3.3 clinical performance

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

Non-invasive ICP Monitoring for HIV-associated Cryptococcal Meningitis

A critically ill adult subject diagnosed with human immunodeficiency virus-associated cryptococcal meningitis received ICP monitoring with a previous sensor version of the B4C System while undergoing standard treatment over thirty-four (34) days. The subject underwent real-time non- invasive ICP monitoring at four defined time points before and after treatment to collect four ICP waveforms. Waveform morphology of the ICP curves at these time points was visually assessed with other recorded clinical parameters to determine whether the waveforms were indicative of the clinical status of the patient. The pulsatile waveform from ICP monitoring on Day 12 before lumbar puncture revealed P2>P1, amplitude of tidal wave greater than that of percussion wave, reflecting characteristics of relative peak height consistent with the presence of neurological symptoms. P1>P2 after lumbar puncture, demonstrating improvement towards the characteristic P1>P2>P3, where P3 is dicrotic wave, as expected with reduction in ICP post-treatment. Morphology of the waveforms obtained from Day 34 were more closely representing normal brain compliance (P1>P2>P3), which is consistent with reduction in ICP following the series of treatment and discharge that same day. Results of this early study demonstrated that the B4C System is able to continuously monitor ICP changes to acquire signals consistent with the patient’s clinical status.

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

Seven adult subjects who were admitted to the neurointensive care unit presenting with severe or moderate traumatic brain injury with secondary neurological deterioration requiring intubation and mechanical ventilation were enrolled in the study. The objective of the study was to verify the similarities between the Codman® Microsensor Basic Kit (iICP) and Braincare (nICP) sensors’ waveforms. This assessment sought to provide evidence for the use of the noninvasive sensor as an alternative to invasive ICP assessments in situations where the waveform can provide supplementary clinical information. In addition, the noninvasive intracranial pressure and arterial blood pressure (ABP) waveforms were compared to verify the possible influence of the extracranial peripheral circulation into the noninvasive intracranial pressure signal, acknowledged as a potential limitation of the B4C System.

Each subject underwent continuous ICP monitoring using an invasive and a previous sensor version of the B4C System concurrently from point of admittance throughout their stay in the neurointensive care unit, with acquisition time ranging from 68-282 hours. ABP measurement directly through the radial artery and partial pressure of Carbon Dioxide (PaCO2) were also recorded simultaneously during the monitoring sessions. Approximately 337 total hours of recordings were analyzed.

The primary endpoint was the comparison of ICP waveform morphology obtained with the nICP and iICP sensors. A secondary endpoint was the comparison of the nICP and ABP waveforms. Waveforms were compared in a lower dimensional space constructed based on signals in the frequency domain. Similarity between the two devices’ signals was inferred from the Euclidean distance between the non-linear projection in a lower dimensional space of the window power spectral densities (PSD) of the respective signals, in which PSD was calculated using the short- term Fourier transform. Intraindividual statistical comparisons were performed using the non- parametric Mann-Whitney U test for not normally distributed data points with a significance level set at p<0.05. Measurement of similarities are presented in the following table.

Table 3.3-1 - Measure of similarities between i-ICP, nICP and ABP

The difference between the iICP-nICP and nICP-ABP was found to be statistically significant for all seven subjects, p<0.05, using the Mann-Whitney U test. Study results demonstrated that a greater similarity exists between the waveforms generated from the signals of the Codman® Microsensor Basic Kit and B4C System than between the B4C System sensor and arterial blood pressure measurements. Although the study had a limited sample size, the intra-individual similarities of the invasive and noninvasive ICP signals as functions of time suggest comparable effectiveness of ICP monitoring between the Braincare Sensor and the invasive Codman® Microsensor Basic Kit, which is representative of the standard of care. Additionally, no adverse events related to the use of the B4C System were reported, supporting safety of the Braincare sensor for monitoring intracranial pressure.

A Prospective Validation Evaluation of a Novel Non-Invasive Sensor Device for Safe and Simplified Intracranial Pressure (ICP) Monitoring

Braincare conducted a prospective, single-center, observational study to assess the comparison of the acquired ICP waveform signal and parameters between the B4C System and standard of care invasive ICP monitoring methods. The study device consisted of the B4C processing and analytical software used with the wired sensor. Although the wired sensor was used in the study, the results reflect the performance of the B4C System.

Thirty-nine adult subjects who had been admitted to the neurointensive care unit and were planned to undergo invasive ICP monitoring and invasive arterial blood pressure monitoring were enrolled in the study. The objective was to verify whether the B4C System waveform and parameters had statistically meaningful correlation with the ICP waveform derived from invasive devices currently used in routine clinical practice. The study evaluated the reliability and accuracy of the Braincare device in assessing ICP waveform in comparison to gold standard invasive ICP monitoring methods such as the external ventricular drain or intraparenchymal micro transducers. It also assessed the ability to accurately and reliably measure relative changes in ICP as well as trends over time. The study hypothesis was that the ICP pulse morphology (waveform) detected by the Braincare noninvasive device presented a statistically significant correlation with the ICP pulse morphology (waveform) detected by the gold standard invasive method(s).

Each subject underwent continued ICP monitoring using both the Braincare device and the invasive method concurrently for at least two 20-30 minute sessions a day, at least 3 hours between sessions, to obtain at least 5 minutes of data with good signal quality. Subjects were also monitored for other physiological parameters including invasive arterial blood pressure (ABP), electrocardiogram (ECG), and oxygen saturation (SpO2). 1129 minutes of signal data from thirty-two subjects were available for analysis.

The primary endpoint was the comparison of the ICP curve morphology obtained with the Braincare and invasive ICP sensors, with focus on the characteristics of peaks P1, P2, P3 amplitudes and their ratios, among other characteristics of the ICP pulse waveform including lags between wave peaks (time to peak) and the absolute curvature of the peaks, as assessed by an independent core laboratory, to determine relative changes and trends over time in ICP and intracranial compliance.

Bland-Altman plots were used to quantify agreement between the invasive and Braincare measured ICP waveform parameters – P2/P1 ratio and time to peak, estimating the differences between the respective averages per minute. Considering the differences in positioning of the invasive and non-invasive sensors (inside the ventricle compared to outside the skull), strong agreement between the signals was not expected. Nevertheless, a relatively large region of agreement between the parameters was observed and demonstrated statistical significance confirmed by additional statistical tests.

Pearson correlation coefficient and normalized mutual information were used to assess statistical dependence of the ICP waveform parameters between the Braincare sensor and invasive sensor. The joint distributions between ICP and B4C parameters presented a nonlinear shape correlation with a statistical dependence between them, that indicates that a more complete model might lead to a map between B4C and ICP parameters.

No adverse events were reported.

These results demonstrated a statistically significant correlation in the ICP signal and waveform parameters between the B4C System and the gold standard invasive ICP monitoring device measured over time. While the study had a limited sample size, and further data may be necessary to develop a mapping between the B4C and invasive ICP parameters, the study outcomes demonstrate comparable effectiveness between the Braincare device and commonly used invasive ICP devices for use in monitoring and assessing variations in ICP waveform parameters over time.