Vocorder Device Validation in Clinical Settings - Continuous Monitoring of Individuals (Vocorder Clinical Validation-VCV)

Study design The hypothesis In the study of breathomics, several VOCs, VOC patterns and relationships among changes in VOC patterns are found to be related to different types of diseases. Therefore, changes in VOC patterns of the exhaled air correlate with particular conditions, as measured by specific disease-related VOC profiles.

Background and Objectives of the study This clinical study is being conducted as part of the HORIZON-EIC-2022 PATHFINDER CHALLENGES-01-04 project entitled Vocorder, a new technology for breath analyses. Breath sample collection for VOC analysis (patients and control group), VOCs may already be present at a base level. However, the VOCORDER instrument will be capable of resolving those concentration differences caused by changes in the metabolism and discriminate against those which may already be present in the environmental air. Thus, the analyser will allow an in-situ time-resolved measurement of different gases (e.g., VOCs), recording their concentration profile within single breaths with minimal supervision and almost no strict methodology. However, in this validation phase strict methodology will be applied to ensure the validity of the approach and the unobtrusiveness of the method.

The breath analyses will be performed using laser-based breath analyser prototypes capable to detect small number of gases simultaneously. QCL mid-IR Array-based self-mixing analyser for the detection of VOCs with measurement range in the 10-100 ppb, limit of detection close to 1 ppb, resolution close to 1 ppb and accuracy near ± 1 ppb. Identification of compounds will rely on a NIST mass spectral library and the comparison of their retention indices with the library of indices obtained for reference standards. The initial breath analyser will be able to be tested in healthy and incubated patients alike, since the sampling tube can be connected to the ventilator directly, in addition to its original use.

This clinical study will address the correlation analysis between breath VOCs profiles as detected by the VOCORDER breath analyser and Electronic medical data collected by medical professionals. The obtained results are expected to be essential for tailoring the technology of breath analysis in the VOCORDER breath analyser towards the early detection of diseases of interest.

The main objectives of this clinical study are as follows:

1. To use the developed device in clinical setting and determine its operating parameters (respiratory volume, number, and frequency of clinical sampling). 2. To validate the performance of the device and its measurements produced in comparison with other relevant technologies and/or the established reference method. 3. To investigate the potential main correlations between the gases detected in breath analysis and the specific diseases chosen for this study.

Primary and secondary endpoint(s)

Primary endpoints:

To validate the effectiveness of the VOCORDER device in clinical practice and to promote further the technology of breath analyses.

Secondary endpoints:

1. Identify and define the operational parameters of the new technology of breath analyses in clinical practice. 2. Compare the performance and outcomes of VOCORDER technology against the GC-MS reference method. 3. Investigate the correlation between known pre-existing conditions and significant VOC biomarkers in exhaled breath for selected diseases. 4. Explore the potential of VOC biomarkers in exhaled breath for the early detection of diseases, facilitating timely diagnosis through correlation with key medical parameters.

Requirements for the conduct of the clinical study Research center for the implementation and the current approval status of the Ethics Committees The study will be conducted at MITERA Hospital. MITERA General Clinic, Maternity / Gynecological Clinic \& Children's Hospital has established itself as a leading healthcare facility, serving as a comprehensive care center for individuals of all ages. With 45 years of operation, MITERA stands out as one of Greece's most esteemed private hospitals, offering a wide range of high-quality health services aimed at the prevention, diagnosis and treatment across various medical fields. MITERA is home to three clinics: the General Clinic, the MITERA Maternity / Gynecological Clinic and the most comprehensive private pediatric clinic in Greece, the MITERA Children's Hospital. The commitment to providing exceptional nursing care and services is of high quality at MITERA Clinics, where a dedicated team of physicians, nurses, and midwives, backed by comprehensive administrative and technical support, are available around the clock, every day of the year, to address any medical emergency.

The hospital's Scientific Council has authorized the clinical study. The study will be conducted by the MITERA research team. Regulatory status

1. The requirements of the General Data Protection Regulation (GDPR) 2. Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons about the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC• WP29: Opinion 05/2014 on anonymization techniques. 3. The best practices of treatments/standard of care will be followed. The patients will be diagnosed according to these best practices. 4. Even though the clinical study does not include drug treatments, the general principles of Good Clinical Practice will be followed to ensure ethical and scientific quality. 5. The principles defined in the guidelines of Health Technology Assessment agencies, such as EUnetHTA, will be considered, especially the following:

* Comparators \& Comparisons. Criteria for the choice of the most appropriate comparator(s). * Summary of current policies and best practice guidelines. * Endpoint Criteria for Relative Effectiveness Assessment: Clinical Endpoints 6. The study will be designed and analyzed in accordance with the Statistical Principles for Clinical Trials (CPMP/ICH/363/96), ICH Topic E9 7. AEPD: AEPD Guidelines on Personal Data Anonymisation Procedures will provide a framework for ensuring privacy and data protection. 8. ENISA: Recommendations will be followed to align technology developments with GDPR, particularly regarding data pseudonymization techniques. 9. The joint AEPD-EDPS paper on using hash functions for personal data pseudonymization will serve as a reference for data protection strategies. 10. World Medical Association: The Declaration of Helsinki on ethical principles for medical research involving human subjects Informed Consent and Information Within VOCORDER, the responsible institution follows specific procedures and uses the consent form, ensuring compliance with the minimum information requirements for valid consent as outlined in the above frameworks. Participation in the VOCORDER research will be entirely voluntary for all individuals, with the right to withdraw from any stage of the research activities without facing any repercussions or penalties. A comprehensive information sheet outlining the purpose, procedure, risks, etc., of the VOCORDER research will be furnished to participants along with the consent form. A protocol and draft templates for information consent forms can be retrieved upon request. They will also be added in the Data Management Plan. Physicians with appropriate scientific training and qualifications will give the information. The medical staff will be capable of answering questions posed by the individuals and explaining the process to be followed, what is requested from the participant, and the anticipated results. It will be ensured that potential participants have fully understood the information.

The consent will be given freely by the participants. It will be guaranteed that they do not feel obliged to or coerced in any way into giving consent. Participants will consent in writing, particularly by signing the informed consent form and information sheets presented below. If consent cannot be given in writing, for example, because of illiteracy, non-written consent must be formally documented and independently witnessed. Consent is a continuing process, especially in long-term trials like the one of VOCORDER. The responsible project partners will foster a continuous dialogue with participants and inform them of anything different/new related to the trial.

Approval by Ethics Committee To enhance oversight of ethical procedures throughout the project lifecycle, an IEC of VOCORDER will be established. This committee will play a dominant role in ensuring compliance to the ethical principle prescribed in legislation at all stages of the project, from protocol development to findings publication. Further, the committee will collaborate with local ethics committees in the six participating countries to address any participant complaints arising during the study. The IEC will be tasked with compiling and submitting safety and interim reports to the relevant national ethics committees when necessary.

Appointment of contact points for ethical and legal matters In accordance with their respective activities and national regulatory framework, each partner involved in VOCORDER will appoint a Data Protection Officer (DPO) and/or designate a contact person responsible for addressing legal and ethical concerns related to the project's research activities.

Monitoring and reporting Regular reports on ethics risk monitoring during project meetings will be provided. The formulation and distribution of an ethics questionnaire internally to the partners involved in the technical advancement is under consideration to ensure the alignment with the ethical requirements. The IEC will be responsible for addressing any question raised by the partners of the project at all instances and cooperate with the respective representative of legal and ethical matters defined by each entity. VOCORDER will assess its outcomes at all phases of the project implementation against these requirements to ensure comprehensive coverage.

Phases of the clinical study

The clinical study is a prospective cohort study and will be conducted in two phases:

* 1st Phase: Baseline phase (October 2024-August 2025) * 2nd Phase: Validation phase - VOCORDED technology validation (May-December 2026)

Phases of the clinical study

The clinical study is a prospective cohort study and will be conducted in two phases:

* 1st Phase: Baseline phase (October 2024-August 2025) * 2nd Phase: Validation phase - VOCORDED technology validation (May-December 2026) Baseline phase The implementation of this phase is considered necessary to define the basic operating parameters of the manufactured technology in order to allow the transition to the final validation of the device in the clinical field. The above objective will be achieved with the contribution of the artificial intelligence mechanism (WP.4) and the analysis of the raw data of the technological research teams involved in the design of the breath analyser. In this phase, patients and healthy controls are enrolled and the measurements of the gases produced are analysed using the GC-MS reference method.

Validation phase (VOCORDER validation phase) During this stage, the VOCORDER technology undergoes clinical evaluation by both patients and healthy volunteers. The analysis involves measuring the gases emitted by the participants, utilizing both the standard reference method and the VOCORDER technology for comparison.

Diseases

The following diseases will be investigated:

1. Lung cancer 2. Gastric and colon cancer 3. Breast cancer 4. Kidney insufficiency 5. Infections - Pneumonia (community-acquired and hospital-acquired) The selection of these diseases was based on the ETH team's review of existing literature (Task 2.1) and the subsequent adaptation of the findings to align with VOCORDER's capabilities to detect specific gas biomarkers for the e

• Operational parameters of Vocorder [Срок оценки: At least 1 breath sample will be collected at 1 time point from each paricipant]
• VOCORDER technology vs reference method [Срок оценки: At least 1 breath sample will be collected at 1 time point from each paricipant]
• VOC biomarkers linked to diseases under study [Срок оценки: At least 1 breath sample will be collected at 1 time point from each paricipant]
• VOC biomarkers for the early detection of diseases [Срок оценки: At least 1 breath sample will be collected at 1 time point from each paricipant]