R-TF-015-004 Clinical Investigation Plan Legit.Health_AIHS_Confirmatory_2026

Scope

The purpose of this Clinical Investigation Plan (CIP) is to set out the rationale, objectives, design, methodology, conduct, implementation, record-keeping and the method of analysis for the clinical investigation.

CIP Identification

	CIP
Title of the clinical investigation	Confirmatory Validation of an Artificial Intelligence Algorithm for the Automated Severity Assessment of Hidradenitis Suppurativa
Device under investigation	Legit.Health Plus (version 1.1.0.0)
Protocol version	1.0
Date	To be assigned upon CIP approval
Protocol code	Legit.Health_AIHS_Confirmatory_2026
Sponsor	AI LABS GROUP S.L.
Coordinating Investigator	Dr. Antonio Martorell Calatayud
Principal Investigator(s)	Dr. Antonio Martorell Calatayud
Collaborating Investigator(s)	To be confirmed prior to study initiation
Investigational site(s)	To be confirmed prior to study initiation
Ethics Committee	To be confirmed prior to study initiation

Table of contents

• Scope
• CIP Identification
• Compliance statement
• Abbreviations and Definitions
• CIP or protocol specifications
  • Principal Investigator
  • Coordinating Investigator(s)
  • Collaborating Investigator(s)
  • Investigational sites
  • Funding
• Product Identification and Description
  • Device Accountability (SaMD specific)
• Justification of the design
  • Background and rationale
  • Regulatory framework
  • Risks and benefits of the product in investigation and clinical research
  • Evaluation of preclinical and clinical data
• Hypothesis
• Objectives
  • Primary objective(s)
  • Secondary objective(s)
• Summary of the study
• Design and Methods
  • Type of clinical research
  • Population
  • Duration
  • Acceptance criteria
  • Inclusion and exclusion criteria
    • Gold Standard Definition
    • Inclusion criteria
    • Exclusion criteria
  • Variables
  • Condition of interest
  • Quality control
  • Limitations of clinical research
• Ethical considerations
  • Data confidentiality
  • Information to subjects and informed consent
  • Bias minimization measures
  • Calendar
  • Monitoring plan
  • Subject follow-up procedures
  • Completion of the investigation
  • Statistical analysis
  • Procedures
  • 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 Event to Product (AEP)
  • Product deficiencies
  • Serious Adverse Events, serious adverse events to product and serious and unexpected adverse events to the product
  • Non-reportable Adverse Events
  • Notification Process
  • Foreseeable adverse events and adverse events to product
  • Emergency contact
  • Data Monitoring Committee (DMC)
• Vulnerable population (if applicable)
• Suspension or early termination of clinical research
• Publication policy
• Bibliography
• Annexes
  • Annex I. Clinical Utility and Satisfaction questionnaire

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.

This clinical investigation will be conducted in accordance with the ethical principles originating from the World Medical Association's Declaration of Helsinki, as well as the standard ISO 14155:2020 (Clinical investigation of medical devices for human subjects — Good clinical practice).

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

• HS: Hidradenitis Suppurativa
• IHS4: International Hidradenitis Suppurativa Severity Score System
• AIHS4: Automatic International Hidradenitis Suppurativa Severity Score System
• ICC: Intraclass Correlation Coefficient
• MAE: Mean Absolute Error
• LoA: Limits of Agreement
• eCRF: Electronic Case Report Form
• DMC: Data Monitoring Committee

CIP or protocol specifications

Principal Investigator

Dr. Antonio Martorell Calatayud

Investigational site address to be confirmed prior to study initiation.

Coordinating Investigator(s)

Dr. Antonio Martorell Calatayud

Collaborating Investigator(s)

To be confirmed prior to study initiation.

Investigational sites

To be confirmed prior to study initiation.

Funding

This study has no external funding. AI LABS GROUP S.L. will provide the device to participating sites at no cost for the duration of the study as an in-kind contribution.

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

Device Accountability (SaMD specific)

The sponsor (AI LABS GROUP S.L.) is responsible for product control. Access to the Legit.Health Plus software will be restricted via secure user credentials (username and password). The sponsor will establish procedures for tracking software usage. Access to unused, expired, or malfunctioning versions of the software will be immediately revoked by the sponsor.

Justification of the design

Background and rationale

Hidradenitis suppurativa (HS) is a chronic, recurrent, and debilitating inflammatory skin disease affecting the hair follicles. It is characterised by painful, deep-seated nodules, abscesses, sinus tracts, and scarring, primarily in intertriginous areas such as the axillae, groin, and perineum. HS significantly impairs quality of life and requires long-term medical management. Accurate and reproducible severity assessment is critical for treatment decision-making, clinical trial endpoints, and longitudinal monitoring of disease progression.

The International Hidradenitis Suppurativa Severity Score System (IHS4) is a validated severity scoring tool that counts inflammatory lesions — nodules, abscesses, and draining sinus tracts — weighted by clinical relevance. While IHS4 offers improved objectivity compared to earlier HS severity scales, manual scoring remains time-consuming and subject to interobserver variability, particularly in the accurate counting of individual lesion types across multiple anatomical regions.

To address these limitations, the AIHS4 (Automatic International Hidradenitis Suppurativa Severity Score System) algorithm has been developed and integrated into the device. AIHS4 uses deep learning-based image analysis to automatically identify and enumerate the lesion types defined by IHS4, computing a standardised severity score from device-captured clinical images.

The stand-alone analytical performance of the AIHS4 algorithm (Pillar 2 Technical Performance under MDCG 2020-1) was established pre-market in the AIHS4_2023 severity-validation study — a peer-reviewed investigation using 221 images independently scored by six expert dermatologists — which demonstrated algorithmic agreement with the most expert reader across the IHS4 scoring task. A retrospective proof-of-concept feasibility study (Legit.Health_AIHS4_2025, supporting evidence only, n = 2 patients, 16 longitudinal assessments) provided an initial signal (ICC 0.727, temporal variation 6.7%), confirming that algorithm performance carries forward to longitudinal clinical images, but with a sample too small to deliver statistically robust Pillar 3 Clinical Performance evidence. The present investigation delivers that Pillar 3 Clinical Performance evidence by prospectively recruiting 100 patients under real-world clinical conditions, confirming clinical benefit 5RB (Objective severity measurement) and directly addressing the sample-size limitation of the pilot. This study corresponds to Activity B.5 of the Post-Market Clinical Follow-up (PMCF) Plan and addresses the Clinical Evaluation Report (R-TF-015-003) identified need for prospective Pillar 3 Clinical Performance confirmation of the AIHS4 severity-assessment output under real-world clinical conditions.

Regulatory framework

Under the MDCG 2020-1 clinical evaluation framework, this investigation provides Pillar 3 Clinical Performance evidence, evaluating the agreement of the device-integrated AIHS4 severity score — as computed and presented to the clinician under routine clinical conditions — against an expert-consensus gold standard. Under the MDCG 2020-6 Appendix III methodological hierarchy, the study sits at Ranks 2–4 as a prospective observational investigation conducted on real patients in the target clinical population. This positioning is distinct from simulated-use reader studies (which sit at Rank 11); this study uses multiple expert readers exclusively to construct a robust consensus gold standard, not to simulate the reader population. The investigation confirms clinical benefit 5RB (Objective severity measurement) and builds on the pre-market Pillar 2 Technical Performance evidence provided by AIHS4_2023.

Risks and benefits of the product in investigation and clinical research

The subjects recruited in this study will not be exposed to any procedure that could endanger their safety. No adverse reactions related to the investigational product are expected. The evaluation is based solely on the acquisition of standard skin photographs and clinical assessment during routine dermatological visits, which are non-invasive procedures.

The expected benefits include:

• Improved precision and objectivity in HS severity assessment by reducing interobserver variability.
• Reduction of clinical time, optimising dermatology workflows.
• Standardised longitudinal monitoring of HS disease progression.
• Facilitation of telemedicine-based assessments for HS patients.

Evaluation of preclinical and clinical data

These evaluations can be consulted in the Investigator's Brochure (R-TF-015-005).

Hypothesis

The AIHS4 algorithm, integrated into the device, provides a valid and reliable automated assessment of HS severity using device-captured clinical images, achieving agreement with the expert dermatologist consensus gold standard (ICC ≥ 0.75) and demonstrating a Mean Absolute Error below 10% of the gold standard mean IHS4 score, and Bland-Altman limits of agreement within ±15 points on the IHS4 scale.

Objectives

Primary objective(s)

To confirm clinical benefit 5RB (Objective severity measurement) by demonstrating that the AIHS4 algorithm, integrated into the device, agrees with the expert dermatologist consensus gold standard IHS4 score (ICC ≥ 0.75) in a prospective observational investigation of 100 patients with hidradenitis suppurativa under real-world clinical conditions (Pillar 3 Clinical Performance, MDCG 2020-1).

Secondary objective(s)

• To evaluate the Mean Absolute Error (MAE) between the AIHS4 automated score and the gold standard IHS4 expert consensus score.
• To characterise the systematic and random error components of the AIHS4 algorithm through Bland-Altman analysis.
• To assess the performance of the AIHS4 algorithm across different HS severity strata (mild, moderate, severe).
• To compare the interobserver variability among participating dermatologists in manual IHS4 scoring against the AIHS4 automated scoring.
• To evaluate AIHS4 performance across different anatomical regions.

Summary of the study

This is a prospective, observational, real-patient clinical investigation evaluating the AIHS4 algorithm for automated severity assessment of hidradenitis suppurativa. The study will recruit 100 adult patients with a confirmed HS diagnosis. During routine dermatological visits, standardised clinical images of HS-affected areas will be captured using the device. Multiple expert dermatologists will independently score the images using the IHS4 scoring system to establish a consensus gold standard; expert readers are used solely to produce a robust reference standard and are not the study population of interest. The AIHS4 algorithm will compute automated severity scores for the same images, as presented to the clinician through the device's clinical workflow. Agreement between the automated AIHS4 scores and the expert consensus gold standard will be evaluated using ICC, MAE, and Bland-Altman analysis.

Design and Methods

Type of clinical research

Prospective, observational, real-patient clinical investigation with multiple independent expert readers establishing the consensus gold standard.

Population

Adult patients (≥ 18 years) with a confirmed diagnosis of hidradenitis suppurativa who attend the dermatology clinic for routine clinical assessment or follow-up.

Duration

The total duration of the study is estimated at 4 months:

• Patient recruitment: September 2026 to November 2026 (3 months).
• Data analysis and final report: December 2026 (1 month).

Acceptance criteria

• Agreement (ICC) for severity assessment: ICC ≥ 0.75 (good to excellent reliability per the Cicchetti classification).
• Mean Absolute Error (MAE): < 10% of the gold standard mean IHS4 score.
• Bland-Altman analysis: Mean bias < 5 points and 95% limits of agreement within ±15 points on the IHS4 scale.

Inclusion and exclusion criteria

Gold Standard Definition

The gold standard is defined as the consensus IHS4 score derived from independent manual scoring by at least two expert HS dermatologists using standardised lesion identification methodology. In the event of significant interrater disagreement (defined as an absolute IHS4 difference > 10 points between readers), a third expert reviewer adjudicates to reach consensus.

Inclusion criteria

• Patients aged 18 years or older.
• Patients with a confirmed clinical diagnosis of hidradenitis suppurativa (all Hurley stages).
• Patients presenting with active HS lesions in at least one body region accessible for standardised image capture.
• Patients who provide their written informed consent.
• Availability of high-quality clinical images of HS-affected areas suitable for lesion identification and IHS4 scoring.

Exclusion criteria

• Patients under 18 years of age.
• Patients whose images are of insufficient quality to allow reliable lesion identification and IHS4 scoring by expert reviewers.
• Patients with concurrent inflammatory skin conditions (e.g., psoriasis, atopic dermatitis) in the same body regions that could confound IHS4 lesion counting.
• Patients who withdraw their informed consent prior to image capture.

Variables

Primary variable: Agreement between the AIHS4 automated score and the gold standard expert consensus IHS4 score, quantified by the Intraclass Correlation Coefficient. The AIHS4 automated score evaluated is the score as computed and emitted by the device under its intended-use configuration — the score presented to the clinician through the device's clinical workflow, not a stand-alone algorithm output measured outside the device's intended use context.

Secondary variables:

• Mean Absolute Error between the AIHS4 automated score and the gold standard IHS4 expert consensus score.
• Bland-Altman mean bias and 95% limits of agreement.
• AIHS4 performance stratified by HS severity category (mild: IHS4 < 4, moderate: IHS4 4–10, severe: IHS4 > 10).
• Interobserver agreement among manual IHS4 expert readers.
• AIHS4 performance stratified by anatomical region.
• AIHS4 performance stratified by Fitzpatrick phototype (I–II, III–IV, V–VI) — pre-specified as a descriptive exploratory analysis, reported with 95% confidence intervals.
• Demographic variables: sex, age, Fitzpatrick phototype, Hurley stage, disease duration.

Condition of interest

Hidradenitis suppurativa (all Hurley stages).

Quality control

The principal investigator is responsible for reviewing and approving the study protocol, ensuring data quality, and approving the final report. An image quality review will be conducted prior to inclusion of each case in the analysis to confirm that image resolution and coverage are sufficient for reliable lesion identification; this review is performed blinded to both the AIHS4 automated score and the gold standard readers' scores, following pre-specified criteria defined in the Image Capture Guide. All image exclusions will be documented with reasons and reported in the Clinical Investigation Report. Standardised image capture procedures will be followed using a documented Image Capture Guide. Inconsistencies in the case report form will be controlled through computerised validation filters and manual review by the sponsor's data management team.

Limitations of clinical research

• Image quality variability: Differences in lighting, colour rendering, focus, and image framing may affect AIHS4 lesion identification accuracy. This is mitigated by a standardised image capture protocol.
• Reader heterogeneity: Variability in expert dermatologists' IHS4 scoring practices may influence the gold standard. This is controlled by defining a formal consensus procedure and applying a third-reader adjudication rule for cases with significant interrater disagreement.
• Lesion accessibility: HS lesions in certain anatomical locations (e.g., perianal, perineal) may be difficult to capture in standardised photographs, potentially reducing the representativeness of the image dataset.
• Hurley stage distribution: Depending on the clinical profile of recruited patients, certain Hurley stages may be under-represented, limiting generalisability across the full spectrum of HS severity.
• Hawthorne effect: Awareness of participation in a study may influence investigator behaviour during image capture. Mitigation: investigators are not provided with the AIHS4 automated score during the image capture process; the score is computed post-hoc from the uploaded images, ensuring that investigator behaviour during capture is not influenced by the device's scoring output.

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.

Patients will be assigned a unique anonymised identification code. Images will be de-identified prior to analysis. All data will be stored and processed in compliance with Regulation (EU) 2016/679 (GDPR) and applicable Spanish data protection legislation (LOPDGDD). Upon study completion, all personal data held on the device platform will be deleted in accordance with the data retention policy and applicable regulation.

Information to subjects and informed consent

Patients will receive objective information in non-technical language describing the study objectives, methodology, expected benefits, and risks. Written informed consent will be obtained from each participant prior to inclusion in the study. Patients have the right to withdraw their consent at any time without penalty. If consent is withdrawn, data collected up to that point may be retained in anonymised form as permitted by applicable regulations.

Bias minimization measures

• Standardised image capture protocols (lighting, distance, angle, capture device) to reduce intra- and inter-site variability.
• Independent blinded scoring by expert readers to avoid anchoring bias.
• Third-reader adjudication for cases with significant interrater disagreement.
• Pre-specified analysis plan and acceptance criteria to prevent post-hoc endpoint modification.

Calendar

• Ethical and regulatory approval: prior to study initiation.
• Patient recruitment: September–November 2026 (3 months).
• Image processing and automated scoring: concurrent with recruitment.
• Data analysis and final report preparation: December 2026 (1 month).

Monitoring plan

The sponsor's clinical team will hold a study initiation meeting with the participating investigators prior to recruitment commencement. Ongoing monitoring will review data quality, protocol compliance, and image capture standardisation at regular intervals during the recruitment phase. A study closure meeting will be held at the end of the recruitment period.

Subject follow-up procedures

Subject participation is limited to a single routine clinical visit during which images are captured and consent is documented. No active follow-up is required beyond this visit. If a subject withdraws consent after image capture but before data analysis, their data will be excluded from the analysis set and destroyed in accordance with applicable data protection regulations.

Completion of the investigation

Upon reaching the planned sample size of 100 patients, or upon decision by the sponsor or competent authorities if there is justified cause for early termination, the database will be closed and the statistical analysis will be conducted. A final Clinical Investigation Report (R-TF-015-006) will be prepared and submitted to the ethics committee.

Statistical analysis

The statistical analysis is designed to evaluate the agreement between the AIHS4 automated severity score and the expert dermatologist consensus gold standard IHS4 score across the full cohort of 100 patients.

Primary Analysis: A two-way mixed-effects ICC model (ICC(3,1)) will be computed to quantify agreement between AIHS4 automated scores and the gold standard IHS4 consensus scores across all 100 cases. ICC ≥ 0.75 constitutes achievement of the primary acceptance criterion. ICC values will be reported with 95% confidence intervals.

Secondary Analyses:

• MAE: Calculated as the mean of the absolute differences between the AIHS4 score and the gold standard IHS4 score. MAE < 10% of the gold standard mean IHS4 score constitutes achievement of the secondary criterion.
• Bland-Altman analysis: A Bland-Altman plot will be generated to characterise the mean bias (systematic error) and 95% limits of agreement (random error) between AIHS4 and gold standard IHS4 scores. Achievement of the secondary criterion requires mean bias < 5 points AND 95% LoA within ±15 points on the IHS4 scale.
• Subgroup ICC analyses: ICC stratified by HS severity category (mild, moderate, severe), by anatomical region, by participating reader, and by Fitzpatrick phototype (I–II, III–IV, V–VI; pre-specified descriptive exploratory analysis).
• Interobserver reliability of manual IHS4 scoring: ICC computed among the expert readers to characterise baseline manual scoring variability for comparison with the AIHS4 automated performance.

All confidence intervals will be computed at the 95% level. Analyses will be performed using validated statistical software (SPSS or R), with the specific software and version recorded in the Clinical Investigation Report.

Sample size justification: A sample size of 100 patients is estimated to provide 80% statistical power to detect an ICC of 0.75 or greater (one-sided test at α = 0.05), using the Bonett (2002) sample-size formula for ICC hypothesis testing in two-way mixed-effects models [7]. This sample size also enables meaningful subgroup analyses across HS severity strata and anatomical regions, and directly addresses the primary limitation of the pilot study (n = 2), which was insufficient to deliver statistically robust agreement estimates.

Procedures

1. Obtaining written informed consent.
2. Clinical assessment and IHS4 scoring by the principal investigator or collaborating investigator during routine dermatological visit.
3. Standardised capture of clinical images of HS-affected anatomical areas according to the Image Capture Guide.
4. Upload of de-identified images to the device platform under the subject's anonymised study code.
5. Independent blinded IHS4 scoring of the same images by at least two expert dermatologists (gold standard readers).
6. Computation of the AIHS4 automated severity score by the device.
7. Data entry into the electronic Case Report Form (eCRF).
8. Third-reader adjudication for cases where the two gold standard readers disagree by more than 10 IHS4 points.
9. Statistical analysis and final report preparation.

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.

The transfer of data from the paper CRF (if applicable) to the electronic database will be carried out through double data entry. Computerised filters and logical validation rules will be applied to control for inconsistencies and missing data.

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.

Any substantial modification must be approved by both the Ethics Committee (CEIm) and the Competent Authority (AEMPS) before implementation, as required by Article 75 of MDR 2017/745.

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.

The use of waivers from the Clinical Investigation Plan is strictly prohibited. The sponsor will establish clear measures for tracking and managing any deviations from the CIP.

Start, follow-up and end reports

The start of the study will be notified to the ethics committee. Follow-up reports will be submitted as required by the applicable regulatory framework.

The sponsor will comply with the obligation to notify Member States of the end, temporary halt, or early termination of the investigation within the legal timeframes (15 days for end, 24 hours for safety-related halts) as per Article 77 of MDR 2017/745.

Upon obtaining the study conclusions, a final report (R-TF-015-006 Clinical Investigation Report) will be prepared and submitted to the ethics committee. The study must be registered in a public database (e.g., EUDAMED), and the CIR will be published within 1 year of completion (or 3 months in case of early termination) as per Annex XV of MDR 2017/745.

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.

The statement regarding the funding of the clinical investigation, along with the description of the agreement between the sponsor and the research centres and between the sponsor and the principal investigator, can be found in the respective site agreements.

Informed Consent process

The patient, or in their absence, the family member or legally authorised representative, must provide written consent before their inclusion in the clinical investigation. This will occur after they have understood, through a prior interview with the principal investigator or a member of the research team, the objectives of the investigation, its risks, inconveniences, and benefits, as well as the conditions under which it will be conducted, and after being informed of their right to withdraw from the investigation at any time without explanation and without incurring any responsibility or prejudice.

The principal investigator will discuss the study with the subject and provide the information objectively, without coercion or influence, and without offering any inappropriate or undue incentive. The principal investigator will use non-technical language in the subject's native language (or that of the spouse/closest relative or legally authorised representative) for better understanding and will allow sufficient time for reading and comprehending the information.

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

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

Adverse events, adverse product reactions and product deficiencies

Adverse Events (AE) and Adverse Event 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 and whether intended or unintended.

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

Given these definitions, potential AEPs or AEs are documented in the product's IFU.

Product deficiencies

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

Considering this definition, the following issues could arise:

• Malfunctions, such as application crashes or failure to process images.
• Use errors, such as capturing poor quality photographs or incorrect data entry.
• Inadequate information provided by the manufacturer, such as a complex IFU and/or labeling.

Product deficiencies in the investigation will be managed by the sponsor according to non-conforming product control procedures. When appropriate, corrective and/or preventive actions will be taken to protect the safety of subjects, users, and other individuals.

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

According to UNE-EN ISO 14155:2021:

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

Taking into account these definitions, there are no SAEP, SAEs or SUAEPs related to the use of the product.

Non-reportable Adverse Events

Not applicable. Since this is an observational study based on routine clinical photography, subjects are not exposed to any interventions that could give rise to reportable adverse events beyond those of standard clinical practice.

Notification Process

Any SAEP, product deficiency or finding related to the above will be duly documented and reported in accordance with the provisions of document MDCG 2020-10/1 "Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745".

In the situations detailed in the previous paragraph, the principal investigator must notify the sponsor immediately (but no later than 3 days after becoming aware of the event). The sponsor will then use the form published as an annex to said document, MDCG 2020-10/2 "Guidance safety report form".

This form must be completed or updated for each reportable event or for new findings or updates of events already reported. It will be transmitted to all National Competent Authorities (NCA) where the clinical investigation is being conducted. In this case, the AEMPS. Once EUDAMED is available and fully operational, the obligations and requirements related to the preparation of safety reports through EUDAMED will apply from six months after the date of publication of the notice in the Official Journal of the European Union.

The notification period of the sponsor to the NCA(s) will be immediately (but no later than 2 days after becoming aware of the event) for reportable events that involve an imminent risk of death, serious injury or serious illness and that require immediate corrective action, or new findings or updates of related events. For the rest of reportable events or new findings or updates, the notification period will be immediately (but no later than 7 days after becoming aware of the event).

Likewise, as indicated in the UNE-EN ISO 14155:2021 regulation, the IRB must be notified of the SAEs, if the IRB so requires.

Foreseeable adverse events and adverse events to product

The 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.

Emergency contact

• Name: Dr. Antonio Martorell Calatayud
• Professional role: Principal Investigator
• E-mail: To be confirmed prior to study initiation

Data Monitoring Committee (DMC)

Not established for this study. Given the observational design and the absence of any therapeutic intervention or anticipated patient safety risk, a Data Monitoring Committee is not considered necessary.

Vulnerable population (if applicable)

Not applicable. Subjects are adults (≥ 18 years old) with decision-making capacity, and the study involves no interventions beyond standard clinical photography and routine clinical assessment.

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.

Publication policy

The description of the clinical investigation will be recorded in a publicly accessible database (e.g., EUDAMED) before the recruitment of the first subject. Its content will be updated during the conduct of the clinical investigation.

After the final closure of the clinical investigation, a Clinical Investigation Report (R-TF-015-006) will be prepared, even if the investigation has been suspended or terminated early. The CIR will be provided to the IRB and the AEMPS. The results obtained (whether positive, inconclusive, or negative) will be incorporated into the registry of the aforementioned publicly accessible database.

Results must be available within 1 year of completion (or 3 months in case of early termination) as per Annex XV of MDR 2017/745. In addition, if deemed appropriate, the results obtained will be published in scientific journals. The ethics committee that has approved this clinical investigation will be mentioned, and the anonymity of the subjects participating in the clinical investigation will be maintained at all times. All publications and communications must be accepted and approved by the parties involved.

Bibliography

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Annexes

Annex I. Clinical Utility and Satisfaction questionnaire

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

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