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Trial registered on ANZCTR


Registration number
ACTRN12612000422820
Ethics application status
Approved
Date submitted
11/04/2012
Date registered
16/04/2012
Date last updated
16/04/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised study of IVF patients to assess whether freezing all of the embryos and transferring them in a later natural, unstimulated cycle results in a higher pregnancy rate than transferring an embryo 5 days after egg collection
Scientific title
A Randomised Controlled Trial to determine the effect of Elective Embryo Cryopreservation and Subsequent Transfer in a Natural Menstrual Cycle on clinical pregnancy rates in infertile females.
Secondary ID [1] 280294 0
nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infertility 286250 0
Condition category
Condition code
Reproductive Health and Childbirth 286470 286470 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Both study groups will undertake a stimulated IVF cycle.
The first( intervention) group will have all embryos cryostored electively for transfer in a later natural menstrual cycle.
The second group will have the best quality embryo transferred to the endometrial cavity fresh and all remaining embryos cryostored.
The protocol for the second group is standard practice today.
Both groups undertake the same drug regime therefore there is no difference in drug intervention
Intervention code [1] 284647 0
Treatment: Other
Comparator / control treatment
All cycles will be using a standard antagonist protocol - Day 1 FSH <12, Oestrogen < 200pmol/L

Commence FSH stimulation on day 2 of cycle with rFSH (Puregon, Organon) 150 Units +/- 50 Units per day (dose decided by physician based on BMI and age)

Fixed daily dose of Orgalutran 0.25micrograms subcutaneous injection per day commenced on day 5 of stimulation

Estradiol levels will be measured on Day 3/4 and Oestradiol, Progesterone, LH level and follicle measurements on day 8 and 10 of stimulation

FSH and Orgalutran injections continued until there are 2 or more lead follicles greater than 17mm in diameter. On that day Ovidrel Serono 250 micrograms subcutaneous injection will be used to trigger ovulation

Trans-vaginal oocyte collection thirty-six hours after trigger injection under local anaesthetic and sedation or General anaesthetic.

IVF or ICSI in the laboratory as per Genea laboratory protocol

There must be at minimum 2 embryos for cryostorage at 9:00 am on day 5.
One blastocyst will be transferred in the fresh embryo group and vitrification of all other suitable embryos.


All embryos will be vitrified in the elective freezing group.
Luteal phase support with Pregnyl 1500 U subcutaneous injection on day two and six post OPU or Cinone 8% vaginal suppository if judged to be at higher risk of hyper-stimulation syndrome.

All frozen embryo transfers will be in a natural cryo cycle with transfer of a single thawed embryo on
ovulation day +5. Ovulation will be determined by LH surge > 20 IU Endometrial thickness must be >6mm.

The whole cycle will last approximately 28 days
Control group
Active

Outcomes
Primary outcome [1] 286919 0
The primary endpoint is the clinical pregnancy rate in each group, defined as a fetal heartbeat seen on ultrasound at 7 weeks.
Timepoint [1] 286919 0
Outcome is assessed by transvaginal ultrasound at 7 weeks.
Secondary outcome [1] 296990 0
The number of good-quality embryos by assessment of morphology by embryologist
Timepoint [1] 296990 0
At completion of study
Secondary outcome [2] 296991 0
Proportion of subjects in each group that had 2 or more embryos suitable for vitrification
Timepoint [2] 296991 0
At completion of study
Secondary outcome [3] 296992 0
Cumulative clinical pregnancy rates
Timepoint [3] 296992 0
At completion of study
Secondary outcome [4] 296993 0
Implantation rate assessed by positive beta hCG serology on day of pregnancy test.

Clinical miscarriage rate assessed by finding of an intrauterine sac on transvaginal ultrasound but no resulting on going pregnancy
Timepoint [4] 296993 0
At completion of study
Secondary outcome [5] 296994 0
Live birth rates
Timepoint [5] 296994 0
2 years following completion of study
Secondary outcome [6] 296995 0
Perinatal complications of placentation
Timepoint [6] 296995 0
2 years following completion of study
Secondary outcome [7] 296996 0
Blastulation anomalies
Timepoint [7] 296996 0
2 years following completion of study

Eligibility
Key inclusion criteria
Females of infertile couples for whom controlled ovarian stimulation and IVF with or without ICSI is indicated
Age at least 20 years but not more than 38 years at the time of screening
Regular menstrual cycles with a range of 24-33 days
BMI 18-28
AMH 5-20
Minimum age
20 Years
Maximum age
38 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Previous IVF treatment cycle that resulted in <6 follicles on Day 8 ultrasound
More than 2 previous unsuccessful stimulated cycles
History of/or current endocrine abnormality such as polycystic ovary syndrome or evidence of ovarian dysfunction
Any clinically significant abnormal laboratory value (TSH, PRL, SHBG, Test)
Any ovarian and/or abdominal abnormality that would interfere with adequate ultrasound investigation of at least one ovary
Only one ovary
Contra-indications for the use of gonadotrophins
Alcohol or drug abuse, or history thereof, within the 12 months preceding signing informed consent
Smokers

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)
Randomisation will occur at the time of nurse interview by opening an opaque envelope and allocating the patient to one of the 2 treatment groups. The 1st group will have the best embryo transferred in that cycle and all others frozen.
the 2nd group will have all embryos frozen and transferred in a natural frozen cycle at a later date
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using sealed opaque envelope and allocating
the patient to one of the 2 treatment groups dependant on the content of the envelope.
There will be 100 envelopes allocating the patient to treatment in each group
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2012
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 285068 0
Self funded/Unfunded
Name [1] 285068 0
Country [1] 285068 0
Australia
Primary sponsor type
Individual
Name
Mark Livingstone
Address
Level 3,
23 - 25 O'Connell Street,
Sydney
NSW 2000
Country
Australia
Secondary sponsor category [1] 283930 0
Commercial sector/Industry
Name [1] 283930 0
Genea
Address [1] 283930 0
321 Kent Street,
Sydney,
NSW 2000
Country [1] 283930 0
Australia
Other collaborator category [1] 260716 0
Individual
Name [1] 260716 0
Steven MacArthur
Address [1] 260716 0
321 Kent Street,
Sydney,
NSW 2000
Country [1] 260716 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287075 0
Genea ethics committee
Ethics committee address [1] 287075 0
321 Kent Street,
Sydney,
NSW 2010
Ethics committee country [1] 287075 0
Australia
Date submitted for ethics approval [1] 287075 0
Approval date [1] 287075 0
23/03/2012
Ethics approval number [1] 287075 0

Summary
Brief summary
At Genea frozen embryo transfer pregnancy success rates have improved to a level close to fresh embryo transfer success rates. The embryos used in the frozen cycles are the second and third best embryos - as graded for development rate and morphology- compared to the embryos transferred in the fresh cycles when the best quality embryo is selected for transfer to the uterus. The hormone stimulation undertaken prior to oocyte collection may affect the endometrium (uterine lining) - advancing it to a stage whereby the embryo implantation prospect could be impaired and therefore reducing the chance of an ongoing pregnancy. The hypothesis is that freezing of all embryos may help to overcome any reduction in implantation potential by allowing improved synchronisation between the embryo and the endometrium, leading to both higher implantation and pregnancy rates.


There are a number of causes of pregnancy failure following IVF treatment including genetically abnormal embryos, poor quality embryos and potentially a non-receptive uterine environment. The transfer of genetically and morphologically normal embryos into a non-receptive uterine environment will likely not achieve a pregnancy. Generally the suitability of the uterine environment is measured by ultrasound. However such measurement is not able to provide full information on how the uterus has developed under the influence of hormone stimulation drugs used routinely in an IVF treatment cycle.

Genea has extensive experience with vitrification technology having been the first clinic to introduce the procedure into routine clinical practise in Australia, January 2006. Subsequently the technology has been performed routinely in all Genea laboratories following IVF, ICSI and PGD treatment cycles. More than 1000 babies have now been born after vitrification at Genea.

The vitrification procedure used in this study will be applied to embryos cultured at the Genea Kent Street laboratory for 5 days (blastocyst stage).

By vitrifying and NOT TRANSFERRING embryos in “routine” IVF cycle fresh, we wish to see if this will:
increase the chance of fetal heart pregnancy and increase the chance of a live born baby
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34039 0
Address 34039 0
Country 34039 0
Phone 34039 0
Fax 34039 0
Email 34039 0
Contact person for public queries
Name 17286 0
Mark Livingstone
Address 17286 0
23-25 O'Connell Street
Sydney
NSW 2000
Country 17286 0
Australia
Phone 17286 0
+61407325720
Fax 17286 0
+61292323416
Email 17286 0
[email protected]
Contact person for scientific queries
Name 8214 0
Mark Livingstone
Address 8214 0
23-25 O'Connell Street
Sydney
NSW 2000
Country 8214 0
Australia
Phone 8214 0
+61407325720
Fax 8214 0
+61292323416
Email 8214 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

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