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Trial registered on ANZCTR


Registration number
ACTRN12620001180909p
Ethics application status
Submitted, not yet approved
Date submitted
8/09/2020
Date registered
9/11/2020
Date last updated
9/11/2020
Date data sharing statement initially provided
9/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
VAlidation of Non-invasive fetal ECG monitor in high risk pregnancies (VANIE) - Pilot study
Scientific title
VAlidation of Non-invasive fetal ECG monitor in high risk pregnancies (VANIE) - Pilot study
Secondary ID [1] 302237 0
None
Universal Trial Number (UTN)
U1111-1257-9658
Trial acronym
VANIE Pilot Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pregnancy 318949 0
High risk pregnancy 319357 0
Condition category
Condition code
Reproductive Health and Childbirth 316920 316920 0 0
Antenatal care
Reproductive Health and Childbirth 317315 317315 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Non invasive monitoring of pregnant women of at least 28 weeks' gestation with a new device known as 'Femom' which utilises abdominal electrocardiogram as a basis for operation. For data collection, the device connects to 5 wet-gel electrodes which will be attached to the abdomen of the participating pregnant woman. The device will measure maternal and fetal physiologic parameters and uterine activity, on one occasion per women, for a minimum of 20 minutes.
Participating women will be concomitantly monitored with the cardiotocograph (CTG), currently standard care.
The intervention will be administered by registered midwives employed by the clinical site (Royal North Shore Hospital) to conduct fetal monitoring as deemed necessary by treating obstetricians at the site.
The intervention will be delivered in the Day Assessment Unit at the Royal North Shore Hospital where women routinely receive fetal monitoring during pregnancy.
Intervention code [1] 318527 0
Diagnosis / Prognosis
Comparator / control treatment
The comparator is the cardiotocograph (CTG), currently standard care. The Femom is the intervention. The two devices will be worn concomitantly by each participating woman, Measurements will be compared to demonstrate non-inferiority of the Femom. Only the CTG will be used to make clinical decisions about the woman and her fetus.
Control group
Active

Outcomes
Primary outcome [1] 325026 0
Assessment of mean differences and limits of agreement of fetal heart rate output from Femom and CTG.
Timepoint [1] 325026 0
Mean fetal heart rate will be estimated for 0.25 second segments of data for each participant using outputs obtained from Femom and CTG through digital processing for a 20 minute session of monitoring collected from each participant.
Primary outcome [2] 325027 0
Assessment of mean differences and limits of agreement of maternal heart rate output from Femom and CTG.
Timepoint [2] 325027 0
Mean differences and limits of agreement in maternal heart rate will be assessed
for each participant using outputs obtained from Femom and CTG through digital processing for a 20 minute session of monitoring collected from each participant.
Primary outcome [3] 325030 0
Assessment of mean differences and limits of agreement of STV output from Femom and CTG for a 20 minute session of monitoring collected from each participant.
Timepoint [3] 325030 0
Mean differences in STV will be assessed will be estimated using 3.75 second epochs of data for each participant using outputs obtained from Femom and CTG through digital processing for a 20 minute session of monitoring collected from each participant.,Test validity will be based on an assessment of the similarity.
Secondary outcome [1] 386589 0
Assessment of Positive Percent Agreement of the uterine activity measurements from Femom and CTG.
Timepoint [1] 386589 0
Mean differences and limits of agreement in uterine activity will be assessed
for each participant using outputs obtained from Femom and CTG through digital processing for a 20 minute session of monitoring collected from each participant.,

Eligibility
Key inclusion criteria
Singleton pregnancy
At or above 28 weeks' gestation.
Able to understand English or have access to an interpreter
Able to provide informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Multiple pregnancy
Below 18 years of age
Intellectual impairment
Known allergy or sensitivity to ECG gel electrodes
In labour, experiencing painful contractions
Known fetal cardiac or genetic abnormality
Pacemaker

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
FHR, MHR, UA and STV from each femom and CTG trace will be extracted, with CTG as the reference standard. Clinical decision making will not be undertaken on the output from femom; the femom data will be extracted retrospectively for analysis and will not influence routine clinical care. The magnitude of the differences in overall values between devices will be assessed using a Bland-Altman (B-A) plot showing the mean difference and giving 95% limits of agreement (LoA). The LoA are calculated as (d ) ¯±1.96s_d, where (d ) ¯ is the sample mean difference and s_d is the sample standard deviation of the differences. 95% of differences in STV values are expected to fall within the limits of agreement.
Sufficiently precise estimates of the B-A LoA are critical to the assessment of device comparability and will depend primarily on estimating the standard deviation of the differences with high precision.
Data inclusion criteria for statistical analysis is as follows:
femom and CTG traces for comparison are at least 20 minutes long each.

The primary endpoint will be determining the mean difference and Limits of Agreement (LoA) for FHR (bpm) between femom and the CTG. Mean FHR will be estimated for each participant using outputs obtained from femom, CTG in a manner consistent with actual clinical practice. Differences in mean FHR between devices will be calculated and (i) presented as a Bland-Altman plot (ii) plotted against a 45 degree line in a scatter plot and (iii) a straight line fitted to the data (non-parametric) Passing-Bablok regression which takes into account measurement deviations in both femom and CTG values.
In addition, as another measure of device concordance for FHR, outputs on femom and CTG will be measured and compared electronically using the Percentage Positive Agreement (PPA) method. The FHR output file from the CTG is processed to generate a timeline plot of FHR data, in which epochs with no data (due to signal loss) are removed to create interpretable FHR data. A corresponding femom file is generated that has the same time epochs as the CTG FHR data set, but containing the femom FHR data and uninterpretable data (i.e. no FHR value due to signal loss). PPA (%) = 100·a/(a+b), where a represents the number of 0.25sec epochs for which femom is within ±10% of the CTG FHR, and b is the number of 0.25sec epochs in which femom is not within ±10% of the CTG FHR, or is absent. The same approach will be utilised to determine device measurement agreement for MHR. The criteria for a successful outcome as regards the FHR PPA will be set at 85%. The justification for this is that a device that is similar to the femom (MONICA AN24) and is both CE marked and FDA510k approved, achieved a PPA of 84.85%. The criteria for a successful outcome as regards the MHR PPA will be set at 95%. The justification for this is that a similar device to the femom (MONICA AN24) and is both CE marked and FDA510k approved, achieved a PPA of 99.3% (Clinicaltrials, 2013). .
From the FHR, cardiac time intervals (CTIs) such as the QT interval, QTc, QRS duration and PR interval, as well as the phase-rectified signal averaging (PRSA) can be derived. These metrics shall be evaluated solely for the purposes of data collection; no statistical analysis for comparison with the CTG shall be performed (Smith et al., 2018). These data would be directed towards establishing reliable CTIs across various weeks of gestational age, especially between the 28 to 32 weeks of gestation, where the fetal ECG signal is attenuated due to vernix caseosa. CTI data would help demonstrate the benefits and potential of utilising CTIs in fetal diagnostics .
For UA, interpretable data will be defined as all data above 20% of full scale given the subjective nature of calibration of the toco transducer required by the staff performing the fetal monitoring.
Reliability of uterine activity output of the femom and CTG will be derived via the PPA method. This is the percentage of time that the device generates an interpretable UA tracing as the same time as the CTG. Reliability expresses the success rate of the femom in creating a valid output in the presence of a simultaneous valid signal from the CTG.
The criteria for a successful outcome as regards the UA PPA will be set at 95%. The justification for this is that a similar device to femom (MONICA AN24) and is both CE marked and FDA 510k approved, achieved a PPA of 96.6%. The PPA for UA will be derived under two conditions:
UA values (relative units) of 0-100
UA values (relative units) of 20-100
The reason for (b) is that CTG UA is characterised by ‘baseline creep’ which can only be corrected by a tocography reset function on the CTG machine itself. Failure to reset the tocography will result in spurious UA values with relative units of 0-20. Hence, this will lead to apparent ‘missed’ uterine contractions (i.e. uterine contractions which were apparently failed to be detected by the femom device). To account for this phenomenon of ‘baseline creep’, the PPA shall be calculated for UA values of 20-100 as well.
The single overall STV value from each femom and CTG trace will be extracted. The differences between the devices will be presented on a B-A plot with the CTG value as the standard. 95% confidence intervals on the limits of agreement will be calculated as described above for FHR. The mean differences and LoA of STV output from femom vis-à-vis CTG shall be determined.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
18/01/2021
Actual
Date of last participant enrolment
Anticipated
12/04/2021
Actual
Date of last data collection
Anticipated
12/04/2021
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 17437 0
North Shore Private Hospital - St Leonards
Recruitment postcode(s) [1] 31166 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 306661 0
Commercial sector/Industry
Name [1] 306661 0
Biorithm Pte Ltd
Country [1] 306661 0
Singapore
Primary sponsor type
University
Name
University of Technology Sydney
Address
PO Box 123
Ultimo 2007
NSW
Country
Australia
Secondary sponsor category [1] 307211 0
None
Name [1] 307211 0
Address [1] 307211 0
Country [1] 307211 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 306841 0
Ramsay Health NSW-Vic HREC
Ethics committee address [1] 306841 0
St Leonards NSW
Ethics committee country [1] 306841 0
Australia
Date submitted for ethics approval [1] 306841 0
21/09/2020
Approval date [1] 306841 0
Ethics approval number [1] 306841 0
Ethics committee name [2] 306843 0
University of Technology Sydney Medical HREC
Ethics committee address [2] 306843 0
PO Box 123, Ultimo 2007
Ethics committee country [2] 306843 0
Australia
Date submitted for ethics approval [2] 306843 0
19/10/2020
Approval date [2] 306843 0
Ethics approval number [2] 306843 0

Summary
Brief summary
During pregnancy, one modality of ensuring the well-being of the fetus is by measuring the heart rate. At present, the mainstay of such fetal surveillance is carried out by utilising cardiotocography (CTG). The CTG utilises Doppler ultrasound to approximate the FHR by detecting the movement of cardiac structures, which requires signal modulation and auto correlation to provide accurate quality recordings of FHR (Smith et al. 2018).
Some of the main limitations with CTG are its inability to support mobile, ambulatory and accurate FHR monitoring. This is particularly worse in women with obesity, where there is the need for clinician oversight during its placement so as to ensure that the maternal heart rate (MHR) is not wrongly monitored over the FHR and that an interpretable trace is obtained.
The limitations of CTG use prompted a Singapore based medical technology company, Biorithm, to investigate new methods of fetal monitoring using fetal ECG. This subsequently led to the prototyping of a new device, Femom, which can obtain and analyse fetal heart rate patterns in an outpatient setting. The output from the device will mirror available CTG technology and will therefore be interpreted in line with pre-existing available CTG guidelines.
Femom utilises trans-abdominal electrocardiogram (ECG) to measure the fetal and maternal heart rates. Routine data collection at the National University Hospital in Singapore and Monash Medical Centre in Melbourne supports the ability of Femom to collect FHR patterns and contractions. No adverse effects were reported. This study will pilot a clinical trial aiming to examine the efficacy of Femom. Similar technology has also been previously used to monitor the fetus of women in clinical populations with no documented adverse effects (Reinhard et al., 2012).
The device presently comprises of 5 electrodes which will be attached to the woman’s abdomen. Our primary research focus encompasses pilot testing the efficacy of Femom in comparison to traditional CTG monitoring to evaluate the quality of tracing obtained. The aims of the project are:
1. to assess the similarity between fetal heart rate (FHR), maternal heart rate (MHR) and uterine activity (UA) measured by Femom vs CTG, and
2. to assess whether there are any differences in fetal heart short term variation (STV) measured by Femom versus CTG
3. to pilot and inform the design of a future confirmatory study
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105194 0
Dr Vinayak Smith
Address 105194 0
Monash University (Medicine)
21 Chancellors Walk
Clayton VIC 3800
Country 105194 0
Australia
Phone 105194 0
+61 431330754
Fax 105194 0
Email 105194 0
[email protected]
Contact person for public queries
Name 105195 0
Deborah Fox
Address 105195 0
University of Technology Sydney
PO Box 123
Ultimo
NSW 2007
Country 105195 0
Australia
Phone 105195 0
+61 2 95147982
Fax 105195 0
Email 105195 0
[email protected]
Contact person for scientific queries
Name 105196 0
Deborah Fox
Address 105196 0
University of Technology Sydney
PO Box 123
Ultimo
NSW 2007
Country 105196 0
Australia
Phone 105196 0
+61 2 95147982
Fax 105196 0
Email 105196 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.