Clinical Investigation of Eye C Better's Photobionic Intraocular Pressure Biomonitor Tonometer

Background of the problem: epidemiology, prevalence/incidence

Glaucoma is the leading source of irreversible blindness and the second leading cause of the condition, resulting in a global burden on a massive scale, especially in developing countries. The disease is characterized by a series of progressive optic neuropathies, defined by the deterioration of retinal ganglion cells and retinal nerve fiber layers, causing abnormalities in the optical nerve head. High intraocular pressure (IOP) leads to optic nerve degeneration and the death of the retinal ganglion cells. Vision loss from this disease can be prevented with early detection and treatment . More than 5 million Americans have glaucoma and over 100 million people are affected globally. Vision loss and glaucoma can lead to depression and those with already known depression struggle with medication adherence and medical follow-ups which can subsequently lead to further vision loss. The fear and distress associated with vision loss is so great that healthcare providers screen for elevations of eye pressure at each eye examination done every day, all over the world.

IOP is a dynamic physiological factor having regular circadian and random variations over short and extended periods as the subject's muscular tone and physiologic state alternate. Over the course of a 24-hour period, IOP normally varies from 2 to 6mm Hg as a result of imperfect synchronization of aqueous secretion and drainage. However, practitioners recognized decades ago that, unlike normal subjects, glaucoma patients could have fluctuations greater than 10mmHg. Reliable IOP monitoring is thus a critical clinical element in glaucoma management. Contemporary glaucoma treatments often include frequent IOP assessments during office hours, however this provides inadequate definition of the IOP's fluctuating nature.

Goldmann applanation tonometry (GAT) is the most extensively used ophthalmic tool for measuring IOP. Although GAT is the clinical gold standard, it is influenced by inter-individual variances owing to differences in corneal thickness and stiffness. The method is intrusive and necessitates administration of anesthetic eye drops with subsequent applanation of the eye with a prism, limiting IOP monitoring over time. The data acquisition requires human interpretation of the prism rings and can introduce bias. In addition, the GAT needs a trained healthcare professional to perform the readings and is not viable for remote use. The iCare tonometer is the only FDA approved device for home measurement, however the 95% limit of agreement between iCare and GAT is -5.8 to 5.3 mmHg suggesting the devices are not interchangeable . Concerns of iCare's accuracy combined with patient reluctance to have the iCare's probe poking their eye has led to suboptimal adoption.

Our new methodology, Photonic IOP Biomonitoring (PIB), allows high-precision, non-contact, non-air puff, reproducible and semi-continuous IOP monitoring not requiring clinician interpretation. PIB is based on observations in fish and porcine eyes that sound waves induce scleral oscillations in an IOP dependent fashion. Our system measures these nanometric oscillations by monitoring speckle patterns generated with an eye-safe infrared laser reflected by the sclera. A high-speed camera records the speckle patterns and physical modelling combined with machine learning (ML) algorithms, processes this data to determine the IOP. Preliminary testing relying solely on ML algorithms indicates that ML alone may not be sufficient to match GAT performance. Prior to this clinical trial, PIB IOP measurements will be performed in the ECB lab using porcine eyeballs pressurized to clinically significant pressures to inform the ML model. IOP data obtained during the clinical trial study visit will be used to further inform the ML model and improve the PIB and GAT correlation. Subsequent to these efforts, ECB will perform regression analysis based in part or entirely on biomechanical models to realize the full potential of this method.

This study aims to evaluate the Primary Objective which is to evaluate IOP repeatability as measured by PIB in a side-by-side comparison of PIB and GAT. A secondary objective will be to evaluate the safety and comfort of PIB as compared to GAT. By providing a non-contact means of measuring IOP without the need for clinician interpretation, PIB seeks to be a diagnostic tool to allow the patient accurate, repeatable and precise IOP measurements comfortably and safely outside of the clinical setting. In so doing, diurnal/nocturnal IOP fluctuations will be captured and electronically stored and reported to the physician for quicker diagnosis and treatment to slow glaucoma progression. Ultimately, the development of effective and readily accessible IOP diagnostic tools used to inform Glaucoma is essential for improving patient outcomes, reducing healthcare costs, and enhancing the overall well-being of affected individuals.

Proposed hypothesis (justification including the benefits)

This study aims to investigate the ability of ECB's PIB diagnostic device to measure IOP in human subjects where the main hypotheses are:

PIB repeatability in human eyes is equal to that of previously measured comparable data from porcine eyes.

PIB will be found innocuous. This hypothesis will be evaluated by findings of comparable or fewer adverse events than GAT and comparable or greater comfort.

This is a preliminary study and use of the PIB device and will have no immediate benefit to the subject. This technology will eventually be configurable as a physician office-based platform and as a home-based device allowing the patient to self-measure IOP's frequently outside of the clinical setting for earlier detection and treatment of increased IOP. The possible benefits of this technology include:

• IOP measurement, conducted without touching the eye, reducing the risk of infection and discomfort
• Accuracy, repeatability and precision exceeding that of GAT
• No need for calibration
• Fast measurement time (≤3 seconds) for efficient patient care
• Limited need for physician/patient instruction or training
• The ability to store and transmit data electronically to improve recordkeeping and facilitate communication between healthcare providers as well as allow for remote use
• A tonometer suited for use in all patient populations regardless of age, race, or gender
• A low cost (<$500) tonometer that can be deployed to underserved populations allowing for remote IOP treatments for those without access to healthcare

Objectives Main Objectives in relation to the hypothesis To evaluate IOP as measured by PIB in a side-by-side comparison of PIB and GAT in 30 human eyes (15 human subjects) with or without a glaucoma diagnosis. Note: This sample size is unlikely to provide enough ML training to test accuracy. Instead, this data will be tested on a pig eye ML model to assess repeatability.

This data will also be used to inform our statistical analysis that will guide a subsequent accuracy study sample size.

Secondary Objectives in relation to the Study To assess the safety and comfort of PIB as compared to GAT in 15 subjects.

Exploratory Objectives:

To determine if repeated, sequential PIB and GAT measurements significantly influence IOP.

Study Design Description of the study design This study will employ a prospective, non-randomized study design to address the safety and comfort of PIB as compared to GAT. As PIB does not require eye contact and anesthetic drops, the PIB test will be performed first to prevent any confounding influences of eye contact and anesthetic drops required by the GAT test. A PIB test following the GAT test will be performed to verify that the act of repeated measurements does not significantly influence IOP (exploratory aim).

IOP data obtained from this testing will be used to assess repeatability of measurements in human subjects and to inform the size of a subsequent human trial aiming to refine the PIB IOP model.

The study will be conducted at Retina Institute of California dba Acuity Eye Group and is expected to enroll approximately 15 participants over a period of 1 month.

Interactions with participants

Consenting:

Prior to any study-related procedures, potential participants will be provided with comprehensive information about the study, including its objectives, procedures, potential risks and benefits, and their right to withdraw at any time. Written informed consent will be obtained from all eligible participants who voluntarily agree to participate.

Screening and Enrollment:

Potential participants will undergo a screening process to determine eligibility based on predefined inclusion and exclusion criteria. Eligible participants will be invited to enroll in the study and will be provided with a unique study identification number.

Study Visit:

During normal office hours, subjects will be identified as eligible. After consenting and giving voluntary permission to proceed, they will enter the study. The duration of study visits will range from 15 to 60 minutes.

Interventions:

Participants will receive both PIB and GAT exams at study visits. The GAT exam will necessitate use of anesthetic eye drops. There will be no randomization.

Study Visit:

Following the informed consent process and signature, baseline testing will include:

• Measurement of visual acuity in both eyes - Snellen Chart
• Prior to instillation of any eye drops or test strips or fluorescein the clinician will perform a slit lamp exam to note any baseline areas of dryness or abnormalities prior to performing the first measurements of IOP using PIB. Perform the PIB IOP measurements 3 times and record each valid measurement on the Clinical Report Form.

• Clinician will ask participants if they felt anything or had any discomfort during the data capture. Response will be noted on the Clinical Report Form.
• Clinician will perform a slit lamp exam looking for any areas of dryness (superficial punctate epithelial erosions), abrasions, or changes from baseline exam.
• For all PIB and GAT measurements there will be a moment of no less than 5 seconds where the measurement instrument is completely disengaged from the subject prior to its following measurement.
• Eye drops, test strips, or fluorescein can now be used, Measurement of IOP using GAT

• Anesthetize the selected eye of the subject.
• Stain with sodium fluorescein. NOTE - these steps may be combined by using an anesthetic to which sodium fluorescein has already been added.
• Set the tonometer drum to a force corresponding to an IOP of 10 mmHg. Wherever possible, the eyelid will not be touched with the fingers in order to open the palpebral aperture. If the palpebral aperture is not wide enough to allow the tonometer cone to make contact, instruct the subject to open their eyes wider.
• Direct the subject to view a distance fixation point. NOTE - If distance fixation cannot be maintained and near fixation is used, this fact should be recorded on the Clinical Report Form.
• Measure the intraocular pressure for the mean of the ocular pulse and remove the tonometer from the eye.
• Repeat steps (c), (d), and (e) if the measurement was not valid, because;

i) The subject felt a sensation; ii) The eyelid was touched; iii) The fluorescein ring was too broad or too small; iv) Any other circumstances suggest that the measurement may have been inaccurate;

• If there is any evidence that the anesthetic is no longer fully effective, then readminister the anesthetic.
• Repeat steps (c), (d), (e), and (f) an additional 2 times and record all 3 valid measurements on the Clinical Report Form.

• Clinician will ask participant if they felt anything or had any discomfort during the data capture. Response will be noted on the Clinical Report Form.
• Clinician will perform a slit lamp exam looking for any areas of dryness (superficial punctate epithelial erosions), abrasions, or changes from baseline exam.
• Following these initial PIB and GAT measurements, repeat the PIB measurements 3 times and record each valid measurement on the Clinical Report Form.

• Clinician will again ask participant if they felt anything or had any discomfort during the data capture. Response will be noted on the Clinical Report Form.
• Clinician will perform a slit lamp exam looking for any areas of dryness (superficial punctate epithelial erosions), abrasions, or changes from baseline exam.
• Remainder of the subject's exam for the clinical visit can resume as necessary. Data Collection

Data will be collected through various methods, including but not limited to:

• Self-reported questions recorded on the case report forms
• Clinical assessments and examinations
• Electronic data capture systems
• Medical record review Data collection will occur throughout the study visit in real time. Study completion Participants will be informed in real time of the IOP measurements being collected and upon completion will be thanked for their contributions to the research.

Data privacy And Confidentiality

Robust data privacy and confidentiality will be implemented to protect participant information. This includes:

• De-identification of data/Anonymous data collection
• Secure data storage
• Compliance with relevant data protection regulations

Medical Diagnosis/Medical Interventions Intervention Arms This is a single-arm study in which the participants will receive both PIB and GAT exams at their study visit. The GAT exam will necessitate use of anesthetic eye drops. There will be no randomization.

Intervention Delivery and Adherence The PIB and GAT procedures will be performed by Joel Solano, MD, a board certified opthalmologist who has undergone rigorous training on the study protocol and intervention procedures. To ensure adherence to the study protocol, Eye C Better Quality Control personnel will collect and review data sheets which have been formulated to ensure compliance with the protocol.

Intervention Modification Any modifications to the intervention regimen, including frequency of test administration, treatment interruptions, or early discontinuation, will be documented in accordance with the study protocol. A protocol deviation form will be completed for each modification, detailing the reason for the change and the actions taken.

Device Being Tested The PIB is a benchtop optical/acoustic measurement system mounted on an optical breadboard. A small loudspeaker, coupled to a 3D-printed conical waveguide, generates a brief, audible-range acoustic pulse that produces an oscillating air pressure of approximately 4 Pa (≈25,000× lower than atmospheric pressure) at the scleral surface. Simultaneously, a low-power infrared laser illuminates a small (≈1-2 mm diameter) region of exposed sclera approximately 4 mm from the limbus. The reflected speckle pattern is recorded by a dedicated high-speed camera while a separate tracking camera continuously monitors pupil position. If the pupil moves outside a predefined safe zone, the laser is shut off automatically within one video frame (≈33 ms). Captured speckle and tracking videos are processed off-device to derive an IOP estimate. ECB (Sponsor) has determined that the PIB device studied in this research is a Non-Significant Risk device and FDA Investigational Device Exemption has not yet been requested.

Accessory Materials:

In addition to the PIB system components, the following accessory materials are required at the study site for the safe and effective use of the device:

• 70% isopropyl alcohol wipes for cleaning subject-contact surfaces between subjects.
• Single-use lens tissue (for use only by ECB technical personnel for cleaning of optical components).
• Preservative-free artificial tears, available for subject comfort if mild transient ocular dryness is reported.
• Standard ophthalmic exam-room lighting and seating; chair height adjustable for the subject.
• Dedicated host computer (supplied by ECB) running the PIB acquisition software, with secure local storage and an encrypted-media or encrypted file-transfer pathway for periodic data export.

Device/Equipment Safety:

Risk assessments were performed for the PIB device in accordance with ISO 14971- Application of Risk Management to Medical Devices and the ECB Quality System in consultation with board certified, fellowship trained glaucoma specialists. The laser and acoustic energy sources directed at the subject may lead to the potential adverse events were identified during use of the PIB device:

• Significant corneal dryness
• Superficial punctate epithelial erosions
• Subject discomfort

Laser energy:

The PIB is a Group 1 instrument which is considered non-hazardous as defined by ANSI Z80.36 Light Hazard Protection for Opthalmic Instruments and ISO 15004-2 Opthalmic Instruments - Fundamental requirements and test methods - Part 2: Light hazard protection.

The PIB device also employs an eye tracking system that cuts off laser power when the pupil center deviates a preset distance from the nominal position. The pupil deviation limit is set to prevent exposure of the pupil, cornea and retina to laser radiation.

Acoustic energy:

Acoustic energy is not considered a credible hazard. Relevant scientific literature indicates that low-frequency acoustic exposure at the levels used in the PIB system is not expected to result in mechanical tissue damage affecting the cornea, lens, ocular structures, or intraocular pressure. The potential for thermal damage is negligible as indicated in comparison to the extreme worst case specified in the safety standard for ultrasonic physiotherapy equipment (IEC 60101-2-5).

Pressure-induced injury is not considered a credible risk as PIB operates at a sound pressure 25,000 times less than atmospheric pressure and significantly below the air pressure applied by FDA cleared puff tonometers intended to measure IOP.

Ocular surface dryness is a potential hazard . As reviewed by board-certified and fellowship trained ophthalmologists, the eye dryness hazard is mild, transient, and manageable with the following identified mitigation efforts

• Short Exposure Duration: Measurements limited to ~1-2 seconds per capture
• Intermittent Operation: Multiple captures separated by pauses as needed for comfort
• Operator Control: Testing can be stopped at any time
• Subject Response: Natural blinking between exposures; subject feedback monitored
• Remediation: Artificial tears may be used if dryness occurs
• Ongoing Evaluation: Early clinical observations will be used to update the risk assessment as needed

Auditory exposure risk is minimal or negligible when evaluated against OSHA 1910.95 requirements.

Data Acquisition and Management:

The PIB acquisition software writes all raw and derived data to the host computer during each session. The on-device data structure is organized per subject as summarized in Table 2: Data Storage Structure.

Table 2: Data Storage Structure Level Contents Subject directory Named only by an integer study ID. The mapping between subject identity and study ID is held by site personnel separately and is not stored on the PIB host computer.

Eye subdirectory (L / R) One subdirectory per eye, created at first measurement of that eye for the subject.

Per-test files Speckle camera video, tracking camera video, and a per-test log file containing acquisition parameters, timestamps, alignment metadata, and cumulative laser exposure for the test.

Data Transfer and Security:

Captured data are stored locally on the PIB host computer at the study site. Data are not transmitted automatically to any external server during the visit. Periodically, de-identified data are transferred to ECB on encrypted media (or via an encrypted, access-controlled file transfer) for offline analysis using the PIB machine-learning model. No protected health information (PHI) is stored on the PIB host computer; only the integer subject ID, eye, and acquisition parameters are retained on-device. Site personnel maintain the subject identity key in accordance with the site's standard operating procedures and HIPAA requirements.

Training of the Research Team/Operators:

Personnel will be instructed by Dr. Solano to clean the subject touching chin and forehead rest with 70% isopropyl alcohol wipes. Dr Solano is a board-certified ophthalmologist and has extensive training and experience with GAT technique. He will be instructed in use of the PIB device by Eye C Batter technical personnel. These same Eye C Better personnel will be in attendance at the first few subject procedures to ensure that Dr. Solano is adequately trained in PIB use. Once the subject is situated comfortably with their chin and forehead in place, they will be instructed to direct their gaze at the fixation light and the PIB IOP capture button will be depressed for IOP measurement.

ECB (Sponsor) has determined that the PIB device studied in this research is a Non-Significant Risk device. The device uses only light, sound, and a camera to capture reflected light from the ocular surface. No contact is made with the ocular surface.

The device is NOT intended as an implant that presents a potential for serious risk to the health, safety, or welfare of a subject.

The device is NOT purported or represented to be for a use in supporting or sustaining human life that presents a potential for serious risk to the health, safety, or welfare of a subject.

The device is NOT for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health that presents a potential for serious risk to the health, safety, or welfare of a subject.

The device does NOT otherwise present a potential for serious risk to the health, safety, or welfare of a subject.

Inclusion criteria

• Subject is a female or male;
• Subject is with or without a prior glaucoma diagnosis;
• Subject is 18 years or older;
• Subject is willing and able to sign an informed consent;
• Subjects considered to be vulnerable (i.e. individuals with impaired consent capacity and/or lack or loss of autonomy on the condition that written consent is provided by a legally authorized representative.

Exclusion criteria

• Subjects who are prisoners
• Subject refuses or is unable to sign the informed consent;
• Subjects with only one functional eye;
• Those with poor or eccentric fixation in one or both eyes;
• Those with corneal scarring or who have had corneal surgery including corneal laser surgery;
• Those with a history of incisional glaucoma or incisional retinal surgery;
• Microphthalmos;
• Buphthalmos;
• Contact lens use within the last three months;
• Symptoms of Dry Eye Syndrome and signs of dry eye on examination of cornea;
• Known history of difficulty in obtaining GAT IOP measurements;
• Lid squeezers or blepharospasm;
• Nystagmus;
• Keratoconus;
• Any corneal or conjunctival pathology or infection;
• Any conjunctival thickening or opacification that reduces the clear view to the sclera;
• Central corneal thickness greater than 0.600 mm or less than 0.500 mm (2 standard deviations about the human mean);
• Cataract Extraction within the last three months.