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Trial registered on ANZCTR

Registration number

ACTRN12617000230358

Ethics application status

Approved

Date submitted

25/01/2017

Date registered

13/02/2017

Date last updated

25/11/2019

Date data sharing statement initially provided

20/12/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

The impact of pH on fertilisation in human oocytes

Scientific title

The impact of pH on fertilisation in human oocytes retrieved from women receiving ovarian hyperstimulation as part of IVF (in vitro fertilisation) or ICSI (intra-cytoplasmic sperm injection) treatment.

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1182-9015

Trial acronym

n/a

Linked study record

n/a

Health condition

Health condition(s) or problem(s) studied:

IVF

Infertility

Condition category

Condition code

Reproductive Health and Childbirth

Fertility including in vitro fertilisation

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a prospective randomized controlled study. The population to be included as part of this study will be patients already undergoing (having had cycles previously) or about to commence fertility treatment for the first time at Westmead Fertility Centre.
This study will focus on the oocytes collected from these women following ovarian hyperstimulation, which is part of a normal treatment cycle. We will only analyse oocytes from women who have greater than or equal to 8 eggs collected (so that eggs can be randomly assigned to the two different culture pH treatment groups).
Patients undergoing either IVF (in vitro fertilisation) or ICSI (intra-cytoplasmic sperm injection) treatment cycles will be considered for this study. The treatment route (IVF vs. ICSI) is predefined in accordance with the Westmead Fertility Centre protocol, and based on a series of tests (semen analyses etc.) before entering into the study.
The duration of participation is relatively brief as it will be within their treatment cycle, from the point of egg collection that the study commences, and runs until the fertilisation check (approximately 16-19 hours later).
For participants undergoing an IVF cycle, their eggs (in the form of cumulus-oocyte-complexes) will be washed and split evenly between two separate dishes containing different pH G-IVF labelled with A and B. pH of solution A is 7.3 and pH of solution B is 7.45
The eggs will be maintained in the incubator at 37 degrees centigrade and 5 percent CO2 (as standard) until insemination with her partners’ sperm 3-4 hours after egg collection.
Insemination will be using 100,000 sperm (as standard) overnight in the incubator. Fertilisation check will be carried out early morning the next day. Results will be recorded in the WFC database initially, then transferred to the results table for this study.
For participants undergoing an ICSI cycle, the process differs slightly. After egg collection oocytes will be denuded of their surrounding cumulus cells (as standard), split evenly into two separate dishes containing different pH G-IVF labelled A and B (pH of solution A is 7.3 and pH of solution B is 7.45) and left in the incubator at 37 degrees centigrade and 5 percent CO2 for 1 hour to rest (as standard).
After 1 hour, oocytes from dish A will be transferred into ICSI dish A (containing GMOPS media of the same pH, solution A is 7.3 and pH of solution B is 7.45), the spindle will first be visualised and its retardance measured using the Oosight polarised light microscope, before being injected with the partner sperm. The eggs will then be transferred back to a new dish A containing GIVF of the same pH. The same process will be repeated for dish B oocytes. The same embryologist will carry out the ICSI for type A and B eggs.
The eggs will then be placed in the incubator overnight to allow for fertilisation. Fertilisation check will be carried out early morning the next day. Results will be recorded in the WFC database initially, then transferred to the results table for this study.

Intervention code [1]

Treatment: Other

Comparator / control treatment

The control group will be the eggs from the patient which are placed in solution A, as this is at pH 7.3, and the standard pH of media used in our clinic. The eggs which are placed in solution B will act as the treatment group, with the results being compared to those from solution A.

Control group

Active

Outcomes

Primary outcome [1]

Number of eggs fertilised in solution A (control group) will be compared with the number of eggs fertilised in solution B (treatment group). Fertilisation will be compared by positively identifying the presence of two pronuclei inside the egg the day after it has been exposed to sperm (either via in vitro fertilisation or intra-cytoplasmic sperm injection).

Timepoint [1]

16-19hrs post exposure to partner sperm

Secondary outcome [1]

The fertilised eggs will be kept in the lab for upto 5 days for pre-implantation development before they are transferred back to the patients uterus.
The eggs which were fertilised in solution A (control) will be kept separately from the eggs fertilised in solution B (treatment group) throughout the pre-implantation development period. Embryo grading will be performed on all embryos on the day of transfer (as standard) this could be day 2, 3 or 5 of embryo development. Grades will be recorded per embryo to allow for retrospective analysis to understand if pH at the time of fertilisation has an impact on embryo quality.

Timepoint [1]

Embryo grades are awarded on the day of embryo transfer - this may be either 2, 3 or 5 days after fertilisation has taken place (routine practice). The grade will be recorded in the patient notes and then transferred to our secure database.
Embryo grading is carried out using the Gardner Scoring System, which is used universally to score embryos.

Eligibility

Key inclusion criteria

Patients will be asked if they would like to participate if they present for fertility treatment at WFC and fulfil the following:
1) Good understanding/ability of English language to enable them to give an informed consent
2) Less than 42 years old at the time of her treatment cycle
3) Equal to or greater than 8 oocytes collected
4) No more than one prior failed fresh cycle at WFC
5) Heterosexual and same sex couples will be offered to take part

Minimum age

18 Years

Maximum age

41 Years

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

Patients will be excluded from this study if;
1) There is severe male factor infertility requiring sperm extraction via microdissection/open biopsy (PESA/TESA patients can be included)
2) A prior history of poor fertilisation (less than 50 percent oocytes fertilising normally)
3) Oncology patients
4) Unable to speak English without assistance of an interpreter

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)

For IVF cases, allocation is not concealed as the eggs will be split evenly between solution A (control) and solution B (treatment). In cases where there is an odd number of eggs the embryologist will randomly decide whether the extra egg goes in solution A or B.
For ICSI cases, allocation concealment will be applied when the embryologist has to divide the eggs into either solution A (control) or solution B (treatment pH). Eggs will be washed first and all placed together in a single dish, eggs will then be denuded using hyaluronic acid (as per standard treatment).
After denudation eggs will be randomly split into dish A or dish B based on the number of MII (mature).
MI eggs (not yet mature) will be assigned a number from a random generator (www.random.org) and if an even number is generated then they will be assigned to dish A, if odd then dish B. From this point eggs will remain either A or B and left for one hour in the incubator prior to injection with partner sperm.
ICSI will be carried out in either an A or B dish, with eggs being transferred to either an A or B GIVF dish for incubation overnight to allow for fertilisation.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

www.random.org will be used to assign eggs to A or B (even numbers Group A and odd numbers Group B).

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people administering the treatment/s

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

The primary outcome of fertilisation rate in both treatment groups will be analysed using Fisher’s non-parametric permutation test for paired observations.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

6/03/2017

Actual

10/04/2017

Date of last participant enrolment

Anticipated

28/08/2020

Actual

Date of last data collection

Anticipated

28/08/2020

Actual

Sample size

Target

300

Accrual to date

240

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Westmead Hospital - Westmead

Recruitment postcode(s) [1]

2145 - Westmead

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Westmead Fertility Centre

Address [1]

G Block, Level 2
Westmead Hospital
Westmead
NSW 2145

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Westmead Fertility Centre

Address

G Block, Level 2
Westmead Hospital
Westmead
NSW 2145

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry Limited

Ethics committee address [1]

129 Glen Osmond Road Eastwood South Australia 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/06/2016

Approval date [1]

12/07/2016

Ethics approval number [1]

2016-01-055

Summary

Brief summary

This study is being undertaken to test the hypothesis that the pH of the media used to hold human eggs during IVF treatment can impact fertilisation rates
We propose that pH has a profound effect on the assembly and functioning of a component of the egg called the spindle. We have already demonstrated this in mice.
We believe that incorrect spindle function can cause lower than expected fertilisation rates, and should fertilisation occur the resulting embryo is of poorer quality. Therefore if pH can effect the spindle, it could have an effect on overall fertilisation. 	
This has significant relevance for the culture systems utilised in IVF clinics worldwide.
pH is the term used to describe the balance of acidity (+) and alkalinity (-) of a liquid. The pH scale is from 1-14. If a liquid produces more hydrogen (H+) it is an acid, if it produces more hydroxide (OH-) it is an alkaline. 
A liquid with a low pH value (less than 7) has lots of hydrogen and is described as acidic, an example of an acidic liquid is lemon juice.
A liquid with a high pH value (more than 7) has lots of hydroxide and is described as alkaline, an example of an alkaline substance is bleach or most cleaning products.
A liquid which has an equal amount of hydrogen and hydroxide is described as neutral, with a pH of 7. Pure water is usually neutral.
The pH inside the human body varies, however the pH of the environment in the ovaries and reproductive tract is slightly alkaline. This is the usual pH of the liquid in which we keep eggs in when they are outside the body. 
In our laboratory we use media and products from a company called Vitrolife. We will be investigating 2 of their solutions which have been specially manufactured by Vitrolife to be at 2 distinctly different pHs – one at pH 7.2 (the normal pH used in our laboratory), the other will be pH 7.4 (this level is used by some other clinics around the world). 
We intend to determine which is the optimum pH level to give us the highest rates of fertilisation so that we can try and achieve better results for our patients in the future.

Trial website

n/a

Trial related presentations / publications

n/a

Public notes

n/a

Attachments [1]

/AnzctrAttachments/371354-ApprovalLetter-HREC2016-01-055.pdf (Ethics approval)

Contacts

Principal investigator

Name

Dr Cecilia Sjoblom

Address

Westmead Fertility Centre
Westmead Hospital
G Block, Level 2
Westmead NSW 2145

Country

Australia

Phone

+61 2 9845 7484

Fax

cecilia.sjoblom@sydney.edu.au

Contact person for public queries

Name

Harriet Swearman

Address

Westmead Fertility Centre
Westmead Hospital
G Block, Level 2
Westmead NSW 2145

Country

Australia

Phone

+61412874668

Fax

Hswe5346@uni.sydney.edu.au

Contact person for scientific queries

Name

Harriet Swearman

Address

Westmead Fertility Centre
Westmead Hospital
G Block, Level 2
Westmead NSW 2145

Country

Australia

Phone

+61412874668

Fax

Harriet.swearman@gmail.com

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Data is anonymised

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.

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