Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000643471
Ethics application status
Approved
Date submitted
24/03/2016
Date registered
18/05/2016
Date last updated
18/05/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparison of the probability of live birth after elective freezing of all embryos versus standard fresh embryo transfer in patients undergoing in-vitro fertilisation (IVF)
Scientific title
Fresh vs. Elective Frozen Embryo Transfer after IVF: a randomised controlled trial
Secondary ID [1] 288814 0
None
Universal Trial Number (UTN)
Trial acronym
FAST
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Subfertility 298082 0
Condition category
Condition code
Reproductive Health and Childbirth 298248 298248 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Triggering of final oocyte maturation will be performed in the freeze-all arm with a bolus subcutaneous injection of 2 mg of leuprolide acetate when at least three follicles equal to or greater than 17mm in mean diameter are present at ultrasound. Oocyte retrieval will be performed at 34-36h after leuprolide administration.
Embryos will be cultured for 5 days using the standard protocol of each clinic. All day 5 embryos of top and good quality (at least at early blastocyst stage and of ICM/Trophectoderm: AA, AB, BA, BB) will be cryopreserved using the method of vitrification. If only one embryo is available, this embryo will be vitrified regardless of quality as long as full embryo compaction has occurred. Delayed embryos will be allowed to be vitrified on day 6 as long as they fulfill the quality criteria (at least at early blastocyst stage and of ICM/Trophectoderm: AA, AB, BA, BB).
Prior to freezing of embryos the developmental stage and quality of the blastocysts will be recorded (based on the judgement of the embryologist). Each blastocyst will be frozen in it’s own straw. Based on the pre-vitrification morphological quality, the best blastocyst will be thawed for the next embryo transfer. If the blastocyst does not survive, the next best blastocyst (based again on the pre-vitrification morphological criteria) will be thawed.
The maximum period of embryo cryopreservation is theoretically indefinite, however it rarely exceeds five years. For the primary outcome of this study, the embryo cryopreservation period is estimated between 20 days-3 months. Hence, thawing and embryo transfer is expected to occur within this timeframe.
Vitrification will be performed according to established local laboratory protocols with the use of TGA approved Vitrification solutions (Vitrolife or Sage). Vitrification will be performed at either 37 degrees Celsius or room temperature.
Intervention code [1] 294268 0
Treatment: Other
Comparator / control treatment
Triggering of final oocyte maturation will be performed in the fresh transfer arm with a bolus subcutaneous injection of 250 mcg of r-hCG when at least three follicles of equal to or greater than 17mm in mean diameter are present at ultrasound. Oocyte retrieval will be performed at 34-36h after r-hCG administration.
Embryos will be cultured for 5 days using the standard protocol of each clinic. On day 5 of embryo culture the developmental stage and quality of the blastocysts will be recorded including ICM and Trophectoderm grading. The morphologically best day 5 embryo (according to the judgement of the embryologist) will be transferred.
All remaining day 5 embryos of top and good quality (at least at early blastocyst stage and of ICM/Trophectoderm: AA, AB, BA, BB) will be cryopreserved using the method of vitrification. Delayed embryos will be allowed to be vitrified on day 6 as long as they fulfill the quality criteria (at least at early blastocyst stage and of ICM/Trophectoderm: AA, AB, BA, BB).
Vitrification will be performed according to established local laboratory protocols with the use of TGA approved Vitrification solutions (Vitrolife or Sage). Vitrification will be performed at either 37 degrees Celsius or room temperature.
The maximum period of embryo cryopreservation is theoretically indefinite, however it rarely exceeds five years. Usually, these embryos remain cryopreserved for future use, if fresh transfer does not result in a pregnancy or for future pregnancies after a live birth. However, the primary outcome measure of this study is live birth after the first embryo transfer (fresh vs. frozen-thawed).
Control group
Active

Outcomes
Primary outcome [1] 297738 0
Live Birth after the transfer of the first embryo by review of patients medical records
Timepoint [1] 297738 0
Delivery of a live baby after the 20th week of gestation
Secondary outcome [1] 322098 0
Ongoing pregnancy diagnosed by ultrasonography as presence of foetal heart activity at 10-12 weeks of gestation
Timepoint [1] 322098 0
Once at 10-12 weeks of gestation depending on the time of appointment
Secondary outcome [2] 322099 0
Clinical pregnancy diagnosed by ultrasound as presence of foetal heart activity at 6-8 weeks of gestation
Timepoint [2] 322099 0
At 6-8 weeks of gestation depending on time of appointment
Secondary outcome [3] 322100 0
Biochemical pregnancy as assessed by blood serum b-hCG>20 IU/L
Timepoint [3] 322100 0
At 11-16 days after embryo transfer depending on time of appointment
Secondary outcome [4] 322101 0
First trimester miscarriage, defined as a biochemical pregnancy (assessed by serum hCG) at 11-16 days after embryo transfer but no foetal heart activity at 10-12 weeks of gestation as assessed by ultrasonography.
Timepoint [4] 322101 0
Biochemical pregnancy diagnosed by serum hCG at 11-16 days following embryo transfer and ongoing pregnancy diagnosed by ultrasonography at 10-12 weeks gestation.
Secondary outcome [5] 322102 0
Occurrence of severe OHSS by review of medical records
Timepoint [5] 322102 0
Within the first 20 days after triggering final oocyte maturation
Secondary outcome [6] 322103 0
Number of cryopreserved embryos by review of medical records
Timepoint [6] 322103 0
7-8 days after randomisation
Secondary outcome [7] 322104 0
Number of cryopreserved embryos remaining after first embryo transfer by review of medical records
Timepoint [7] 322104 0
After first embryo transfer
Secondary outcome [8] 322105 0
Pre-term labour (defined as delivery <37 weeks of gestation) by review of medical records
Timepoint [8] 322105 0
<37 weeks of gestation
Secondary outcome [9] 322106 0
Mode of delivery (normal vaginal delivery, assisted vaginal delivery, caesarean section) by review of medical records
Timepoint [9] 322106 0
Up to 42 weeks of gestation
Secondary outcome [10] 322107 0
Neonatal birthweight by review of medical records
Timepoint [10] 322107 0
Up to 42 weeks of gestation
Secondary outcome [11] 322108 0
Stillbirth by review of medical records
Timepoint [11] 322108 0
Up to 42 weeks of gestation
Secondary outcome [12] 322109 0
Neonatal mortality by review of medical records
Timepoint [12] 322109 0
Death within the first 28 days of life
Secondary outcome [13] 322110 0
Intrauterine growth restriction by review of medical records
Timepoint [13] 322110 0
Up to 40 weeks of pregnancy
Secondary outcome [14] 322111 0
Hypertensive disorders of pregnancy (including gestational hypertension, pre-eclampsia, eclampsia) by review of medical records
Timepoint [14] 322111 0
Up to 42 weeks go gestation
Secondary outcome [15] 322115 0
Gestational Diabetes Mellitus by review of medical records
Timepoint [15] 322115 0
From 20 weeks of gestation until delivery

Eligibility
Key inclusion criteria
1) Indication for COS and IVF or ICSI with autologous gametes
2) Age: 18-39 years
3) BMI: 18-32 kg/m2
4) Presence of both ovaries
5) Normal menstruating cycles: 21-35 days
6) Cycle where prevention of premature LH rise is achieved using a GnRH antagonist
7) 8-19 follicles equal to or greater than 10mm in mean diameter on the day of triggering
Minimum age
18 Years
Maximum age
39 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Endometriosis Stage>II
2) Indication for PGD/PGS
3) History of OHSS
4) Previous participation in the RCT
5) >3 previous unsuccessful stimulated cycles
6) History of hypothalamic dysfunction or history of inadequate pituitary response to GnRH agonist triggering

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will be randomly allocated to one of the study groups on the day of triggering final oocyte maturation. This allocation will be performed centrally (web-based) using an online database specifically designed for that purpose. Prior to randomization, the nurse will have to enter patient data (unique identifier).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be performed with the use of a list of random numbers produced by dedicated software. Random permutation blocks stratified by each centre participating in this trial will be used.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Study Sample size and power calculations:
Assuming a difference of 15% in live birth rates between the two treatments arms (35% vs. 50%), 183 patients in each group are required using a two-sided Fisher’s Exact test, with an alpha=0.05 and beta=0.20. To account for a ~10% drop-out rate, 200 patients in each group are planned to be randomized.

Statistical Analysis:
Dichotomous data will be expressed as proportions and will be compared between groups with the use of Fisher’s Exact test. Continuous variables will be described with the use of the mean/standard deviation or the median/interquartile range, depending on the normality of the distribution.
An adjusted analysis will also be performed with the use of logistic regression analyses, accounting for the different IVF clinics, the differences in age, BMI and indication for treatment. Exploratory analyses will be performed to assess the potential moderating effect of the quality of embryos on day 5 of embryo culture and levels of serum progesterone on the day of hCG of the stimulated cycle.
Logistic regression analyses will be also employed to explore the potential moderating effect of patient or stimulation characteristics (e.g. endometrial thickness on the day of progesterone initiation in FRET cycles) on live birth rates.
The main analysis will be performed according to the intention-to-treat principle. Per protocol analyses will also be performed.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
27/05/2016
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
400
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC

Funding & Sponsors
Funding source category [1] 293174 0
Commercial sector/Industry
Name [1] 293174 0
IVFAustralia Pty L.t.d.
Country [1] 293174 0
Australia
Funding source category [2] 293175 0
Commercial sector/Industry
Name [2] 293175 0
Melbourne IVF
Country [2] 293175 0
Australia
Funding source category [3] 293447 0
Commercial sector/Industry
Name [3] 293447 0
Virtus Health Limited
Country [3] 293447 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
IVFAustralia Pty L.t.d.
Address
IVFAustralia
Level 3
176 Pacific Highway
Greenwich NSW 2065
Country
Australia
Secondary sponsor category [1] 291969 0
Commercial sector/Industry
Name [1] 291969 0
Melbourne IVF
Address [1] 291969 0
East Melbourne IVF
344 Victoria Parade,
East Melbourne VIC 3002
Country [1] 291969 0
Australia
Secondary sponsor category [2] 292269 0
Commercial sector/Industry
Name [2] 292269 0
Virtus Health Limited
Address [2] 292269 0
Level 3, 176 Pacific Highway
Greenwich NSW 2065,
Australia
Country [2] 292269 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294665 0
IVFAustralia Human Research Ethics Committee
Ethics committee address [1] 294665 0
Ethics committee country [1] 294665 0
Australia
Date submitted for ethics approval [1] 294665 0
25/11/2015
Approval date [1] 294665 0
07/03/2016
Ethics approval number [1] 294665 0
117
Ethics committee name [2] 294666 0
Melbourne IVF Human Research Ethics Committee
Ethics committee address [2] 294666 0
Ethics committee country [2] 294666 0
Australia
Date submitted for ethics approval [2] 294666 0
Approval date [2] 294666 0
24/12/2015
Ethics approval number [2] 294666 0
43/15-MIVF

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64550 0
Dr Christos Venetis
Address 64550 0
IVFAustralia Southern Sydney
Level 3, Suite 15
St George Private Hospital
Kogarah 2217 NSw
Country 64550 0
Australia
Phone 64550 0
+61 2 8567 6955
Fax 64550 0
Email 64550 0
[email protected]
Contact person for public queries
Name 64551 0
Christos Venetis
Address 64551 0
IVFAustralia Southern Sydney
Level 3, Suite 15
St George Private Hospital
Kogarah 2217 NSw
Country 64551 0
Australia
Phone 64551 0
+61 2 8567 6955
Fax 64551 0
Email 64551 0
[email protected]
Contact person for scientific queries
Name 64552 0
Christos Venetis
Address 64552 0
IVFAustralia Southern Sydney
Level 3, Suite 15
St George Private Hospital
Kogarah 2217 NSw
Country 64552 0
Australia
Phone 64552 0
+61 2 8567 6955
Fax 64552 0
Email 64552 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.