# The CARMEN-France registry of adult patients with immune thrombocytopenia and autoimmune hemolytic anemia in France

Guillaume Moulis, Marc Michel, Bernard Bonnotte, Bertrand Godeau, Felix Ackermann, Daniel Adoue, Jean-François Alexandra, Laurent Alric, Baptiste Andre, Sophie Arista, et al.

► To cite this version:

Guillaume Moulis, Marc Michel, Bernard Bonnotte, Bertrand Godeau, Felix Ackermann, et al. The CARMEN-France registry of adult patients with immune thrombocytopenia and autoimmune hemolytic anemia in France. La Revue de Médecine Interne, 2024, 45 (9), pp.543-548. 10.1016/j.revmed.2024.06.006. hal-04886338

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Interdisciplinary medicine

# The CARMEN-France registry of adult patients with immune thrombocytopenia and autoimmune hemolytic anemia in France

## Le registre CARMEN-France : registre des patients adultes atteints de purpura thrombopénique immunologique et d'anémie hémolytique auto-immune en France

Guillaume Moulis<sup>a,b,*</sup>, Marc Michel<sup>c</sup>, Bernard Bonnotte<sup>d</sup>, Bertrand Godeau<sup>c</sup>, the CARMEN-France investigators group Collaborators (the CARMEN-France investigators group)

<figure><img src="image_2.png" /></figure>

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## INFO ARTICLE

Historique de l'article :
Disponible sur Internet le 2 July 2024

Keywords :
Immune thrombocytopenia
Autoimmune immune hemolytic anemia
Registry
Epidemiology
Postmarketing evaluation
Pharmacoepidemiology
Real-world data
Real-world evidence

Mots clés :
Purpura thrombopénique immunologique
Anémie hémolytique auto-immune
Registres
Épidémiologie
Pharmaco-épidémiologique
Évaluation post-marketing
Données de vraie vie

## ABSTRACT

The CARMEN-France registry is a prospective, multicenter registry in France including adult patients with a new diagnosis of immune thrombocytopenia or of autoimmune immune hemolytic anemia (2402 patients included in December 31, 2023). The recording of clinical, biological and treatment data allows detailed epidemiological and pharmacoepidemiological real-world studies. This review summarizes the CARMEN-France registry protocol, gives examples of studies conducted in the registry, and indicates future directions such as inclusion of patient reported outcomes, linkage with the French national health insurance database and linkage with other registries in Europe.

© 2024 L'Auteur(s). Published by Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

## RÉSUMÉ

Le registre CARMEN-France est un registre prospectif multicentrique en France, qui suit des patients adultes avec un purpura thrombopénique immunologique ou une anémie hémolytique auto-immune nouvellement diagnostiqués (2402 patients inclus au 31 décembre 2023). Le recueil des données cliniques, biologiques et des expositions thérapeutiques permet des études épidémiologiques et pharmaco-épidémiologiques détaillées « de vraie vie ». Cet article résume le protocole du registre CARMEN-France, donne des exemples d'études déjà conduites avec génération de « preuves de vraie vie », et indique les futures directions du registre avec implémentation de données rapportées par le patient, chaînage avec les données du système national des données de santé et avec d'autres registres de cytopénies auto-immunes en Europe.

© 2024 L'Auteur(s). Published by Elsevier Masson SAS au nom de Société Nationale Française de Médecine Interne (SNFMI). Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

<footnote><sup>a</sup> Service de médecine interne, centre de référence constitutif des cytopénies auto-immunes de l'adulte, CHU de Toulouse, Toulouse, France</footnote>

<footnote><sup>b</sup> CIC 1436, CHU de Toulouse, Toulouse, France</footnote>

<footnote><sup>c</sup> Service de médecine interne, centre de référence coordonnateur des cytopénies auto-immunes de l'adulte, CHU Henri-Mondor, AP-HP, Créteil, France</footnote>

<footnote><sup>d</sup> Service de médecine interne, centre de référence constitutif des cytopénies auto-immunes de l'adulte, CHU de Dijon, Dijon, France</footnote>

<footnote>* Corresponding author at: Service de médecine interne, salle Le Tallec, pavillon URM, CHU Purpan, place du Dr-Baylac, TSA 40031, 31059 Toulouse cedex 9, France.
Adresse e-mail: moulis.g@chu-toulouse.fr (G. Moulis).</footnote>
# 1. Introduction

Real-world data are essential to improve the knowledge on rare diseases [1,2]. This is the case for both immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA). Real-world data led to a better understanding of ITP and AIHA epidemiology. In particular, evidence has been provided regarding the natural history of the diseases, the frequency of associated diseases, and the major causes of morbidity and mortality like bleeding in ITP, as well as infection and thrombosis in both diseases [3-11]. Real-world evidence is also needed to assess the benefit over risk ratio of ancient drugs when no randomized trial is available, and also upon request from health authorities for post-marketing evaluation of newly licensed drugs in ITP and AIHA. In this latter case, real-world evidence is provided about the population exposed (including subgroups of patients excluded from phase III trials), the effectiveness on strong outcomes in accordance with management guidelines (that often differ from those used in randomized controlled trials), and the safety on the long-term and in specific subgroups. Real-world data are also useful to help building future randomized controlled trials, e.g. assessing the potential number of patients satisfying the inclusion criteria in a given country and evaluating the expected frequency of outcomes [1].

Three main sources of real-world data are used in rare diseases, which are complementary: patient-generated data, claims databases and clinical registries [1,2]. Patient-generated data are essential for quantifying the quality of life and the perception of the disease burden. Claims databases record electronic health data in medico-administrative databases with completeness of data in a given territory (hospital, region, country) or for a group of patients (e.g. retired patients or patients affiliated to a given insurance scheme). They are used in epidemiology and pharmacoepidemiology to measure the incidence and the prevalence of diseases, as well as some questions that need a large number of patients. However, the cohorts of patients identified in such databases are built a posteriori, with an identification based on diagnosis codes. They do not usually contain prescription data and detailed clinical data. Most of them do not contain laboratory test results, or without the completeness of data. For these reasons, prospective clinical registries are needed to provide real-world evidence in rare diseases. The ideal clinical registry of patients with ITP and AIHA records detailed clinical events, prescription data, and laboratory test results during follow-up.

We here describe the protocol of the CARMEN-France registry (NCT02877706), a prospective, multicenter cohort of adult patients with newly diagnosed ITP and AIHA in France. This registry is restricted to adult patients because there is another registry of pediatric patients with chronic ITP and with AIHA in France, named OBS'CEREVANCE [12-14].

The CARMEN-France registry is registered amongst the data sources certified by the French National health authority (Haute Autorité de santé [HAS]) to assess post-marketing real-world studies of newly licensed drugs in ITP and AIHA.

# 2. The CARMEN-France registry

## 2.1. Objectives

The objectives of the CARMEN-France registry are:

* to describe the epidemiology of ITP and AIHA in adult patients in France;

* to describe the management of ITP and AIHA in adult patients in France, particularly the accordance with guidelines;

<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Map of participating centers to the CARMEN-France registry with by years of opening. Numbers in largest circles correspond to the numbers of sites open in the corresponding city.</figcaption></figure>

* to describe the exposure to ITP and AIHA treatments in the real world in France (population characteristics, time from diagnosis to exposure, duration of exposure...);

* to assess the effectiveness of ITP and AIHA treatments in the real world in France and to identify the factors associated with effectiveness outcomes;

* to assess the occurrence of adverse drug reactions to ITP and AIHA drugs in the real world, including post-marketing surveys in conjunction with health authorities and manufacturers.

## 2.2. Participating centers

The CARMEN registry includes all adult patients with a new diagnosis of ITP (since June 2013) and AIHA (since January 2016) in the Midi-Pyrénées region (South of France, 3 million inhabitants). The CARMEN registry is aimed at the completeness of case recording within the region (participating centers in Supplementary Material, Fig. S1 and Table S1).

Since 2015, the registry was extended to other centers in France, taking the name of CARMEN-France, mapping the network of the French reference centers for autoimmune cytopenias (Henri-Mondor University hospital, Créteil, Paris, Pr. Godeau), including reference centers but also smaller non-university hospitals like in Occitania, Aquitaine region and the North-West of France (Fig. 1 and Supplementary material, Table S2).

In total, 50 centers participate actively to the registry in 2024.

## 2.3. Inclusion criteria

The inclusion criteria in the CARMEN-France registry are:

* newly diagnosed (< 3 months) ITP/AIHA, defined by international guidelines; both primary and secondary ITP/AIHA are included;

* adult patients (≥ 18 year-old at time of diagnosis);

* no opposition to data collection after detailed information about the registry and about patient rights regarding the participation to real world health studies according to French and European laws.

The centers participating in the registry are committed to including all patients with newly diagnosed ITP or AIHA without exclusion to avoid bias, whether diagnosed on an outpatient or inpatient basis. For AIHA, both warm AIHA and cold disease are included.
<table><caption>**Table 1**
Summary of data collected in the CARMEN-France registry.</caption><thead><tr><th>Categories</th><th>Variables</th><th>Initiation visit of newly diagnosed patients</th><th>Initiation visit of non-newly diagnosed patients initiating a newly marketed drug</th><th>Follow-up visits</th></tr></thead><tbody><tr><td rowspan="4">Sociodemographics</td><td>Year of birth</td><td>X</td><td>X</td><td></td></tr><tr><td>Sex</td><td>X</td><td>X</td><td></td></tr><tr><td>Weight</td><td>X</td><td>X</td><td></td></tr><tr><td>Occupation</td><td>X</td><td>X</td><td></td></tr><tr><td rowspan="7">Medical background</td><td>History of autoimmune diseases</td><td>X</td><td>X</td><td></td></tr><tr><td>History of cancer</td><td>X</td><td>X</td><td></td></tr><tr><td>History of chronic infection (HCV, HBV, HIV)</td><td>X</td><td>X</td><td></td></tr><tr><td>Cardiovascular risk factors</td><td>X</td><td>X</td><td></td></tr><tr><td>History of venous thrombosis</td><td>X</td><td>X</td><td></td></tr><tr><td>Comorbidities from the Charlson's index</td><td>X</td><td>X</td><td></td></tr><tr><td>Other comorbidities, (free text)</td><td>X</td><td>X</td><td></td></tr><tr><td rowspan="10">ITP/AIHA</td><td>Date of diagnosis</td><td>X</td><td>X</td><td></td></tr><tr><td>Date of first symptoms</td><td>X</td><td></td><td></td></tr><tr><td>Symptoms (bleeding signs/anemia syndrome) at ITP/AIHA diagnosis</td><td>X</td><td>X</td><td></td></tr><tr><td>Symptoms (bleeding signs/anemia syndrome) at ITP/AIHA from diagnosis to initiation visit</td><td></td><td>X</td><td></td></tr><tr><td>Symptoms (bleeding signs/anemia syndrome) at each visit</td><td>X</td><td>X</td><td>X</td></tr><tr><td>All drug exposures during the 8 weeks before the first symptoms of ITP/AIHA</td><td>X</td><td></td><td></td></tr><tr><td>Toxicologic exposure before the diagnosis of ITP/AIHA</td><td>X</td><td></td><td></td></tr><tr><td>Infection during the 6 weeks before the first symptoms of ITP/AIHA</td><td>X</td><td></td><td></td></tr><tr><td>Platelet count/haemoglobin level and hemolysis parameters at diagnosis</td><td>X</td><td>X</td><td></td></tr><tr><td>Platelet count/haemoglobin level and hemolysis parameters at each visit</td><td>X</td><td>X</td><td>X</td></tr><tr><td rowspan="5">History of treatments for ITP/AIHA</td><td>Full blood count at ITP/AIHA diagnosis</td><td>X</td><td></td><td></td></tr><tr><td>Tests performed at diagnosis<sup>a</sup></td><td>X</td><td></td><td></td></tr><tr><td>Direct antiglobulin test and search for cold agglutinins (AIHA)</td><td>X</td><td>X</td><td></td></tr><tr><td>Diagnosis of primary versus secondary ITP/AIHA</td><td>X</td><td>X</td><td></td></tr><tr><td>Type of AIHA (AIHA; warm/cold/mixed/other)</td><td>X</td><td>X</td><td></td></tr><tr><td>Treatments for ITP/AIHA during the follow-up</td><td>Name</td><td>X</td><td>X</td><td>X</td></tr><tr><td rowspan="3">Achievement of response/complete response according to the international terms</td><td>Dates of start and of end</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Dose<sup>b</sup></td><td>X</td><td>X</td><td>X</td></tr><tr><td>If withdrawal, reason for withdrawal<sup>c</sup></td><td>X</td><td>X</td><td>X</td></tr><tr><td>Adverse drug reactions</td><td>Date</td><td>X</td><td>X</td><td>X</td></tr><tr><td rowspan="7">Any medical event</td><td>Name</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Date of start and of end</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Causality WHO assessment scale</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Seriousness</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Outcome</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Name</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Date of start and of end</td><td>X</td><td>X</td><td>X</td></tr><tr><td rowspan="3">Burden</td><td>Seriousness</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Outcome</td><td>X</td><td>X</td><td>X</td></tr><tr><td>Number of outpatient visits, days of hospitalizations, day hospital related to ITP/AIHA</td><td>X</td><td>X</td><td>X</td></tr></tbody></table>

AIHA: autoimmune hemolytic anemia; CMV: cytomegalovirus; CT: computed tomography; EBV: Epstein-Barr virus; ITP: immune thrombocytopenia; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; TSH: thyroid stimulating hormone; WHO: World Health Organization.

<sup>a</sup> Are listed (recorded only if performed by the physician in charge of the patient): bone marrow, blood smear, C reactive protein, coagulation tests, creatinine, liver tests, antinuclear antibodies, lupus anticoagulant, anticardiolipin antibody, anti-β2-GPI antibody, serum complement, TSH; HIV, HBV, HCV, CMV, EBV, parvovirus B19, *Mycoplasma pneumoniae* (AIHA) serologies; serum protein electrophoresis, immunoglobulin levels, immunophenotyping of circulating lymphocytes, antiplatelet antibodies, CT-scan.

<sup>b</sup> Only for steroids before 2020.

<sup>c</sup> From 2021.

Because this registry is also aimed at assessing the use, the effectiveness and the safety of newly marketed drugs in these diseases, including in non-newly diagnosed patients, the patients initiating a newly marketed drug are also included. In that case, an assessment of disease history is recorded, and the prospective follow-up starts at the initiation of the new drug. This is the case for instance for adult ITP patients who have initiated fostamatinib since the commercialization of the drug in France in October 2021.

## 2.4. Follow-up and collected data

Patients are followed prospectively, with data recorded at each visit by the referring specialist physician. Follow-up is made

according to the real-world management of patients (mean: 3–4 visits/year). It ends at death, end of follow-up decided by the specialized physician in charge of the patient, emigration outside of the center in charge of the patient, or withdrawal of consent to data collection by the patient.

The data collected are indicated in Table 1. They include socio-demographic data, comorbidities, disease history, tests performed at the diagnosis of ITP/AIHA (recorded only if they are done according to the real-world management), prescriptions of treatments for ITP/AIHA, clinical signs of disease activity, routine blood cell counts, medical events during follow-up as well as adverse drug reactions due to treatments of ITP/AIHA according to the investigators.
## 2.5. Data quality

Data quality is regularly checked (twice a year up to mid-2024 then monthly) for a core set of 100+ variables for each patient. This core set of variables includes demographics, history of ITP/AIHA, treatments for ITP/AIHA, platelet counts, hemoglobin levels, bleeding during follow-up (for ITP) as well as other events and adverse drug reactions. Missing and aberrant data are identified and corrected.

Moreover, an on-site monitoring in each center has been performed in 2023-2024 with a random selection of patients with ITP and AIHA, corresponding to about 20% of the patients included in January 2023 in the database. No major issue was observed.

## 2.6. Ethics and rules

### 2.6.1. Approval

The CARMEN registry obtained authorization from the Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé in February 2012 (numbered 12.067) and from the Commission nationale de l'informatique et des libertés (CNIL) in July 2012 (decision numbered 2012-438). The Toulouse University Hospital Ethic Committee gave its approval in May 2012 (decision numbered 27-0512). The CNIL authorization was extended to the CARMEN-France registry in 2018. Information about the registry is dispensed to all patients at inclusion. This information form includes the website address of Toulouse University hospital where all studies conducted in the registry are explained.

### 2.6.2. Data property

The Toulouse University Hospital is the sponsor of the registry; it is responsible of data treatment and storage. Each participating center has the property of its data, and the whole database is a shared property of all centers.

### 2.6.3. Scientific committee

The scientific committee of the registry is the scientific committee of the French referral center network for autoimmune cytopenia in adults. Participants are representative of each academic referral center implicated in translational or clinical research in ITP in France. Meetings are hold quarterly to discuss protocols of future studies and ongoing studies as well as their results.

### 2.6.4. How to conduct a study in the CARMEN-France registry

The possibility of partnerships with public entities or pharmaceutical companies for funding the CARMEN-France registry or for conducting dedicated studies in the registry is mentioned in the information form dispensed to the patient at inclusion. The studies need an approval by the scientific committee of the French referral center for autoimmune cytopenias in adults. Each center keeps the property of its data. In case of dedicated study funded by a partner, a report of study results on aggregated data is transferred to the partner, with no access to raw data.

# 3. Number of patients. Examples of studies conducted in the CARMEN-France registry

## 3.1. Number of inclusions

On October, 15th 2023, 1911 patients with newly diagnosed ITP and 349 patients with newly diagnosed AIHA had been included.

## 3.2. Epidemiology

At the time of this manuscript, only the cohort of patients with ITP led to publications. The proportions of patients entering the

different phases of the disease (persistence, chronicity) have been assessed [11] as well as the frequency of bleeding at ITP diagnosis [15], quoted in major review papers [16]. We assessed the bleeding pattern depending on the platelet count at ITP diagnosis [15], resulting in the lowering of the platelet count threshold to hospitalize patients and initiate treatment in recent guidelines [17,18]. We were also able to show that the presence of antinuclear antibodies at high titer (≥ 1:160) in adults patients with ITP was not associated with a particular phenotype of the disease at onset [19], but was more frequently associated with a persistent/chronic outcome [11]. The large number of patients included in the registry allowed the assessment of platelet count thresholds associated to bleeding in small but challenging subgroups, like patients exposed to antiplatelet drugs [20] or yet very elderly patients (≥ 80 years) [21].

## 3.3. Pharmacoepidemiology

The prospective recording of ITP/AIHA treatments and outcomes allows for rigorous assessments of effectiveness and safety of ancient drugs and of newly marketed drugs on request of the health authorities, like eltrombopag and fostamatinib. Subgroups of patients excluded from clinical trials can be considered, like those exposed to TPO-receptor agonists during the newly diagnosed phase [22], resulting in changes in the indications for these drugs.

## 3.4. Designing clinical trials

The CARMEN-France registry is currently used to help designing clinical trials for new drugs, assessing the expected rates of response in control arms or for drugs similar to experimental drug.

## 3.5. Estimating the population target in the real-world

The registry is also used to estimate the population target of new drugs. We assessed the proportion of patients, and described the characteristics and the burden of tITP in patients who needed another drug after the exposure to the two TPO-receptor agonists marketed in France (eltrombopag and romiplostim) [23]. Indeed, this subgroup of patients represents an important subpopulation who may benefit from new drugs [24].

# 4. Future of the registry

## 4.1. Patient reported outcomes

During 2024, the inclusion of patient reported outcomes will be experimented in the most active centers. These outcomes will cover the signs of the disease (bleeding, fatigue), quality of life scores, and platelet count/hemoglobin levels measured at community laboratories and directly collected by the patients.

## 4.2. Linkage with the national health system database (SNDS)

Le national health system database (SNDS) is a claim database that links for every individual in France sociodemographics data, hospital data (including diagnoses coded using the international classification of diseases, 10th version; expensive drugs like rituximab; procedures such as splenectomy), and out-of-hospital data like chronic diseases coded by general practitioners and every reimbursed expenditures like drug dispensing at community pharmacies. It also contains data about sick leaves [25,26]. The linkage of these data to patients included in the CARMEN-France registry will allow the full vision of the health care system use by patients,
as well as pharmacoeconomics studies measuring direct costs (hospitalizations, drugs...) and indirect costs (transportation to health providers, sick leaves...). However, the database is fully anonymized and the process to link clinical data from registry to this database at the individual level is complex.

### 4.3. Linkage to other registries in Europe

The linkage to other registries in Europe is important to assess rare events, describe the disease in subpopulations, and identify biomarkers of effectiveness of drugs. It also facilitates the selection of patients for clinical trials depending on the countries. To date, there are prospective ITP registries in the United Kingdom, Italy, Switzerland, Norway and Germany. The possibilities to link these registries have been described [27]. A first parallel study using a common analysis model has been conducted in 2024 to describe the pattern of lines of treatment in ITP across countries. The next step will be the linkage of data and the individual level. This linkage is part of a European Research Consortium for ITP (ERCI, https://www.ercigroup.org/) initiative.

### 4.4. Biobanking

To date, no systematic biological collection is appended to the CARMEN-France registry. However, such collections of serum and bone marrow samples do exist locally in the main referral centers participating to the registry. Consequently, for a given question, a local linkage of these biological collection to the data prospectively recorded in the registry is feasible.

## 5. Conclusion

Some important epidemiological and pharmacoepidemiological studies have been conducted in patients with ITP in the prospective CARMEN-France registry. Studies describing AIHA epidemiology management will be conducted soon. Future directions will include implementation of patient reported outcomes, linkage with other registries in Europe and with health insurance data.

## Disclosure of interest

The CARMEN-France registry receives support from Amgen, CSL Behring, Grifols, Novartis and Sanofi. GM: research funding from Amgen, Grifols, Novartis, Sanofi; advisory board for Alpine, Amgen, Argenx, Grifols, Novartis, Sanofi, Sobi; meeting attendance grants from Amgen, Grifols and Novartis; speaker at educational sessions for Amgen, Grifols, Novartis. BB: speaker at educational sessions for Novartis, Amgen and Grifols. MM: advisory board and speaker at educational sessions for Alexion, Amgen, Argenx, Novartis, Sobi, UCB. BG: advisory board and speaker at educational sessions for Amgen, Grifols, Novartis, Sobi.

## Author contributions

G.M., the coordinator of the registry, wrote the manuscript, which was critically reviewed by the leaders of the scientific committee (M.M. and B.B.), and the head of the French national network for autoimmune cytopenia in adults (B.G.).

## Acknowledgements

We first thank all the patients and investigators. We also thank the sponsors of the CARMEN-France registry: Toulouse University Hospital, the French National Society of Internal Medicine, Amgen, CSL Behring, Grifols, Novartis and Sanofi. We thank all

research assistants who acquired the data: Cédric Castex (Reims), Astrid de Rendinger (Paris), Elodie Deruche (Amiens), Quentin Ducrocq (Lille), Hélène Duval (Caen), Fatima Farhi (Paris), Céline Feugere (Clermont-Ferrand), Nelly Francois (Nancy), Cindy Fraysse (Toulouse), Fanny Gallo (Nancy), Claudia Gillet (Toulouse), Amandine Hubert (Amiens), Aude Jouinot (Périgueux), Laetitia Languille (Paris), Carine Lopez (Bordeaux), Nathalie Marchand (Paris), Emilie Mathiotte (Lyon), Chloe McAvoy (Paris), Kewin Panel (Paris), Marie Pereira (Paris), Valérie Predan (Dijon), Onja Rarison (Marseille), Jessica Rousson (Lyon), Jamila Sahraoui (Montpellier), Nithurya Uthayakumar (Paris), Joanne Velazquez (Toulouse, Saint-Exupery Private Hospital) and the coordination team of the registry: Johanne Germain, Laurie Chabbert, Marianne Navarra, Charline Daguzan, Christophe Morin, Milena Preti, Manuela Rueter, Marie-Aline Sarda, Agnès Sommet.

## Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.revmed.2024.06.006.

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