 9 participants |
| Race/Ethnicity, Customized Non-Hispanic | 54 participants | 59 participants | 113 participants |
| Race/Ethnicity, Customized White/Caucasian | 42 participants | 47 participants | 89 participants |
| Region of Enrollment United States | 60 participants | 62 participants | 122 participants |
| Sex: Female, Male Female | 60 Participants | 62 Participants | 122 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 29 / 60 | 30 / 62 |
| serious Total, serious adverse events | 0 / 60 | 0 / 62 |
Outcome results
Primary
Fertilization Rate
The fertilization rate was defined for each participant and calculated as the number of 2 pronuclei (fertilized) (2PN) oocytes divided by the total number of oocytes retrieved multiplied by 100.
Time frame: approximately day 13 (16-20 hours post insemination by in vitro fertilization (IVF) insemination or intracytoplasmic sperm injection (ICSI))
Population: Intent to treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Menopur and Bravelle Combination | Fertilization Rate | 63.14 percentage of oocytes retrieved | Standard Deviation 21.567 |
| Menopur Alone | Fertilization Rate | 59.56 percentage of oocytes retrieved | Standard Deviation 22.46 |
95% CI: [-4.3, 11.5]
Secondary
Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS)
A treatment-emergent AE was any AE occurring after start of investigational medicinal product (IMP) and within the time of residual drug effect, or a pretreatment AE or pre-existing medical condition that worsened in intensity after start of IMP and within the time of residual drug effect. The time of residual drug effect was the estimated period of time after the last dose of the IMP, where the effect of the product was still considered to be present based on pharmacokinetic, pharmacodynamic, or other IMP characteristics.
Time frame: Day 1 up to Day 20
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Menopur and Bravelle Combination | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Drug-related Serious TEAEs | 0 participants |
| Menopur and Bravelle Combination | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Drug-related TEAEs | 9 participants |
| Menopur and Bravelle Combination | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Cycle cancellation due to OHSS | 0 participants |
| Menopur and Bravelle Combination | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Severe TEAEs | 0 participants |
| Menopur and Bravelle Combination | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Participants who died | 0 participants |
| Menopur and Bravelle Combination | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Serious TEAEs | 0 participants |
| Menopur and Bravelle Combination | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Participants with OHSS | 5 participants |
| Menopur and Bravelle Combination | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Any TEAEs resulting in study discontinuation | 0 participants |
| Menopur and Bravelle Combination | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Any TEAEs | 29 participants |
| Menopur Alone | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Any TEAEs resulting in study discontinuation | 0 participants |
| Menopur Alone | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Any TEAEs | 30 participants |
| Menopur Alone | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Drug-related Serious TEAEs | 0 participants |
| Menopur Alone | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Participants who died | 0 participants |
| Menopur Alone | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Cycle cancellation due to OHSS | 0 participants |
| Menopur Alone | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Participants with OHSS | 3 participants |
| Menopur Alone | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Drug-related TEAEs | 13 participants |
| Menopur Alone | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Severe TEAEs | 1 participants |
| Menopur Alone | Participants With Treatment Emergent Adverse Events (TEAEs), Including Ovarian Hyperstimulation Syndrome (OHSS) | Serious TEAEs | 0 participants |
Secondary
Summary of Assessor Questionnaire on Day 1
Participants assigned to the Menopur and Bravelle treatment arm read the Mixing Instructions Guide on how to mix and administer the medications at home. Participants were given enough time to read and understand the instructions and ask any questions. After completing the SCQ, participants prepared and self-administered her assigned first daily dose in the presence of the study coordinator or designee assessor. The assessor then completed a 7 question questionnaire with YES or NO answers to document their assessment of participant understanding of drug administration procedures. Reported data represent the number of participants for whom the assessor answered the question YES. Gonadotropins are referred to as investigational medicinal product (IMP).
Time frame: Day 1
Population: Intent to treat population for the combination treatment arm only
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 1 | Acknowledged understanding of mixing instructions | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 1 | Filled the syringe with saline solution correctly | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 1 | Mixed the first IMP vial with solution correctly | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 1 | Disposed used vials, syringes, needles correctly | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 1 | Mixed additional IMP in same syringe correctly | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 1 | Injected the IMPs correctly | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 1 | Acknowledged understanding of how to store IMPs | 60 participants |
Secondary
Summary of Assessor Questionnaire on Day 6
Participants assigned to the Menopur and Bravelle treatment arm prepared and self-administered her daily dose on Day 6 in the presence of the study coordinator or designee assessor. The assessor then completed a 7 question questionnaire with YES or NO answers to document their assessment of participant understanding of drug administration procedures. Reported data represent the number of participants for whom the assessor answered the question YES. Gonadotropins are referred to as investigational medicinal product (IMP).
Time frame: Day 6
Population: Intent to treat population for the combination treatment arm only
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 6 | Filled the syringe with saline solution correctly | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 6 | Mixed additional IMP in same syringe correctly | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 6 | Injected the IMPs correctly | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 6 | Acknowledged understanding of how to store IMPs | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 6 | Disposed used vials, syringes, needles correctly | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 6 | Acknowledged understanding of mixing instructions | 60 participants |
| Menopur and Bravelle Combination | Summary of Assessor Questionnaire on Day 6 | Mixed the first IMP vial with solution correctly | 60 participants |
Secondary
Summary of the Subject Comprehension Questionnaire (SCQ) on Day 1
Subject comprehension questionnaires were completed on Day 1 only by participants assigned to the Menopur and Bravelle treatment arm. On Day 1, the participant read the Mixing Instructions Guide on how to mix and administer the medications at home. The participant was given enough time to read and understand the instructions and ask any questions. The participant then completed the SCQ which consists of 7 questions with YES/NO answers, to self-gauge their understanding of drug administration procedures. Reported data represent the number of participants who answered the question YES. Gonadotropins are referred to as investigational medicinal product (IMP).
Time frame: Day 1
Population: Intent to treat population for the combination treatment arm only
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 1 | How to mix the first IMP vial with solution | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 1 | How to mix additional vials of IMP in same syringe | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 1 | How to inject the IMPs | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 1 | How to store the IMPs | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 1 | How to dispose of used vials, syringes, needles | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 1 | Overall mixing instructions | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 1 | How to fill the syringe with saline solution | 60 participants |
Secondary
Summary of the Subject Comprehension Questionnaire (SCQ) on Day 6
Subject comprehension questionnaires were repeated on Day 6 after 5 days of combination therapy by participants assigned to the Menopur and Bravelle treatment arm. The SCQ consists of 7 questions with YES/NO answers to self-gauge participants' understanding of drug administration procedures. Reported data represent the number of participants who answered the question YES. Gonadotropins are referred to as investigational medicinal product (IMP).
Time frame: Day 6
Population: Intent to treat population for the combination treatment arm only
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 6 | Overall mixing instructions | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 6 | How to fill the syringe with saline solution | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 6 | How to dispose of used vials, syringes, needles | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 6 | How to mix the first IMP vial with solution | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 6 | How to mix additional vials of IMP in same syringe | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 6 | How to inject the IMPs | 60 participants |
| Menopur and Bravelle Combination | Summary of the Subject Comprehension Questionnaire (SCQ) on Day 6 | How to store the IMPs | 60 participants |