Infertility
Conditions
Keywords
ESPART, Reproductive Techniques, Assisted, Infertility, Pergoveris®, GONAL-f®
Brief summary
This is a Phase 3, randomized, controlled, single-blind, multicenter, parallel-arm trial to assess the safety and efficacy of Pergoveris® (recombinant human follicle stimulating hormone \[r-hFSH\]/recombinant human luteinising hormone \[r-hLH\]) and GONAL-f® for multifollicular development as part of an assisted reproductive technology (ART) treatment cycle in poor ovarian responders, as aligned with the 2011 Consensus Meeting of the European Society of Human Reproduction and Embryology (ESHRE) criteria.
Interventions
DRUGPergoveris®
Pergoveris (follitropin alfa and lutropin alfa) was administered subcutaneously once daily with a starting dose of 300 International Unit (IU) recombinant human follicular stimulating hormone (rhFSH)/ 150 IU recombinant human luteinizing hormone (rhLH) after confirmation of down regulation up to 21 days. After follicle attained mean diameter of 17-18 millimeter (mm); 250 microgram (mcg) of r-hCG (Ovidrel) was administered once subcutaneously to trigger final follicular maturation as per site standard practice. The dose adjustment for r-hFSH was allowed in 75 IU increments while maintaining the 2:1 ratio of r hFSH to r-hLH in the Pergoveris group based on the subject's response per site standard clinical practice.
DRUGGONAL-f®
GONAL-f (r-hFSH) was self-administered subcutaneously once daily at a starting dose of 300 IU after confirmation of down regulation up to 21 days. After follicle attained mean diameter of 17-18 mm; 250 mcg of r-hCG was administered once subcutaneously to trigger final follicular maturation as per site standard practice. The dose adjustment for r-hFSH was allowed in 75 IU increments based on the subject's response per site standard clinical practice.
On r-hCG day, 250 mcg of r-hCG was administered once subcutaneously
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 41 Years
Healthy volunteers
No
Inclusion criteria
* Poor ovarian responders according to specific criteria that are aligned with poor ovarian response (POR) criteria defined by the 2011 Consensus Meeting of the European Society of Human Reproduction and Embryology (ESHRE) as mentioned in the protocol * Female subjects, less than (\<) 41 years of age (according to date of birth at time of informed consent) who are eligible for ovarian stimulation and ART treatment, including intracytoplasmic sperm injection (ICSI) * Absence of anatomical abnormalities of the reproductive tract that would interfere with implantation or pregnancy * Absence of any medical condition in which pregnancy is contraindicated * Body mass index 18 to 30 kilogram per square meter (kg/m\^2), inclusive * Motile, ejaculatory sperm must be available (donated and/or cryopreserved sperm is allowed). Intracytoplasmic sperm injection will be allowed during this trial * Minimum of 1 month without treatment with either clomiphene citrate or gonadotrophins prior to screening * Signed and dated informed consent indicating that the subject has been informed of all the pertinent aspects of the trial prior to enrollment
Exclusion criteria
* Two episodes of POR after maximal stimulation * History or presence of tumors of the hypothalamus or pituitary gland * History or presence of ovarian enlargement or cyst of unknown etiology, or presence of an ovarian cyst greater than 25 mm on the day of randomization * Presence of endometriosis Grade III - IV, confirmed or suspected * Presence of uni- or bilateral hydrosalpinx * Abnormal gynecological bleeding of undetermined origin * Contraindication to being pregnant and/or carrying a pregnancy to term * History or presence of ovarian, uterine or mammary cancer * Use of testicular or epididymal sperm * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Oocytes Retrieved | At approximately 34 to 38 hours after r-hCG administration (Day 113) | Mean number of oocytes retrieved on the day of ovum pick up (OPU) was calculated. Oocyte retrieval was a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ongoing Pregnancy Rate | 70 days after embryo transfer (Day 185) | Ongoing pregnancy rate was defined as the percentage of subjects with a ultrasound confirmation of at least one viable fetus (positive fetal heart beat). |
| Live Birth Rate | Approximately 180 days following ongoing pregnancy determination (Day 365) | Live birth rate was defined as the percentage of subjects with at least one live-born neonate. |
| Embryo Implantation Rate | 35-42 days post r-hCG administration (Day 154) | Embryo implantation rate was measured as the number of gestational sacs observed divided by the number of embryos transferred multiplied by 100. |
| Clinical Pregnancy Rate | 35-42 days post r-hCG administration (Day 154) | Clinical pregnancy rate defined as the percentage of subjects with a ultrasound confirmation of a gestational sac, with or without fetal heart activity. |
| Biochemical Pregnancy Rate | 15 to 20 days post r-hCG administration (Day 132) | Biochemical pregnancy rate was defined as the percentage of subjects with a positive beta-hCG result from the serum pregnancy test. |
Countries
Germany
Participant flow
Recruitment details
The study was conducted at 101 sites in 15 countries.
Participants by arm
| Arm | Count |
|---|---|
| Pergoveris Pergoveris (follitropin alfa and lutropin alfa) was administered subcutaneously once daily with a starting dose of 300 IU rhFSH/150 IU rhLH after confirmation of down regulation up to 21 days. After follicle attained mean diameter of 17-18 mm; 250 mcg of r-hCG was administered once subcutaneously to trigger final follicular maturation as per site standard practice. The dose adjustment for r-hFSH was allowed in 75 IU increments while maintaining the 2:1 ratio of r hFSH to r-hLH in the Pergoveris group based on the subject's response per site standard clinical practice. | 462 |
| GONAL-f GONAL-f (r-hFSH) was self-administered subcutaneously once daily at a starting dose of 300 IU after confirmation of down regulation up to 21 days. After follicle attained mean diameter of 17-18 mm; 250 mcg of r-hCG was administered once subcutaneously to trigger final follicular maturation as per site standard practice. The dose adjustment for r-hFSH was allowed in 75 IU increments based on the subject's response per site standard clinical practice. | 477 |
| Total | 939 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | All embryos discarded | 12 | 11 |
| Overall Study | Intention to freeze all embryos | 1 | 0 |
| Overall Study | Lack of ovarian response to stimulation | 35 | 32 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | No fertilization | 61 | 51 |
| Overall Study | No oocytes retrieved | 21 | 20 |
| Overall Study | Other | 10 | 9 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Spontaneous pregnancy | 1 | 0 |
Baseline characteristics
| Characteristic | Pergoveris | GONAL-f | Total |
|---|---|---|---|
| Age, Continuous | 38.3 years STANDARD_DEVIATION 2.9 | 38.3 years STANDARD_DEVIATION 3 | 38.3 years STANDARD_DEVIATION 3 |
| Sex: Female, Male Female | 462 Participants | 477 Participants | 939 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 | 111 / 462 | 151 / 477 |
| serious Total, serious adverse events | 8 / 462 | 17 / 477 |
Outcome results
Primary
Number of Oocytes Retrieved
Mean number of oocytes retrieved on the day of ovum pick up (OPU) was calculated. Oocyte retrieval was a technique used in in-vitro fertilization in order to remove oocytes from the ovary of the female, enabling fertilization outside the body.
Time frame: At approximately 34 to 38 hours after r-hCG administration (Day 113)
Population: Intent-to-treat (ITT) analysis set included all subjects randomized who received at least 1 dose of GONAL-f or Pergoveris.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pergoveris | Number of Oocytes Retrieved | 3.3 oocytes | Standard Deviation 2.71 |
| GONAL-f | Number of Oocytes Retrieved | 3.6 oocytes | Standard Deviation 2.82 |
p-value: 0.05495% CI: [-0.4741, 0.003]Poisson Regression Model
Secondary
Biochemical Pregnancy Rate
Biochemical pregnancy rate was defined as the percentage of subjects with a positive beta-hCG result from the serum pregnancy test.
Time frame: 15 to 20 days post r-hCG administration (Day 132)
Population: MITT Analysis Set included all randomized subjects who received at least 1 dose of GONAL-f or Pergoveris and did not have spontaneous pregnancy or death at approximately 34-38 hours after rhCG administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pergoveris | Biochemical Pregnancy Rate | 17.3 percentage of subjects |
| GONAL-f | Biochemical Pregnancy Rate | 23.9 percentage of subjects |
Secondary
Clinical Pregnancy Rate
Clinical pregnancy rate defined as the percentage of subjects with a ultrasound confirmation of a gestational sac, with or without fetal heart activity.
Time frame: 35-42 days post r-hCG administration (Day 154)
Population: MITT analysis set included all randomized subjects who received at least 1 dose of GONAL-f or Pergoveris and did not have spontaneous pregnancy or death at approximately 34-38 hours after rhCG administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pergoveris | Clinical Pregnancy Rate | 14.1 percentage of subjects |
| GONAL-f | Clinical Pregnancy Rate | 16.8 percentage of subjects |
Secondary
Embryo Implantation Rate
Embryo implantation rate was measured as the number of gestational sacs observed divided by the number of embryos transferred multiplied by 100.
Time frame: 35-42 days post r-hCG administration (Day 154)
Population: MITT analysis set included all randomized subjects who received at least 1 dose of GONAL-f or Pergoveris and did not have spontaneous pregnancy or death at approximately 34-38 hours after rhCG administration. Here Number of subjects analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pergoveris | Embryo Implantation Rate | 14.7 percent sacs per embryo |
| GONAL-f | Embryo Implantation Rate | 15.6 percent sacs per embryo |
Secondary
Live Birth Rate
Live birth rate was defined as the percentage of subjects with at least one live-born neonate.
Time frame: Approximately 180 days following ongoing pregnancy determination (Day 365)
Population: MITT analysis set included all randomized subjects who received at least 1 dose of GONAL-f or Pergoveris and did not have spontaneous pregnancy or death at approximately 34-38 hours after rhCG administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pergoveris | Live Birth Rate | 10.6 percentage of subjects |
| GONAL-f | Live Birth Rate | 11.7 percentage of subjects |
Secondary
Ongoing Pregnancy Rate
Ongoing pregnancy rate was defined as the percentage of subjects with a ultrasound confirmation of at least one viable fetus (positive fetal heart beat).
Time frame: 70 days after embryo transfer (Day 185)
Population: Modified intent-to-treat (MITT) analysis set included all randomized subjects who received at least 1 dose of GONAL-f or Pergoveris and did not have spontaneous pregnancy or death at approximately 34-38 hours after rhCG administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pergoveris | Ongoing Pregnancy Rate | 11.0 percentage of subjects |
| GONAL-f | Ongoing Pregnancy Rate | 12.4 percentage of subjects |