Identifying biomarkers of treatment response to ciclosporin in atopic dermatitis through multiomic predictive modelling: DERMATOMICS study protocol

Abstract

Introduction

There is a need to optimise the management of atopic dermatitis (AD), improving the efficacy of treatments and reducing the toxicity associated with them. Although the efficacy of ciclosporine (CsA) in the treatment of AD has been thoroughly documented in the literature, the optimal dose has not been yet established. The use of multiomic predictive models of treatment response could optimise CsA therapy in AD.

Methods and analysis

The study is a low-intervention phase 4 trial to optimise the treatment of patients with moderate-severe AD requiring systemic treatment. The primary objectives are to identify biomarkers that could allow for the selection of responders and non-responders to first-line treatment with CsA and to develop a response prediction model to optimise the CsA dose and treatment regimen in responding patients based on these biomarkers. The study is divided into two cohorts: the first comprised of patients starting treatment with CsA (cohort 1), and the second, of patients already receiving or who have received CsA therapy (cohort 2).

Ethics and dissemination

The study activities began following authorisation by the Spanish Regulatory Agency (AEMPS) and the Clinical Research Ethics Committee of La Paz University Hospital approval. Trial results will be submitted for publication in an open access peer-reviewed medical speciality-specific publication.

Trial registration of this study can be located at the EU Clinical Trials Register, available from https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en. Our clinical trial was registered in the website before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according the WHO. Once our trial was included in a primary and official registry, in order to extend the accessibility to our research, we also registered it retrospectively in clinicaltrials.gov; however, this is not mandatory as per our regulation.

Trial registration number

NCT05692843.

STRENGTHS AND LIMITATIONS OF THIS STUDY

• This is a single-centre clinical trial with a limited number of patients.

• The study is neither randomised nor controlled. However, this does not cause bias, since the primary objective is to identify response biomarkers and to generate prediction models that will subsequently be validated in a multicentre clinical trial with a larger sample size.

• Some data from the retrospective cohort may not be available.

• Carrying out a pragmatic low-intervention clinical trial minimises the risks of the study and the difficulties to recruit patients.

• High number of clinical, genetic, immunological and analytical data will be collected, which facilitates the development of effective predictive models.

Introduction

Atopic dermatitis (AD) is an inflammatory, chronically relapsing disease with a significant impact on the quality of life of patients due to symptoms such as intense pruritus and the associated risk of infections. In mild forms, topical corticosteroids and calcineurin inhibitors are used as treatment, but in moderate-severe forms, systemic immunosuppressive drugs are necessary. The development of biological therapies for the treatment of this disease, as well as the rise in its incidence and prevalence in recent years has increased its impact on the Public Healthcare System.¹

The therapeutic arsenal with an authorised indication for the treatment of AD available today includes:

• Ciclosporin (CsA): authorised for the treatment of severe AD in patients requiring systemic therapy. The recommended dose is 3‒5 mg/kg/day, and the time to onset of effect ranges between 4 and 6 weeks.

• Dupilumab: biological drug authorised for the treatment of moderate-severe AD in adult and adolescent patients aged ≥12 years; it has been recently approved for the treatment of severe AD in children aged 6‒11 years. The recommended dose in adolescents weighing <60 kg is 400 mg (two 200 mg injections) followed by a maintenance dose of 200 mg/2 weeks. In adults and adolescents weighing >60 kg, an initial dose of 600 mg is administered followed by 300 mg every 2 weeks.

• Upadacitinib and baricitinib: selective and reversible Janus kinase (JAK) inhibitors. Upadacitinib is indicated for the treatment of moderate to severe AD in adults and adolescents 12 years and older candidates for systemic therapy. Baricitinib is indicated for the treatment of moderate to severe AD in adults.

• Tralokinumab: recombinant humanised IgG4 monoclonal antibody that inhibits interleukin 13 (IL-13) signalling. It is indicated for the treatment of moderate to severe AD in adult patients candidates for systemic therapy.

In the coming years, numerous new biological drugs that are currently in the final stages of clinical development are expected to be authorised. According to the therapeutic positioning report, the use of these biological therapies is only indicated in those patients previously treated with CsA with poor response or those who cannot receive CsA due to intolerance.

The monthly cost of CsA treatment per patient is approximately 105 euros (assuming a dose of 100 mg/12 hours) while the monthly cost of dupilumab and tralokinumab treatment per adult patient is 1318.15 euros; the monthly cost of upadacitinib ranges between 1036.58 and 2015.01 euros depending on the dose; and the monthly cost of baricitinib is approximately 869.35 euros. Biological drugs represent a considerable economic burden for the National Health System (NHS), and adequate positioning is of paramount importance, particularly in diseases such as AD that are becoming more prevalent. In light of these circumstances, the ability to identify a priori those patients who will respond adequately to CsA is critical to optimising the initial selection of treatment and dose, improving therapeutic outcomes through individualised treatment, thus saving the NHS unnecessary costs.

Although the efficacy of CsA in the treatment of AD has been previously demonstrated, the optimal dose has not been yet established.^{2 3} One of the challenges in CsA treatment is its narrow therapeutic range along with the wide interpatient variability in its pharmacokinetics. This interindividual variability in the pharmacokinetics of CsA depends on different covariates, including demographic, clinical or genetic factors.⁴

CsA is extensively metabolised,⁵ with less than 1% of the parent drug excreted unchanged in the urine. After entering the enterocytes, it is metabolised by gastrointestinal isoenzymes of the cytochrome P450 pathway, mainly CYP3A4 and to a lesser extent CYP3A5. The drug that escapes intestinal metabolism is metabolised in the liver by CYP3A4 and CYP3A5.

In addition, CsA is a substrate of P-glycoprotein (P-gp), a membrane protein that functions as an efflux pump for various drugs and that is encoded by the ABCB1 gene. This protein is expressed in the intestine, liver and kidneys, where it transports substrates from the cytoplasm to the extracellular space.⁶

Variants in some of the genes coding these proteins involved in CsA metabolism are known to contribute to the variability in its pharmacokinetics. There are studies indicating that the presence of genetic variants related to CYP3A4 enzymatic activity may contribute to up to 56% of the clearance of CsA and up to 32% of the peak concentrations in blood. Regarding CYP3A5, the most frequent variant in Caucasian populations is CYP3A5*3, which is associated with the absence of catalytic activity. In subjects carrying two functional alleles, CYP3A5 can represent up to 50% of the total hepatic metabolism of CYP3A. Multiple polymorphisms have been described for ABCB1, but their impact on P-gp expression and function is not yet well defined.⁷ All these variants are potential biomarkers that could help individualise CsA treatment.

Numerous reports have been published recently in the literature on biomarkers related to AD, in particular biomarkers correlated with clinical severity, such as lactate dehydrogenase, C reactive protein and eosinophils. In this regard, studies have been conducted on cytokines such as IL-13 and IL-22, and chemokines such as CCL17, CCL26, CCL27, CCL18, CCL22 that also correlate with disease severity.⁸ The impact of CsA on the different profiles of T cells in peripheral blood is another aspect that needs to be defined.

Despite the substantial amount of information available, to date, there are neither dose recommendations nor treatment algorithms based on genetic or other omics biomarkers to optimise CsA therapy.⁹

A first step toward individualised treatment is to find those biomarkers associated with drug efficacy and toxicity and to use these along with other data such as age or sex to develop predictive models intended to optimise therapeutic management. Different software is available to develop predictive models, including PhysPK, which provides models with standards, protocols, resources and data for the simulation and modelling of multiple libraries of complex physiological systems with PBPK/PK/PD methodologies for the analysis of individuals and populations.

This software makes it possible: i) to conduct the main modelling, ii) to efficiently incorporate new biological processes, iii) to perform population analysis, and iv) to generate independent executable applications for routine clinical use.

In this context, the implementation in clinical practice of a multidisciplinary strategy that integrates the use of different biomarkers including monitoring of serum drug concentrations, pharmacogenetic data and other immunological biomarkers related to the efficacy and safety of CsA, will lead to the optimisation of AD management, contributing to the efficiency, sustainability and solidarity of the Public Healthcare System.

Methods and analysis

The study protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) recommendations.

Hypothesis and objectives of the trial

The hypothesis of the study is that the assessment of clinical, kinetic, pharmacogenetic and immunological variables related to CsA response in patients with moderate-severe AD will lead to therapy optimisation. It will make it possible to identify individuals with a high likelihood of being non-responders to CsA treatment, and those who are highly likely responders, in whom individualised treatment could be performed through the development of dose prediction models that will improve efficacy and reduce toxicity.

The general objective of the trial is to optimise the treatment of patients with moderate-severe AD who require systemic treatment. Two main objectives were set for this trial: (1) to identify biomarkers that allow for the selection of responders and non-responders to first-line treatment with CsA, developing a response prediction model using these biomarkers and (2) to optimise the dosage and treatment regimen with CsA in responding patients through the development of response predictive models (physiologically based pharmacokinetic/pharmacokinetics/pharmacodynamics (PBPK/PK/PD)) that include omics, clinical and demographic variables.

Trial design, sites and study period

DermAtOmics is a single-centre, open-label, low-intervention phase 4 trial. A 12-month recruitment period is planned for a total of 100 patients.

The study will include two cohorts: cohort 1 includes patients diagnosed with moderate-severe AD for whom treatment with CsA is planned; cohort 2 includes patients with moderate-severe AD who are already receiving or have previously received CsA therapy. All patients will be recruited in the Dermatology Department of La Paz University Hospital. Each patient will be followed for a maximum of 48 weeks.

The trial is funded by the Carlos III Health Institute, Spanish Ministry of Science and Innovation (PI21/01219). The development of the study protocol follows the SPIRIT 2013 Checklist.

Selection and enrolment

All patients will be recruited in the Dermatology Department of La Paz University Hospital. Inclusion and exclusion criteria are detailed in table 1. Eligible subjects will be informed before the beginning of the study about the objectives and procedures, as well as the potential risks derived from participation in the study. All patients will sign the informed consent document prior to inclusion in the study. Participation in the study is voluntary, and patients may withdraw from the study at any time. Subjects will be discontinued from the study if they experience lack of efficacy, intolerance or unacceptable toxicity, or contraindications due to a new condition.

Table 1.

Inclusion and exclusion criteria for participating in the DermAtOmics trial

Inclusion criteria

Exclusion criteria

Cohort 1: Subjects diagnosed with moderate-severe atopic dermatitis who are going to receive treatment with ciclosporine. Participants must be willing and able to provide written informed consent prior to the initiation of any study procedure. For children, a parent/legal guardian must provide written informed consent. If aged >11 years, the minor must give assent. Participants willing and able to adhere to the procedures specified in this protocol. Cohort 2: Subjects diagnosed with moderate-severe atopic dermatitis who are receiving or have received treatment with ciclosporine in the past. Participants must be willing and able to provide written informed consent prior to the initiation of any study procedure. For children, a parent/legal guardian must provide written informed consent. If aged >11 years, the minor must give assent. Participants willing and able to adhere to the procedures specified in this protocol.

Subjects participating in a clinical trial in the last 3 months. Any condition or situation precluding or interfering with compliance with the protocol. Persons of childbearing potential with a positive urine pregnancy test at screening and day 0. Persons of childbearing potential who do not agree not to become pregnant. They must be willing to use highly effective contraceptive methods or practice sexual abstinence during the study. Highly effective contraceptive methods include oral, intravaginal or transdermal combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation; oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device; intrauterine hormone-releasing system; bilateral tubal ligation; vasectomised partner and sexual abstinence.

Interventions and study treatment

This is a non-randomised clinical trial. Patients will be managed following clinical practice, and CsA will be used in accordance with the terms of the marketing authorisation; however, participants will be submitted to additional monitoring procedures (biological sample extraction and follow-up visits). This procedure will not pose more than minimal additional risk to the safety of the subjects compared with normal clinical practice.

Patients will be selected and included in both cohorts simultaneously. Patients starting CsA treatment will be selected for cohort 1. In this cohort, patients will be managed according to standard clinical practice, although some additional procedures will be performed: the frequency of follow-up visits will be increased in order to collect data related to clinical efficacy, safety and quality of life and some biological samples (blood and urine) will be obtained for biochemical, kinetic, pharmacogenetic and immunological biomarker analysis, to identify variables associated with CsA treatment.

Patients who have already started CsA therapy or who received CsA in the past will be selected for cohort 2. In those patients continuing to receive CsA, a blood sample for pharmacogenetic analysis will be obtained at screening, and at the discretion of the treating physician, biological samples (blood and urine) will be obtained in this visit and/or in the follow-up visits to assess biochemical and kinetic variables.

If the patient received CsA previously but is no longer under therapy, a blood sample will be extracted at screening for pharmacogenetic analysis. These patients will not attend follow-up visits.

In cohort 2, clinical data (scales) will be collected from clinical records from the start of CsA treatment until CsA failure or toxicity, or until study inclusion in the case of those patients still receiving CsA. Data will be collected prospectively for these patients.

Patients in cohort 1 will receive the starting dose used in routine clinical practice (maximum dose of 3 mg/kg/day is standard practice in our centre). Subsequent dose adjustments will be carried out at the discretion of the treating physician (up to a maximum of 5 mg/kg/day). CsA is approved in Spain and will be used through the normal provision of the on-site Hospital Pharmacy. At the time of study initiation, patients will continue to receive all concomitant medications prescribed by their physicians.

Study endpoints

The primary endpoint is the percentage of patients presenting primary non-response to treatment with CsA, defined as not achieving a 75% improvement in the Eczema Area Severity Index (EASI) score at week 16 of follow-up. The CsA dose must be at least 3 mg/kg/day to assess this endpoint.

Secondary endpoints are described in table 2.

Table 2.

Endpoints in DermAtOmics

Endpoint	Description	Time point
Primary endpoint
Percentage of patients with primary non-response to treatment with CsA	Failure to achieve EASI-75 (a 75% improvement in EASI score)	Week 16
Secondary endpoints
Percentage of patients achieving EASI-75	Failure to achieve EASI-75 (a 75% improvement in EASI score)	Week 6
Percentage of patients achieving EASI-90	Percentage of patients achieving 90% (EASI-90) improvement from baseline during follow-up.	All follow-up visits
Time to treatment failure after week 16	Time to treatment failure with ciclosporine defined as EASI≤50 during follow-up after week 16.	Week 24, week 32, week 40, week 48
Mean per cent change in EASI score	Mean per cent change in EASI score from baseline to week 16.	Week 16
Per cent change in SCORAD	The Scoring of Atopic Dermatitis (SCORAD) is a tool for assessing the severity of atopic dermatitis. It includes the evaluation of the affected areas, the intensity of the lesions and the subjective symptoms of the patient. AD is classified as mild >25, moderate 25–50 and severe >50.	Week 16
Improvement of at least 75% in SCORAD	Percentage of patients experiencing an improvement of at least 75% in SCORAD from the baseline value.	All follow-up visits
Reduction of IGA	Investigator Global Assessment (IGA) is a simple objective measure providing an overall assessment. It uses a five-point scale (clear=0; almost clear=1; mild=2; moderate=3; severe=4).	Week 16
Time to IGA score of 0/1	Time to IGA score of 0/1 (clear or almost clear).	All follow-up visits
Change of BSA	Change of body surface area (BSA) involvement.	Week 16
Change in NRS-11	Peak Pruritus Numerical Rating Scale (NRS) is a numerical scale that measures the intensity of pruritus, with 10 being the greatest intensity.	Week 16
Percentage of patients having a variation of 4 points of improvement in the DLQI	The Dermatology Life Quality Index (DLQI) is a validated and widely used 10-item questionnaire with paediatric versions (0–3 and 4–16 years). A variation of 4 points is considered a clinically meaningful endpoint.	All follow-up visits
Change in POEM and DLQI	The Patient-Oriented Eczema Measure (POEM) is a validated tool in which the patient self-assesses how many days they experienced seven distinct items (itch, sleep disturbance, bleeding, weeping/oozing, cracking, flaking, dryness of the skin) during a period of 1 week. The maximum score is 28 points.	Week 16
Change in the score of scales	Change in the score of the different scales in the different follow-up visits compared with baseline visit.	All follow-up visits
Rate of adverse events associated with CsA treatment	Any untoward medical occurrence in a patient or clinical trial participant, which does not necessarily have a causal relationship with the research procedures or the investigational medicinal product.	All follow-up visits
Exploratory endpoints
Immunological profile	Immunological profile and its relationship with the clinical outcomes.	Screening, week 24, week 48
Ciclosporin pharmacokinetics	Relationship with the pharmacogenetic data, clinical outcomes and the immunological profile.	All follow-up visits

CsA, ciclosporine.

Follow-up of participants

Patients will be followed for 12 months after the start of CsA treatment or until therapeutic failure or toxicity. Participants from cohort 2 who discontinued CsA before their inclusion in the study will not be followed prospectively.

During the follow-up visits the following procedures will be performed at different time points:

• Medical history and physical examination.

• Scales to assess the severity of the disease and quality of life will be recorded: EASI, SCORing Atopic Dermatitis (SCORAD), Investigator Global Assessment (IGA), Body Surface Area (BSA), Peak Pruritus Numerical Rating Scale (NRS-11), Dermatology Life Quality Index (DLQI), Patient Oriented Eczema Measures (POEMs) and Recap of atopic eczema (RECAP).

• Blood samples for safety analysis: basic biochemistry, renal and hepatic profile and ionogram.

• Pharmacogenetic blood samples.

• Urine samples to assess microalbuminuria.

• Blood samples will be obtained to perform the pharmacokinetic analysis. Trough concentration will be tested. In visit 4 samples will be collected at four different time points: 0, 1.5, 2 and 4 hours post-drug administration in order to calculate the abbreviated area under the curve.

• Blood samples will be obtained to evaluate immunological biomarkers.

• Assessment of toxicity or adverse events (AEs) related to CsA treatment.

Study visits and procedures are displayed in online supplemental table 1. During the follow-up visits, the CsA dose may be adjusted in accordance with clinical criteria up to a maximum dose of 5 mg/kg/day.

Biological samples

Blood samples will be processed according to standard clinical practice.

Genotyping will be carried out at the Institute of Medical and Molecular Genetics (INGEMM) of La Paz University Hospital (HULP) using its custom SNP-array platform, which allows for the simultaneous genotyping of 120 SNPs relevant to drug response. Among these mutations are the most relevant variants of CYP3A5, a gene that is related to serum levels of CsA (2B evidence level in PharmGKB). The most relevant variants of CYP3A4, ABCB1 and ABCC2 genes with a possible impact on the kinetics of CsA will also be analysed.

The serum determinations of CsA will be carried out in the Therapeutic Drug Monitoring Laboratory of the HULP Clinical Pharmacology Department using a Siemens Dimension EXL 200 automated analyser. The automated Dimension CsA method provides quantitative results (concentrations in ng/mL) and uses a heterogeneous ELISA technique using a method-specific Flex reagent cartridge. The determination is performed on EDTA whole blood samples that will be collected according to standard extraction procedures. The results of this test will be interpreted taking into account each patient’s medical history, clinical symptoms and other observations.

Regarding the evaluation of immunological biomarkers, multiplex cartridges will be used to measure 8‒16 cytokines and chemokines (third-generation interferon-gamma, IL-10, IL-17A, IL-1ra/IL-1F3, IL-2, IL-4, IL-6 second gene and second-generation tumour necrosis factor-alpha). In addition to each sample, several aliquots will be obtained to make a serum library of the patients studied. Cellular immunophenotyping will also be performed using multiparametric flow cytometry: distribution and absolute number of major subpopulations, memory CD4+ and CD8+ subpopulations, markers of specialisation of effector CD4+ T cell subpopulations, regulatory T cell, memory B subpopulations and the determination of co-expression of CD25/CD134 in basal and activated CD4+ lymphocytes following incubation with CD3/anti-CD28 and their correlation with CsA pharmacodynamics.

Sample size

A total of 100 patients are estimated to be included in this trial over a 1-year period, including the adult and paediatric populations of both cohorts. This sample size is based on clinical considerations, the feasibility of recruitment and the investigational product rather than statistical considerations.

Statistical analysis

Statistical analysis will be performed with appropriate techniques for the prespecified variables. Frequency results will be expressed in absolute terms, as percentages (relative) and CIs. Continuous variables will be expressed as mean (SD) and median (IQR) according to the normality test (Kolmogorov-Smirnov test).

In the case of the primary endpoint (failure of primary response to treatment with CsA), we will start with a generalised logistic model, to subsequently go on to use ‘elastic net’ techniques and, lastly, more advanced Statistical Learning methods. The predictive ability will be calculated using receiver operating characteristic curves.

In the case of the secondary endpoints (time to failure of treatment with CsA and various endpoints evaluating the change in the score of scales related to disease severity and quality of life), a survival analysis will be performed using Kaplan-Meier curves to test the Cox proportional hazards model and the Weibull model. A two-sided significance level of 0.05 and two-sided 95% CIs will be assumed.

The statistical software R (R Core Team (2014). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria) will be used for the analysis.

For the development of simulation models that, integrating the variables collected throughout the study, are capable of predicting therapeutic failure and optimising therapeutic management, the PhysPK software developed by Empresarios Agrupados SA, with which this research group already has previous experience, will be used.¹⁰

Safety and AE reporting

Investigators will monitor and systematically collect the AEs starting from the date of signing the informed consent form until the final follow-up visit of each subject. The occurrence of AEs will be sought by non-directive questioning of the subjects at each visit. AEs may also be detected through physical examination, laboratory test findings or other assessments. AE follow-up will be conducted in accordance with standard procedures and European Medicine Agency (EMA) regulations. The sponsor assumes responsibility for reporting safety information to the corresponding regulatory authorities.

Data collection and outcome measures

The handling, communication and transfer of personal data will be protected, complying with the basic ethical principles of Biomedical Research and applicable regulations: Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data and repealing Directive 95/46/EC (General Data Protection Regulation) and Act 41/2002, of 14 November, regulating patient autonomy and rights and obligations regarding clinical information and documentation. An electronic case report form has been designed using MACRO Electronic Data Capture by Elsevier. To ensure the quality of data, data management will be performed by a data manager of the Spanish Clinical Research Network (SCReN), located at HULP. The data management plan has been approved by the principal investigator. Data collection forms will be included in the final report.

Coordination, management, monitoring, data management and statistical analysis of the study will be performed by the Clinical Trial Unit of La Paz University Hospital in Madrid.

Patient and public involvement

The Association of Affected by Atopic Dermatitis (AADA) was involved in the design of our research. A web page is being created where participants will be able to post their opinion and suggestions about their participation in the study.

Ethics and dissemination

Ethics

This study follows the principles of the 2013 Declaration of Helsinki. It was designed and shall be implemented, executed and reported in accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local regulations on clinical studies and patient data confidentiality. The study was reviewed and approved by the Spanish Regulatory Agency (AEMPS) and by the Clinical Research Ethics Committee of La Paz University Hospital (HULP code: 6211).

Any protocol amendment will be identified by a consecutive number and must be approved and signed by the sponsor and the principal investigator. If relevant, approval by the Ethics Committee and the Spanish Agency of Medication and Health Products, must occur before any changes are implemented.

The investigators ascertain they will apply due diligence to avoid protocol deviations. If deviations occur, the investigator must inform the monitor, and the consequences of such deviations will be reviewed and discussed by the team. All protocol deviations will be documented/recorded specifying the reason, data, action taken and consequences to patients and the study.

This clinical trial has been classified by AEMPS as a ‘low-intervention clinical trial’. The additional diagnostic or monitoring procedures do not pose more than a minimal additional risk or burden to the safety of the subjects compared with normal clinical practice. In accordance with the protocol, any possible damage that could be sustained by a subject resulting from their participation in the study is covered by the applicable compensation system already in place.

Dissemination of trial results

Anonymised individual participant data will be made available when the trial is complete, on request to the corresponding authors and approval by the scientific committee. Once a proposal has been approved, data will be shared through a secure online platform. In addition, after study completion and finalisation of the study report, the results of this trial will be submitted for publication in a scientific journal or will be made public, complying with the Declaration of Helsinki.

Access to data

A copy of the database of data collected during the trial will be attached as an appendix to the publication resulting from this clinical trial. Data will be available at the same time as the results are published and will be kept available to everyone without any time limit. Data will be available indefinitely on the publisher’s website, as long as it is kept by the publisher, for anyone who wishes to access the data, for non-commercial purposes.

Discussion

Most studies about CsA used in the treatment of AD are old and out-of-date.^11–14 There is no updated literature evaluating the actual role of this drug in AD or assessing the efficacy and safety in real clinical practice. Likewise, there are no studies seeking to identify those patients that will respond properly to CsA treatment. In the context of personalised medicine, increased safety standards and a need to control pharmacoeconomic impact, the optimisation of CsA treatment and an adequate positioning of new biological therapies are of immense importance in the management of AD.

The criteria for poor response or intolerance to CsA are not well defined, which could lead to an early replacement of this drug by dupilumab, upadacitinib, baricitinib or tralokinumab. However, some patients could have clinical benefit by maintaining CsA if the treatment is tailored to their characteristics. In AD as well as other dermatological entities, therapeutic level monitoring is not performed routinely and the therapeutic range associated with control of the disease has not been well established. Therapeutic monitoring of CsA levels in the treatment of AD could be useful in monitoring the efficacy and toxicity of treatment,¹⁵ but it would be advantageous to define a more precise monitoring strategy. Many biomarkers of different types (pharmacogenetic, biochemical, immunological, etc) have been suggested in association with the safety and pharmacokinetics of CsA and with treatment response in AD; however, few are used in clinical practice.

The development of this trial would help improve the management of AD, a disease with a significant impact on the quality of life of patients and on the Public Healthcare System, for which therapeutic management is not yet well defined and that is not exempt from risks. The identification of biomarkers related to drug response and the development of these predictive models will help improve the efficacy of treatments and reduce the toxicity associated with them.

Biological drugs represent a considerable economic burden on the National Health System, and adequate positioning is of paramount importance, particularly in diseases such as AD that are becoming more prevalent. In light of these circumstances, the ability to identify a priori those patients who will respond adequately to CsA is critical to optimising the initial selection of treatment and dose, improving therapeutic outcomes through individualised treatment and thus saving the NHS unnecessary costs.

Trial status

• Study funding communicated on 1 December 2021, available for study expenses beginning 1 January 2022.

• Authorisation from the Spanish Regulatory Authority obtained on 13 June 2022.

• Ethics Committee approval obtained on 18 July 2022.

• First patient inclusion for the study occurred on 10 October 2022.

Ethics statements

Patient consent for publication

Not applicable.