Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05896709 |
| Other study ID # |
2022.661 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
July 17, 2023 |
| Est. completion date |
December 2026 |
Study information
| Verified date |
March 2024 |
| Source |
Chinese University of Hong Kong |
| Contact |
PUI WAH JACQUELINE CHUNG |
| Phone |
+852 35051537 |
| Email |
jacquelinechung[@]cuhk.edu.hk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
During assisted reproductive technology treatment, embryo selection is an important process
that may affect the clinical pregnancy rate. Many assisted reproductive technology units over
the world have tried different approaches to increase the clinical pregnancy rate.
Conventionally, the morphology of the embryo is assessed by the embryologist with naked eyes
only. Nowadays, artificial intelligence (AI) has been used to assist in morphological
assessment of the embryo. Our pilot study showed that the AI-enhanced morphokinetic (MK)
analysis increased the accuracy in embryo selection by ~9%, while the detection rate for
abnormal chromosomes in embryo has also been increased by Raman spectroscopy (RS) analysis.
The combined MK-RS analysis will be able to complete embryo assessment within 5-6 days after
fertilization. This method needs shorter time and is at lower cost when compared to invasive
preimplantation genetic testing for aneuploidies (PGT-A).
In this study, we have combined the following non-invasive techniques to assist in embryo
screening.
1. Using time-lapse imaging (i.e. images of embryo being taken every 10 minutes inside the
incubator) with AI)-enhanced MK analysis to assess the entire morphological changes of
the embryo.
2. As the embryo releases metabolites during its growth, the spent culture medium will be
collected after culture of the embryo and then be used for RS analysis, which is a kind
of metabolomics-based non-invasive PGT-A, for screening chromosomal abnormalities of the
embryo.
This study will include two phases. In Phase I, it is a retrospective part. We will collect
data to train the convolutional neural network (CNN)-enhanced MK with RS method on embryo
selection, leading to the integrated approach (MK-RS). In Phase II, it is a randomized
controlled trial and participants will be randomised into 2 groups. For the experimental
group, embryo selection will be based on the MK-RS method, whereas embryo selection for the
control group will rely on the traditional embryo assessment results alone. Then we will
assess the clinical pregnancy rate and evaluate the efficacy of our approach finally.
Patients who receive in vitro fertilisation (IVF)/ intracytoplasmic sperm injection (ICSI)
treatment from The Assisted Reproductive Technology (ART) Unit of The Chinese University of
Hong Kong, Prince of Wales Hospital will be recruited.
Description:
Our study will include two phases. In Phase I (a retrospective study), archived data will be
collected to train the CNN-enhanced MK with RS method on embryo selection, leading to the
integrated approach (MK-RS). In Phase II (a prospective study), the integrated MK-RS method
established will be used to select embryos, assess the clinical pregnancy rate and evaluate
the efficacy of our approach in a randomized controlled trial.
In Phase I, images of the embryo will be captured every 10 minutes by the in-built microscope
and camera in the time-lapse incubator. Images will then be assessed by the CNN algorithm for
day one human embryo segmentation to identify three distinct features: the zona pellucida
(ZP), cytoplasm and pronucleus (PN). The morphodynamics of these three features during the
fertilisation to first division will be wrapped up as time series data for the integration.
The morphology changes after the first division will be semi-auto annotated, which will be
analysed by the commercial MK scoring system (KID Score).
After removal of embryos/blastocysts from the culture dish, the corresponding spent culture
medium (SCM) will be collected in sterile polymerase chain reaction (PCR) tubes. Blank
culture mediums will also be collected with the same operating standard. A specifically
designed sampler will be used to pipette 7μL SCM of each sample, passing through the oil
layer of the SCM, and then drop it onto a disposable quartz glass slide and illuminated by RS
system (Basecare Raman 200, China). The RS system will be calibrated to 520.5 cm-1 by silicon
wafer before testing. Laser excitation parameters are set as follows: 785 nm wavelength, 320
mW power and 100 μm laser spot diameter. Signals are captured in standard mode with a
chargecoupled device (CCD) camera with a 20-seconds integration time. Three replicates will
be done for each aliquot. Re-calibration is essential when different culture media is tested,
considering that G-1 medium is used for embryos before Day 3 and G-2 medium is used for
embryos after Day 3. All obtained spectra will be pre-processed by subtracting the background
signal. Spectroscopy signals within the near-infrared region (600 cm-1- 1800 cm-1) are
analysed for vector normalisation using Labspec 6 software (Horiba, Japan). Our previous SCM
samples with known TE ploidy results will be used as a training dataset to establish
euploid-aneuploid classification standards. Stacking classification algorithm will be
adopted, considering its high overall accuracy (95.9%, unpublished data).
As the segmented time series of CNN algorithm, KID Score annotations and RS profiling results
have hundreds of subparameters, we will assemble them together with the ensemble learning,
which considers each subparameter as a weak classifier and re-allocated their weights during
the training. The primary index for the training is the clinical pregnancy outcome and for
the ultimation of the information beneath CNN-enhanced MK and RS, the blastocyst formation
results will be used as a secondary index. The ratio of the training set and test set will be
1:1 and in the training set, a 5-fold cross-validation will be performed for monitoring the
overfitting.
Phase II will comprise a prospective, single-blinded, randomised controlled trial designed to
validate the trained MK-RS method for embryo selection. Metabolomic SCM profiling using RS
with CNN-enhanced MK analysis will be used to assess embryo developmental potential along
with traditional morphological embryo assessments. The embryo developmental potential results
will be used to select the best quality of embryos. Sensitivity and specificity will be
assessed using the patient's TE biopsy or non-invasive prenatal testing (NIPT) results will
further confirm the scoring of MK-RS method, if available.
Randomisation:
In Phase II, participants who fulfil all the inclusion and exclusion criteria and consent to
join the study will be randomised into experimental group and control group in 1 to 1 ratio
using a computer-generated randomisation list. For the experimental group, embryo selection
will be based on the MK-RS method established in Phase I, whereas embryo selection for the
control group will rely on the traditional embryo morphology grading results alone. All
participants will be blinded in this trial.
