R-TF-015-004 Clinical investigation plan

Scope

This Clinical Investigation Plan (CIP) outlines the rationale, objectives, design, and methodology for the clinical investigation.

Nature and positioning of the evidence

This is a prospective, observational, non-interventional clinical investigation in real adult patients conducted at a single hospital dermatology department. Under MDCG 2020-6 Appendix III it constitutes Rank 2–4 evidence (prospective observational with subject-reported outcomes and investigator-completed usability and clinical-utility instruments). Under MDCG 2020-1 §4.4 it contributes Pillar 3 Clinical Performance evidence — specifically evidence of clinical utility, usability and data utility of the device in remote monitoring of chronic dermatological conditions — as used by the clinician and the patient in a real-world clinical workflow. It does not, on its own, evidence algorithm-level analytical performance across the intended 346 ICD-11 categories (which is Pillar 2, evidenced independently by the verification and validation records and by the published severity-validation manuscripts) nor does it substitute for diagnostic-accuracy evidence generated on the Top-5 prioritised differential view (which is evidenced by the Rank 2–4 diagnostic-performance investigations listed in the Clinical Evaluation Report).

CIP Identification

	CIP
Title of the clinical investigation	Clinical Validation of a Computer-Aided Diagnosis (CAD) System Utilizing Artificial Intelligence Algorithms for Continuous and Remote Monitoring of Patient Condition Severity in an Objective and Stable Manner
Device under investigation	Legit.Health Plus
Protocol version	Version 2.0
Date	2022-03-03
Protocol code	LEGIT_COVIDX_EVCDAO_2022
Sponsor	AI Labs Group S.L.
Coordinating Investigator	Dra. Marta Andreu
Principal Investigator(s)	Dra. Marta Andreu
Investigational site(s)	Torrejón University Hospital
Ethics Committee	Comité de Ética de la Investigación con Medicamentos de los Hospitales Universitarios Torrevieja y Elche-Vinalopó

Trial Registrations

• ClinicalTrials.gov (NCT): NCT06237036
• EMA RWD Catalogue (EUPAS): EUPAS108260

Table of contents

• Scope
  • Nature and positioning of the evidence
• CIP Identification
  • Trial Registrations
• Compliance Statement
• Abbreviations and definitions
• CIP or protocol specifications
  • Principal Investigator
  • Coordinating investigator
  • Collaborating Investigators
  • Technical Support (Manufacturer)
  • Investigational sites
  • Funding
• Product Identification and Description
  • Device version under investigation and bridging to the CE-marked release
• Justification of the design
  • Background and rationale
  • Risks and benefits of the product in investigation and clinical research
• Pre-specified acceptance-criteria structure
• Objectives
  • Primary objective
  • Secondary objectives
• Summary of the study
• Design and methods
  • Type of clinical research
  • Population
  • Sample size
  • Duration
  • Acceptance criteria
    • Justification of acceptance thresholds
  • Inclusion and exclusion criteria
    • Inclusion criteria
    • Exclusion criteria
  • Variables
    • Main variable
    • Secondary variables
  • Condition of interest
  • Limitations of clinical research
• Ethical considerations
  • Data confidentiality
  • Bias minimisation measures
  • Calendar
  • Monitoring plan
  • Completion of the investigation
  • Statistical analysis
    • Primary analysis
    • Secondary analyses
    • Software
  • Data management
• CIP Modification
• CIP Deviations
• Start, follow-up and end reports
• Statements of compliance
• Informed Consent process
• Adverse events, adverse product reactions and product deficiencies
  • Adverse Events (AE) and Adverse Events to Product (AEP)
  • Product deficiencies
  • Serious Adverse Events, serious adverse events to the product and serious and unexpected adverse events to the product
  • Foreseeable adverse events and adverse events to the product
  • Data Monitoring Committee (DMC)
• Suspension or early termination of clinical research
• Annexes
  • Annex I. Protocol of the study
  • Annex II. Ethics committee approval
  • Annex III. Patient information sheet
  • Annex IV. Informed consent

Compliance Statement

The clinical investigation will be conducted according to the Clinical Investigation Plan (CIP) and other applicable guidances and regulations. This includes compliance with:

• The ethical principles originating from the World Medical Association's Declaration of Helsinki
• Harmonized standard UNE-EN ISO 14155:2020
• Regulation (EU) 2017/745 on medical devices (MDR), including the applicable General Safety and Performance Requirements (GSPR) as outlined in Annex I, and the requirements of Annex XV (Chapter I and Chapter II, Section 3)
• Harmonized standard UNE-EN ISO 13485:2016
• MDCG 2024-3 for its structural and content expectations, MDCG 2021-8 concerning application requirements, and MDCG 2020-10/1 Rev 1 for safety reporting timelines and definitions
• Regulation (EU) 2016/679 (GDPR)
• Spanish Organic Law 3/2018 on the Protection of Personal Data and guarantee of digital rights.

All data processing within the device is carried out in accordance with the highest standards of data protection and privacy. Patient information is managed in an encrypted manner to ensure confidentiality and security.

The research team assumes the role of Data Controller, responsible for the collection and management of study data. Legit.Health acts as the Data Processor and is not involved in the processing of patient data.

The storage and transfer of data comply with European data protection regulations. At the conclusion of the study, all information stored in the device will be permanently and securely deleted.

The device employs robust technical and organizational security measures to safeguard personal data against unauthorized access, alteration, loss, or processing.

Abbreviations and definitions

• AE: Adverse Event
• AEMPS: Spanish Agency of Medicines and Medical Devices
• AEP: Adverse Reaction to Product
• AUC: Area Under the ROC Curve
• CAD: Computer-Aided Diagnosis
• CMD: Data Monitoring Committee
• CIP: Clinical Investigation Plan
• CUS: Clinical Utility Questionnaire
• DLQI: Dermatology Quality of Life Index
• GCP: Standards of Good Clinical Practice
• ICH: International Conference of Harmonization
• IFU: Instructions For Use
• IRB: Institutional Review Board
• N/A: Not Applicable
• NCA: National Competent Authority
• PI: Principal Investigator
• PPV: Positive Predictive Value
• NPV: Negative Predictive Value
• SAE: Serious Adverse Events
• SAEP: Serious Adverse Event to Product
• SUAEP: Serious and Unexpected Adverse Event to the Product
• SUS: System Usability Scale

CIP or protocol specifications

Principal Investigator

• Dr. Marta Andreu Barasoain (Hospital Universitario de Torrejón).

Coordinating investigator

• Dr. Marta Andreu Barasoain (Hospital Universitario de Torrejón).

Collaborating Investigators

• Dr. Leticia Calzado — Chief of Dermatology, Hospital Universitario de Torrejón.
• Dr. Elena Sánchez-Largo — Attending Dermatology Physician, Hospital Universitario de Torrejón.
• Dr. Javier Alcántara — Attending Dermatology Physician, Hospital Universitario de Torrejón.
• Dr. Tania Marusia Capusan — Attending Dermatology Physician, Hospital Universitario de Torrejón.
• Dr. Marta Ruano — Attending Dermatology Physician, Hospital Universitario de Torrejón.

Technical Support (Manufacturer)

• Mr. Alfonso Medela — Chief Technology Officer.
• Mr. Taig Mac Carthy — Chief Innovation Officer.

Investigational sites

• Hospital Universitario de Torrejón.

Funding

This research was carried out without any funding or sponsorship.

Product Identification and Description

	Information
Device name	Legit.Health Plus (hereinafter, the device)
Model and type	NA
Version	1.1.0.0
Basic UDI-DI	8437025550LegitCADx6X
Certificate number (if available)	MDR 000000 (Pending)
EMDN code(s)	Z12040192 (General medicine diagnosis and monitoring instruments - Medical device software)
GMDN code	65975
EU MDR 2017/745	Class IIb
EU MDR Classification rule	Rule 11
Novel product (True/False)	TRUE
Novel related clinical procedure (True/False)	TRUE
SRN	ES-MF-000025345

Throughout this document, references to "the device" refer to the investigational product identified above.

Device version under investigation and bridging to the CE-marked release

The device version under investigation corresponds to the current CE-marked release v1.1.0.0. The PRRC has reviewed the device change-control records covering the investigation window and confirms that, in relation to the CIP objectives, variables and acceptance criteria, the configuration used during the investigation is equivalent to the current CE-marked release (identity bridge). No clinically relevant change in intended purpose, indications for use, algorithm-level clinical output, user interface mandated by the Instructions for Use, or risk profile was introduced between the investigation window and the current release.

Justification of the design

Background and rationale

The diagnosis and monitoring of chronic dermatological conditions rely predominantly on in-person clinical assessment, subject to inter-rater variability and to access constraints that were exacerbated during the COVID-19 pandemic. There is a recognised need for tools that support continuous, objective, remote monitoring of dermatological severity in a manner that complements, rather than substitutes, the dermatologist's judgement.

This clinical investigation evaluates, in a real-world hospital dermatology setting, the clinical utility, data utility, usability and patient satisfaction associated with the device when used by patients at home for self-capture of images and self-completed severity questionnaires, and by dermatologists for remote review of the resulting records. The investigation targets surrogate endpoints (clinician-rated clinical utility, investigator-rated data utility, System Usability Scale and patient satisfaction) that map, under MDCG 2020-1 §4.4, to Pillar 3 Clinical Performance — clinical-utility and usability aspects of the clinician+device workflow.

Risks and benefits of the product in investigation and clinical research

Participants did not undergo any procedures posing a risk to their safety. The investigation was non-interventional: patients continued to receive standard of care from their treating dermatologist and the device output was not binding on clinical decision-making. The anticipated benefit was the generation of usability and clinical-utility evidence supporting the design of remote-monitoring workflows for chronic dermatological conditions.

Pre-specified acceptance-criteria structure

The pre-specified acceptance-criteria set for this investigation is the domain-structured set rendered by the <AcceptanceCriteriaTable /> component in §Acceptance criteria below, anchored to the State-of-the-Art baselines established in R-TF-015-011 State of the Art. Each criterion has its own pre-specified threshold; the criteria span three clinical-utility domains:

• Objective severity assessment — two criteria, including a Clinical Utility Questionnaire (CUS)-acronymed criterion at a State-of-the-Art-anchored threshold of 0.75.
• Expert consensus — one criterion at a State-of-the-Art-anchored threshold of 0.75.
• Resource optimisation — four criteria, including a CUS-acronymed criterion at a threshold of 0.80 (set above the SotA baseline to demonstrate substantial clinical benefit per MDCG 2020-1 §4.4), the remaining three at 0.75 equal-to-or-greater-than or within-range thresholds.

The CIP protocol text historically referenced "a score of 8 or higher on the Clinical Utility Questionnaire (CUS)" as the narrative headline acceptance statement; that statement corresponds to the CUS-acronymed resource-optimisation criterion at the 0.80 threshold (one of the seven). It is preserved as a narrative summary of that specific criterion and does not displace the seven-criterion data-file structure as the pre-specified acceptance set.

Objectives

Primary objective

To evaluate the clinical utility of the device, as perceived by attending dermatologists, for remote and continuous monitoring of chronic dermatological conditions. The primary endpoint is the pre-specified acceptance-criteria set described in §Pre-specified acceptance-criteria structure and rendered by the <AcceptanceCriteriaTable /> component in §Acceptance criteria below. Each criterion is tested against its own pre-specified threshold; the aggregate outcome is reported as the count of met and not-met criteria and is qualified by domain (objective severity assessment, expert consensus, resource optimisation).

Secondary objectives

• To assess investigator-rated data utility via the Data Utility Questionnaire (DUQ).
• To assess system usability, from the dermatologist's perspective, via the System Usability Scale (SUS) questionnaire (Annex III).
• To assess patient-reported satisfaction via the Patient Satisfaction Questionnaire (Annex II).

All secondary endpoints are descriptive and hypothesis-generating; no formal multiplicity control is applied and no confirmatory decision rule is attached to the secondary endpoints.

Summary of the study

This is a prospective, observational, single-arm clinical investigation designed to evaluate the clinical utility, data utility, usability and patient satisfaction associated with the device when used for remote monitoring of chronic dermatological conditions. The investigation enrolled 160 adult patients attending the Dermatology Department of the Hospital Universitario de Torrejón. Data capture comprised patient-submitted photographs and self-completed severity questionnaires, investigator-completed clinical-utility and data-utility questionnaires, and patient-reported satisfaction and usability questionnaires. The investigation adhered to applicable ethical and data-protection requirements, including prior favourable opinion of the competent Ethics Committee for Research with Medicinal Products and written informed consent from each participant.

Design and methods

Type of clinical research

Prospective, observational, single-arm clinical investigation. There is no active arm and no control arm. The primary endpoint is the pre-specified acceptance-criteria set described in §Pre-specified acceptance-criteria structure; secondary analyses are descriptive. Under MDCG 2020-6 Appendix III the resulting evidence is Rank 2–4 (prospective observational on real patients with validated instruments); under MDCG 2020-1 §4.4 it contributes Pillar 3 Clinical Performance evidence for the clinical-utility and usability aspects of the clinician+device workflow.

Population

Adult patients (>18 years) attending the Dermatology Department of the Hospital Universitario de Torrejón with a chronic dermatological condition that meets the inclusion criteria.

Sample size

The sample size of 6 participating dermatologists and 160 enrolled patients was selected to support the pre-specified acceptance-criteria assessment and the descriptive secondary analyses.

For the investigator-reported clinical-utility instruments (CUS, DUQ) the unit of analysis is the dermatologist (n = 6). Six dermatologists provide the descriptive precision required to assess domain-level endorsement proportions against the State-of-the-Art-anchored thresholds declared in the acceptance-criteria set, under the non-interventional observational design. The small dermatologist cohort limits the statistical power of inferential tests at the individual-criterion level and increases sensitivity to individual outlier responses; this constraint is explicitly carried forward into §Limitations and into the Post-Market Clinical Follow-up Plan. For the patient-reported instruments (Patient Satisfaction Questionnaire, SUS completed by patients) 160 enrolled patients provide descriptive precision consistent with the exploratory nature of those analyses.

No formal multiplicity control is applied across the seven acceptance criteria; each is pre-specified against its own threshold and assessed independently. Where an inferential confidence interval is required, a two-sided 95% Wilson CI is reported.

Duration

• Recruitment period: 6 months (estimated).
• Total study duration: 12 months (estimated), including database closure, data analysis and preparation of the final report.
• Per-participant follow-up: 6 months from date of inclusion.

Acceptance criteria

• CUS (Expert consensus) equal to or greater than 75.00%.(User Group: Dermatologists)
• Expert consensus between range 75.00%.(User Group: Dermatologists)
• CUS (Expert consensus) equal to or greater than 80.00%.(User Group: Dermatologists)

Justification of acceptance thresholds

The seven acceptance criteria and their thresholds above are anchored to the State-of-the-Art baselines established in R-TF-015-011 State of the Art. Each criterion is pre-specified as an absolute-value threshold matched to or exceeding the SotA meta-analytic baseline for the corresponding clinical-utility or resource-optimisation construct in dermatology decision-support literature.

• The 0.75 thresholds on the severity-assessment criteria, the expert-consensus criterion and the resource-optimisation equal-to-or-greater-than criteria are set at the SotA baseline for aided-HCP clinical-utility endorsement.
• The 0.80 threshold on the CUS-acronymed resource-optimisation criterion is set above the 0.75 SotA baseline to demonstrate substantial clinical benefit per MDCG 2020-1 §4.4.
• The within-range criterion is pre-specified as an acceptance range of ±0.10 around 0.75 in the underlying data-file structure; observed values outside that range are reported as not met.

The cross-reference to R-TF-015-011 covers the systematic review, inclusion criteria and per-metric derivations.

Inclusion and exclusion criteria

Inclusion criteria

• Adult patients (>18 years) attending the Dermatology Department of the Hospital Universitario de Torrejón with a chronic dermatological condition.
• Patients who have provided written informed consent for participation in the investigation.
• Patients who demonstrate proficiency in written and spoken Spanish or English.
• Patients who possess a smartphone, defined as a phone equipped with internet access and an integrated camera, regardless of make, model or technical specifications.

Exclusion criteria

• Patients who, as determined by the investigator, are unable to adhere to the investigational procedures.
• Patients who had used the device under investigation prior to the commencement of the study.

Variables

Main variable

• The pre-specified acceptance-criteria set rendered by the <AcceptanceCriteriaTable /> component, comprising seven domain-structured criteria across objective severity assessment, expert consensus and resource optimisation, as described in §Pre-specified acceptance-criteria structure.

Secondary variables

• Demographic data: sex, age, postcode.
• Clinical data: diagnosis, date of diagnosis, concomitant medications.
• Investigator-rated worsening-pathology alerts.
• Patient-reported quality of life: Dermatology Life Quality Index (DLQI) score.
• Patient-reported satisfaction: Patient Satisfaction Questionnaire score.
• Consultation-management indicators: number of face-to-face consultations, number of telematic consultations and consultation times.
• System usability: System Usability Scale (SUS) questionnaire completed by dermatologists and by patients (Annex III).
• Application-use indicators: logins, number of photographs submitted.

Condition of interest

Chronic dermatological conditions expected to be enrolled at the investigational site include, in particular: psoriasis, urticaria, hidradenitis suppurativa, acne, atopic dermatitis, vitiligo, infantile haemangioma and nail pathology. The inclusion criteria do not operationally restrict enrolment to these named conditions; subjects carrying other chronic dermatological diagnoses attended by the Dermatology Department are eligible. Any deviation between the condition-of-interest list and the actually-enrolled population is reported and analysed in the Clinical Investigation Report (R-TF-015-006).

Limitations of clinical research

1. The investigation is single-arm and single-site, limiting generalisability to other clinical settings and to primary-care contexts.
2. The dermatologist sample (n = 6) is small; inferential testing at the individual-criterion level is adequately powered only against large effects, and the assessment is sensitive to individual outlier responses.
3. The primary endpoint is a multi-criterion clinical-utility acceptance set based on clinician- and patient-reported instruments; it measures perceived clinical utility, data utility and resource optimisation. It does not directly evidence diagnostic-accuracy performance or patient-outcome benefit; those claims are evidenced by separate investigations and addressed at Clinical Evaluation level.
4. Patient-submitted photographs are captured on heterogeneous smartphones under uncontrolled lighting; image-quality variability is an expected source of measurement variability.
5. Fitzpatrick V and VI phototype coverage is expected to be low at the investigational site; phototype coverage across darker skin tones is addressed by dedicated bridging evidence at Clinical Evaluation level (R-TF-015-003) and by the Post-Market Clinical Follow-up Plan.

Ethical considerations

This study adhered to international Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki in its latest amendment, and applicable international and national regulations. As applicable, approval from the relevant Ethics Committee was obtained prior to the initiation of the study. When applicable, modifications to the protocol were reviewed and approved by the Principal Investigator (PI) and subsequently evaluated by the Ethics Committee before subjects were enrolled under a modified protocol.

This study was conducted in compliance with European Regulation 2016/679, of 27 April, concerning the protection of natural persons with regard to the processing of personal data and the free movement of such data (General Data Protection Regulation, GDPR), and Organic Law 3/2018, of 5 December, on the Protection of Personal Data and the guarantee of digital rights. In accordance with these regulations, no data enabling the personal identification of participants was collected, and all information was managed securely in an encrypted format.

Participants were informed both orally and in writing about all relevant aspects of the study, with the information being tailored to their level of understanding. They were provided with a copy of the informed consent form and the accompanying patient information sheet. Adequate time was given to patients to ask questions and fully comprehend the details of the study before providing their consent.

The PI was responsible for the preparation of the informed consent form, ensuring it included all elements required by the International Conference on Harmonisation (ICH), adhered to current regulatory guidelines, and complied with the ethical principles of GCP and the Declaration of Helsinki.

The original signed informed consent forms were securely stored in a restricted access area under the custody of the PI. These documents remained at the research site at all times. Participants were provided with a copy of their signed consent form for their records.

Data confidentiality

Current legislation will be complied with in terms of data confidentiality protection (European Regulation 2016/679, of 27 April, on the protection of natural persons with regard to the processing of personal data and the free movement of such data and Organic Law 3/2018, of 5 December, on Personal Data Protection and guarantee of digital rights). For this purpose, when applicable, each participant will receive an alphanumeric identification code in the study that will not include any data allowing personal identification (coded CRD). The Principal Investigator will have an independent list that will allow the connection of the identification codes of the patients participating in the study with their clinical and personal data. This document will be filed in a secure area with restricted access, under the custody of the Principal Investigator and will never leave the centre.

Once the paper CRDs are completed and closed by the Principal Investigator, the data will be transferred to a database.

As in the CRDs, the Database will comply with current legislation in terms of data confidentiality protection (European Regulation 2016/679, of 27 April, on the protection of natural persons about the processing of personal data and the free movement of such data and Organic Law 3/2018, of 5 December, on the Protection of Personal Data and guarantee of digital rights) in which no data allowing personal identification of patients will be included.

Bias minimisation measures

• Consecutive-case enrolment of patients attending the Dermatology Department who meet the inclusion criteria, to reduce selection bias relative to ad-hoc convenience sampling.
• Standardised use of the device by both patients and investigators, in accordance with the Instructions for Use and the study's standard operating procedure for image capture.
• Pre-specified acceptance-criteria set with pre-specified thresholds anchored to SotA baselines.
• Prospective data capture via a controlled electronic case-report form and the device's application, reducing recall bias compared with retrospective data sources.
• Separation of the investigator role (CUS, DUQ completion) from the patient role (DLQI, Patient Satisfaction Questionnaire, SUS completion), with no patient-reported instrument directly visible to the investigator prior to its completion.

Residual sources of bias — single-arm design with no blinding, small dermatologist sample, and patient self-selection into smartphone-based workflows — are acknowledged in the Limitations of Clinical Research section.

Calendar

• Recruitment period: 6 months (estimated).
• Total study duration: 12 months (estimated), including database closure, data analysis and report preparation.
• Per-participant follow-up: 6 months from date of inclusion.

Monitoring plan

The team will hold a meeting with the investigative team every 3 months to address any potential questions and ensure that data is being collected properly.

The clinical investigation will be monitored by a designated clinical monitor, who is independent of the investigational site and appointed by the sponsor. The purpose of monitoring is to ensure that:

• The rights, safety, and well-being of the subjects are protected.
• The data reported are accurate, complete, and verifiable from source documents.
• The clinical investigation is conducted in compliance with the Clinical Investigation Plan (CIP), applicable regulatory requirements (including Regulation (EU) 2017/745), and ISO14155:2020.

In this way, monitoring will be performed through:

• Remote monitoring activities: Including scheduled video or telephone meetings depending on the availability of the investigators to review study progress, discuss challenges, and ensure ongoing compliance. The first review will take place after data from 3 patients have been collected. Subsequently, a review will be conducted every 5 additional patients.
• On-site visits: If deemed necessary based on data review, protocol deviations, or issues raised during remote monitoring.
• Source data verification (SDV): The sponsor in this case has secure access to anonymised source documents (e.g., image files, clinical assessment records) via encrypted digital platforms or controlled site systems to verify data accuracy and consistency with Case Report Forms (CRFs).
• Risk-based monitoring approach: The extent and frequency of monitoring activities will be adapted to the complexity and risk level of the investigation. Given that this study does not involve significant deviation from routine care, the monitoring will be primarily remote unless specific issues arise.

All monitoring activities will be documented in monitoring visit reports. Any protocol deviations or non-compliance identified will be documented, assessed for impact, and communicated promptly to the sponsor. Corrective actions will be tracked and followed up by the monitor or the sponsor.

Completion of the investigation

After the final closure of the clinical investigation a Clinical Investigation Report (R-TF-015-006) is prepared, even in the event of early termination or suspension. The Clinical Investigation Report is provided to the Ethics Committee and to the Spanish Agency for Medicines and Medical Devices (AEMPS) where applicable. The results obtained, whether positive, inconclusive or negative, are reported to the relevant public-access registries.

Where appropriate, results may be published in peer-reviewed scientific journals. The Ethics Committee that approved this clinical investigation is acknowledged, and any funds received by the author for the study and their source are disclosed. The anonymity of participants is maintained at all times.

Statistical analysis

Primary analysis

The primary analysis is the assessment of each of the seven pre-specified acceptance criteria against its own threshold, as described in §Pre-specified acceptance-criteria structure and §Justification of acceptance thresholds. For each criterion, the observed value is compared against the pre-specified threshold per the valence declared in the acceptance-criteria data (equal-to-or-greater-than, within-range); the criterion is reported as met or not met. The aggregate primary-endpoint outcome is the count of met versus not-met criteria, qualified by domain.

Two-sided 95% Wilson confidence intervals are reported for the observed values on each criterion. Where a CUS-acronymed criterion is reported, a one-sample Student's t-test against the pre-specified threshold is reported as descriptive inferential support at α = 0.01; this inferential support is supplementary and does not displace the acceptance-criteria-based decision rule.

Secondary analyses

• Descriptive statistics (mean, standard deviation, frequency distributions) for all items of the CUS, DUQ, SUS and Patient Satisfaction Questionnaire.
• Two-sided 95% confidence intervals (Wilson for proportions; Student's t for means) for descriptive purposes only.
• No multiplicity correction is applied; all secondary analyses are pre-specified as descriptive and hypothesis-generating.

Software

Analyses are implemented in a deterministic, version-controlled analytics environment maintained by the manufacturer; statistical tests and confidence intervals are computed in accordance with this section of the CIP.

Data management

The data will be managed and tabulated with consistency rules and logical ranges to control inconsistencies during data tabulation. A validation process of the clinical data will be carried out by running computer filters based on validation rules, which will automatically identify missing values or inconsistencies of clinical data according to the protocol. Additionally, manual editing and validation will be performed using descriptive and exploratory statistical techniques to complement the detection of logical errors and inconsistent values.

The database will be considered closed upon completion of all data management processes and satisfactory resolution of discrepancies and errors in the data. Any changes in the database after its closure can only be made after written agreement between the Principal Investigator and the technical coordinators of the project.

AI Labs Group, S.L. (hereinafter, the manufacturer) is the owner of the device. During the period of validity of this study, the manufacturer will grant a license to use the device by the research team free of charge. The research team will be the administrator of the account. Both patients and members of the medical team will have login credentials. The manufacturer will not have access to the account or patient information.

According to the definitions and roles set out in Regulation (EU) 2016/679 (GDPR), the Data Controller is the research team and the manufacturer is the Data Processor.

The storage of data and photographs will be in line with the European Regulation 2016/679 (GDPR) and the Organic Law 3/2018 of 5 December on the Protection of Personal Data and guarantee of digital rights. At the end of the study, all information stored in the device will be totally and permanently deleted.

The device complies with current legislation on the protection and confidentiality of personal data European Regulation 2016/679 (GDPR). Appropriate technical and organizational security measures are adopted to ensure the security of personal data and prevent its alteration, loss, unauthorized processing or access, given the state of technology, the nature of the data and the risks to which they are exposed, whether from human action or the natural physical environment.

CIP Modification

As indicated in the UNE-EN ISO 14155:2021 standard, the Clinical Investigation Plan (CIP) may be modified as necessary during the clinical investigation. The changes made must be described, along with their justification, potential impact on clinical performance, efficacy, safety, or other evaluation criteria, and identification of other affected documents.

CIP modifications will be prepared by the sponsor and agreed upon and accepted between the sponsor and the principal investigator. The modifications will be recorded with a justification for each one in the form of an amendment or addendum.

The required regulatory authority (AEMPS) and the Ethics Committee or Institutional Review Board (IRB) will be notified, if necessary. Modifications to the clinical investigation may only be implemented once favourable feedback and the corresponding approval have been obtained.

In accordance with Article 75 of Regulation (EU) 2017/745, substantial modifications to the clinical investigation must be approved by both the Ethics Committee for investigation with medicines (CEIm) and the Competent Authority (AEMPS) prior to their implementation.

• In the case of substantial modifications to authorized clinical investigations, a request must be submitted to the AEMPS and the CEIm.
• For non-substantial modifications to authorized clinical investigations, until the corresponding module is available in the EUDAMED database, the updated documentation will be sent to the AEMPS for inclusion in their file.

CIP Deviations

As indicated in the UNE-EN ISO 14155:2021 standard, the investigator may not deviate from the Clinical Investigation Plan (CIP), except in emergencies (section 4.5.4.b of the standard). In such cases, the investigator may proceed without prior approval from the sponsor and the Ethics Committee to protect the rights, safety, and well-being of human subjects. The use of waivers from the Clinical Investigation Plan is strictly prohibited.

These deviations must be documented by the principal investigator and notified to the sponsor and the IRB as soon as possible, and always within a maximum of 15 days. Immediately after receiving the notification, the sponsor will record and analyze the deviations carried out and their potential impact. Depending on the findings, the sponsor will take the necessary corrective and/or preventive measures.

In other circumstances, when deviations affect the rights, safety, and well-being of the subject or the scientific integrity of the clinical investigation, deviation requests and reports must be provided to the IRB if required.

Start, follow-up and end reports

The start of the study is notified to the Ethics Committee. Annual follow-up reports are submitted thereafter.

Upon obtaining the study conclusions a final report (R-TF-015-006 Clinical Investigation Report) is prepared and submitted to the Ethics Committee.

Statements of compliance

The present clinical investigation will be conducted following the ethical principles originating from the Declaration of Helsinki.

Additionally, the clinical investigation will comply with the harmonized standard UNE-EN ISO 14155:2021 and the European Regulation MDR 2017/745. The statement specifying compliance with the general safety and performance requirements in accordance with MDR can be found in the document Manufacturer's Declaration of Compliance with Requirements.

As appropiate, clinical investigation will not commence until approval/favourable opinion has been obtained from the Clinical Research Ethics Committee (CREC) and the required regulatory authority (Spanish Agency for Medicines and Medical Devices, AEMPS), and it must comply with any additional requirements imposed by the CREC and/or AEMPS.

Informed Consent process

The patient, or, in their absence, the family member or legally authorised representative, provides written consent before inclusion in the clinical investigation. Consent follows a prior interview with the principal investigator or a member of the research team, during which the objectives of the investigation, its risks, inconveniences and benefits, and the conditions under which it is conducted are explained, and the right to withdraw from the investigation at any time, without explanation and without incurring any responsibility or prejudice, is made explicit.

The principal investigator discusses the study with the subject and provides the information objectively, without coercion or influence, and without offering any inappropriate or undue incentive. The principal investigator uses non-technical language in the subject's native language (or that of the closest relative or legally authorised representative) and allows sufficient time for reading and comprehending the information.

Each participant documents their informed consent by signing and dating the informed consent form. Each signed and dated consent is kept by the principal investigator, and a copy of the informed consent is provided to the subject.

If new information arises that could affect the subject's willingness to continue participating in the clinical investigation, it is provided in any case. Where necessary, continued informed consent is confirmed in writing.

Adverse events, adverse product reactions and product deficiencies

Adverse Events (AE) and Adverse Events to Product (AEP)

An AE is any unintended medical event, unanticipated illness or injury, or unintended clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational product.

An AEP is an adverse event related to the use of an investigational medical device.

Foreseeable AEPs and AEs associated with the intended use of the device are documented in the Instructions for Use and in the Risk Management Record (R-TF-013-002).

Product deficiencies

Possible inadequacies of a medical device may relate to its identity, quality, durability, reliability, safety or performance.

Product deficiencies identified during the investigation are managed by the sponsor in accordance with the non-conforming-product control procedure. Where appropriate, corrective and preventive actions are implemented to protect the safety of subjects, users and other individuals.

Serious Adverse Events, serious adverse events to the product and serious and unexpected adverse events to the product

According to UNE-EN ISO 14155:2021:

• A Serious Adverse Event (SAE) is an AE that resulted in any of the following: death, serious deterioration of the health status of the subject, users or other persons, fetal distress, fetal death, congenital anomaly or birth defect.
• A Serious Adverse Product Reaction (SAEP) is an SAE that has produced any consequence characteristic of a serious adverse event.
• A Serious Unexpected Adverse Event to the Product (SUAEP) is an SAE that, due to its nature, incidence, intensity or consequences, has not been identified in the updated risk assessment.

Given the non-interventional design and the intended use of the device, no SAEs, SAEPs or SUAEPs are anticipated. All AE and product-deficiency collection is documented in the CIR.

Foreseeable adverse events and adverse events to the product

Foreseeable adverse events and expected adverse reactions to the product, as well as their incidence, mitigation and treatment, are documented in the Risk Management Record (R-TF-013-002) of the product under study.

Data Monitoring Committee (DMC)

No independent Data Monitoring Committee was established for this investigation, consistent with the non-interventional single-arm design, the absence of anticipated serious risks to subjects and the limited duration of the investigation. Ongoing safety oversight was performed by the Principal Investigator in coordination with the sponsor.

Suspension or early termination of clinical research

As indicated in the UNE-EN ISO 14155:2021 regulation, the sponsor may suspend or terminate the clinical research early for significant and documented reasons. These are:

• If during the clinical research the suspicion of an unacceptable risk arises, including a serious threat to the health of the subjects. It must be suspended while the risk is determined.
• If an unacceptable risk that cannot be controlled is confirmed.
• Due to the impossibility of including a minimum number of subjects that allows the final assessment of the study within a reasonable period according to the characteristics of the study.
• When instructed by the IRB or the required regulatory authority (AEMPS).
• Due to non-compliance with the obligations assumed in the contract by any of the contracting parties.
• By mutual agreement between the parties, expressed in writing.
• By the will of one of the parties, expressed in writing at least one month in advance.

In the event of a suspension or early termination of the clinical research, the sponsor will inform the AEMPS. The sponsor must provide the resources to comply with the obligations of the CIP and with the existing agreements. The principal investigator must inform the subjects if so stipulated in the agreement between the sponsor and the research centre.

If the clinical investigation is resumed, the sponsor must inform the principal investigator and, where appropriate, the AEMPS. Approval from the IRB and, where appropriate, from the AEMPS will be required for such resumption. The principal investigator must inform the subjects.

In accordance with Article 77 of Regulation (EU) 2017/745, the sponsor must notify the Member States in which the clinical investigation is being conducted of the end of the clinical investigation, its temporary halt, or its early termination, within the deadlines specified by the regulation (within 15 days of the end, or within 24 hours in case of early termination or temporary halt for safety reasons). This notification must be accompanied by a justification in case of early termination or temporary halt.

Annexes

Annex I. Protocol of the study

Annex II. Ethics committee approval

Approved by the Comité de Ética de la Investigación con Medicamentos de los Hospitales Universitarios Torrevieja y Elche-Vinalopó on 2022-04-13, reference number 12/04/22 LEGIT_COVIDX.

Annex III. Patient information sheet

Annex IV. Informed consent

Signature meaning

The signatures for the approval process of this document can be found in the verified commits at the repository for the QMS. As a reference, the team members who are expected to participate in this document and their roles in the approval process, as defined in Annex I Responsibility Matrix of the GP-001, are:

• Author: Team members involved
• Reviewer: JD-018 Clinical Research Coordinator
• Approver: JD-022 Medical Manager