Intracytoplasmic Sperm Injection, In Vitro Fertilization
Conditions
Keywords
Cetrotide, IVF, ICSI, Treatment protocol
Brief summary
Rationale: In daily practice fertility treatment is increasingly patient focused and innovative medication and standardized treatment guidelines are being developed to improve patient convenience. GnRH antagonist cotreatment to prevent premature luteinization during ovarian stimulation for IVF and ICSI greatly reduces the burden of treatment, partly by reducing the number of injections by around 21 compared with the optimal GnRH agonist 'long' protocol. However, the optimal GnRH antagonist protocol is still not known. There are a number of reasons to suggest that both the simplicity of treatment and clinical outcomes could be further improved by commencing GnRH antagonist treatment on the same day on which ovarian stimulation is started. These include more synchronized follicle development and reduced rates of premature luteinization. This study will investigate whether a novel early fixed start protocol improves outcomes in comparison to the widely employed late fixed start protocol. Objective: To demonstrate whether an early fixed start antagonist protocol improves the live birth rate compared with a late fixed start antagonist protocol by 5%. Study design: Prospective, multicenter, investigator sponsored, randomized controlled trial Study population: * Normo-ovulatory women \< 39 years with an indication for IVF or ICSI * No more than 2 previous unsuccessful IVF/ICSI cycles * BMI ≤ 32 kg/m2 Intervention: Two different GnRH antagonist treatment protocols used in daily practice will be compared. Patients will be randomized to receive one of the following two treatments: * Early fixed start: start GnRH antagonist treatment with Cetrotide 0.25 mg on the same day as FSH, cycle day 2. * Late fixed start: FSH will be administered from cycle day 2. GnRH antagonist treatment with Cetrotide 0.25 mg will commence on cycle day 6. Main study parameters/endpoints: The primary endpoint is the live birth rate per started cycle. A secondary endpoint is the number of embryos available for transfer. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: In addition to recording clinical outcomes, endocrine studies will be carried out at the UMC Utrecht in a sample of 200 participants who will be subjected to blood sampling at three points during the treatment cycle: prior to commencing treatment on cycle day 2, cycle day 6 and the day of hCG administration.The aim of this substudy was therefore to prospectively compare the effect of a cycle day 2 versus cycle day 6 fixed start GnRH antagonist protocol on LH, estradiol and progesterone levels in the mid and late follicular phase. In order to investigate whether the early fixed protocol exerts a significant extra burden on patients compared to the late start protocol, another group of 200 participants at the UMCU will be requested to complete the HADS questionnaire (Hospital Anxiety and Depression Scale).
Interventions
DRUGCetrotide (Ovarian stimulation)
Fixed start of a daily dose of 0.25mg Cetrotide on cycle day 2
Sponsors
Bart CJM Fauser
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 39 Years
Healthy volunteers
Yes
Inclusion criteria
* Normo-ovulatory women \< 39 years with an indication for IVF or ICSI
Exclusion criteria
* More than 2 previous unsuccessful IVF/ICSI cycles * BMI \> 32 kg/m2
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Live Birth Rate Per Started Cycle and Live Birth From Cryopreserved Embryos Originating From, and Occurring Within 6 Months of the Initial Treatment Cycle Will be Included in the Total Live Birth Rate Per Started Cycle. | 2 years |
Secondary
| Measure | Time frame |
|---|---|
| Cumulative Ongoing Pregnancy Rate | 2 years |
Other
| Measure | Time frame | Description |
|---|---|---|
| Endocrine Profile in the Early, Mid and Late Follicular Phase. | 2 years | 1. difference in endocrine profile between the 2 arms during the mid and late follicular phase 2. influence of early elevated follicular phase progesterone levels on clinical outcome |
Countries
Netherlands
Participant flow
Recruitment details
Recruitment period: September 2009 - July 2011 Six hundred and seventeen women undergoing IVF or ICSI were recruited from the IVF outpatient clinics of 13 fertility centres.
Pre-assignment details
None were excluded before assignment.
Participants by arm
| Arm | Count |
|---|---|
| Early Start CD2 Early fixed start of a daily dose of 0.25mg Cetrotide on cycle day 2, together with the initiation of daily treatment with exogenous gonadotropins. | 308 |
| Late Start CD6 Late fixed start of a daily dose of 0.25mg Cetrotide on cycle day 6. As in the other arm of the study, exogenous gonadotropins will commence on cycle day 2. | 309 |
| Total | 617 |
Baseline characteristics
| Characteristic | Late Start CD6 | Early Start CD2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 309 Participants | 308 Participants | 617 Participants |
| Age, Continuous | 32.2 years STANDARD_DEVIATION 4.2 | 32.1 years STANDARD_DEVIATION 3.9 | 32.2 years STANDARD_DEVIATION 4 |
| Region of Enrollment Netherlands | 309 participants | 308 participants | 617 participants |
| Sex: Female, Male Female | 309 Participants | 308 Participants | 617 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 | 20 / 308 | 18 / 309 |
| serious Total, serious adverse events | 4 / 308 | 8 / 309 |
Outcome results
Primary
Live Birth Rate Per Started Cycle and Live Birth From Cryopreserved Embryos Originating From, and Occurring Within 6 Months of the Initial Treatment Cycle Will be Included in the Total Live Birth Rate Per Started Cycle.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Start CD2 | Live Birth Rate Per Started Cycle and Live Birth From Cryopreserved Embryos Originating From, and Occurring Within 6 Months of the Initial Treatment Cycle Will be Included in the Total Live Birth Rate Per Started Cycle. | 26.7 Cumulative live birth rate (%) |
| Late Start CD6 | Live Birth Rate Per Started Cycle and Live Birth From Cryopreserved Embryos Originating From, and Occurring Within 6 Months of the Initial Treatment Cycle Will be Included in the Total Live Birth Rate Per Started Cycle. | 29.9 Cumulative live birth rate (%) |
Secondary
Cumulative Ongoing Pregnancy Rate
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Start CD2 | Cumulative Ongoing Pregnancy Rate | 27.6 cumulative ongoing pregnancy rate (%) |
| Late Start CD6 | Cumulative Ongoing Pregnancy Rate | 31.4 cumulative ongoing pregnancy rate (%) |
Other Pre-specified
Endocrine Profile in the Early, Mid and Late Follicular Phase.
1. difference in endocrine profile between the 2 arms during the mid and late follicular phase 2. influence of early elevated follicular phase progesterone levels on clinical outcome
Time frame: 2 years