R-TF-015-004 Clinical investigation plan
Scope
This Clinical Investigation Plan (CIP) outlines the rationale, objectives, design, methodology, and analysis methods for the clinical investigation.
CIP Identification
| CIP | |
|---|---|
| Title of the clinical investigation | Evaluation of AIHS4 Performance in the M-27134-01 Clinical Trial for Hidradenitis Suppurativa |
| Device under investigation | Legit.Health Plus |
| Protocol version | Version 1.0 |
| Date | 2025-02-19 |
| Code | Legit.Health AIHS4 2025 |
| Sponsor | AI Labs Group S.L. |
| Coordinating Investigator | Dr. Antonio Martorell Calatayud |
| Principal Investigator(s) | Dr. Antonio Martorell Calatayud |
| Investigational site(s) | This study was conducted remotely based on clinical trial image evaluations. |
| Ethics Committee | This study did not require an Ethics Committee approval due to its observational non-interventional nature. |
Table of contents
- Scope
- CIP Identification
- Compliance Statement
- Abbreviations and definitions
- CIP or protocol specifications
- Product Identification and Description
- Justification of the design
- Hypothesis
- Objectives
- Summary of the study
- Design and methods
- Ethical considerations
- CIP Modification
- CIP Deviations
- Start, follow-up and end reports
- Statements of compliance
- Informed Consent process
- Adverse events, adverse product reactions and product deficiencies
Compliance Statement
The clinical investigation was perforfed according to the Clinical Investigation Plan (CIP) and other applicable guidances and regulations. This includes compliance with:
- Harmonized standard
UNE-EN ISO 14155:2021 Regulation (EU) 2017/745 on medical devices (MDR)- Harmonized standard
UNE-EN ISO 13485:2016s Regulation (EU) 2016/679(GDPR).- Spanish
Organic Law 3/2018on 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
- 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. Antonio Martorell Calatayud
Coordinating investigator
- Dr. Antonio Martorell Calatayud
Collaborating Investigators
- Dr. Gema Ochando
- AI Labs Group S.L.
- Mr. Alfonso Medela
- Mr. Victor Gisbert
- Mrs. Alba Rodríguez
Investigational sites
This study was conducted remotely by sending the images to the participating dermatologists.
Funding
This research was conducted 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 792790 |
| 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 |
Justification of the design
Background and rationale
Hidradenitis suppurativa (HS) is a chronic inflammatory disease that requires objective, accurate, and reproducible evaluations. Traditional manual scoring systems are highly time-consuming and exhibit significant interobserver variability. This highlights the need for systems that standardise the evaluation of these conditions, ensure accurate severity assessment, and help reduce time. To address this issue, automated measurement systems such as AIHS4 (Automatic International Hidradenitis Suppurativa Severity Scoring System) have been developed.
This study aims to assess whether the AIHS4 system, integrated into the medical device, is a valid tool for evaluating the severity of HS with an accuracy and a reliability comparable to the IHS4 scoring used by clinical experts. Clinical trial data is used to evaluate AIHS4's agreement with clinical experts and the gold standard along with its potential as a standardised severity assessment tool.
Risks and benefits of the product in investigation and clinical research
This study does not involve subject recruitment, as images used are sourced from clinical trial databases. However, the use of AIHS4 could optimise the severity assessment of HS, reduce time and costs, and improve subject treatment.
Hypothesis
The AIHS4 system is a valid tool for assessing the severity of HS and improves the accuracy and reliability of Healthcare Professionals (HCPs) in its measurement using the IHS4 scoring system.
Objectives
Primary objective
To evaluate the accuracy and reliability of the AIHS4 system, integrated into the device, by comparing it with clinical experts using IHS4 and a gold standard in the context of the phase 1 clinical trial M-27134-01 for Hidradenitis Suppurativa (HS).
Secondary objectives
- To compare AIHS4 performance with interobserver agreement levels reported in the literature.
- To assess temporal variability in AIHS4 scoring across consecutive visits.
- To analyse AIHS4 performance by anatomical region.
Summary of the study
This is a retrospective, observational and longitudinal study designed to evaluate whether the use of the AIHS4 system, integrated into the device, can enhance severity assessment for HS. The study included two subjects diagnosed with HS, followed for 43 days with 16 evaluations in total.
Design and methods
Type of clinical research
This is a retrospective, observational and longitudinal study assessing AIHS4 impact on HS severity assessment. The study compares AIHS4 assessments with those made by clinical trial investigators and expert dermatologists using IHS4. The gold standard will be an expert dermatologist individually identifying and annotating the hidradenitis suppurativa lesions through bounding boxes. Subsequently, these values will be entered to calculate the IHS4 score.
Population
- In this study, two subjects diagnosed with hidradenitis suppurativa and participating in the M-27134-01 Clinical Trial will be included.
- Evaluations would be conducted at four time points (Day 1, Day 15, Day 29, and Day 43).
Duration
The total duration of the study is estimated at 6 weeks.
Acceptance criteria
- AIHS4 improves severity assessment compared to interobserver agreement.
- AIHS4 maintains temporal consistency across visits, temporal variability acceptable is ≤15%.
- AIHS4 achieves high agreement in lesion classification across anatomical regions, ICC=70%.
Inclusion criteria
- Confirmed diagnosis of Hidradenitis Suppurativa.
- Availability of high-quality clinical images across multiple time points.
- Consensus from both expert dermatologists on lesion classification.
Exclusion criteria
- Low-quality clinical images.
- Cases where expert dermatologists could not reach a consensus on lesion classification.
Variables
Main variable
- Accuracy of AIHS4 vs gold standard expert evaluation in severity assessment.
Secondary variables
- Consensus of AIHS4 with individual clinical trial investigators.
- Temporal stability of AIHS4 lesion classifications.
- Performance variation across anatomical regions.
Condition of interest
Subjects diagnosed with HS or presenting lesions consistent with HS, as evaluated in the M-27134-01 clinical trial.
Limitations of clinical research
The main limitations of the pilot include several factors that may influence the perception and effectiveness of the AI-based device. Firstly, the acceptance and trust of healthcare professionals in these emerging technologies can vary significantly. The device's effectiveness may be compromised if users are not fully convinced of its accuracy or usefulness, thereby affecting the overall perception of its performance.
Additionally, image quality is crucial for the device's performance. Issues such as low-quality photographs, errors in cropping lesions, or variations in lighting and focus can deteriorate the quality of the data received by the system, which may negatively influence the evaluation and perception of its effectiveness by the researchers.
Variability in image conditions is also an important aspect to consider. Differences in lighting, colour, shape, size, and focus of the images, along with the number of images available for each subject, can affect the accuracy of the results. High variability in images of the same subject or an insufficient number of representative images can lead to a decrease in the expected diagnostic accuracy of the device.
Additionally, the consistency of investigators in using the device is crucial. Variations in how diligently investigators use the device can impact the study's findings. If the investigators are not consistent in their use of the device, it can lead to unreliable results and affect the overall assessment of its efficacy.
Another limitation is the Hawthorne effect, where pilot subjects may change their behaviour simply because they know they are being observed. This awareness can influence their decisions and actions within the pilot, potentially skewing the results and not accurately reflecting how the device would be used in a non-study environment.
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
In clinical research, minimising bias is essential to ensure the validity and reliability of the study's results. In this study, investigators will be randomly selected to participate. Thus, outcomes will not be influenced by pre-existing characteristics of the participants. Furthermore, we will use standardised protocols, using standardised procedures for conducting the study and measuring outcomes ensures that all participants are treated and evaluated in the same way, reducing variability due to differences in how the intervention is applied or how outcomes are assessed. Along with this, before the study begins we define primary and secondary outcomes, which prevents selective reporting of only favorable outcomes. This ensures that all relevant data, whether positive or negative, are considered.
Calendar
The total duration of the study is estimated at 6 weeks, covering:
- Data collection and analysis of clinical images.
- Comparison of AIHS4 and investigator evaluations by using IHS4.
- Statistical validation of AIHS4 accuracy and reliability.
- Preparation and submission of the final Clinical Investigation Report (CIR).
Monitoring plan
The Legit.Health team will hold a meeting with the participating investigators at the beginning of the study to address any potential questions, ensure that data is being collected properly and show the correct compliance of the Case Report Form.
Additionally, when the study is completed, the Legit.Health team will organise a study closure meeting with the research team to verify consistency in AIHS4 assessments and investigator evaluations.
Completion of the investigation
After the final closure of the clinical investigation, a Clinical Investigation Report (CIR: T-015-006 Clinical Investigation Report) will be drafted, even in the event of early termination or suspension. The results obtained (whether positive, inconclusive, or negative) will be included in the previously mentioned public access database.
Additionally, if deemed appropriate, the results may be published in scientific journals. All the investigators who approved this clinical investigation will be acknowledged, and any funds received by the author for the study and its source of funding will be disclosed. The anonymity of participants in the clinical investigation will be maintained at all times.
Upon completion of the study, the results of the clinical performance evaluation may be presented at conferences and scientific meetings, subject to prior authorisation by both parties. Press releases and other communications may also be issued to share the study's results. All publications and communications must be reviewed and approved by the parties involved.
Statistical analysis
The statistical analysis will be designed to evaluate the performance of the AIHS4 system by comparing its accuracy against the gold standard (expert dermatologist consensus). The following metrics were analysed:
- Agreement per visit (AIHS4 vs. gold standard).
- Accuracy across anatomical locations (left axilla, right axilla).
- Temporal consistency of AIHS4 across consecutive visits.
- Overall agreement between AIHS4 and clinical investigators.
Accuracy was calculated as the percentage of correct classifications when compared to the gold standard annotations. The agreement between AIHS4 and human evaluators was analysed by comparing the lesion count and classification at each time point.
All analyses were conducted using standard statistical tools for accuracy assessment.
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 the case of substantial modifications to authorized clinical investigations, a request must be submitted to the AEMPS.
- 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.
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 will be notified to the principal investigator and all the participant investigators.
Upon obtaining the study conclusions, a final report (T-015-006 Clinical Investigation Report (CIR)) will be prepared and submitted to the sponsor of the study.
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
For this study, Informed Consent will not be collected, due to its observational, retrospective and non-interventional nature. In this case, we will not analyse personal identification data or sensitive health care data. Furthermore, all the data will be encrypted and anonymised, preventing direct or indirect identification of subjects. Owing to these reasons, this study does not need to collect Informed Consent from subjects or investigators.
Adverse events, adverse product reactions and product deficiencies
Adverse Events (AE) and Adverse Events to the 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 deficencies
Possible inadequacies of a medical device may relate to its identity, quality, durability, reliability, safety, or performance.
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 results in any of the following events: 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 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.
Foreseeable adverse events and adverse events to the product
The foreseeable adverse events and expected adverse reactions to the product, as well as their incidence, mitigation and treatment are documented in the T-013-002 Risk management record of the product under study.
Data Monitoring Committee (DMC)
This is an independent committee that the sponsor may establish to evaluate, at indicated intervals, the progress of the clinical investigation, the safety data or the critical clinical performance or efficacy endpoints and to recommend to the sponsor whether to continue, suspend, modify, or stop the clinical investigation. In this study, there will be no established DMC.
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.
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-003, JD-004
- Approver: JD-005