Abstract
Background and purpose
The Food and Drug Administration approved two disease‐modifying treatments (DMTs) for Alzheimer's disease (AD), aducanumab and lecanemab, with limited clinical impact but significant biomarker changes. Identifying suitable candidates for these DMTs outside randomized clinical trials (RCTs) remains uncertain.
Methods
This cross‐sectional study, conducted in an Italian tertiary centre for cognitive disorders, aimed to evaluate how the RCT eligibility criteria for DMT treatments applies to participants with early AD. The broader Cummings et al. (Journal of Prevention of Alzheimer's Disease, 2021, 2023) criteria and the clinical differences between DMT candidates were also assessed.
Results
The study involved 408 participants (mean age 71.1 ± 8.5 years, 48% male) with a clinical diagnosis of mild cognitive impairment (161/408, 39.5%) or mild dementia (247/408, 60.5%). Amongst them, 169 individuals (41%) showed positive AD pathology biomarkers. Eligibility RCT assessment revealed 14 patients eligible for aducanumab (3.43% of 408) and 28 for lecanemab (6.86% of 408). Following Cummings' real‐world criteria, aducanumab eligibility increased to 9.56%, whereas lecanemab eligibility rose to 8.33%. Applying selection criteria to only the amyloid positive (169 out of 408), the selection for DMTs was 8.3% for aducanumab and 16.5% for lecanemab.
Conclusion
Amongst subjects diagnosed with mild AD and mild cognitive impairment in a tertiary centre for cognitive disorders, only a small percentage of patients using RCT diagnostic criteria are eligible for DMT. The application of Cummings criteria strongly increased the DMT candidates. Nevertheless, the majority of patients with cognitive disorders have been excluded from DMTs approved so far.
Keywords: aducanumab, Alzheimer, disease‐modifying, DMT, lecanemab
INTRODUCTION
The Food and Drug Administration (FDA) recently approved two disease‐modifying treatments (DMTs) for Alzheimer's disease (AD). Aducanumab and lecanemab respectively were approved with an accelerated procedure in 2021 and, with an accelerated procedure followed by the regular procedure, in 2023 for use in mild cognitive impairment (MCI) and mild dementia due to AD; a third DMT is in the course of FDA and European Medicines Agency evaluation (donanemab) [1].
In phase 3 trials, lecanemab and aducanumab showed a small effect on clinical measures and a much larger effect on biomarkers [2, 3]. The effect looks to be increasing over time with a dose‐dependent effect, as a DMT is expected to determine [4].
A critical point to determine the effect is the selection of patients for DMTs: this is firmly established in the randomized clinical trial (RCT) setting but it is not clear how it works in a real‐world scenario of clinical care for cognitive disorders. Possible sites for AD care are extremely heterogeneous for referral, organization, technical capacity and expertise of specialists involved in the clinical care; the definition of the clinical setting is therefore critical. Several studies have addressed the question of what percentage of patients with mild AD would be available for DMT. This was done in Italy in centres for the clinical care of dementia named CDCD [5, 6], in Ireland in a specialist geriatric‐based cognitive service [7] and in the United States with medical services claims [8] and in a population‐based study in Rochester (MN) [9]. The latter study was the only one to consider also lecanemab. When the inclusion and exclusion criteria of the DMT RCT were applied, all studies showed the number of candidates for DMT on average <10% of subjects initially recruited in each setting for DMT treatment. The only exception was the Irish study [7], in a setting with neurological and geriatric expertise, with a larger proportion of subjects (27%). In this case, the authors applied the less restrictive, real‐world criteria, as proposed for the use of aducanumab by Cummings et al. [10].
These results are only partially consistent with the results of a study by the RAND Corporation [11] developing predictions in six European countries, starting with a target population of subjects over 55, about 105 million in Europe. They identified several restricting steps that reduced the candidates for DMT therapy to only 2.3 million (2.7%). This study identified three main constraints in the health system for using DMT: availability of dementia specialists, availability of biomarker testing, and infusion delivery capacity. Notwithstanding the large and structural differences in the two health systems, a similar proportion of DMT candidates have been reported by this group in the United States [12]. There is a substantial numerical difference between subjects with cognitive impairment in the general population and subjects amongst them who are referred to the medical system for diagnosis and care. Only a part of subjects with MCI and mild AD in the general population are referred to the medical system and are then taken in charge for diagnosis and medical care in tertiary referral centres.
Therefore, the referral population of tertiary centres for cognitive disorders with a clinical diagnosis of MCI and mild AD is the key and starting element in the selection process determining DMT candidates. A study in a tertiary referral centre for cognitive disorders in Italy was conducted with three goals:
to assess the proportion of patients referred from the primary and secondary health system to a tertiary centre, labelled as candidates for DMT after applying the inclusion and the exclusion RCT criteria for the two major DMTs in AD, aducanumab and lecanemab;
to assess the proportion of patient candidates using the real‐world criteria proposed by Cummings et al. in the same tertiary setting;
to understand the clinical differences between different candidates for different DMTs.
MATERIALS AND METHODS
Design of the study
The present retrospective cohort study aimed to apply the clinical trial eligibility criteria for aducanumab and lecanemab treatments to consecutive subjects clinically diagnosed with MCI and early AD at the Centre for Neurodegenerative Diseases and the Aging Brain of the University of Bari Aldo Moro at Pia Fondazione ‘Card. G. Panico’ located in Tricase (LE, Italy), a tertiary referral centre for neurodegenerative disorders, primary hub for cognitive disorder in the Puglia region, an area of about 4 million people.
The complete eligibility criteria for the treatments have been reported in the study protocols by Haeberlein et al. [2] for aducanumab and van Dyck et al. [3] for lecanemab.
In addition, appropriate use recommendation (AUR) criteria by Cummings et al. [10, 13] were followed for both treatments to compare the eligibility selection processes. Eligibility criteria were returned both for inclusion and exclusion criteria by providing a thorough evaluation process, useful for the selection of patients. Results were provided in frequencies and were graphically presented by Venn diagrams and bar plots. Data were extracted from the clinical registry of the centre considering the time interval (accessed on 6 November 2023). The local Medical Ethics Committee approved the protocol for using the clinical data for research purposes (Protocol No. 6, 25 July 2017). Written informed consent was obtained from patients or proxies.
Clinical data collection and assessment
Patients underwent a standardized assessment, including neurological examination, neuropsychological tests, imaging, and either amyloid measurement in the cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) to determine the amyloid‐positive status. Participants provided information concerning their personal and familial medical backgrounds, demographics, neuropsychiatric symptoms and medication usage. The severity of functional impairment in patients was evaluated using the Clinical Dementia Rating Scale (CDR). Cognitive screening was assessed using the Mini‐Mental State Examination (MMSE). Furthermore, a neuropsychologist administered a neuropsychological examination across five cognitive domains (memory, language, attention, executive function and visuospatial abilities), as listed in the Supplementary Material. All assessments were conducted by trained neuropsychologists and neurologists. All the above mentioned assessments were performed within a close timeframe (<4 weeks) from the patient's enrolment to minimize variability due to disease progression or other factors. Magnetic resonance imaging (MRI) was conducted using a 3‐T scanner (Philips Ingenia). For each participant structural T1‐weighted magnetization prepared rapid gradient echo and fluid‐attenuated inversion recovery images were examined. These images were used to detect and classify lacunar and cortical infarctions according to established criteria [14]. Additionally, cerebral microbleeds were assessed using T2* gradient recalled echo sequences on 3‐T MRI scans, following consensus criteria [15]. As part of the diagnostic procedure, the lumbar puncture for CSF biomarker analysis (Aβ42, t‐tau, p‐tau) was performed. Within 1 h, the CSF samples were centrifuged at room temperature for 10 min at 2000 g (RCF), aliquoted and stored at −80°C until analysis, according to international biomarker recommendations [16]. The CSF Aβ42, tau and p‐tau181 levels were measured by chemiluminescent immunoassay CLEIA (Lumipulse G β‐amyloid 1–42, total tau, phosphorylated tau 181, Fujirebio Europe N.V., Gent, Belgium) on a fully automatic platform (Lumipulse G600II, Fujirebio Europe). For the interpretation of the CSF biomarker results, the following cut‐off values, provided by the manufacturer, were considered pathological: Aβ42 < 599 pg/mL, tau > 342 pg/mL, p‐tau181 > 57.6 pg/mL. During each visit the final diagnosis was determined through consensus amongst the study coordinator, neurologist and neuropsychologist. The clinical diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders 5th ed. [17]. Briefly, a mild neurocognitive disorder (formerly MCI) was suspected when there was a modest, steadily progressive, decline in cognitive performance, especially memory and learning, from a previous level of functioning without interfering with independence in daily living, after carefully exclusion of delirium or other mental disorders; a patient with a mild major neurocognitive disorder (mild AD) required assistance in instrumental activities of daily living.
According to the National Institute on Aging and Alzheimer's Association criteria, an in vivo biological diagnosis of AD was based on concomitant demonstration of amyloid pathology (either amyloid‐PET or lower Aβ42 levels) and aggregated tau pathology (neurofibrillary tangles) through CSF p‐tau181 levels [18]. The final diagnosis and evaluation were made following a comprehensive review of all available information, including imaging, pertaining to each participant.
Eligibility criteria
The variables involved in the sieving processes are shown in Table 1. The inclusion and exclusion published criteria for the RCTs and AUR criteria of aducanumab and lecanemab are reported in Tables S1 and S2 in the Supplementary Material.
TABLE 1.
Inclusion and exclusion criteria: list of variables.
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Abbreviations: APOE, Apolipoprotein E; BMI, body mass index; CDR, Clinical Dementia Rating Scale; MMSE, Mini‐Mental State Examination; MRI, magnetic resonance imaging.
Statistical analysis
A statistical analysis was performed on the variables age, sex, education, MMSE, Aβ42, tau and p‐tau in order to compare the raw eligibility (in relation to the positive amyloid patients), treatment‐specified eligibility and full eligibility (vs. non‐full eligibility with positive amyloid), that is, whether patients were eligible to both treatments across both criteria (RCT and AUR). Median and interquartile range or frequencies were computed as descriptive statistics, and Mann–Whitney or Fisher's exact tests were applied as appropriate (p value <0.05 set the significance).
RESULTS
Study sample
The study population consisted of 408 participants (mean age 71.1 [SD 8.5] years, 196 [48.0%] male) with a clinical diagnosis of MCI (n = 161) or mild dementia (possible or probable AD; n = 247). Out of these, 169 (41%) individuals had positive biomarkers for AD amyloid pathology (CSF markers or amyloid‐PET; MCI, n = 95; mild AD, n = 74).
Aducanumab eligibility criteria
When the aducanumab inclusion criteria were applied to our study population (N = 408), two participants were excluded based on their age, one participant based on years of education, 10 participants based on a CDR global score other than 0.5, 239 participants for non‐positive biomarkers for brain amyloid pathology and 123 participants based on an MMSE below 24 (Figure 1). Four participants were also excluded for not fulfilling the memory assessment criteria. Consequently, 29 individuals (7.1% of 408 clinically diagnosed; 17.2% out of 169 amyloid positive) met the aducanumab clinical trial's inclusion criteria. However, applying the aducanumab exclusion criteria further reduced the number of eligible participants to 14 (3.43% of 408; 8.3% out of 169 amyloid positive). Noteworthy exclusions (Figure 1) were medical criteria (nine), MRI criteria (four) and contraindications (two). The medical reasons for exclusion were (i) six medical or neurological conditions, (ii) two psychiatric diseases and (iii) one immunological disease (Table S3). The MRI criteria for exclusion were more than four microhaemorrhages in two individuals, and critical infarct in two individuals.
FIGURE 1.
Application of the RCT eligibility criteria to real‐world patients. RCT, randomized clinical trial.
Lecanemab eligibility criteria
Upon applying the lecanemab inclusion criteria from the RCT to our cohort, one participant was disqualified based on age. Additionally, 239 individuals did not exhibit positive biomarkers for brain amyloid pathology, 101 patients were excluded due to an MMSE score below 22, and two participants were excluded for not meeting the CDR requirements. Furthermore, eight patients did not fulfill the inclusion criteria for memory assessment. An additional patient was excluded due to body mass index restrictions, and one more participant was ineligible in relation to the educational level (Figure 1). As a result, 55 participants (13.5% of the total 408; 32.3% of amyloid positive) fulfilled the inclusion criteria outlined in the lecanemab RCT. Nevertheless, the application of exclusion criteria led to the exclusion of an additional 27 patients. Amongst them, 18 individuals were excluded due to medical concerns, seven because of MRI limitations and two based on other contraindications. The specific medical and MRI exclusion reasons for each patient can be found in Table S3. At the end of the sieving process, 28 patients (6.86% out of 408 clinically diagnosed; 16.5% out of 169 amyloid positive) were suitable for lecanemab.
Aducanumab eligibility according to AUR
For the 408 participants in our study population, the aducanumab inclusion AUR criteria were applied and one participant was excluded for their education level, 90 for scoring <21 on the MMSE and 239 participants for non‐positive biomarkers for brain amyloid pathology (Figure S1). As a result, 78 participants (19.1% out of 408; 46.2% out of 169 amyloid positive) qualified for the aducanumab inclusion criteria. When applying the aducanumab exclusion AUR criteria, 39 participants (9.56% of 408; 23% out of 169 amyloid positive) remained eligible. The main reasons for exclusion (Figure 1) were medical criteria (25), MRI criteria [10], concomitant medication (one) and contraindications (three). The medical criteria excluded 17 participants for having medical or neurological conditions, three for having psychiatric diseases, one for having an immunological disease, one for bleeding conditions and three for other medical conditions (Table S3). The MRI criteria excluded four participants for having more than four microhaemorrhages, five for critical infarct and one for findings that, in the opinion of the investigator, might be a contributing cause of the subject's dementia and might pose a risk to the subject.
Lecanemab eligibility according to AUR
In line with the AUR, a total of 66 patients (16.2% out of 408; 39% out of 169 amyloid positive) were potentially eligible for lecanemab based on inclusion criteria. Specifically, 239 patients were excluded as they did not show amyloid positivity at CSF examination, 102 patients were excluded due to MMSE scores below 22, and one patient was excluded based on educational level. The application of exclusion criteria revealed that 22 patients had medical comorbidities, seven presented MRI abnormalities and three had contraindications. Ultimately, 34 patients (8.33% of 408; 20% out of 169 amyloid positive) were deemed suitable for lecanemab treatment (Figure S1). Detailed information regarding patients excluded due to medical and MRI concerns is provided in Table S3. Overall, Table 2 shows the descriptive statistics of the relevant characteristics of participants who met the eligibility criteria.
TABLE 2.
Characteristics of participants who met the eligibility criteria according to RCT and AUR criteria.
| Variables | Aducanumab (RCT) median (IQR) or frequencies | Lecanemab (RCT) median (IQR) or frequencies | Aducanumab (AUR) median (IQR) or frequencies | Lecanemab (AUR) median (IQR) or frequencies |
|---|---|---|---|---|
| n | 14 | 28 | 39 | 34 |
| Age (years) | 70.5 (64; 74.75) | 68.5 (63.75; 75) | 69 (64; 74.5) | 69 (63.25; 74.5) |
| Sex (M/F) | 4/10 (28.6/71.42) | 9/19 (32.1/67.9) | 13/26 (33.3/66.6) | 11/23 (32.3/67.6) |
| Education (years) | 8 (8; 13) | 13 (8; 13) | 11 (8; 13) | 9.5 (8; 13) |
| MMSE | 25 (24.25; 28) | 24 (22.75; 26) | 24 (22; 25.5) | 24 (23; 26) |
| CDR | 0.5 (0.5; 0.5) | 0.5 (0.5; 1) | 0.5 (0.5; 1) | 0.5 (0.5; 0.5) |
| Aβ (pg/mL) | 527 (457; 541) | 492 (423; 539) | 489 (428.2; 536.2) | 492 (436; 541) |
| Tau (pg/mL) | 737 (479; 1208) | 635 (355; 868.5) | 592 (358; 863.2) | 568 (341; 790) |
| p‐tau (pg/mL) | 139 (62.3; 172.9) | 92.9 (52.75; 146.15) | 83.25 (52.77; 142.57) | 81 (52.7; 131.7) |
Note: n, eligible patients.
Abbreviations: AUR, appropriate use recommendation; CDR, Clinical Dementia Rating Scale; F, female; IQR, interquartile range; M, male; MMSE, Mini‐Mental State Examination; RCT, randomized clinical trial.
Finally, to have an immediate graphical summary of the overall results Figures 2 and S2 were generated. The first shows the Venn diagram of the eligible patients to the two treatments across criteria; concerning that, the percentages are out of 40 eligible patients. In the second one, a treatment‐stratified bar plot shows the eligibility frequencies on the clinical registry data.
FIGURE 2.
Venn diagram: eligibility for DMT therapies according to RCT and AUR criteria. AUR, appropriate use recommendation; RCT, randomized clinical trial.
Statistical analysis
In the Supplementary Material are reported text and tables (Tables S4–S9) concerning the results on the statistical analysis in relation to eligibility.
DISCUSSION
This study confirms that the strict application of RCT criteria restricted the number of eligible patients with a clinical diagnosis of MCI or mild dementia to <10% for both aducanumab and lecanemab. This percentage was obtained after all subjects with a diagnosis of MCI and mild AD went through a thorough selection process with the use of CSF and PET findings to identify the amyloid‐positive patients whilst the exclusion of subjects with several comorbid conditions and medications were identified by history, physical examination and neuroimaging. The application in the same cohort of less stringent criteria as proposed by Cummings et al. for aducanumab determined a modest increase of the eligibility percentage [10]. This was due mainly to the choice of relaxing the limits for age, MMSE (including patients with a score of 21 from the 24 used in the RCT) and not considering the disease stage with CDR and the results of the memory test with RBANS within the inclusion and exclusion criteria. This study confirms that FDA‐approved DMTs are suitable only for a limited number of subjects and the majority of subjects with MCI and mild AD remain excluded from access to DMTs. This is due primarily to the high prevalence in the possible DMT candidates of comorbid conditions. This is only partially consistent with a previous study where, in a geriatric and neurological setting for cognitive disorders in Ireland, the excluded subjects were more than 70% after applying less stringent criteria [7].
When the inclusion and exclusion criteria were applied to the amyloid‐positive cases selected based on CSF results from the clinically diagnosed, the percentages were higher but in the less restrictive scenario with AUR still around 20%.
In this complex approach, RCTs increase the internal validity with strict inclusion and exclusion criteria but reduce the generalizability of the findings to the real world because older patients present several conditions with high prevalence amongst older adults like hypertension, diabetes, dyslipidaemia, heart and kidney diseases. Multimorbidity after age 65 is common and tends to increase exponentially both in men and women with many subjects presenting five comorbid conditions and more [19].
In this direction it is important that different stakeholders involved in RCTs of ageing related diseases such as AD identify subjects who are representative of the target population in the clinical practice. The European Medicines Agency is proposing to do this with the Darwin initiative [20], favouring the collection of real‐world data both in RCT and observational studies (https://www.ema.europa.eu/en/about‐us/how‐we‐work/big‐data/data‐analysis‐and‐real‐world‐interrogation‐network‐darwin‐eu, accessed 6 January 2024).
Identifying those eligible for DMTs is also valuable to predict the economic costs for the health systems. One of the main gaps in knowledge is that the numbers of subjects identified from epidemiological studies are extremely numerous: more than 15 million according to one of the most recent estimates [21]. The barriers to diagnostic procedures, especially for the elderly, and difficulties of the healthcare systems in identifying cases reduce the number of people who can enter the choice of eligible subjects to DMTs. Many subjects do not receive a proper diagnosis: the number of subjects who access a tertiary clinical centre has been identified at more than 5 million subjects in the European Union with 27 countries [22] and more than 7 million in Europe according to the study of the Rand Corporation. Based on these starting numbers and after selecting procedures, the DMT candidates would be more than 2 million both in Europe and in the United States [11, 12]. The cascades proposed in all these studies are established on successive steps on undefined parameters and quite arbitrary selection choices. Treating all patients with cognitive decline present in the community in Europe at the present time is an unrealistic scenario. DMTs should be offered only in specialized memory clinics with rapid access to neuropsychological testing, imaging, and CSF and blood‐based biomarkers [4]. This is a more realistic approach to identifying patients within a specialized setting of a tertiary centre for cognitive disorders where an early diagnosis, selection process and an accurate identification and care of the possible side effects are possible. Thus, it is necessary to start with patients referred to tertiary centres with MCI and mild AD, select the amyloid positive and finally identify the percentage of possible candidates for DMTs. Our study was therefore planned in this realistic clinical care scenario and nevertheless presents several strengths and limitations. First, the patient's eligibility was compared to the two FDA approved DMTs with inclusion and exclusion RCT criteria [2, 3] and, finally, the same procedure recommendations for real‐world scenarios were checked, as proposed by Cummings et al. [10, 13]. Additionally, our study employed a selection process that thoroughly assessed all listed criteria. The presented data are built on a robust foundation, derived from a comprehensive multidimensional dataset, established in our tertiary centre. However, certain limitations were identified, primarily associated with the retrospective approach used to assess DMT eligibility. Furthermore, frailty and unwillingness to undergo a complex new treatment regimen were not formally evaluated. One notable limitation is the sequence in the selection of ‘amyloid‐positive status’ as the first inclusion criterion in our process. In a real‐world scenario, the biological diagnosis of AD is the last part of a diagnostic process that includes evaluating comorbidities, assessing medication history, conducting neuropsychological assessments and reviewing MRI results. Another limitation is linked to the definition of amyloid positive. Regarding the different CSF Aβ biomarkers, the level of Aβ42 was used, and the Aβ42/Aβ40 ratio was not considered due to the absence of Aβ40 measurements in our dataset. This approach may have determined the possible inclusion of patients with non‐Alzheimer's disease pathology [23]. However, the number of such subjects is likely to be very limited; in the future, having a biomarker of tau downstream pathology is an additional piece of information that will be used as in the most recent donanemab trial [1].
Our study identifies a small percentage of patients as eligible for DMTs in <10% of subjects diagnosed with mild AD and MCI in a tertiary centre for cognitive disorders when applying the RCT criteria and about 15% with AUR. This offers a more realistic scenario to identify costs for the healthcare system in case a European Union licence should be granted. However, the majority of patients with cognitive disorders will be excluded from DMT use, even when real‐world less restricting criteria are properly used. The upgrade of the diagnostic system in community and primary care of cognitive disorders, primarily for MCI, with the use of blood‐based biomarkers is a necessary condition to increase the number of subject candidates for DMT in an early stage of AD.
AUTHOR CONTRIBUTIONS
G. Logroscino: Conceptualization; methodology; investigation; supervision; writing – original draft; resources; project administration; funding acquisition; formal analysis; data curation. D. Urso: Conceptualization; methodology; data curation; investigation; formal analysis; supervision; writing – original draft; project administration. V. Gnoni: Investigation. A. Giugno: Investigation. D. Vilella: Investigation. A. Castri: Data curation; methodology. R. Barone: Data curation. S. Nigro: Data curation. C. Zecca: Data curation. R. De Blasi: Data curation; writing – review and editing. A. Introna: Conceptualization; methodology; investigation; formal analysis; writing – original draft.
FUNDING INFORMATION
This work has been supported by the funding of Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione D.G.R. n. 2117 of 21.11.2018 (B84I18000540002) and ‘Fondo Alzheimer e Demenza’ Project—Regione Puglia D.G.R. n. 1284 of 19 September 2022.
CONFLICT OF INTEREST STATEMENT
Giancarlo Logroscino has served as investigator for clinical trials sponsored by Biogen Pharmaceuticals, Axovant, Alector, Denali, Roche, Eisai, Genentech, Amylyx, PIAM Farmaceutici SpA. He has served as a consultant and has given lectures for EISAI, Roche, Lilly, Piam Farmaceutici Spa, Biogen.
ETHICS STATEMENT
All participants gave written informed consent. The study was approved by the local Ethics Committee of the local Medical Ethics Committee (Protocol No. 6, 25 July 2017).
Supporting information
Data S1:
Logroscino G, Urso D, Gnoni V, et al. Mild cognitive impairment and early Alzheimer's disease eligibility for disease modification therapies in a tertiary centre for cognitive disorders: A simultaneous real‐word study on aducanumab and lecanemab. Eur J Neurol. 2025;32:e16534. doi: 10.1111/ene.16534
DATA AVAILABILITY STATEMENT
The ethical requirement to ensure patient confidentiality precludes public archiving of our data. Researchers who wish to obtain the raw data should reach out to the corresponding author, who will coordinate with the ethics committee that authorized the study. Based on their approval, the necessary data will be provided to replicate the findings to the individual researcher.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1:
Data Availability Statement
The ethical requirement to ensure patient confidentiality precludes public archiving of our data. Researchers who wish to obtain the raw data should reach out to the corresponding author, who will coordinate with the ethics committee that authorized the study. Based on their approval, the necessary data will be provided to replicate the findings to the individual researcher.