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Trial registered on ANZCTR


Registration number
ACTRN12616001539426
Ethics application status
Approved
Date submitted
2/11/2016
Date registered
8/11/2016
Date last updated
17/06/2019
Date data sharing statement initially provided
26/11/2018
Date results information initially provided
4/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of ovarian stimulation on oocyte quality and embryonic aneuploidy: a prospective, randomised controlled trial
Scientific title
Effect of ovarian stimulation on oocyte quality and embryonic aneuploidy in women undergoing IVF: a prospective, randomised controlled trial
Secondary ID [1] 290042 0
Nil known
Universal Trial Number (UTN)
U1111-1186-9969
Trial acronym
STREAM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Subfertility 300091 0
Condition category
Condition code
Reproductive Health and Childbirth 299977 299977 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients undergoing ovarian stimulation will be randomised into a mild and moderate starting dose of gonadotrophins.

Mild stimulation: 150 international units (IU) Menopur subcutaneous injection daily for 7 days starting on Day 2-3 (D2-3) of natural menstruation without oral contraceptive pill (OCP) pretreatment. Gonadotrophin-Releasing Hormone (GnRH) antagonist subcutaneous injection daily to commence Day 5 (D5) of Menopur until trigger criteria reached. Injections administered by fertility nurse with minimum five years' experience or patient under direction of nurse. First bloods and scan Day 5 (D5) of Menopur. Alternate day bloods and scan to monitor response until trigger criteria reached (see below). No dose adjustment allowed. If >16 days follicle stimulating hormone (FSH) without meeting trigger criteria patient withdrawn from study. Patient compliance measured by monitoring remaining gonadotrophin doses from prescription.

Trigger criteria: Leuprolide acetate or triptorelin acetate 0.2mg administered by subcutaneous injection to patients according to treating physician choice within 24 hours of developing 3 follicles of 17mm diameter or greater.

Oocyte Pick Up (OPU): 34-38 hours after trigger. Aspirate all follicles greater than 12mm. Definition of oocyte retrieved equivalent to cumulus oocyte complexes (COCs).

In vitro fertilisation/Intracytoplasmic Sperm Injection (IVF/ICSI) according to unit clinical protocols.

Culture to blastocyst stage then trophectoderm biopsy at D5 or D6 all BB stage or above.

Vitrify all biopsied blastocysts.

Preimplantation genetic screening (PGS): Next-generation sequencing (NGS)-based preimplantation genetic screening using VeriSeq protocol as per Illumina.

Transfer euploid embryos sequentially in frozen cycles with appropriate endometrial preparation.

Overall duration of intervention equivalent to standard IVF cycle and will be abandoned if > 16 days FSH injections without adequate clinical response.
Intervention code [1] 295766 0
Treatment: Drugs
Comparator / control treatment
Moderate stimulation: 300 international units (IU) Menopur subcutaneous injection daily for 7 days starting on Day 2-3 (D2-3) of natural menstruation without oral contraceptive pill (OCP) pretreatment. Gonadotrophin-Releasing Hormone (GnRH) antagonist subcutaneous injection daily to commence Day 5 (D5) of Menopur until trigger criteria reached. Injections administered by fertility nurse with minimum five years' experience or patient under direction of nurse. Dose adjustment permitted from 300IU to 225 IU per day or cancel cycle any day after Day 5 if clinician judges unacceptable risk of ovarian hyperstimulation. First bloods and scan Day 5 (D5) of Menopur. Alternate day bloods and scan to monitor response until trigger criteria reached (see below). If >16 days follicle stimulating hormone (FSH) without meeting trigger criteria patient withdrawn from study. Patient compliance measured by monitoring remaining gonadotrophin doses from prescription.

Trigger criteria: Leuprolide acetate or triptorelin acetate 0.2mg administered by subcutaneous injection to patients according to treating physician choice within 24 hours of developing 3 follicles of 17mm diameter or greater.

Oocyte Pick Up (OPU): 34-38 hours after trigger. Aspirate all follicles greater than 12mm. Definition of oocyte retrieved equivalent to cumulus oocyte complexes (COCs).

In vitro fertilisation/Intracytoplasmic Sperm Injection (IVF/ICSI) according to unit clinical protocols.

Culture to blastocyst stage then trophectoderm biopsy at D5 or D6 all BB stage or above.

Vitrify all biopsied blastocysts.

Preimplantation genetic screening (PGS): Next-generation sequencing (NGS)-based preimplantation genetic screening using VeriSeq protocol as per Illumina.

Transfer euploid embryos sequentially in frozen cycles with appropriate endometrial preparation.

Overall duration of intervention equivalent to standard IVF cycle and will be abandoned if > 16 days FSH injections without adequate clinical response
Control group
Dose comparison

Outcomes
Primary outcome [1] 299458 0
Proportion of euploid embryos per patient assessed by preimplantation genetic screening.
Timepoint [1] 299458 0
Preimplantation genetic screening performed at Day 5-6 of embryo culture.
Secondary outcome [1] 327222 0
Quality of embryos generated using mtDNA copy number.
Timepoint [1] 327222 0
D5 of development (at time of preimplantation genetic screening).
Secondary outcome [2] 328946 0
Safety as measured by ovarian hyperstimulation syndrome (OHSS) resulting in hospitalization, incidence of dose adjustment or cycle cancellation.
Timepoint [2] 328946 0
4 weeks post conclusion of treatment cycle.

Eligibility
Key inclusion criteria
Female age 21- 40 years (randomised before 41st birthday) and projected normal responder based on AMH 8-25 pmol/L on Roche Elecsys measurement, BMI 18.0-35. Additional inclusion criteria include: primary diagnosis of infertility (see exclusion criteria); access to ejaculated sperm suitable for IVF/ICSI (including donor sperm; see exclusion criteria re: severe male factor infertility); trying for pregnancy >12 months before randomization; regular menstrual cycles of 24–35 days; hysterosalpingography, hysteroscopy, or transvaginal ultrasound documenting a uterus consistent with expected normal function; transvaginal ultrasound documenting presence and adequate visualization of both ovaries without evidence of abnormality; the trial cycle being the first or second COS cycle ever or the first or second COS cycle after having achieved pregnancy in a previous COS cycle.
Minimum age
21 Years
Maximum age
40 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Those not meeting the inclusion criteria plus patients with significant pre-existing physical or mental health condition inconsistent with ART, unable to give fully informed consent to participation, requiring PGD for single gene disorders or parental chromosomal abnormalities. Additional: Women with polycystic ovaries (defined as ovarian volume > 10 mL or > 25 follicles per ovary) or endometrioma >2 cm diameter, severe male factor defined as <1million/mL total number sperm per ejaculate; poor response in a previous COS cycle, defined as either >16 days of gonadotropin stimulation, cancellation due to limited follicular response, or development of fewer than four follicles >15 mm; severe ovarian hyperstimulation syndrome (OHSS) in a previous COS cycle; history of recurrent miscarriage; current or past (up to 12 months before randomization); abuse of alcohol or drugs; intake of more than 14 units of alcohol per week during the past month or smoking more than ten cigarettes per day within 3 months before randomization. Use of adjuvants recorded and discouraged.

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)
Central randomisation by phone
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We have powered the study to show a difference in proportion of euploid embryos per group based on the Baart et al. (2007) study. In addition, we will conduct a post-hoc non-inferiority analysis if possible based on the recorded standard deviation (analysis below).

Study Sample size and power calculations:

To show a difference in proportion of euploid embryos from 37% to 55% (moderate stimulation versus mild stimulation, based on Baart et al. 2007) with 0.8 power and 0.05 type 1 error rate the study requires 120 patients per group (240 patients total).

Statistical Analysis:

Depending on the recorded variance our study will be able to demonstrate a non-inferiority margin of 0.75 embryos per patient if SD </= 1.75 based on expected recruitment.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 6557 0
Monash IVF Geelong - Geelong
Recruitment postcode(s) [1] 14155 0
3220 - Geelong

Funding & Sponsors
Funding source category [1] 294411 0
Commercial sector/Industry
Name [1] 294411 0
Ferring Pharmaceuticals
Address [1] 294411 0
1/20 Bridge St,
Pymble
NSW 2073
Country [1] 294411 0
Australia
Primary sponsor type
University
Name
University New South Wales - Medicine
Address
Wallace Wurth Building,
18 High St,
Kensington
NSW 2052
Country
Australia
Secondary sponsor category [1] 293259 0
Commercial sector/Industry
Name [1] 293259 0
Illumina Australia and New Zealand
Address [1] 293259 0
1 International Court
Scoresby, Victoria, 3179
Australia
Country [1] 293259 0
Australia
Secondary sponsor category [2] 293687 0
Commercial sector/Industry
Name [2] 293687 0
Roche Diagnostics
Address [2] 293687 0
108 Power St
Hawthorn VIC 3122
Country [2] 293687 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295830 0
Monash Health HREC
Ethics committee address [1] 295830 0
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Ethics committee country [1] 295830 0
Australia
Date submitted for ethics approval [1] 295830 0
18/07/2016
Approval date [1] 295830 0
07/11/2016
Ethics approval number [1] 295830 0
16317A
Ethics committee name [2] 296371 0
Melbourne IVF
Ethics committee address [2] 296371 0
Suite 4/320 Victoria Parade
East Melbourne VIC 3002
Ethics committee country [2] 296371 0
Australia
Date submitted for ethics approval [2] 296371 0
10/10/2016
Approval date [2] 296371 0
07/11/2016
Ethics approval number [2] 296371 0
49/16-MIVF

Summary
Brief summary
Hypothesis:
Controlled ovarian hyperstimulation using conventional ovarian stimulation leads to a lower proportion of euploid embryos per patient than using mild ovarian stimulation when tested using the gold standard of 24 chromosome screening at D5-D6 of development.

Primary Objective:
To determine and compare the mean proportion of oocytes that develop to provide euploid vitrified blastocysts per patient resulting from conventional vs low dose stimulation protocol.

Secondary Objectives:
Number of euploid vitrified blastocysts per patient, number of 2PN preembryos
generated, total number of embryos surviving to D5-D6 and total number of blastocysts biopsied. Quality of the oocytes generated using conventional vs. low dose stimulation protocols using mtDNA copy number. OHSS resulting in hospitalisation. Incidence of dose adjustment or cycle cancellation.
Trial website
Trial related presentations / publications
Public notes
Other Fertility sites that are participating in this study:
Melbourne IVF
Queensland Fertility Group
Fertility SA
Fertility Specialists of Western Australia
IVF Australia
Care Fertility QLD
Attachments [1] 1076 1076 0 0
Attachments [2] 1077 1077 0 0
Attachments [3] 1930 1930 0 0
Attachments [4] 1931 1931 0 0

Contacts
Principal investigator
Name 68650 0
Prof William Ledger
Address 68650 0
School of Women’s & Children’s Health
UNSW MEDICINE
UNSW SYDNEY NSW 2052 AUSTRALIA
Level 1, Royal Hospital for Women
Barker Street, RANDWICK NSW 2031
Country 68650 0
Australia
Phone 68650 0
+61 2 93826515
Fax 68650 0
+61 2 93826444
Email 68650 0
w.ledger@unsw.edu.au
Contact person for public queries
Name 68651 0
Mrs Rachel Jose
Address 68651 0
School of Women’s & Children’s Health
UNSW MEDICINE
UNSW SYDNEY NSW 2052 AUSTRALIA
Level 1, Royal Hospital for Women
Barker Street, RANDWICK NSW 2031
Country 68651 0
Australia
Phone 68651 0
+61 478726695
Fax 68651 0
+61 2 93826444
Email 68651 0
r.jose@unsw.edu.au
Contact person for scientific queries
Name 68652 0
Dr Tristan Hardy
Address 68652 0
UNSW MEDICINE
UNSW SYDNEY NSW 2052 AUSTRALIA
Level 1, Royal Hospital for Women
Barker Street, RANDWICK NSW 2031
Country 68652 0
Australia
Phone 68652 0
+ 61 426821820
Fax 68652 0
+61 2 93826444
Email 68652 0
tristan.hardy@trainee.ranzcog.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This trial is looking at the number of euploid embryos per dose arm, therefore it is not necessary for IPD to be published. This is a randomised controlled clinical trial with an approved drug, menopur by Ferring Pharmaceuticals.
What supporting documents are/will be available?
Study protocol
Informed consent form
How or where can supporting documents be obtained?
Type [1] 207 0
Study protocol
Citation [1] 207 0
Link [1] 207 0
Email [1] 207 0
Other [1] 207 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary