3.2 clinical performance

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Three clinical studies have demonstrated the safety and effectiveness of the B4C System and its intended use.

Study 1 - Non-invasive ICP Monitoring for HIV-associated Cryptococcal Meningitis

A critically ill adult diagnosed with human immunodeficiency virus-associated cryptococcal meningitis underwent ICP monitoring using a previous version of the B4C System during a 34-day standard treatment period. Non-invasive ICP monitoring was conducted in real-time at four specific time points before and after treatment to collect corresponding ICP waveforms. These waveforms were visually assessed alongside other clinical parameters to evaluate their correlation with the patient’s clinical status.

On Day 12, the ICP waveform measurement, taken just before a lumbar puncture procedure, indicated that P2 > P1, where the amplitude of the tidal wave exceeded that of the percussion wave, correlating with neurological symptoms. After the lumbar puncture, the waveform the waveform’s morphology changed such that P1 > P2, demonstrating improvement towards the characteristic P1>P2>P3 pattern, with P3 being the dicrotic wave, as expected with reduced ICP post-treatment.

By Day 34, the waveforms more closely resembled normal brain compliance (P1>P2>P3), consistent with a reduction in ICP following the treatment series, leading to the patient’s discharge that same day.

This early study demonstrated that the B4C System can continuously monitor ICP changes, providing signals that reflect the patient’s clinical status.

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Study 2 - Analysis of a Non-Invasive ICP Monitoring Method in Patients with Traumatic Brain Injury

Seven adult subjects admitted to the neurointensive care unit with severe or moderate traumatic brain injury and secondary neurological deterioration requiring intubation and mechanical ventilation were enrolled in the study. The objective was to compare the waveform similarities between the Codman® Microsensor Basic Kit (iICP) and the Braincare (nICP) sensors, aiming to evaluate the noninvasive sensor as a potential alternative to invasive ICP assessments, particularly where waveform data can offer supplementary clinical insights. Additionally, the study compared noninvasive intracranial pressure (nICP) waveforms with arterial blood pressure (ABP) waveforms to assess the potential influence of extracranial peripheral circulation on the nICP signal, recognized as a possible limitation of the B4C System.

Each subject underwent continuous ICP monitoring using both an invasive sensor and a previous version of the B4C System sensor simultaneously from admission and for the duration of their stay in the neurointensive care unit, with monitoring durations ranging from 68 to 282 hours. Simultaneous ABP measurements via the radial artery and partial pressure of carbon dioxide (PaCO2) were also recorded during these sessions. A total of approximately 337 hours of recordings were analyzed.

The primary endpoint was the comparison of ICP waveform morphology obtained from the nICP and iICP sensors. The secondary endpoint involved comparing the nICP and ABP waveforms. Waveforms were analyzed in a lower-dimensional space based on signals in the frequency domain. The similarity between the two devices’ signals was inferred by calculating the Euclidean distance between the non-linear projection in the lower-dimensional space of the window power spectral densities (PSD) of the respective signals, with PSD calculated using the short-term Fourier transform. Intra-individual statistical comparisons were performed using the non-parametric Mann-Whitney U test for non-normally distributed data, with a significance level set at p<0.05. The measurement of similarities is presented in the following table.

Measure of similarities between iICP, nICP and ABP

The difference between the iICP-nICP and nICP-ABP waveforms was found to be statistically significant for all seven subjects (p<0.05) using the Mann-Whitney U test. The study results indicated a greater similarity between the waveforms generated by the Codman® Microsensor Basic Kit and the B4C System compared to those between the B4C System sensor and arterial blood pressure (ABP) measurements.

Although the study had a limited sample size, the intra-individual similarities between the invasive and noninvasive ICP signals over time suggest that the Braincare Sensor provides ICP monitoring effectiveness comparable to that of the Codman® Microsensor Basic Kit, which is a standard of care. Additionally, no adverse events related to the use of the B4C System were reported, supporting the safety of the Braincare sensor for monitoring intracranial pressure.

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Study 3 - Evaluation of Multi-Center Clinical Data On a Novel Non-Invasive Sensor Device for Safe and Simplified Intracranial Pressure (ICP) Monitoring

Braincare conducted a combined prospective/retrospective, multi-center, observational study to compare the ICP waveform signals and parameters obtained from the B4C System with those from standard invasive ICP monitoring methods. The study utilized the B4C processing and analytical software in conjunction with the wired sensor (K182073). Although a wired sensor was used during the study, the results are representative of the B4C System's overall performance. 

Dataset Description 

• Total number of centers: 4

• Total number of subjects: 123 enrolled, 107 after device label check, 85 after data quality check (78 adults, 7 pediatric)

• Collected data: ICP Surrogate Waveform (BcSs-PICNI-2000(K182073) or B4C System) ; Invasive Arterial Blood Pressure, Invasive ICP Waveform (EVD or Bolt)

• Range of acquisition sessions time: 5 min to 3.5 hours

• Total number of monitoring sessions that passed quality check: 159

• Total acquisition time that passed quality check: 4800 minutes (98% adult, 2% pediatric)

Analyzed participants

Seventy-eight adults (18 and over) who met all eligibility criteria and were admitted to the neurointensive care unit, undergoing both invasive ICP and invasive arterial blood pressure monitoring, were included in the dataset. Due to the limited number of pediatric subjects, the analysis was only able to demonstrate statistically significant performance for the adult population.

• Total number of analyzed subjects: 78 adults

• Total acquisition time analyzed: 4695 minutes

• Age of analyzed subjects: 52.7±19.4

• Gender of analyzed subjects: 47% female ; 53% male

Study Objective

The analysis aimed to determine whether Braincare's new medical device consistently correlates its recorded ICP waveforms with those from invasive devices currently used in clinical practice. Specifically, the objective was to evaluate the reliability and accuracy of the Braincare device in monitoring ICP waveforms compared to gold standard invasive methods, such as external ventricular drains and intraparenchymal microtransducers. This evaluation was conducted across different centers and medical settings within the target adult population.

Study Procedures

All centers used Braincare’s non-invasive sensors, adhering to identical operational principles (three centers used the BcSs-PICNI-2000 sensor [K182073], while one center used the B4C System wireless sensor). At each site, the sensors were positioned according to standardized protocols, specifically in the temporal region, avoiding arteries, and adjusted until an waveform of acceptable quality was achieved—mirroring real-world usage. Invasive, non-invasive, and ABP waveforms were captured for patients across all sites.

Study Outcomes 

The primary objective was to compare the ICP curve morphology obtained from Braincare's non-invasive sensors with that from invasive ICP sensors. The focus was on analyzing the characteristics of the P1, P2, and P3 peaks, their amplitudes and ratios, as well as other aspects of the ICP pulse waveform, including the lags between wave peaks (time to peak) and the absolute curvature of the peaks. This analysis aimed to assess relative changes and trends over time in ICP and brain compliance.

The goal was to evaluate the reliability and accuracy of the Braincare device in monitoring ICP waveforms compared to gold standard invasive methods, such as external ventricular drains or intraparenchymal microtransducers. Additionally, the study aimed to assess the device's ability to track relative changes in ICP and trends over time. The hypothesis was that the ICP pulse morphology detected by the Braincare non-invasive device would show a statistically significant correlation with the ICP pulse morphology detected by the gold standard invasive methods.

Bland-Altman plots and Deming regression analyses were used to quantify the agreement between the invasive ICP waveform and the Braincare surrogate ICP waveform parameters—specifically the estimated P2/P1 ratio and normalized time to peak (TTP), by estimating the differences between their respective minute-by-minute averages. Furthermore, Spearman and normalized mutual information methods were applied to assess the non-linear behavior between the waveforms.

Given the positional differences between the invasive sensors (inside the cranium) and the non-invasive sensors (outside the skull), strong agreement between the signals was not anticipated. However, the study observed a relatively large region of agreement and a significant correlation between the parameters, as confirmed by additional statistical tests.

Correlation analysis: 

Spearman correlation and normalized mutual information were used to assess the statistical dependence of ICP waveform parameters between the Braincare sensor and the invasive sensor.

• For the normalized time to peak, the Spearman correlation was 0.318 [0.291, 0.345], with p<.0001. The statistical dependence between parameters, as estimated using normalized mutual information, was 0.612 [0.564, 0.643].

• For the estimated P2/P1 ratio, the Spearman correlation was 0.495 [0.471, 0.517], with p<.0001. The statistical dependence between parameters, as estimated using normalized mutual information, was 0.561 [0.531, 0.606].

The joint distributions between ICP and B4C parameters demonstrated statistical dependence, confirming a statistically significant correlation between the ICP pulse morphology (waveform) detected by the gold standard invasive methods and the B4C technology, specifically in terms of the P2/P1 ratio and Time to Peak (TTP).

Agreement analysis: 

Bland-Altman plots and Deming regression models were used to quantify the agreement between the invasive and Braincare-measured ICP waveform parameters—specifically the estimated P2/P1 ratio and normalized time to peak. These analyses estimated the differences between the respective minute-by-minute averages. Given the differing sensor placements (inside the ventricle for invasive sensors and outside the skull for non-invasive sensors), a strong agreement between the signals was not anticipated. However, a relatively large region of agreement between the parameters was observed, demonstrating statistical significance as confirmed by additional tests.

• Bland-Altman Analysis:

  • P2/P1 Ratio: The limits of agreement ranged from -0.723 to 0.761, with a mean difference (bias) of 0.019 (95% CI: -0.060, 0.101).

  • Normalized Time to Peak: The limits of agreement ranged from -0.183 to 0.245, with a mean difference (bias) of 0.031 (95% CI: 0.011, 0.050).

• Deming Regression Estimates (95% CI):

  • P2/P1 Ratio: Y = -0.67 [-1.85, 0.02] + 1.60 [0.97, 2.69]X

  • Time to Peak: Y = 0.00 [-0.11, 0.09] + 0.84 [0.38, 1.39]X

The Bland-Altman results indicate that while the mean difference in P2/P1 between the Braincare device and invasive ICP is not significantly different from zero, there were instances where the P2/P1 ratio measured by the device differed from that measured by invasive ICP by more than 0.7. Similarly, the Braincare device tended to generate larger Time to Peak observations compared to invasive ICP, with some differences exceeding 0.2.

Both classes of analysis—Bland-Altman/Deming Regression, which evaluate agreement, and Normalized Mutual Information/Spearman, which evaluate correlation—presented statistically meaningful results.

Safety:

No adverse events were reported. 

Study Conclusion

The results of this study demonstrated a statistically significant correlation in the ICP signal and waveform parameters between the B4C System and the gold standard invasive ICP monitoring devices over time. The outcomes indicate that the Braincare device offers comparable effectiveness to commonly used invasive ICP devices for monitoring and assessing variations in ICP waveform-associated parameters over time.

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