Infertility, Female
Conditions
Keywords
in vitro fertilization
Brief summary
The purpose of this study is to show equivalence with regard to the number of oocytes retrieved between follitropin alfa (pen-injectors) Primapur® and Gonal-f® in woman undergoing IVF/ICSI
Interventions
Subcutaneous injection, fixed starting dose 150 IU for 5 days, maximum of 16 days of ovarian hyperstimulation
Subcutaneous injection, fixed starting dose 150 IU for 5 days, maximum of 16 days of ovarian hyperstimulation
Sponsors
BridgePharm LLC
GlobalPharma LLC
IVFarma LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
* Infertility due to tubal factor and/or male factor * Age between 20 and 35 years with regular menstrual cycles of 21-35 days * First or second cycle in the present series of ART * BMI (body mass index) ≥ 18 ≤ 30 kg/m2 * Basal FSH (follicle stimulating hormone) \< 10 IU/L (cycle day 2-5) * E2 (estradiol) levels \< 50pg/mL (cycle day 2) * AMH (anti-mullerian hormone) ≥ 1.0 ng/ml * Antral follicle ≥ 4 to ≤ 15 follicles (both ovaries) * Presence of both ovaries and normal uterine cavity * Informed consent
Exclusion criteria
* Presence of pregnancy * Hypersensitivity to follitropin alfa * Ovarian cysts * History of ≥2 succeeding ART (assisted reproductive technology) cycles IVF (in vitro fertilization) and/or ICSI (Intracytoplasmic sperm injection) before the study cycle * Previous history of severe ovarian hyperstimulation syndrome * Presence of polycystic ovaries (PCO) * Presence of endometriosis and hydrosalpinx * Presence of uterine disorders * History of poor (\< 4 oocytes) or hyper (\> 25 oocytes) responses to FSH treatment at dose 150 IU and GnRH-antagonist (gonadotropin-releasing hormone) protocol * Premature ovarian failure * Ectopic pregnancy (3 month before the study cycle) * Presence of clinically significant systemic disease * Presence of chronic cardiovascular, hepatic, renal or pulmonary disease * Presence of endocrine disorder * Neoplasia * Male infertility without mobile spermatozoa in the ejaculate, that need MESA (Microsurgical epididymal sperm aspiration)/TESE (testicular sperm extraction)/TESA (testicular sperm aspiration) * Smoking \> 10 cigarettes/day * Narcomania, alcoholism * Planned PGS (preimplantation genetic screeneing) /PGD (preimplantation genetic diagnosis)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Oocytes (Intention-to-Treat, ITT) | From date of randomization up to 18 days | The total number of retrieved oocytes at the day of ovum pick-up. No more than 37 hours from the introduction of the trigger of ovulation (hCG or GnRH-agonist). The equivalence in the number of retrieved oocytes was tested using a predetermined equivalence margin of +/- 3.4 oocytes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mature Oocytes | From date of randomization up to 18 days | The number of mature oocytes (MII stage of development) |
| Fertilised Oocytes | From date of randomization up to 19 days | The number of fertilised oocytes with the presence of two pronuclei: 2PN |
| Percentage of Patients With Embryo Transfer | From date of randomization up to 25 days | The number of patients (and percentage) with embryo transfers on days 3 and 5 after ovum pick-up |
| Total Dose of Follitropin Alfa | From date of randomization up to 16 days | The total dose of the follitropin alfa administrated during the ovarian hyperstimulation protocol (measured in International Units - IU) |
| Number of Days of Follitropin Alfa Treatment | From date of randomization up to 16 days | The duration of ovarian hyperstimulation protocol (at the day of trigger of ovulation) |
| Number of Follicles With Size ≥ 16 mm | From date of randomization up to 16 days | The number of follicles 16 mm or over in diameter at the day of hCG (or GnRH-agonist) administration |
| Number of Patients With Cycle Cancellation | From date of randomization up to 16 days | The number of the ovarian hyperstimulation protocol cancellation (at the day of trigger of ovulation) |
| Number of No-responders | From date of randomization up to 8 days | The number of patients with no response to follitropin alfa treatment (absence of growing follicles, no any oocytes obtained at the day of ovum pick-up) |
| Percentage of Patients With Serum hCG More Than 25 IU/l | From date of randomization up to 42 days | Biochemical pregnancy test: serum hCG more than 25 IU/l (days 12-17 after embryo transfer) |
| Percentage of Patients With the Evidence for Clinical Pregnancy | The 10th week after embryo transfer | Confirmation of clinical pregnancy: ultrasound detection of intrauterine gestational sac and heart activity |
| Number of Patients With Follitropin Alfa Dose Correction | From date of randomization up to 16 days | The number of dose adjustments during the ovarian hyperstimulation protocol (increment 25-50 IU) |
Countries
Russia
Participant flow
Recruitment details
Subjects were screened and enrolled at 3 In Vitro Fertilisation (IVF) centers in Russian Federation from 08.02.2017 - 17.08.2018.
Pre-assignment details
Of 118 participants: 8 were reported as screening failures prior the group assignment.
Participants by arm
| Arm | Count |
|---|---|
| Primapur (Follitropin Alfa) Follitropin alfa (Primapur): Subcutaneous injection, fixed starting dose 150 IU for 5 days, maximum of 16 days of ovarian hyperstimulation | 55 |
| Gonal-f (Follitropin Alfa) Follitropin alfa (Gonal-f): Subcutaneous injection, fixed starting dose 150 IU for 5 days, maximum of 16 days of ovarian hyperstimulation | 55 |
| Total | 110 |
Baseline characteristics
| Characteristic | Primapur (Follitropin Alfa) | Total | Gonal-f (Follitropin Alfa) |
|---|---|---|---|
| Age, Continuous | 31.3 years STANDARD_DEVIATION 2.68 | 30.65 years STANDARD_DEVIATION 2.75 | 30.0 years STANDARD_DEVIATION 2.71 |
| Anti-mullerian hormone (AMH) | 4.57 ng per ml STANDARD_DEVIATION 2.96 | 5.02 ng per ml STANDARD_DEVIATION 3.43 | 5.47 ng per ml STANDARD_DEVIATION 3.82 |
| Antral follicle | 11.2 Number of antral follicles STANDARD_DEVIATION 3.2 | 11.80 Number of antral follicles STANDARD_DEVIATION 2.87 | 12.4 Number of antral follicles STANDARD_DEVIATION 2.4 |
| Body Mass Index (BMI) | 22.0 kg/m2 STANDARD_DEVIATION 2.69 | 22.15 kg/m2 STANDARD_DEVIATION 2.87 | 22.3 kg/m2 STANDARD_DEVIATION 3.06 |
| Cause of infertility Male factor | 21 Participants | 48 Participants | 27 Participants |
| Cause of infertility Tubal and male factors | 13 Participants | 23 Participants | 10 Participants |
| Cause of infertility Tubal factor | 21 Participants | 39 Participants | 18 Participants |
| Duration of infertility | 46.4 month STANDARD_DEVIATION 32.4 | 41.65 month STANDARD_DEVIATION 28.22 | 36.9 month STANDARD_DEVIATION 26.6 |
| Estradiol | 35.87 pg/ml STANDARD_DEVIATION 12.67 | 34.85 pg/ml STANDARD_DEVIATION 12.54 | 33.82 pg/ml STANDARD_DEVIATION 12.45 |
| Follicle stimulating hormone (FSH) | 6.46 IU/l STANDARD_DEVIATION 1.86 | 6.61 IU/l STANDARD_DEVIATION 1.87 | 6.76 IU/l STANDARD_DEVIATION 1.89 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 55 Participants | 110 Participants | 55 Participants |
| Region of Enrollment Russia | 55 participants | 110 participants | 55 participants |
| Sex: Female, Male Female | 55 Participants | 110 Participants | 55 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 | 0 / 55 | 0 / 55 |
| other Total, other adverse events | 21 / 55 | 13 / 55 |
| serious Total, serious adverse events | 2 / 55 | 2 / 55 |
Outcome results
Primary
Oocytes (Intention-to-Treat, ITT)
The total number of retrieved oocytes at the day of ovum pick-up. No more than 37 hours from the introduction of the trigger of ovulation (hCG or GnRH-agonist). The equivalence in the number of retrieved oocytes was tested using a predetermined equivalence margin of +/- 3.4 oocytes.
Time frame: From date of randomization up to 18 days
Population: Intention-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Primapur (Follitropin Alfa) | Oocytes (Intention-to-Treat, ITT) | 12.16 Number of retrieved oocytes | Standard Deviation 7.28 |
| Gonal-f (Follitropin Alfa) | Oocytes (Intention-to-Treat, ITT) | 11.62 Number of retrieved oocytes | Standard Deviation 6.29 |
p-value: 0.00295% CI: [-2.026, 3.116]Wilcoxon (Mann-Whitney)
Secondary
Fertilised Oocytes
The number of fertilised oocytes with the presence of two pronuclei: 2PN
Time frame: From date of randomization up to 19 days
Population: Intention-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Primapur (Follitropin Alfa) | Fertilised Oocytes | 8.127 Number of oocytes with 2PN | Standard Deviation 6.608 |
| Gonal-f (Follitropin Alfa) | Fertilised Oocytes | 8.764 Number of oocytes with 2PN | Standard Deviation 5.85 |
p-value: 0.44595% CI: [-2.995, 1.723]Wilcoxon (Mann-Whitney)
Secondary
Mature Oocytes
The number of mature oocytes (MII stage of development)
Time frame: From date of randomization up to 18 days
Population: Intention-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Primapur (Follitropin Alfa) | Mature Oocytes | 9.64 Number of mature oocytes (MII stage) | Standard Deviation 6.27 |
| Gonal-f (Follitropin Alfa) | Mature Oocytes | 9.86 Number of mature oocytes (MII stage) | Standard Deviation 5.546 |
p-value: 0.61795% CI: [-2.455, 2.019]Wilcoxon (Mann-Whitney)
Secondary
Number of Days of Follitropin Alfa Treatment
The duration of ovarian hyperstimulation protocol (at the day of trigger of ovulation)
Time frame: From date of randomization up to 16 days
Population: Intention-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Primapur (Follitropin Alfa) | Number of Days of Follitropin Alfa Treatment | 9.745 Days | Standard Deviation 1.075 |
| Gonal-f (Follitropin Alfa) | Number of Days of Follitropin Alfa Treatment | 9.727 Days | Standard Deviation 1.027 |
p-value: 0.62995% CI: [-0.379, 0.416]Wilcoxon (Mann-Whitney)
Secondary
Number of Follicles With Size ≥ 16 mm
The number of follicles 16 mm or over in diameter at the day of hCG (or GnRH-agonist) administration
Time frame: From date of randomization up to 16 days
Population: Intention-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Primapur (Follitropin Alfa) | Number of Follicles With Size ≥ 16 mm | 12.09 Number of follicles | Standard Deviation 6.159 |
| Gonal-f (Follitropin Alfa) | Number of Follicles With Size ≥ 16 mm | 11.38 Number of follicles | Standard Deviation 4.965 |
p-value: 0.80695% CI: [-1.405, 2.824]Wilcoxon (Mann-Whitney)
Secondary
Number of No-responders
The number of patients with no response to follitropin alfa treatment (absence of growing follicles, no any oocytes obtained at the day of ovum pick-up)
Time frame: From date of randomization up to 8 days
Population: Intention-to-Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Primapur (Follitropin Alfa) | Number of No-responders | 0 Participants |
| Gonal-f (Follitropin Alfa) | Number of No-responders | 0 Participants |
Secondary
Number of Patients With Cycle Cancellation
The number of the ovarian hyperstimulation protocol cancellation (at the day of trigger of ovulation)
Time frame: From date of randomization up to 16 days
Population: Intention-to-Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Primapur (Follitropin Alfa) | Number of Patients With Cycle Cancellation | 0 Participants |
| Gonal-f (Follitropin Alfa) | Number of Patients With Cycle Cancellation | 0 Participants |
Secondary
Number of Patients With Follitropin Alfa Dose Correction
The number of dose adjustments during the ovarian hyperstimulation protocol (increment 25-50 IU)
Time frame: From date of randomization up to 16 days
Population: Intention-to-Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Primapur (Follitropin Alfa) | Number of Patients With Follitropin Alfa Dose Correction | 13 Participants |
| Gonal-f (Follitropin Alfa) | Number of Patients With Follitropin Alfa Dose Correction | 11 Participants |
p-value: 0.644Wilcoxon (Mann-Whitney)
Secondary
Percentage of Patients With Embryo Transfer
The number of patients (and percentage) with embryo transfers on days 3 and 5 after ovum pick-up
Time frame: From date of randomization up to 25 days
Population: Per Protocol
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Primapur (Follitropin Alfa) | Percentage of Patients With Embryo Transfer | Embryo transfer on day 3 (%) | 11 Participants |
| Primapur (Follitropin Alfa) | Percentage of Patients With Embryo Transfer | Embryo transfer on day 5 (%) | 38 Participants |
| Gonal-f (Follitropin Alfa) | Percentage of Patients With Embryo Transfer | Embryo transfer on day 3 (%) | 9 Participants |
| Gonal-f (Follitropin Alfa) | Percentage of Patients With Embryo Transfer | Embryo transfer on day 5 (%) | 40 Participants |
p-value: 0.623ANOVA
Secondary
Percentage of Patients With Serum hCG More Than 25 IU/l
Biochemical pregnancy test: serum hCG more than 25 IU/l (days 12-17 after embryo transfer)
Time frame: From date of randomization up to 42 days
Population: Per Protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Primapur (Follitropin Alfa) | Percentage of Patients With Serum hCG More Than 25 IU/l | 34.7 Percentage of patients (%) |
| Gonal-f (Follitropin Alfa) | Percentage of Patients With Serum hCG More Than 25 IU/l | 36.7 Percentage of patients (%) |
Comparison: 95% confidence intervals (CIs) of point estimates were calculated using the exact binomial distribution (Clopper-Pearson method) for proportions.p-value: 0.83395% CI: [-21, 17]Chi-squared
Secondary
Percentage of Patients With the Evidence for Clinical Pregnancy
Confirmation of clinical pregnancy: ultrasound detection of intrauterine gestational sac and heart activity
Time frame: The 10th week after embryo transfer
Population: Per Protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Primapur (Follitropin Alfa) | Percentage of Patients With the Evidence for Clinical Pregnancy | 26.5 Percentage of patients (%) |
| Gonal-f (Follitropin Alfa) | Percentage of Patients With the Evidence for Clinical Pregnancy | 32.7 Percentage of patients (%) |
Comparison: 95% confidence intervals (CIs) of point estimates were calculated using the exact binomial distribution (Clopper-Pearson method) for proportions.p-value: 0.50795% CI: [-24.3, 11.9]Chi-squared
Secondary
Total Dose of Follitropin Alfa
The total dose of the follitropin alfa administrated during the ovarian hyperstimulation protocol (measured in International Units - IU)
Time frame: From date of randomization up to 16 days
Population: Intention-to-Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Primapur (Follitropin Alfa) | Total Dose of Follitropin Alfa | 1532.7 Total dose (IU) | Standard Deviation 267.2 |
| Gonal-f (Follitropin Alfa) | Total Dose of Follitropin Alfa | 1517.9 Total dose (IU) | Standard Deviation 255.2 |
p-value: 0.48895% CI: [-83.9, 113.6]Wilcoxon (Mann-Whitney)