Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001486718p
Ethics application status
Submitted, not yet approved
Date submitted
7/11/2022
Date registered
28/11/2022
Date last updated
11/01/2024
Date data sharing statement initially provided
28/11/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Continuous mONitoring of recovery iN acutE isChaemic sTroke (CONNECT) - Phase 2
Scientific title
Phase 2 of an investigator-initiated and conducted, multicenter, open-label study to compare the efficacy of the nuroflux device to continuously monitor and detect, abnormal brain function in patients with acute ischaemic stroke from large-vessel occlusion in the anterior circulation of the brain against the gold standard of high-intensity nursing monitoring and routine brain imaging
Secondary ID [1] 308327 0
Nil
Universal Trial Number (UTN)
Trial acronym
CONNECT - Phase 2
Linked study record
'This study is a follow up to 12622001485729'

Health condition
Health condition(s) or problem(s) studied:
Acute Ischaemic Stroke (AIS) 328116 0
Condition category
Condition code
Neurological 325172 325172 0 0
Other neurological disorders
Stroke 325173 325173 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is for participants to wear the study device (nuroflux) as soon as possible after initial diagnostic imaging (baseline) and for at approximately 24 hours until the completion of their routine Day 1 National Institutes of Health Stroke Scale (NIHSS) assessments and brain scanning, occurring at approximately 24 hours after initial diagnostic imaging are completed. The device will be fitted, checked on, and removed by ED/Stroke ward nurses. A semi-circular ring is fitted across the participant's forehead, held in place by attachments on the sides of the device. In addition, the two ECG electrodes connected to the device are to be applied to upper chest on either side. The device will be worn continuously, and must not be removed or get wet at any point. The device is connected to a laptop wirelessly, which will be set up nearby and checked on by the ED/stroke nurse.
The investigational device is intended to provide continuous and objective metrics pertaining to the brain activity and brain blood flow of AIS patients. It is intended to provide an indication of stroke location and severity, patient response to treatment, as well as patient neurological deterioration.

Imaging, both initial and follow-up, will be either computerized tomography (CT) or magnetic resonance imaging. CT is most often used, taking a few minutes, and sometimes involving an intravenously administered iodinated contrast agent. MRI is sometimes chosen instead, taking approximately 20 mins, and sometimes utilising an intravenously administered Gadolinium-based contrast agent. The type of imaging, along with the use, specific type of contrast agent, and doses of the contrast agent, are all decisions made by clinicians completely independent from the investigators. Initial imaging, any follow-up imaging taken within 24hrs of baseline, other medical data outside of the device up to 72 hrs after baseline, and the medical data from the 90 day check-up, are all collected as part of the routine hospital diagnostic examination for AIS. While investigators will record this data, we have no influence over these procedures and these procedures not part of the introduced intervention.

Aside from wearing the device, the only other active procedure introduced as part of the intervention for the participant will be recording subjective discomfort and adverse effect information in a 24hr diary. If the participant is unable to record this information, a nurse will record this information for them. Within this study, this data will not be viewed in real-time and will not influence the decisions of clinicians. The data will only be viewed by the investigators after the 24hr device use period, comparing it’s measurements to data from other diagnostic measurements collected as a test of its accuracy.
Intervention code [1] 324778 0
Early detection / Screening
Comparator / control treatment
This study is intended to assess the accuracy of a device that is intended to screen for neurological deterioration. The data will only be viewed by the investigators after the 24hr device use period. Accuracy will be determined by comparing it’s measurements to data from other diagnostic measurements collected as a test of its accuracy (e.g neurological imaging, NIHSS assessments, etc.)
These other diagnostic measurements include:
- Brain imaging (MRI or CT) will occur immediately before study enrolment and at 24hrs after initial imaging. Additional imaging may occur at the discretion of hospital clinicians separate from study. CT scans last only a few minutes, while MRI scans take around 20 mins. Both procedures may take longer if contrast agents (dyes) are used.
- NIHSS, which is a non-invasive visual and physical assessment of stroke effect, including vision-loss, motor-loss, facial paralysis, etc. It's designed to take less than 10 mins. Data from this assessment will be collected once after Day 1 imaging.
- Glasgow Coma Scale (GCS), which is a non-invasive visual and physical assessment of consciousness, including eye, verbal, and motor responses. It's designed to take only 1-2 minutes. Data from this assessment will be assessed once after Day 1 imaging.
As a note, all imaging, along with the other diagnostic measurements outside of the intervention device, are part of the routine hospital diagnostic examination for AIS, and while investigators will collect medical data from these assessments, we have no influence over these procedures and these procedures not part of the introduced intervention.
Control group
Active

Outcomes
Primary outcome [1] 332990 0
Sensitivity of device on detection of neurological deterioration (defined as increment in the NIHSS score of 1 point or greater) during acute phase after onset of AIS in anterior-circulation due to LVO assessed via comparing device detected neurological deterioration against hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [1] 332990 0
Continuously from Baseline (ASAP after Initial imaging) to 24hrs
Primary outcome [2] 333020 0
Specificity of device on detection of neurological deterioration (defined as increment in the NIHSS score of 1 point or greater) during acute phase after onset of AIS in anterior-circulation due to LVO assessed via comparing device detected neurological deterioration against hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [2] 333020 0
Continuously from Baseline to 24hrs
Secondary outcome [1] 415455 0
Determining positive predictive values [PPV] of the device for neurological deterioration via comparing device detected neurological deterioration against hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [1] 415455 0
Continuously from Baseline to 24hrs
Secondary outcome [2] 415456 0
Determining negative predictive values (NPV) of the device for neurological deterioration via comparing device detected neurological deterioration against hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [2] 415456 0
Continuously from Baseline to 24hrs
Secondary outcome [3] 415457 0
Sensitivity of detection of AIS, assessed by comparing device detected AIS against hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [3] 415457 0
Continuously from Baseline to 24hrs
Secondary outcome [4] 415458 0
Specificity in detection of AIS assessed by the device via comparing device detected AIS against hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [4] 415458 0
Continuously from Baseline to 24hrs
Secondary outcome [5] 415459 0
PPV of the device for detection of AIS assessed via comparing device detected AIS against hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [5] 415459 0
Continuously from Baseline to 24hrs
Secondary outcome [6] 415460 0
NPV of the device for detection of AIS assessed via comparing device NPV against hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [6] 415460 0
Continuously from Baseline to 24hrs
Secondary outcome [7] 415461 0
Correlation between device EBPi measurements and stroke severity of AIS via comparing device EBPi measurements with hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [7] 415461 0
Continuously from Baseline to 24hrs
Secondary outcome [8] 415462 0
Correlation between device EBPi measurements and initial/follow-up imaging parameters (site of arterial occlusion, ischaemic lesion volume, imaging parameters obtained from CT or MRI perfusion [such as cerebral blood flow (CBF) or time-to-maximum]).
Timepoint [8] 415462 0
Baseline, Continuously from Baseline to 24hrs, 24hrs
Secondary outcome [9] 415481 0
Device accuracy measuring response to treatment assessed via comparing device detected response to treatment with modified Thrombolysis In Cerebral Ischaemia [mTICI] score at the end of mechanical thrombectomy procedure or thromblysis treatment
Timepoint [9] 415481 0
Before and after thrombolytic treatment (Treatment occurs usually soon after baseline)
Secondary outcome [10] 415484 0
Device detection of severity of recurrent stroke assessed via device detected severity against medical records and hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [10] 415484 0
Continuously from Baseline to 24hrs
Secondary outcome [11] 415485 0
Device detection of location of recurrent stroke assessed via comparing device detected location against medical records and hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [11] 415485 0
Continuously from Baseline to 24hrs
Secondary outcome [12] 415486 0
Device detection of cerebral oedema (defined as midline shift on follow-up imaging or change in the midline shift from initial to follow-up imaging) assessment via comparing device detected cerebral oedema against medical records and hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [12] 415486 0
Continuously from Baseline to 24hrs
Secondary outcome [13] 415487 0
Device detection of haemorrhagic transformation (especially parenchymal haematoma type 2 in the Heidelberg bleeding classification) assessed via comparing device detected haemorrhagic transformation against medical records and hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [13] 415487 0
Continuously from Baseline to 24hrs
Secondary outcome [14] 415488 0
Device detection of early seizure after study enrolment (defined as use of anticonvulsive medication) assessed via device detected seizure against medical records
Timepoint [14] 415488 0
Continuously from Baseline to 24hrs
Secondary outcome [15] 415489 0
Proportion of time wearing device within the intended period assessed by 24hr diary
Timepoint [15] 415489 0
Continuously from Baseline to 24hrs
Secondary outcome [16] 415490 0
While the only known possible adverse event would be discomfort skin and head for the wearing the device, all serious adverse events (SAEs) and adverse events with special interest (AESI) that occur while wearing the device and during the study period will be prospectively reported, monitored, and reviewed according to standard criteria. These will be recorded and assessed via 24hr diary and medical records.
Timepoint [16] 415490 0
Continuously from Baseline to 24hrs
Secondary outcome [17] 415564 0
Correlation between modified Thrombolysis In Cerebral Ischaemia [mTICI] score at the end of mechanical thrombectomy procedure and device EBPi measurements (before and after successful thrombectomy)
Timepoint [17] 415564 0
Continuously from Baseline to 24hrs
Secondary outcome [18] 416039 0
Correlation between device EBPi measurements and stroke location of AIS via comparing device EBPi measurements with hospital diagnostic measurements (MRI/CT imaging, NIHSS, GCS)
Timepoint [18] 416039 0
Continuously from Baseline to 24hrs

Eligibility
Key inclusion criteria
1. Adults (age >= 18 years);
2. AIS (initial diagnostic scan within 24 hours from symptom onset or last known well time) in anterior circulation due to large vessel occlusion (LVO, occlusion at the internal carotid artery, the middle cerebral artery horizontal or insular segment, or proximal site of the anterior cerebral artery), diagnosed by clinician and confirmed on CT with/without angiography;
3. At least moderate neurological severity (National Institute of Health Stroke Scale [NIHSS] score >4); and
4. Provision of consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Recent (<1 months) brain surgery;
2. Evidence of seizure activity from stroke symptom onset to study inclusion;
3. Having history of severe skin rash due to ECG/EEG electrode patches;
4. Skin conditions on scalp or face that preclude safe use of the device (local infections, rashes, fragile skin, etc.);
5. Having difficulties to wear the device stably (e.g., patients with severe dementia, extreme agitation, or susceptible to stress).
6. Inability to communicate in English either personally or through translator

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The sample size was calculated on the basis of the primary hypothesis. When the sensitivity and specificity of the device is expected to be 0.90 and 0.90, the sample size of 260 is needed to achieve 90% power to detect difference between sensitivity of 0.90 and 0.99 (sensitivity of the gold standard) with 5% probability of type I error, if the prevalence of the outcome (neurological deterioration) is set as 20%. In this case, the power to detect difference between specificity of 0.90 and 0.99 (specificity of the gold standard) is 99%. The prevalence of the outcome was estimated as 20% based on recent large observational registry study, which showed that 21.9% of the acute stroke patients whose initial NIHSS were 5 or more had neurological deterioration, and most of the neurological deterioration occurred within 48 hours from stroke onset. However, having large vessel occlusion is a known predictive factor for neurological deterioration. In addition, the current study will include patients received various treatments; patients without reperfusion treatment and patients treated with reperfusion therapy (with thrombolytic drug, endovascular mechanical clot retrieval, or both). Therefore, there are some uncertainties about the prevalence of the outcome, and the sample size of phase 2 will be recalculated or adjusted as needed after phase 1 results are available.

Phase 2
Statistical analysis will be undertaken to explore the performance of the device (sensitivity, specificity, positive and negative predictive value, and accuracy for clinical outcomes) and correlation to imaging results (such as CBF reduction, ischaemic lesion volume, change in EBPi between before and after recanalisation) or reperfusion therapy outcomes (such as recanalisation status), feasibility (expressed as proportion of time that EBPi was properly recorded).

Sensitivity is the proportion of true positive tests out of all patients with a condition, i.e., neurological deterioration, AIS, recurrent stroke, cerebral oedema, haemorrhagic transformation, early seizure, etc. Sensitivity = (True Positives)/ (True Positives + False Negatives).
Specificity is the percentage of true negatives out of all patients who do not have a condition as outlined above. Specificity = (True Negatives)/ (True Negatives +False Positives).
PPV determines, out of all of the positive findings, how many are true positives. Positive Predictive Value = (True Positives)/ (True Positives +False Positives).
NPV determines, out of all of the negative findings, how many are true negatives. Negative Predictive Value = (True Negatives)/ (True Negatives +False Negatives).
To estimate sensitivity, specificity, PPV and NPV, the outcome of EBPi will be compared to reference clinical standards, i.e., any increase of NIHSS, final diagnosis and brain imaging features. Results will be presented in 2x2 tables comparing the NurofluxTM device outcomes to reference clinical outcomes.
Descriptive statistics will be provided for patient characteristics. Spearman’s rank correlation coefficient (p) will be used to calculate the relationship between Nuroflux device outcome and other secondary outcomes. The following correlation classification was used: no or very low: p = 0–0.25; low: p = 0.26–0.40; moderate: p = 0.41–0.69; high: p = 0.70–0.89; very high: p = 0.90–1.0.

As a note, Phase 1 of this study (registered separately) will involve a smaller sample size at a single site to perform a preliminary assessment of device utility, which will be used to inform the sample size and device thresholds for this Phase 2 study.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2025
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
260
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 23487 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 23488 0
Liverpool Hospital - Liverpool
Recruitment hospital [3] 23489 0
Prince of Wales Hospital - Randwick
Recruitment postcode(s) [1] 38896 0
2031 - Randwick
Recruitment postcode(s) [2] 38894 0
2050 - Camperdown
Recruitment postcode(s) [3] 38895 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 312570 0
Other Collaborative groups
Name [1] 312570 0
The George Institute
Country [1] 312570 0
Australia
Primary sponsor type
Other Collaborative groups
Name
The George Institute
Address
Level 5, 1 King Street, Newtown NSW 2042
Country
Australia
Secondary sponsor category [1] 314178 0
None
Name [1] 314178 0
Address [1] 314178 0
Country [1] 314178 0
Other collaborator category [1] 282471 0
Commercial sector/Industry
Name [1] 282471 0
Nuroflux Pty Ltd
Address [1] 282471 0
202a/7-9 Kent Road, Mascot NSW 2020
Country [1] 282471 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 311897 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 311897 0
Level 11, KGV Building Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 311897 0
Australia
Date submitted for ethics approval [1] 311897 0
27/09/2022
Approval date [1] 311897 0
31/05/2023
Ethics approval number [1] 311897 0
Protocol no. X23-0322 & 2023/ETH00608

Summary
Brief summary
To assess the efficacy of the NurofluxTM device to continuously monitor and detect significant neurological deterioration in patients with acute ischaemic stroke due to large-vessel occlusion (LVO) in anterior cerebral circulation against the gold standard of high-intensity nursing monitoring of vital signs and neurological function, and use of routine brain imaging.

Study Design:
This is an investigator-initiated and conducted, multicentre, open-label, single arm, clinical evaluation feasibility (proof-of-concept) trial. After an internal pilot phase (Phase 1; registered seperately) to rehearse the main study to identify key issues to consider in the next phase of the study, as well as to optimise the device parameters, this study phase (Phase 2) will be rolled out for full assessment of the sensitivity, specificity, and predictive value of monitoring of patients in acute phase across three major teaching hospitals in Sydney under the supervision of leading stroke clinician-scientists.

Phase 2 – Main phase
260 consecutive patients with AIS with LVO in the anterior circulation will be recruited and monitored using the device and followed through the course of regular treatment and management. Device metrics (sensitivity, specificity, and positive/negative predictive values) will be determined against routine clinical and brain imaging (CT/MRI) to determine thresholds for detection of: AIS (severity and location), response to treatment (successful reperfusion) and neurological deterioration (from bleeding [haemorrhagic transformation], cerebral oedema [‘brain swelling’] and/or extension/recurrent stroke).

Phase 2
Primary Outcome:
1. Performance of the device (sensitivity and specificity) on detection of neurological deterioration
Secondary Outcomes:
1. Positive and negative predictive values of the device
2. Detection of acute ischaemic stroke (severity and location)
3. Correlation to initial and follow-up imaging parameters
4. Response to treatment (successful or unsuccessful reperfusion)
5. Detection of recurrent stroke
6. Detection of cerebral oedema, haemorrhagic transformation, and early seizure (after study enrolment)
7. Proportion of time spent wearing the device within the intended period
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122762 0
Prof Craig Anderson
Address 122762 0
The George Institute for Global Health
Level 5, 1 King St, Newtown NSW 2042
Country 122762 0
Australia
Phone 122762 0
+61 2 8052 4521
Fax 122762 0
Email 122762 0
canderson@georgeinstitute.org.au
Contact person for public queries
Name 122763 0
Dr Xiaoying Chen
Address 122763 0
The George Institute for Global Health
Level 5, 1 King St, Newtown NSW 2042
Country 122763 0
Australia
Phone 122763 0
+61 2 8052 4549
Fax 122763 0
Email 122763 0
xchen@georgeinstitute.org.au
Contact person for scientific queries
Name 122764 0
Dr Xiaoying Chen
Address 122764 0
The George Institute for Global Health
Level 5, 1 King St, Newtown NSW 2042
Country 122764 0
Australia
Phone 122764 0
+61 2 8052 4549
Fax 122764 0
Email 122764 0
xchen@georgeinstitute.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Data dictionaries
When will data be available (start and end dates)?
From 12 month after publication of the main results, with no end date.
Available to whom?
Bona fide researchers with experience in medical research, no conflict of interest that may potentially influence their interpretation of any analyses, and employed by a recognised academic institute, health service organisation, commercial research organisation of from the pharmaceutical industry.
Available for what types of analyses?
The data sharing will be only for analyses for the purposes of health and medical research and within the constraints of the consent under which the data were originally gathered.
How or where can data be obtained?
Data can be shared with bona fide researchers after publication of the main results, based on a submitted protocol to the research office of The George Institute for Global Health, Sydney Australia. To initiate the data sharing process, please email that study PI Craig Anderson at canderson@georgeinstitute.org.au


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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