Infertility
Conditions
Keywords
kisspeptin, infertility, in vitro fertilisation
Brief summary
We want to find out if kisspeptin is successful in stimulating oocyte maturation when it is used as a 'trigger' injection during IVF therapy for infertility.
Detailed description
Participants in the study will have a standard Gonadotrophin Releasing Hormone (GnRH) antagonist IVF cycle, but instead of having a trigger injection of hCG (human chorionic gonadotrophin) they will be randomised to receive one of 4 doses of kisspeptin injection. Oocytes will be retrieved and graded by an embryologist to see whether or not they have matured. The reproductive hormones Luteinising hormone, follicle stimulating hormone, oestradiol and progesterone will also be measured
Interventions
DRUGKisspeptin 1.6nmol/kg
single kisspeptin dose 1.6 nmol/kg subcutaneously
DRUGKisspeptin 3.2nmol/kg
single kisspeptin dose 3.2 nmol/kg subcutaneously
DRUGKisspeptin 6.4nmol/kg
single kisspeptin dose 6.4 nmol/kg subcutaneously
DRUGKisspeptin 9.6nmol/kg
single kisspeptin dose 9.6 nmol/kg subcutaneously
DRUGKisspeptin 12.8nmol/kg
single kisspeptin dose 12.8 nmol/kg subcutaneously
DRUGKisspeptin 9.6 nmol/kg double
kisspeptin dose 9.6 nmol/kg given twice 10hrs apart subcutaneously
DRUGKisspeptin 9.6 nmol/kg + saline
kisspeptin dose 9.6 nmol/kg subcutaneously and saline subcutaneously, 10hrs apart
Sponsors
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Masking description
participants and IVF physicians were blinded.
Intervention model description
Different dose for each volunteer
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 34 Years
Healthy volunteers
No
Inclusion criteria
* Aged 18 - 34 years * Body mass index between 18 and 29 kg/m2 * Stable body weight for at least 3 months * Normal early menstrual cycle follicular phase serum FSH concentration * Serum anti-Mullerian hormone (AMH) \> 40pmol/L * No more than one previous IVF treatment cycle * Both ovaries intact
Exclusion criteria
History of any medical, psychological or other condition, or use of any medications, including over-the-counter products, which, in the opinion of the investigators, would either interfere with the study or potentially cause harm to the volunteer * Without access at home to a telephone, or other factor likely to interfere with ability to participate reliably in the study * Treatment with an investigational drug within the preceding 2 months * Donated blood during the preceding 3 months or intention to do so before the end of the study * Previous poor response to IVF treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Oocyte Maturation | 36 hours post Kisspeptin-54 trigger injection | This was assessed by oocyte yield (percentage of mature \[metaphase 2; M2\] oocytes collected from the number of follicles ≥ 14 mm on final ultrasound scan prior to kisspeptin-54 trigger administration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical Pregnancy | 11 days after embryo transfer | Number of participants achieving biochemical pregnancy by serum βhCG \> 10 mIU/mL |
| Occurrence of OHSS | 11 days following embryo transfer | Women were routinely screened for the development of early OHSS and late OHSS. Women were screened by symptoms, blood analysis, and ultrasound parameters |
| Fertilization Rate | 3 days after oocyte retrieval | Percentage of M2 oocytes that fertilize to form two pronuclear \[2PN\] zygotes following intracytoplasmic injection with sperm \[ICSI\] |
| Embryo Formation | 3 days after oocyte retrieval | All embryos were graded at day 3 by an independent embryologist, blinded to doses of kisspeptin administered, using the British Fertility Society and Association of Clinical Embryologist embryo grading scheme for cleavage stage embryos, which describes embryos based on cell number, blastomere size, and fragmentation |
| Number of Participants With Clinical Pregnancy | 6 weeks after embryo transfer | Intrauterine gestational sac with heartbeat on ultrasound at 6 weeks' gestation |
Countries
United Kingdom
Participant flow
Recruitment details
Parallel study, volunteers received only one type of dose
Participants by arm
| Arm | Count |
|---|---|
| Kisspeptin-54 1.6 Single Participant undergoing in vitro fertilisation (IVF) treatment will receive a single trigger injection of Kisspeptin, dose of 1.6 nmol/kg | 2 |
| Kispeptin-54 3.2 Single Participant undergoing in vitro fertilisation (IVF) treatment will receive a single trigger injection of Kisspeptin, dose of 3.2 nmol/kg | 3 |
| Kisspeptin-54 6.4 Single Participant undergoing in vitro fertilisation (IVF) treatment will receive a single trigger injection of Kisspeptin, dose of 6.4 nmol/kg | 24 |
| Kisspeptin-54 12.8 Single Participant undergoing in vitro fertilisation (IVF) treatment will receive a single trigger injection of Kisspeptin, dose of 12.8 nmol/kg | 24 |
| OHSS - Kisspeptin-54 3.2 Single Participant undergoing in vitro fertilisation (IVF) treatment and who is at high risk of ovarian hyper stimulation syndrome (OHSS) will receive a single trigger injection of Kisspeptin, dose of 3.2 nmol/kg | 5 |
| OHSS - Kisspeptin-54 6.4 Single Participant undergoing in vitro fertilisation (IVF) treatment and who is at high risk of ovarian hyper stimulation syndrome (OHSS) will receive a single trigger injection of Kisspeptin, dose of 6.4 nmol/kg | 20 |
| OHSS - Kisspeptin-54 9.6 Single Participant undergoing in vitro fertilisation (IVF) treatment and who is at high risk of ovarian hyper stimulation syndrome (OHSS) will receive a single trigger injection of Kisspeptin, dose of 9.6 nmol/kg | 15 |
| OHSS - Kisspeptin-54 12.8 Single Participant undergoing in vitro fertilisation (IVF) treatment and who is at high risk of ovarian hyper stimulation syndrome (OHSS) will receive a single trigger injection of Kisspeptin, dose of 12.8 nmol/kg | 20 |
| Kisspeptin-54 9.6 + 9.6 Participant undergoing in vitro fertilisation (IVF) treatment and who is at high risk of ovarian hyper stimulation syndrome (OHSS) will receive a trigger injection of Kisspeptin, dose of 9.6 nmol/kg and a further injection of Kisspeptin, dose of 9.6 nmol/kg 10 hours later | 31 |
| Kisspeptin-54 9.6 + Saline Participant undergoing in vitro fertilisation (IVF) treatment and who is at high risk of ovarian hyper stimulation syndrome (OHSS) will receive a trigger injection of Kisspeptin, dose of 9.6 nmol/kg and a further injection of saline10 hours later | 31 |
| Total | 175 |
Baseline characteristics
| Characteristic | Kisspeptin-54 1.6 Single | Kispeptin-54 3.2 Single | Kisspeptin-54 6.4 Single | Kisspeptin-54 12.8 Single | OHSS - Kisspeptin-54 3.2 Single | OHSS - Kisspeptin-54 6.4 Single | OHSS - Kisspeptin-54 9.6 Single | OHSS - Kisspeptin-54 12.8 Single | Kisspeptin-54 9.6 + 9.6 | Kisspeptin-54 9.6 + Saline | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | 30 years | 31 years | 32 years | 30 years | 30 years | 30 years | 32 years | 31 years | 30.9 years | 31.2 years | 31.1 years |
| Anti-mullerian hormone (AMH) | 21 pmol/L STANDARD_DEVIATION 3.7 | 13 pmol/L STANDARD_DEVIATION 5.19 | 18 pmol/L STANDARD_DEVIATION 8.89 | 21 pmol/L STANDARD_DEVIATION 9.63 | 35 pmol/L STANDARD_DEVIATION 15.56 | 48 pmol/L STANDARD_DEVIATION 22.22 | 66 pmol/L STANDARD_DEVIATION 20 | 53 pmol/L STANDARD_DEVIATION 18.52 | 44 pmol/L STANDARD_DEVIATION 16.15 | 52.4 pmol/L STANDARD_DEVIATION 33.33 | 37.12 pmol/L STANDARD_DEVIATION 18.11 |
| Antral Follicle Count (AFC) | 30 Follicles STANDARD_DEVIATION 2.22 | 24 Follicles STANDARD_DEVIATION 5.93 | 20 Follicles STANDARD_DEVIATION 7.41 | 20 Follicles STANDARD_DEVIATION 6.67 | 35 Follicles STANDARD_DEVIATION 15.56 | 48 Follicles STANDARD_DEVIATION 2.22 | 66 Follicles STANDARD_DEVIATION 20 | 53 Follicles STANDARD_DEVIATION 18.52 | 33 Follicles STANDARD_DEVIATION 8.89 | 39 Follicles STANDARD_DEVIATION 16.3 | 36.8 Follicles STANDARD_DEVIATION 15.05 |
| BMI 18-29 | 23 kg/m^2 STANDARD_DEVIATION 0.74 | 22 kg/m^2 STANDARD_DEVIATION 0.74 | 22 kg/m^2 STANDARD_DEVIATION 2.22 | 23 kg/m^2 STANDARD_DEVIATION 1.48 | 22 kg/m^2 STANDARD_DEVIATION 2.96 | 22 kg/m^2 STANDARD_DEVIATION 5.19 | 25 kg/m^2 STANDARD_DEVIATION 2.96 | 24 kg/m^2 STANDARD_DEVIATION 5.19 | 26.6 kg/m^2 STANDARD_DEVIATION 4.52 | 23.9 kg/m^2 STANDARD_DEVIATION 4.074 | 23.35 kg/m^2 STANDARD_DEVIATION 1.547 |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | — | — | — | — | 0 Participants |
| Region of Enrollment United Kingdom | 2 participants | 3 participants | 24 participants | 24 participants | 5 participants | 20 participants | 15 participants | 20 participants | 31 participants | 31 participants | 175 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 24 Participants | 24 Participants | 5 Participants | 20 Participants | 15 Participants | 20 Participants | 31 Participants | 31 Participants | 175 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 3 | 0 / 24 | 0 / 24 | 0 / 5 | 0 / 20 | 0 / 15 | 0 / 20 | 0 / 31 | 0 / 31 |
| other Total, other adverse events | 0 / 2 | 0 / 3 | 0 / 24 | 0 / 24 | 0 / 5 | 0 / 20 | 0 / 15 | 0 / 20 | 0 / 31 | 0 / 31 |
| serious Total, serious adverse events | 0 / 2 | 0 / 3 | 1 / 24 | 2 / 24 | 0 / 5 | 1 / 20 | 2 / 15 | 2 / 20 | 0 / 31 | 1 / 31 |
Outcome results
Primary
Percentage of Oocyte Maturation
This was assessed by oocyte yield (percentage of mature \[metaphase 2; M2\] oocytes collected from the number of follicles ≥ 14 mm on final ultrasound scan prior to kisspeptin-54 trigger administration
Time frame: 36 hours post Kisspeptin-54 trigger injection
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kisspeptin-54 1.6 Nmol/kg Single | Percentage of Oocyte Maturation | 49 percentage of expected oocyte yield | Standard Deviation 29 |
| Kisspeptin-54 3.2nmol/kg Single | Percentage of Oocyte Maturation | 36 percentage of expected oocyte yield | Standard Deviation 18 |
| Kisspeptin-54 6.4 Nmol/kg Single | Percentage of Oocyte Maturation | 76 percentage of expected oocyte yield | Standard Deviation 49 |
| Kisspeptin-54 12.8nmol/kg Single | Percentage of Oocyte Maturation | 103 percentage of expected oocyte yield | Standard Deviation 53 |
| Kisspeptin-54, OHSS 3.2nmol/Kg Single | Percentage of Oocyte Maturation | 53 percentage of expected oocyte yield | Standard Deviation 41 |
| Kisspeptin-54, OHSS 6.4nmol/Kg Single | Percentage of Oocyte Maturation | 86 percentage of expected oocyte yield | Standard Deviation 49 |
| Kisspeptin-54, OHSS 9.6nmol/Kg Single | Percentage of Oocyte Maturation | 86 percentage of expected oocyte yield | Standard Deviation 74 |
| Kisspeptin-54, OHSS 12.8nmol/Kg Single | Percentage of Oocyte Maturation | 121 percentage of expected oocyte yield | Standard Deviation 119 |
| Kisspeptin-54 OHSS, 9.6 + 9.6 | Percentage of Oocyte Maturation | 55 percentage of expected oocyte yield | Standard Deviation 18 |
| Kisspeptin-54 OHSS, 9.6 + Saline | Percentage of Oocyte Maturation | 46 percentage of expected oocyte yield | Standard Deviation 22 |
Comparison: Data presented using descriptive statistics. Confidence intervals were derived for the difference between the means of different doses.
Comparison: Phase 2p-value: <0.05Fisher Exact
Comparison: Phase 3p-value: <0.05Regression, Logistic
Secondary
Biochemical Pregnancy
Number of participants achieving biochemical pregnancy by serum βhCG \> 10 mIU/mL
Time frame: 11 days after embryo transfer
Population: All participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Kisspeptin-54 1.6 Nmol/kg Single | Biochemical Pregnancy | 1 Participants |
| Kisspeptin-54 3.2nmol/kg Single | Biochemical Pregnancy | 1 Participants |
| Kisspeptin-54 6.4 Nmol/kg Single | Biochemical Pregnancy | 11 Participants |
| Kisspeptin-54 12.8nmol/kg Single | Biochemical Pregnancy | 8 Participants |
| Kisspeptin-54, OHSS 3.2nmol/Kg Single | Biochemical Pregnancy | 1 Participants |
| Kisspeptin-54, OHSS 6.4nmol/Kg Single | Biochemical Pregnancy | 10 Participants |
| Kisspeptin-54, OHSS 9.6nmol/Kg Single | Biochemical Pregnancy | 10 Participants |
| Kisspeptin-54, OHSS 12.8nmol/Kg Single | Biochemical Pregnancy | 6 Participants |
| Kisspeptin-54 OHSS, 9.6 + 9.6 | Biochemical Pregnancy | 16 Participants |
| Kisspeptin-54 OHSS, 9.6 + Saline | Biochemical Pregnancy | 10 Participants |
Comparison: Study data were summarised using standard descriptive methods. Continuous variables following a normal distribution have been summarised using mean and SD.
Secondary
Embryo Formation
All embryos were graded at day 3 by an independent embryologist, blinded to doses of kisspeptin administered, using the British Fertility Society and Association of Clinical Embryologist embryo grading scheme for cleavage stage embryos, which describes embryos based on cell number, blastomere size, and fragmentation
Time frame: 3 days after oocyte retrieval
Population: All participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kisspeptin-54 1.6 Nmol/kg Single | Embryo Formation | 0 formed embryos | Standard Deviation 0 |
| Kisspeptin-54 3.2nmol/kg Single | Embryo Formation | 2.33 formed embryos | Standard Deviation 2.31 |
| Kisspeptin-54 6.4 Nmol/kg Single | Embryo Formation | 3.8 formed embryos | Standard Deviation 2.7 |
| Kisspeptin-54 12.8nmol/kg Single | Embryo Formation | 4.5 formed embryos | Standard Deviation 2.7 |
| Kisspeptin-54, OHSS 3.2nmol/Kg Single | Embryo Formation | 5.8 formed embryos | Standard Deviation 4.8 |
| Kisspeptin-54, OHSS 6.4nmol/Kg Single | Embryo Formation | 9.4 formed embryos | Standard Deviation 7 |
| Kisspeptin-54, OHSS 9.6nmol/Kg Single | Embryo Formation | 6.5 formed embryos | Standard Deviation 5.6 |
| Kisspeptin-54, OHSS 12.8nmol/Kg Single | Embryo Formation | 11.1 formed embryos | Standard Deviation 8.4 |
| Kisspeptin-54 OHSS, 9.6 + 9.6 | Embryo Formation | 6 formed embryos | Standard Deviation 4.44 |
| Kisspeptin-54 OHSS, 9.6 + Saline | Embryo Formation | 5 formed embryos | Standard Deviation 3.7 |
Secondary
Fertilization Rate
Percentage of M2 oocytes that fertilize to form two pronuclear \[2PN\] zygotes following intracytoplasmic injection with sperm \[ICSI\]
Time frame: 3 days after oocyte retrieval
Population: All participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Kisspeptin-54 1.6 Nmol/kg Single | Fertilization Rate | 14.28 percentage of 2PN zygotes | Standard Deviation 20.2 |
| Kisspeptin-54 3.2nmol/kg Single | Fertilization Rate | 58.33 percentage of 2PN zygotes | Standard Deviation 30.04 |
| Kisspeptin-54 6.4 Nmol/kg Single | Fertilization Rate | 66.94 percentage of 2PN zygotes | Standard Deviation 26.98 |
| Kisspeptin-54 12.8nmol/kg Single | Fertilization Rate | 76.01 percentage of 2PN zygotes | Standard Deviation 26.28 |
| Kisspeptin-54, OHSS 3.2nmol/Kg Single | Fertilization Rate | 68 percentage of 2PN zygotes | Standard Deviation 39 |
| Kisspeptin-54, OHSS 6.4nmol/Kg Single | Fertilization Rate | 76 percentage of 2PN zygotes | Standard Deviation 29 |
| Kisspeptin-54, OHSS 9.6nmol/Kg Single | Fertilization Rate | 74 percentage of 2PN zygotes | Standard Deviation 33 |
| Kisspeptin-54, OHSS 12.8nmol/Kg Single | Fertilization Rate | 73 percentage of 2PN zygotes | Standard Deviation 21 |
| Kisspeptin-54 OHSS, 9.6 + 9.6 | Fertilization Rate | 78.6 percentage of 2PN zygotes | Standard Deviation 26.2 |
| Kisspeptin-54 OHSS, 9.6 + Saline | Fertilization Rate | 78.9 percentage of 2PN zygotes | Standard Deviation 37.7 |
Secondary
Number of Participants With Clinical Pregnancy
Intrauterine gestational sac with heartbeat on ultrasound at 6 weeks' gestation
Time frame: 6 weeks after embryo transfer
Population: All participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Kisspeptin-54 1.6 Nmol/kg Single | Number of Participants With Clinical Pregnancy | 1 Participants |
| Kisspeptin-54 3.2nmol/kg Single | Number of Participants With Clinical Pregnancy | 0 Participants |
| Kisspeptin-54 6.4 Nmol/kg Single | Number of Participants With Clinical Pregnancy | 7 Participants |
| Kisspeptin-54 12.8nmol/kg Single | Number of Participants With Clinical Pregnancy | 4 Participants |
| Kisspeptin-54, OHSS 3.2nmol/Kg Single | Number of Participants With Clinical Pregnancy | 1 Participants |
| Kisspeptin-54, OHSS 6.4nmol/Kg Single | Number of Participants With Clinical Pregnancy | 10 Participants |
| Kisspeptin-54, OHSS 9.6nmol/Kg Single | Number of Participants With Clinical Pregnancy | 10 Participants |
| Kisspeptin-54, OHSS 12.8nmol/Kg Single | Number of Participants With Clinical Pregnancy | 6 Participants |
| Kisspeptin-54 OHSS, 9.6 + 9.6 | Number of Participants With Clinical Pregnancy | 7 Participants |
| Kisspeptin-54 OHSS, 9.6 + Saline | Number of Participants With Clinical Pregnancy | 12 Participants |
Secondary
Occurrence of OHSS
Women were routinely screened for the development of early OHSS and late OHSS. Women were screened by symptoms, blood analysis, and ultrasound parameters
Time frame: 11 days following embryo transfer
Population: Occurence of OHSS was not analysed in the groups where number of participants analysed is zero as this first phase was to test only the hypothesis that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Kisspeptin-54 1.6 Nmol/kg Single | Occurrence of OHSS | 0 Participants |
| Kisspeptin-54 3.2nmol/kg Single | Occurrence of OHSS | 0 Participants |
| Kisspeptin-54 6.4 Nmol/kg Single | Occurrence of OHSS | 0 Participants |
| Kisspeptin-54 12.8nmol/kg Single | Occurrence of OHSS | 0 Participants |
| Kisspeptin-54, OHSS 3.2nmol/Kg Single | Occurrence of OHSS | 0 Participants |
| Kisspeptin-54, OHSS 6.4nmol/Kg Single | Occurrence of OHSS | 0 Participants |
| Kisspeptin-54, OHSS 9.6nmol/Kg Single | Occurrence of OHSS | 0 Participants |
| Kisspeptin-54, OHSS 12.8nmol/Kg Single | Occurrence of OHSS | 4 Participants |
| Kisspeptin-54 OHSS, 9.6 + 9.6 | Occurrence of OHSS | 1 Participants |
| Kisspeptin-54 OHSS, 9.6 + Saline | Occurrence of OHSS | 1 Participants |