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Trial registered on ANZCTR


Registration number
ACTRN12618001479291
Ethics application status
Approved
Date submitted
24/08/2018
Date registered
4/09/2018
Date last updated
6/06/2022
Date data sharing statement initially provided
9/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparisons of human embryonic development in culture medium with and without antioxidant supplementation
Scientific title
Comparisons of human embryonic development in culture medium with and without antioxidant supplementation
Secondary ID [1] 295896 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
infertility 309360 0
Condition category
Condition code
Reproductive Health and Childbirth 308228 308228 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
- Participation in this research involves patients agreeing to scientists culturing their embryos in either standard culture media or culture media supplemented with antioxidants.
- The study will compare embryo morphokinetics, blastocyst development and implantation using two different media, G-TL versus G-TL supplemented with antioxidants (10uM Acetyl-L-carnitine (ALC), 10uM N-acetyl-L-cysteine (NAC) and 5uM a-lipoic acid (ALA))
- the supplementation of the antioxidants occurs during media preparation, i.e. prior to gamete collection and fertilization of eggs. Fertilised eggs are then cultured in this media. From day 1 of embryo culture, embryos will be placed in the media to which they have been randomised too.
- The embryologist (scientist) is responsible for administering the intervention
Intervention code [1] 312223 0
Treatment: Other
Comparator / control treatment
The control is embryos cultured in G-TL media (standard of care). The comparator is G-TL supplemented with antioxidants (10uM Acetyl-L-carnitine (ALC), 10uM N-acetyl-L-cysteine (NAC) and 5uM a-lipoic acid (ALA))
Control group
Active

Outcomes
Primary outcome [1] 307196 0
Clinical pregnancy rate per randomised couple.
Clinical records will be used to gather this data for analysis
Timepoint [1] 307196 0
6 weeks post embryo transfer (foetal heart scan)
Secondary outcome [1] 351086 0
Embryo development (time-lapse imaging incubator which will be the tool used to asses embryo development and the Gardner embryo scoring system which is used world-wide will also be used).
Timepoint [1] 351086 0
at day 2 post fertilization of the egg at day 3 post fertilization of the egg at day 4 post fertilization of the egg at day 5 post fertilization of the egg at day 6 post fertilization of the egg and at day7 post fertilisation of the egg
Secondary outcome [2] 351088 0
Embryo quality (time-lapse imaging incubator which will be the tool used to asses embryo development and the Gardner embryo scoring system which is used world-wide will also be used).
Timepoint [2] 351088 0
day 3 post fertilization of the egg day 4 post fertilization of the egg day 5 post fertilization of the egg day 6 post fertilization of the egg and at day 7 post fertilisation of the egg
Secondary outcome [3] 351089 0
Total blastocyst formation (time-lapse imaging incubator which will be the tool used to asses embryo development and the Gardner embryo scoring system which is used world-wide will also be used).
Timepoint [3] 351089 0
day 5 post fertilization of the egg, day 6 post fertilization of the egg and day 7 post fertilisation of the egg
Secondary outcome [4] 351090 0
Utilization rate
Timepoint [4] 351090 0
embryos available for transfer and cryopreservation at day 5, 6 or 7 days post fertilization of the egg
Secondary outcome [5] 351092 0
Clinical pregnancy rate
Timepoint [5] 351092 0
pregnancy blood test (14 days post embryo transfer)
Secondary outcome [6] 351093 0
Neonatal outcomes: gestational age
(data will be collected from medical records)
Timepoint [6] 351093 0
gestational age calculated from date of conception to birth
Secondary outcome [7] 351359 0
neonatal outcome: birth weight
(data will be collected from medical records)
Timepoint [7] 351359 0
calculated at delivery of baby
Secondary outcome [8] 351360 0
neonatal outcomes: congenital abnormalities
(data will be collected from medical records)
Timepoint [8] 351360 0
assessed by paediatrician at delivery of the baby
Secondary outcome [9] 410278 0
Rate of fertilisation (number of 2PN per inseminated oocyte)
Outcome will be assessed by audit of embryology clinical records
Timepoint [9] 410278 0
post egg insemination
Secondary outcome [10] 410279 0
Post vitrification survival (includes embryo quality and day of freezing)
Clinical embryology records will be used to gather this data for analysis
Timepoint [10] 410279 0
at time of embryo thaw procedure the embryo age will be known.
Secondary outcome [11] 410280 0
Biochemical pregnancy rate for all frozen embryo transfers
Clinical records will be used to gather this data for analysis
Timepoint [11] 410280 0
2 weeks post post frozen embryo transfer biochemical pregnancy outcome will be known,
Secondary outcome [12] 410281 0
Embryo quality, euploidy rate, and day of freezing for all embryos that had genetic testing before freezing. Clinical embryology records will be used to gather this data for analysis
Timepoint [12] 410281 0
Genetic testing outcomes are known post assessment of DNA retrieved from biopsied cells of the embryos trophectoderm. On day of embryo thaw (for genetically normal, useable embryos), the embryo age will be known as will the quality of the embryo.
Secondary outcome [13] 410282 0
Clinical pregnancy rate for all frozen embryo transfers
Clinical embryology records will be used to gather this data for analysis
Timepoint [13] 410282 0
6 weeks post embryo transfer the clinical pregnancy outcome will be known
Secondary outcome [14] 410283 0
Birth outcomes (live births, miscarriage rates, still birth or neonatal death, sex, birthweight and gestational age) for all frozen embryo transfers
Clinical records will be used to gather this data for analysis
Timepoint [14] 410283 0
and birth outcomes will be known at delivery
Secondary outcome [15] 410284 0
Pregnancy outcomes (complications or fetal abnormalities) for all frozen embryo transfers for all frozen embryo transfers
Clinical records will be used to gather this data for analysis
Timepoint [15] 410284 0
pregnancy outcomes will be known at delivery
Secondary outcome [16] 410285 0
Biochemical pregnancy rate for all embryos that had genetic testing before freezing.
Clinical and embryology records will be used to gather this data for analysis
Timepoint [16] 410285 0
Genetic testing outcomes are known post assessment of DNA retrieved from biopsied cells of the embryos trophectoderm. 2 weeks post frozen embryo transfer of genetically normal embryos, biochemical pregnancy outcome will be known
Clinical and embryology records will be used to gather this data for analysis
Secondary outcome [17] 410286 0
Clinical pregnancy rate for all embryos that had genetic testing before freezing.
Clinical and embryology records will be used to gather this data for analysis
Timepoint [17] 410286 0
Genetic testing outcomes are known post assessment of DNA retrieved from biopsied cells of the embryos trophectoderm. 6 weeks post embryo transfer of genetically normal embryos, the clinical pregnancy outcome will be known
Secondary outcome [18] 410287 0
Birth outcomes (live births, miscarriage rates, still birth or neonatal death, sex, birthweight and gestational age) for all embryos that had genetic testing before freezing.
Clinical records will be used to gather this data for analysis
Timepoint [18] 410287 0
Genetic testing outcomes are known post assessment of DNA retrieved from biopsied cells of the embryos trophectoderm. Birth and pregnancy outcomes will be known at delivery,
Secondary outcome [19] 410288 0
Pregnancy outcomes (complications or fetal abnormalities) for all embryos that had genetic testing before freezing.
Clinical records will be used to gather this data for analysis
Timepoint [19] 410288 0
Genetic testing outcomes are known post assessment of DNA retrieved from biopsied cells of the embryos trophectoderm. Pregnancy outcomes will be known at delivery

Eligibility
Key inclusion criteria
• Couples with female, male or unexplained infertility intending to undergo IVF or ICSI and where there are no medical contraindications to perform the treatment.
• The couple should have received verbal and written information/consent about the study.
• Blastocyst culture and fresh transfer on day 5 of a single embryo.
• Concomitant medications (eg; use of any oral antioxidants) will be recorded
Minimum age
20 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Previous participation in the study.
• Use of PGS where frozen embryo transfer is planned
• Testicular biopsy patients (TESA/TESE)
• Total freeze and no transfer possible.

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 computer
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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
From retrospective data from pilot studies overseas (Yoshida et al., 2018), which reported an absolute increase in implantation rates of 7% when antioxidants were present in the media, in order to find a difference in 7% in implantation rate between the two media with power 80% with paired T-test 741 couples will be needed in each arm, i.e. 1,482 in total. Implantation rate of embryos is currently 20% across all ages. Data will be analyzed through logistic regression analysis.
Definition of Study Populations
Intention-to-treat analysis (ITT): All randomized subjects will be included in the ITT population.

Full analysis set (FAS): All randomized subjects without missing data for the primary outcome.


Per-Protocol (PP) population: All measurement to subjects in FAS population without significant protocol violation will be included in the PP population.
The final decisions regarding the FAS and the PP population will be taken at the clean file meeting before database lock.

General Statistical Methodology
This is a superiority study and all main analysis will be performed on the ITT population. Complementary analyses will be performed on the FAS and PP population. No imputation will be performed.
For unadjusted comparison between the two randomized groups Fisher’s exact test will be used for dichotomous variables, Fisher’s non-parametric permutation test for continuous variables, Mantel-Haenszel chi-square test for ordered categorical variables and Chi-Square test for non-ordered categorical variables.
If baseline confounders are found, variables that differ between the two randomised group and has a causal relation to the outcome variable, then complementary analyses will be performed adjusted for these variables.
For adjusted comparison between the two randomized groups, multivariable binary regression analysis, with link function = log will be used for dichotomous variables and analysis of covariance for continuous variables.
The most important efficacy analyses both for unadjusted and adjusted analyses will be the calculation of the mean difference between the Antioxidant group and the Control group with 95% Confidence interval (CI). For dichotomous variables relative risk with 95% CI will also be calculated between the randomised groups.
Continuous variable will be described with mean, SD, median, Q1, Q3, minimum and maximum and categorical variables with numbers and percentages.
For analyses on embryo level and blastocyst level where there is more than one observation per woman then descriptive analyses will be given on embryo level and blastocyst level, but the statistical analysis will be adjusted for the dependence within each woman. All significance tests will be two-sided and conducted at the 5% significance level. All analyses will be performed by using SAS® v9.4 (Cary, NC) or later.

Primary efficacy analysis
Primary efficacy analysis will be the unadjusted comparison between the Antioxidant group and the Control group regarding clinical pregnancy per randomized couple with two-sided Fisher’s non-parametric permutation test on ITT at 5% significance level. Mean % difference in percentage clinical pregnancy between the two groups with 95% CI will be given together relative risk (RR) with 95% CI. The proportions of clinical pregnancy within each randomized group will be given with exact 95% CI.
If baseline confounders are found, variables that differ between the two randomized group and has a causal relation with clinical pregnancy, then complementary analyses will be performed adjusted for these variables.

Secondary efficacy analysis
Secondary efficacy analyses will be the analyses of all secondary variables specified above in section “Secondary end points” applied to the statistical methods given in section “General Statistical Methodology” above.

Exploratory Interaction analyses between treatment and baseline variables.
Interaction analyses between baseline variables and treatment for primary efficacy variable and selected secondary variables will be performed. Interactions with p-values<0.1 will be followed up with subgroup analyses.

Interim analysis
Interim analyses will be performed when 50% of the planned patients have been evaluated on the primary endpoint. The result of this interim analysis should not be distributed to anyone outside the steering group, except for the case where the steering committee decides to terminate the study. The primary analysis and selected secondary analyses on the ITT population will be included in the interim analysis.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/10/2018
Actual
28/01/2019
Date of last participant enrolment
Anticipated
31/12/2020
Actual
13/10/2021
Date of last data collection
Anticipated
31/12/2023
Actual
Sample size
Target
1482
Accrual to date
Final
1482
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11713 0
East Melbourne Specialist Day Hospital - East Melbourne
Recruitment postcode(s) [1] 23795 0
3002 - East Melbourne

Funding & Sponsors
Funding source category [1] 300488 0
Commercial sector/Industry
Name [1] 300488 0
Melbourne IVF
Country [1] 300488 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Melbourne IVF
Address
344 Victoria Parade
EAST MELBOURNE VIC 3002
Country
Australia
Secondary sponsor category [1] 299962 0
None
Name [1] 299962 0
Address [1] 299962 0
Country [1] 299962 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301288 0
Melbourne IVF HREC
Ethics committee address [1] 301288 0
Ethics committee country [1] 301288 0
Australia
Date submitted for ethics approval [1] 301288 0
17/04/2018
Approval date [1] 301288 0
21/08/2018
Ethics approval number [1] 301288 0
61/18

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

Contacts
Principal investigator
Name 86502 0
Prof David Gardner
Address 86502 0
Melbourne IVF
344 Victoria Parade
EAST MELBOURNE VIC 3002
Country 86502 0
Australia
Phone 86502 0
+61 3 94734441
Fax 86502 0
Email 86502 0
David.Gardner@mivf.com.au
Contact person for public queries
Name 86503 0
David Gardner
Address 86503 0
Melbourne IVF
344 Victoria Parade
EAST MELBOURNE VIC 3002
Country 86503 0
Australia
Phone 86503 0
+61 3 94734441
Fax 86503 0
Email 86503 0
David.Gardner@mivf.com.au
Contact person for scientific queries
Name 86504 0
David Gardner
Address 86504 0
Melbourne IVF
344 Victoria Parade
EAST MELBOURNE VIC 3002
Country 86504 0
Australia
Phone 86504 0
+61 3 94734441
Fax 86504 0
Email 86504 0
David.Gardner@mivf.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD is against our ethics approval; we have reassured participants that they will not be publically identified and that only aggregate data will be publically available at the conclusion of the study in a peer reviewed journal or for presentation at relevant conferences


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.