Condition category
Pregnancy and Childbirth
Date applied
04/04/2018
Date assigned
18/04/2018
Last edited
05/07/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Suspended

Plain English Summary

Background and study aims
In vitro fertilisation (IVF) techniques can help people with fertility problems to have a baby. In IVF an egg is fertilized by sperm in a test tube to create an embryo. The current methods of selecting the best embryo for replacement into the womb during IVF are imprecise. The resulting success rates for this expensive treatment are less than ideal. Success rates might be improved by a new technology that uses time-lapse imaging, where embryos are grown in a special incubator, and an inbuilt microscope and camera allows embryos to be assessed without having to remove them. In addition, images of the developing embryo are taken every five to fifteen minutes, which can give additional information (morphokinetic parameters) to aid selection. The aim of this study is to find out whether this technology increases the likelihood of live birth following fertility treatment.

Who can participate?
Couples undergoing IVF or ICSI (Intra-Cytoplasmic Sperm Injection) treatment, where the woman is between 18 and 42 years of age and the male partner is at least 18 years of age

What does the study involve?
Participants are randomly allocated to one of three treatment groups. In the first group embryos are grown in the time-lapse incubator using time-lapse imaging for embryo selection. In the second group embryos are grown in the time-lapse incubator using only standard assessment techniques. In the third group embryos are grown in standard incubators. At the end of the incubation (3-6 days after egg collection), the best embryo(s) are transferred. The woman is then followed up until a maximum of 6 weeks after the end of the pregnancy. The number of live births is taken from the patients’ medical notes or by contacting the participant.

What are the possible benefits and risks of participating?
There is no guarantee that taking part in this study will increase the chances of IVF/ICSI being successful, but participants will be helping clinicians and policy makers decide whether current IVF/ICSI guidelines need to be changed. There is no added risk using this technology for the growth and monitoring of embryos. The camera captures embryos in red light for a very short period of time – 15 milliseconds. This is the same amount of light exposure as during manual removal of embryos from the standard incubator and their examination under a standard microscope. The time lapse imaging systems are CE marked.

Where is the study run from?
Barts Research Centre for Women’s Health, Women’s Health Research Unit, Queen Mary University of London, James Cook University Hospital (UK) and The Chinese University of Hong Kong Prince of Wales Hospital (Hong Kong)

When is the study starting and how long is it expected to run for?
September 2017 to August 2021

Who is funding the study?
1. Barts and the London Charity and Related Charities (UK)
2. Pharmasure Ltd (UK)

Who is the main contact?
1. James Heighway
j.heighway@qmul.ac.uk
2. Priya Bhide
priya.bhide@nhs.net

Trial website

https://www.barc-research.org/tilt

Contact information

Type

Scientific

Primary contact

Mr James Heighway

ORCID ID

Contact details

Barts Research Centre for Women’s Health
Institute of Population Health Sciences
Queen Mary University of London
Yvonne Carter Building
58 Turner Street
London
E1 2AB
United Kingdom
+44 (0)20 7882 3272
j.heighway@qmul.ac.uk

Type

Scientific

Additional contact

Dr Priya Bhide

ORCID ID

http://orcid.org/0000-0003-0871-6508

Contact details

Centre for Women's Health
Institute of Population Health Sciences
Bart's and the London School of Medicine and Dentistry
Queen Mary University of London
Yvonne Carter Building
58 Turner Street
London
E1 2AB
United Kingdom
-
priya.bhide@nhs.net

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

37510

Study information

Scientific title

A pragmatic, multi-centre, three-arm randomised controlled trial to assess the clinical effectiveness and safety of time lapse imaging in in-vitro fertilisation treatment

Acronym

TILT

Study hypothesis

Current methods of selecting the best embryo for replacement into the womb during in-vitro fertilisation treatment (IVF) are imprecise. The resulting success rates for this expensive treatment are less than ideal. Success rates might be improved by a new technology that uses time-lapse imaging, where embryos are grown in a special incubator, and an inbuilt microscope and camera allow embryos to be assessed without having to remove them. In addition, images of the developing embryo are taken every five to fifteen minutes, which can give additional information (so-called morphokinetic parameters) to aid selection. Current best evidence for the use of time-lapse imaging is uncertain and of moderate to low quality. The trialists propose to conduct a large-scale study giving high-quality evidence and a definitive answer to whether this technology increases the likelihood of live birth following fertility treatment.

Ethics approval

London Central Research Ethics Committee, provisional approval 08/03/2018, ref: 18/LO/0330

Study design

Randomised; Interventional; Design type: Treatment, Device

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

In vitro fertilization

Intervention

A secure, web based randomisation system hosted by the Barts Women’s Health Research Centre. The randomisation will be stratified by fertility clinic, and minimised by:
1. Participant’s age (<35 years, 35 – 40 years, >40 years)
2. Type of planned first embryo transfer (fresh, frozen).

Participants are randomly allocated to one of three treatment groups:
Time-lapse imaging (intervention group 1): incubation and assessment of embryos within time-lapse imaging systems, using morphokinetic parameters in addition to conventional morphological assessment
Undisturbed culture (intervention group 2): incubation of embryos in undisturbed culture conditions within time-lapse imaging incubators, using conventional morphological embryo assessment only
Standard care (control group): incubation of embryos in standard incubators, using conventional morphological embryo assessment only

At the end of the incubation (3-6 days after egg collection), the best embryo(s) will be transferred. The woman will then be followed up until a maximum of 6 weeks after the end of the pregnancy.

The sample size calculation was based upon the primary outcome of live birth. With a 5% overall significance level (2.5% for each of the two main treatment comparisons: TLI vs. standard care, and undisturbed culture vs. standard care), 514 participants would be required per treatment arm to detect an absolute increase in the primary outcome from 26.5% to 35.25% with 80% power. Allowing for 2% loss-to-follow-up or withdrawal of consent would require 525 participants per treatment arm (1575 in total). The comparison between experimental treatment arms (TLI vs. undisturbed culture) will be performed with no impact on sample size because this statistical test will be carried out conditional to the rejection of at least one of the primary comparisons planned (TLI vs. standard care, or undisturbed culture vs. standard care). This hierarchical approach permits to maintain the overall type I error rate of 5%.

Intervention type

Other

Phase

Drug names

Primary outcome measure

Number of live births, taken from medical notes/contacting the participant; Timepoint(s): Delivery

Secondary outcome measures

Current secondary outcome measures as of 06/04/2020:
Clinical efficacy outcomes:
1. Pregnancy rate measured by pregnancy test taken from medical notes; Timepoint(s): 2 weeks after embryo transfer
2. Successful implantation of embryo(s) into womb measured by total number of gestational sacs seen on ultrasound scan/total number of embryos replaced into the womb taken from medical notes; Timepoint(s): 6-8 weeks after embryo transfer.
3. Successful clinical pregnancy measured by at least one intrauterine gestational sac taken from medical notes/contacting the participant; Timepoint(s): 6-8 weeks after embryo transfer
4. Use of elective single embryo transfer (e-SET) recorded per participant, taken from medical notes; Timepoint(s): At embryo transfer
5. Embryo utilization rate (% of total embryos either transferred or frozen), taken from medical notes; Timepoint: 2-6 days after date of fertilisation check.

Clinical safety outcomes:
1. Multiple pregnancy measured by two or more gestational sacs seen on ultrasound scan taken from medical notes/contacting the participant; Timepoint(s): 6-8 weeks after embryo transfer
2. Pregnancy loss recorded from medical notes/contacting the participant; Timepoint(s):
2.1. Between positive pregnancy test and 6-8 week scan
2.2. Between 6-8 week scan and 12 weeks (early miscarriage)
2.3. Between 12 and 24 weeks
2.4. Stillbirth
3. Incidence of major congenital abnormality at birth recorded as a Serious Adverse Event taken from medical notes/contacting the participant; Timepoint(s): Within 6 weeks of delivery
4. Birth weight, taken from medical notes; Timepoint: Delivery
5. Gestational age, taken from medical notes; Timepoint: Delivery
6. Ectopic pregnancy, taken from medical notes/contacting the participant; Timepoint(s): early pregnancy scan (6-8 weeks) & 24 weeks assessment

Previous secondary outcome measures:
Clinical efficacy outcomes:
1. Pregnancy rate measured by pregnancy test taken from medical notes; Timepoint(s): 2 weeks after embryo transfer
2. Successful implantation of embryo(s) into womb measured by total number of gestational sacs seen on ultrasound scan/total number of embryos replaced into the womb taken from medical notes; Timepoint(s): Two weeks after embryo transfer
3. Successful clinical pregnancy measured by at least one intrauterine gestational sac taken from medical notes/contacting the participant; Timepoint(s): 6-8 weeks after embryo transfer
4. Use of elective single embryo transfer (e-SET) recorded per participant, taken from medical notes; Timepoint(s): At embryo transfer

Clinical safety outcomes:
1. Multiple pregnancy measured by two or more gestational sacs seen on ultrasound scan taken from medical notes/contacting the participant; Timepoint(s): 6-8 weeks after embryo transfer
2. Miscarriage recorded for each pregnancy loss taken from medical notes/contacting the participant; Timepoint(s): Between 6 and 24 weeks gestation
3. Stillbirth recorded as pregnancy loss taken from medical notes/contacting the participant; Timepoint(s): After 24 weeks gestation
4. Incidence of major congenital abnormality at birth recorded as a Serious Adverse Event taken from medical notes/contacting the participant; Timepoint(s): Within 6 weeks of delivery

Overall trial start date

01/09/2017

Overall trial end date

31/08/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

The inclusion criteria are broad in keeping with the latest NICE guidelines (2013) for NHS funded IVF/ICSI treatment.
Participants undergoing IVF/ICSI treatment and:
1. The woman is between 18 and 42 years of age at the time of consent
2. The male partner is at least 18 years of age at the time of consent
3. Receiving the first, second or third IVF/ICSI treatment cycle
4. Both partners give written informed consent
5. Those having at least 3 2PN embryos (showing 2 pro-nucleii which is a sign of normal fertilisation) on day of fertilization check

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 1575; UK Sample Size: 1125, CUHK Sample Size: 450

Participant exclusion criteria

Current exclusion criteria as of 06/04/2020:
1. Participants concomitantly participating in other interventional trials
2. IVF/ICSI treatment using donor gametes
3. Planned pre-implantation genetic diagnostics or screening (PGS/PGD)

Previous exclusion criteria:
1. Participants who have been randomised previously to this trial
2. Participants concomitantly participating in other trials
3. IVF/ICSI treatment using donor gametes
4. Planned pre-implantation genetic diagnostics or screening (PGS/PGD)

Recruitment start date

01/05/2018

Recruitment end date

30/05/2020

Locations

Countries of recruitment

Hong Kong, United Kingdom

Trial participating centre

Homerton University Hospital
Homerton Row
London
E9 6SR
United Kingdom

Trial participating centre

St Bartholomews Hospital
Centre for Reproductive Medicine 1st Floor, Kenton & Lucas Wing West Smithfield
London
EC1A 7BE
United Kingdom

Trial participating centre

Bath Fertility Centre
Roman Way Bath Business Park Peasedown St John
Bath
BA2 8SG
United Kingdom

Trial participating centre

Hammersmith Hospital
Du Cane Road White City
London
W12 0HS
United Kingdom

Trial participating centre

Complete Fertility Centre- Princess Anne Hospital
Mailpoint 105, Level G Coxford Road
Southampton
SO16 5YA
United Kingdom

Trial participating centre

Ocean Suite- Derriford Hospital
South West Centre for Reproductive Medicine Ocean Suite, Level 6 Derriford Hospital
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
United Kingdom

Trial participating centre

Assisted Reproductive Technology (ART) Unit
Department of Obstetrics & Gynaecology The Chinese University of Hong Kong 9F, Special Block EF Prince of Wales Hospital
Shatin, N.T.
-
Hong Kong

Sponsor information

Organisation

Queen Mary University of London

Sponsor details

QMUL Joint Research Management Office
Lower Ground Floor
5 Walden Street
London
E1 2EF
United Kingdom
+44 (0)20 7882 7275
sponsorsrep@bartshealth.nhs.uk

Sponsor type

Hospital/treatment centre

Website

http://www.jrmo.org.uk/

Organisation

Chinese University of Hong Kong

Sponsor details

1/F
Special Block
Department of Obstetrics and Gynaecology
Prince of Wales Hospital
Shatin
-
China
+852 (0)35052800
tinchiu.li@gmail.com

Sponsor type

University/education

Website

http://www.cuhk.edu.hk/english/index.html

Funders

Funder type

Charity

Funder name

Barts and the London Charity and Related Charities; Grant Codes: MGU0374

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Pharmasure Ltd

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

The Chief Investigator (CI) will have primary responsibility and co-ordinate dissemination of data from this trial. A core team consisting of the co-applicants will work closely with QMUL to plan and effectively disseminate the findings of the research to all stakeholders: participants, clinical community, user groups, funding bodies, NHS commissioners and the general public. The clinical trial report and the main manuscript will be reviewed by the Clinical Investigators Group and Trial Steering Committee before publication.

Dissemination to clinicians and clinical professional bodies will be through publications and presentations at major national and international conferences relevant to the speciality. The aim is to publish the findings in the highest impact peer reviewed journals and present them at the annual conferences related to the speciality. The trialists plan to publish the study protocol in an open access journal and to communicate the trial findings to the Cochrane Gynaecology and Fertility Group with a view to incorporate the results into the current Cochrane review.

Dissemination to the participants and the general public will be done through newsletters, NHS websites and through the meetings and websites of local PPI networks and Fertility Networks UK. In consultation with the investigators and appropriate journals, a press release will be issued to the media upon publication of the results.

IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from the CI Dr Priya Bhide (p.bhide@qmul.ac.uk). There will be restrictions on the availability of raw data for this study, due to data confidentiality and patient privacy. Researchers wishing to access the TILT trial data for the purposes of replicating or verifying our analyses can apply to the CI at the BARC (Barts Research Centre for Women’s Health).

Intention to publish date

01/08/2022

Participant level data

Available on request

Basic results (scientific)

Publication list

2020 protocol in https://pubmed.ncbi.nlm.nih.gov/32611445/ (added 05/07/2020)

Publication citations

Additional files

Editorial Notes

05/07/2020: Publication reference added. 06/04/2020: The following changes were made to the trial record: 1. Due to current public health guidance, recruitment for this study has been paused. 2. Trial website added. 3. Contact details, secondary outcome measures and exclusion criteria updated. 4. The target number of participants was changed from 'Planned Sample Size: 1575; UK Sample Size: 1575' to 'Planned Sample Size: 1575; UK Sample Size: 1125, CUHK Sample Size: 450'. 5. James Cook University Hospital and The Chinese University of Hong Kong Prince of Wales Hospital were added to the trial participating centres. 6. Chinese University of Hong Kong was added as a sponsor. 7. The recruitment end date was changed from 30/06/2020 to 30/05/2020. 07/08/2019: The following changes were made to the trial record: 1. The following trial participating centres were added: St Bartholomews Hospital, Bath Fertility Centre, Hammersmith Hospital, Complete Fertility Centre- Princess Anne Hospital, Ocean Suite- Derriford Hospital. 2. The recruitment end date was changed from 01/05/2020 to 30/06/2020. 3. The plain English summary was updated to reflect these changes. 27/03/2019: The condition has been changed from "Specialty: Reproductive health and childbirth, Primary sub-specialty: Other; UKCRC code/ Disease: Reproductive Health and Childbirth/ Other maternal disorders predominantly related to pregnancy" to "In vitro fertilization" following a request from the NIHR.