Endpoint Of Progression Research Articles

Predictors for Disease-Free and Progression-Free Survivals in Metabolic Responders and Non-Responder on Follow-Up 18FDG PET/CT after Chemoradiation in Patients With Nasopharyngeal Cancer.

To determine disease free survival (DFS) and progression free survival (PFS) and their predictors in patients with nasopharyngeal cancer (NPC) having achieved complete (CMR) and partial metabolic response (PMR) on post-chemoradiation (CRT) 18FDG PET/CT. Retro-prospective study conducted at PET/CT Section of JCIA accredited healthcare facility of Pakistan. Total 73 patients of NPC patients who had baseline and post-CRT 18FDG PET/CT were included and prospectively followed till predefined study end points of recurrence or disease progression or death from April-2016 till January 2024. Based on CMR on post-CRT 18FDG PET/CT, 45 patients labelled as responders while 28 with PMR as non-responders. Using logistic regression and ROC analysis, the predictors of recurrence and disease progression were analyzed in both groups. Kaplan Meier's survival plots were analyzed to measure DFS in responders and PFS in non-responders respectively. Body mass index (BMI), SUVmax and Stage-IV disease were found significantly higher in non-responder group. DFS in responders was significantly higher than PFS in non-responder (60.157 month ± 8.047 Vs 8.145 months ± 1.851). DFS was seen in 84% of responder group with 16% recurrence (7/45). Baseline SUVmax >14.2 and primary tumor size (PTS) > 41 mm were found significant predictors of recurrence in responder group. In the non-responder group, the PFS was found in 54% patients while 46% patients (n=13/28; 2 expired) had disease progression. No significant predictor was found for PFS in the non-responder group. In DFS the mean survival was significantly higher in patients with SUVmax ≤14.2 versus >14.2 (Mean Survival 67.390 vs. 38.283 months; Logrank 9.899; p=0.0017*). However, near significant difference was observed in non-responder group in their PFS at SUVmax ≤11.9 vs. >11.9 (Mean Survival 10.00 vs. 7.05 months; Logrank=3.096; p=0.0798). 18FDG PET/CT scan precisely stratifies the treated NPC patients into responders having longer DFS and non-responders having shorter PFS. Higher BMI, SUVmax of primary tumor and metastatic disease were found to have significant association in non-responders. In responders, PTS >41 mm and its SUVmax >14.2 were found significant predictors of recurrence. In non-responders, SUVmax >11.9 was found to have near significant association with disease progression.

Proteinuria as an Endpoint in Clinical Trials of Focal Segmental Glomerulosclerosis

Focal Segmental Glomerulosclerosis (FSGS) is a characteristic histopathological lesion that is indicative of underlying glomerular dysfunction. It is not a single disease entity but rather a heterogeneous disorder that is an important cause of nephrotic syndrome and kidney failure in children and adults. The aim of this Kidney Health Initiative project was to evaluate potential endpoints for clinical trials in FSGS. This paper focuses on the data supporting proteinuria as a surrogate endpoint. Available data support the use of complete remission of proteinuria in patients with heavy proteinuria as a surrogate endpoint for progression to kidney failure. While substantial treatment effects on proteinuria that are short of a complete remission may also predict the effect of a treatment on progression to kidney failure, further work is needed to determine how such an endpoint should be defined. Fortunately, efforts are underway to bring together patient-level data from randomized controlled trials, observational studies, and registries to address this issue.

A Self-led Self-management Intervention Supporting Teens with IBD (ASSIST-IBD): protocol for a feasibility study of a novel digital treatment adherence intervention

IntroductionTreatment non-adherence is common in young people with inflammatory bowel disease (IBD), yet support is lacking. A self-led self-management intervention supporting teens with IBD (ASSIST-IBD) is a new theory-based digital...

1635P Validation of automated bone scan index as a progression endpoint in two phase III studies of metastatic castration resistant prostate cancer (mCRPC) patients

1635P Validation of automated bone scan index as a progression endpoint in two phase III studies of metastatic castration resistant prostate cancer (mCRPC) patients

Association Between MR Elastography Liver Stiffness and Histologic Liver Fibrosis in Children and Young Adults With Autoimmune Liver Disease.

BACKGROUND. Liver fibrosis is an important clinical endpoint of the progression of autoimmune liver disease (AILD); its monitoring would benefit from noninvasive imaging tools. OBJECTIVE. The purpose of this study was to assess the relationship between MR elastography (MRE) liver stiffness measurements and histologic liver fibrosis, as well as to evaluate the performance of MRE and biochemical-based clinical markers for stratifying histologic liver fibrosis severity, in children and young adults with AILD. METHODS. This retrospective study used an existing institutional registry of children and young adults diagnosed with AILD (primary sclerosing cholangitis [PSC], autoimmune sclerosing cholangitis [ASC], or autoimmune hepatitis [AIH]). The registry was searched to identify patients who underwent both a research abdominal 1.5-T MRI examination that included liver MRE (performed for registry enrollment) and a clinically indicated liver biopsy within 6 months of that examination. MRE used a 2D gradient-recalled echo sequence. One analyst measured mean liver shear stiffness (in kilopascals) for each examination. Laboratory markers of liver fibrosis (aspartate aminotransferase-to-platelet ratio index [APRI] and fibrosis-4 [FIB-4] score) were recorded. For investigational purposes, one pathologist, blinded to clinical and MRI data, determined histologic Metavir liver fibrosis stage. The Spearman rank order correlation coefficient was calculated between MRE liver stiffness and Metavir liver fibrosis stage. ROC analysis was used to evaluate diagnostic performance for identifying advanced fibrosis (i.e., differentiating Metavir F0-F1 from F2-F4 fibrosis), and sensitivity and specificity were calculated using the Youden index. RESULTS. The study included 46 patients (median age, 16.6 years [IQR, 13.7-17.8 years]; 20 female patients, 26 male patients); 12 had PSC, 10 had ASC, and 24 had AIH. Median MRE liver stiffness was 2.9 kPa (IQR, 2.2-4.0 kPa). MRE liver stiffness and Metavir fibrosis stage showed strong positive correlation (ρ = 0.68). For identifying advanced liver fibrosis, MRE liver stiffness had an AUC of 0.81, with sensitivity of 65.4% and specificity of 90.0%; APRI had an AUC of 0.72, with sensitivity of 64.0% and specificity of 80.0%; and FIB-4 score had an AUC of 0.71, with sensitivity of 60.0% and specificity of 85.0%. CONCLUSION. MRE liver stiffness measurements were associated with histologic liver fibrosis severity. CLINICAL IMPACT. The findings support a role for MRE in noninvasive monitoring of liver stiffness, a surrogate for fibrosis, in children and young adults with AILD. TRIAL REGISTRATION. ClinicalTrials.gov NCT03175471.

Head-to-head studies on radiographic progression in axial spondyloarthritis

In this review article four clinical comparative studies in axial spondylarthritis (axSpA) are presented and discussed. SURPASS as the only head-to-head study investigated the effect of adalimumab biosimilar disease-modifying antirheumatic drug (bsDMARD) or secukinumab on radiographic progression over a time period of 2 years. Overall, the radiographic progression of the spine was low and no significant difference between adalimumab bsDMARD or secukinumab was noted. The three other studies were not constructed as direct head-to-head studies but compared the efficacy of non-steroidal antirheumatic drugs (NSARD) with and without simultaneous treatment with biological DMARDs (bDMARD). The CONSUL study showed no statistically significant difference in the delay of radiographic progression of the spine over 2 years in radiographic axSpA (r-axSpA) patients, who underwent either combined treatment with golimumab and celecoxib or treatment with golimumab alone over 2 years. The ESTHER study showed that patients with early axSpA active inflammatory lesions, which were detected by whole-body magnetic resonance imaging (MRI), showed a significantly greater improvement under treatment with etanercept than those treated with sulfasalazine. The INFAST study showed that patients with early active axSpA who received a combined treatment of infliximab and naproxen, achieved a clinical remission twice as frequently as those who only received naproxen. Therefore, for the endpoint of radiological progression no difference could be shown in the inhibition of radiological progression between the mechanisms of action investigated. The comparative data for the endpoint of clinical efficacy showed that patients with bDMARDs showed a clearly better response to treatment than patients with NSAR or conventional synthetic DMARDs (csDMARD).

Vestibular Schwannoma International Study of Active Surveillance Versus Stereotactic Radiosurgery: The VISAS Study

BackgroundThe present study assesses the safety and efficacy of stereotactic radiosurgery (SRS) versus observation for Koos grade I and II vestibular schwannoma (VS), benign tumors affecting hearing and neurological function. MethodsThis multicenter study analyzed data from Koos grade I and II VS patients managed with SRS (SRS group) or observation (observation group). Propensity score matching balanced patient demographics, tumor volume, and audiometry. Outcomes measured were tumor control, serviceable hearing preservation (SHP), and neurological outcomes. ResultsIn 125 matched patients in each group with a 36-month median follow-up (p=0.49), SRS yielded superior 5- and 10-year tumor control rates (99%, CI: 97.1%-100%, and 91.9%, CI: 79.4%-100%) vs. observation (45.8%, CI: 36.8%-57.2%, and 22%, CI: 13.2%-36.7%; p<0.001). SHP rates at 5 and 9 years were comparable (SRS 60.4%, CI: 49.9%-73%, vs. observation 51.4%, CI: 41.3%-63.9%, and SRS 27%, CI: 14.5%-50.5%, vs. observation 30%, CI: 17.2%-52.2%; p=0.53). SRS were associated with lower odds of tinnitus (OR=0.39, p=0.01), vestibular dysfunction (OR=0.11, p=0.004), and any cranial nerve palsy (OR=0.36, p=0.003), with no change in cranial nerves V or VII (p>0.05). Composite endpoints of tumor progression and/or any of the previous outcomes showed significant lower odds associated with SRS compared to observation alone (p < 0.001). ConclusionSRS management in matched cohorts of Koos grade I and II VS patients demonstrated superior tumor control, comparable hearing preservation rates, and significantly lower odds of experiencing neurological deficits. These findings delineate the safety and efficacy of SRS in in the management of this patient population.

Predictors of liver disease progression in people living with HIV-HBV co-infection on antiretroviral therapy

In people living with HIV-HBV, liver fibrosis progression can occur even with suppressive antiretroviral therapy (ART). We investigated the relationship between liver fibrosis and biomarkers of inflammation, apoptosis, and microbial translocation. In this observational cohort study adults living with HIV-HBV already on effective ART were recruited in Australia and Thailand and followed for 3 years including 6 monthly clinical review and blood tests and annual transient elastography. Differences in clinical and laboratory predictors of liver fibrosis progression were tested followed by regression analysis adjusted for CD4+ T-cells at study entry. A linear mixed model was fitted to longitudinal data to explore changes over time. 67 participants (85% male, median age 49y) were followed for 175 person-years. Median duration of ART was 10 years (interquartile range (IQR) 8-16 years). We found 11/59 (19%) participants during 3-years follow-up (6/100 person-years) met the primary endpoint of liver disease progression, defined as increased Metavir stage from baseline to final scan. In regression analysis, progressors compared to non-progressors had higher levels of high mobility group box 1 protein (HGMB1), (median (IQR) 3.7 (2.6-5.0) and 2.4ng/mL (1.5-3.4) respectively, adjusted relative risk 1.47, 95% CI [1.00, 2.17]) and lower nadir CD4+ T-cell percentage (median 4% (IQR 2-8) and 11% (4-15) respectively (relative risk 0.93, 95% CI [0.88, 0.98]). Progression in liver fibrosis occurs in people with HIV-HBV on suppressive ART. Fibrosis progression was associated with higher HMGB1 and lower percentage nadir CD4+ T-cell count, highlighting the importance of early initiation of HBV-active ART. This work was supported by NHMRC project grant 1101836; NHMRC practitioner fellowship 1138581 and NHMRC program grant 1149990. The funder had no role in study design, data collection, data analysis, interpretation, writing of this manuscript or decision to submit for publication.

CT pericoronary adipose tissue density predicts coronary allograft vasculopathy and adverse clinical outcomes after cardiac transplantation.

To assess pericoronary adipose tissue (PCAT) density on Coronary Computed Tomography Angiography (CCTA) as a marker of inflammatory disease activity in coronary allograft vasculopathy (CAV). PCAT density, lesion volumes, and total vessel volume-to-myocardial mass ratio (V/M) were retrospectively measured in 126 CCTAs from 94 heart transplant patients (mean age 49 [SD 14.5] years, 40% female) who underwent imaging between 2010 to 2021; age and sex-matched controls; and patients with atherosclerosis. PCAT density was higher in transplant patients with CAV (n = 40; -73.0 HU [SD 9.3]) than without CAV (n = 86; -77.9 HU [SD 8.2]), and controls (n = 12; -86.2 HU [SD 5.4]), p < 0.01 for both. Unlike patients with atherosclerotic coronary artery disease (n = 32), CAV lesions were predominantly non-calcified, comprised of mostly fibrous or fibrofatty tissue. V/M was lower in patients with CAV than without (32.4 mm3/g [SD 9.7] vs. 41.4 mm3/g [SD 12.3], p < 0.0001). PCAT density and V/M improved the ability to predict CAV from AUC 0.75 to 0.85 when added to donor age and donor hypertension status (p < 0.0001). PCAT density above -66 HU was associated with a greater incidence of all-cause mortality (OR 18.0 [95%CI 3.25-99.6], p < 0.01) and the composite endpoint of death, CAV progression, acute rejection, and coronary revascularization (OR 7.47 [95%CI 1.8-31.6], p = 0.01) over 5.3 (SD 2.1) years. Heart transplant patients with CAV have higher PCAT density and lower V/M than those without. Increased PCAT density is associated with adverse clinical outcomes. These CCTA metrics could be useful for diagnosis and monitoring of CAV severity.

Proteomic signatures of physical, cognitive, and imaging outcomes in multiple sclerosis.

A quantitative measurement of serum proteome biomarkers that would associate with disease progression endpoints can provide risk stratification for persons with multiple sclerosis (PwMS) and supplement the clinical decision-making process. In total, 202 PwMS were enrolled in a longitudinal study with measurements at two time points with an average follow-up time of 5.4 years. Clinical measures included the Expanded Disability Status Scale, Timed 25-foot Walk, 9-Hole Peg, and Symbol Digit Modalities Tests. Subjects underwent magnetic resonance imaging to determine the volumetric measures of the whole brain, gray matter, deep gray matter, and lateral ventricles. Serum samples were analyzed using a custom immunoassay panel on the Olink™ platform, and concentrations of 18 protein biomarkers were measured. Linear mixed-effects models and adjustment for multiple comparisons were performed. Subjects had a significant 55.6% increase in chemokine ligand 20 (9.7 pg/mL vs. 15.1 pg/mL, p < 0.001) and neurofilament light polypeptide (10.5 pg/mL vs. 11.5 pg/mL, p = 0.003) at the follow-up time point. Additional changes in CUB domain-containing protein 1, Contactin 2, Glial fibrillary acidic protein, Myelin oligodendrocyte glycoprotein, and Osteopontin were noted but did not survive multiple comparison correction. Worse clinical performance in the 9-HPT was associated with neurofilament light polypeptide (p = 0.001). Increases in several biomarker candidates were correlated with greater neurodegenerative changes as measured by different brain volumes. Multiple proteins, selected from a disease activity test that represent diverse biological pathways, are associated with physical, cognitive, and radiographic outcomes. Future studies should determine the utility of multiple protein assays in routine clinical care.

Real-world effectiveness and safety of nirmatrelvir-ritonavir (Paxlovid)-treated for COVID-19 patients with onset of more than 5days: a retrospective cohort study.

Nirmatrelvir-ritonavir (Paxlovid) has received emergency use authorization from the US Food and Drug Administration owing to its effectiveness and safety. However, data on the effectiveness and safety of Paxlovid use in COVID-19 patients with onset of more than 5days are lacking. A real-world retrospective study was performed during the outbreak involving the SARS-CoV-2 BA.5.2 subvariant. Hospitalized COVID-19 patients (including mild, moderate, severe and critical cases) were divided into three groups: Paxlovid treatment within (Group A) or more than (Group B) 5days of COVID-19 onset and no Paxlovid treatment during more than 5days of COVID-19 onset with only basic symptomatic treatment (Group C). Endpoints were all-cause 28-day mortality, improvement in clinical classification, and a composite endpoint of disease progression, viral load and virus elimination time. Safety was assessed by comparing adverse events reported during treatment in each group. During the period, 248 hospitalized COVID-19 patients, including 55 in Group A, 170 in Group B, and 23 in Group C, were enrolled. There were no significant differences in the clinical classification improvement rate [80.0% (16/20) vs. 81.3% (52/64), p = 1.000; 60.0% (21/35) vs. 55.7% (59/106), p = 0.653, respectively] or all-cause 28-day mortality [0% (0/20) vs. 1.6% (1/64), p = 1.000; 11.4% (4/35) vs. 6.6% (7/106), p = 0.576, respectively] between Groups A and B for nonsevere and severe cases. However, the clinical classification improvement rate in Group B was markedly higher than that in Group C [81.3% (52/64) vs. 50.0% (6/12), p = 0.049] among nonsevere cases. Cycle threshold values of the N and ORF genes in Group B were significantly increased after Paxlovid treatment [31.14 (IQR 26.81-33.93) vs. 38.14 (IQR 36.92-40.00), p < 0.001; 31.33 (IQR 26.00-33.47) vs. 38.62 (IQR 35.62-40.00), p < 0.001, respectively]. No significant differences in reported adverse events of neurological disease (p = 0.571), liver injury (p = 0.960) or kidney injury (p = 0.193) between Group A and Group B were found. Paxlovid treatment within 10days of onset can shorten the disease course of COVID-19 by reducing the viral load. Paxlovid is effective and safe in treating COVID-19 with onset of more than five or even 10days when patients have a high viral load.

CT pericoronary adipose tissue density predicts coronary allograft vasculopathy and adverse clinical outcomes after cardiac transplantation

Abstract Background Coronary allograft vasculopathy (CAV) is a common cause of heart transplant failure. Coronary Computed Tomography Angiography (CCTA) is used to assess for luminal stenoses in patients with suspected CAV, but additional non-invasive markers are needed to detect early disease and guide the use of treatments that can prevent or slow CAV progression. Purpose We tested the hypotheses that: 1) coronary artery inflammation assessed by pericoronary adipose tissue (PCAT) density and/or total vessel volume-to-myocardial mass ratio (V/M) measured by CCTA could improve the ability to detect CAV in heart transplant patients; and 2) these semi-automated quantitative CCTA metrics would be associated with adverse clinical outcomes. Methods In this retrospective observational cohort study, PCAT density, V/M, and lesion composition were measured in consecutive CCTAs from patients who underwent heart transplantation at a single site between 2010 to 2021. These parameters were incorporated into predictive models for CAV as defined by International Society for Heart &amp; Lung Transplant criteria, and evaluated against long-term clinical outcomes. Results A total of 126 CCTAs were analysed from 94 patients after heart transplant (mean age 49 [SD 14.5] years, 40% female) without CAV (n=86) and with CAV (n=40). PCAT density was higher in transplant patients with CAV (-73.0 HU [SD 9.26]) than without CAV (-77.9 HU [SD 8.23]), and age and sex-matched controls (n=12; -86.19 HU, [SD 5.38]), p&amp;lt;0.001 for both. Unlike patients with atherosclerotic coronary artery disease (n=32), CAV lesions were predominately non-calcified, comprised of mostly fibrous or fibrofatty tissue. V/M was lower in patients with CAV than without (32.4 mm3/g vs. 44.4 mm3/g, p&amp;lt;0.001). PCAT density and V/M improved the ability to predict CAV from AUC 0.78 to 0.87 on receiver operating characteristic analysis (Figure A) when added to donor age and donor/recipient hypertension status (p&amp;lt;0.0001). PCAT density above -66 HU was associated with a greater incidence of all-cause mortality (OR 16.6 95%CI 2.88-109.98, p&amp;lt;0.01; Figure B, box-plot) and the composite endpoint of death, CAV progression, acute rejection, and coronary revascularisation (OR 6.3 95%CI 1.6-32.9, p=0.01) over 5.25 (SD 2.1) years. Conclusions Heart transplant patients with CAV have higher PCAT density and lower V/M than those without. Patients with very high PCAT density on CT had markedly increased incidence of all-cause mortality and major adverse clinical events. These semi-automated metrics could be a useful addition to standard clinical CCTA reporting for diagnosis and monitoring of CAV.Diagnostic Benefit of CTCA MetricsPCAT is predictor of Future Mortality

Validating Trend-Based End Points for Neuroprotection Trials in Glaucoma.

The purpose of this study was to evaluate the power of trend-based visual field (VF) progression end points against long-term development of event-based end points accepted by the US Food and Drug Administration (FDA). One eye from 3352 patients with ≥10 24-2 VFs (median = 11 years) follow-up were analyzed. Two FDA-compatible criteria were applied to these series to label "true-progressed" eyes: ≥5 locations changing from baseline by more than 7 dB (FDA-7) or by more than the expected test-retest variability (GPA-like) in 2 consecutive tests. Observed rates of progression (RoP) were used to simulate trial-like series (2 years) randomly assigned (1000 times) to a "placebo" or a "treatment" arm. We simulated neuroprotective "treatment" effects by changing the proportion of "true progressed" eyes in the two arms. Two trend-based methods for mean deviation (MD) were assessed: (1) linear mixed model (LMM), testing average difference in RoP between the two arms, and (2) time-to-progression (TTP), calculated by linear regression as time needed for MD to decline by predefined cutoffs from baseline. Power curves with 95% confidence intervals were calculated for trend and event-based methods on the simulated series. The FDA-7 and GPA-like progression was achieved by 45% and 55% of the eyes in the clinical database. LMM and TTP had similar power, significantly superior to the event-based methods, none of which reached 80% power. All methods had a 5% false-positive rate. The trend-based methods can efficiently detect treatment effects defined by long-term FDA-compatible progression. The assessment of the power of trend-based methods to detect clinically relevant progression end points.

Resistance Analysis Following Sotrovimab Treatment in Participants with COVID-19 During the Phase III COMET-ICE Study

Aim: Sotrovimab is an engineered human monoclonal antibody that binds a conserved region of the SARS-CoV-2 spike protein. The COMET-ICE phase III study evaluated sotrovimab for treatment of mild to moderate COVID-19 in nonhospitalized participants with ≥1 risk factor for severe disease progression. Materials &amp; methods: We evaluated the presence of circulating SARS-CoV-2 variants of concern or interest (VOCs/VOIs) and characterized the presence of baseline, post-baseline and emergent amino acid substitutions detected in the epitope of sotrovimab in SARS-CoV-2. Results: None of the sotrovimab-treated participants with baseline epitope substitutions, and 1 of 48 sotrovimab-treated participants with post-baseline epitope substitutions, met the primary clinical endpoint for progression. Conclusion: Overall, progression was not associated with identified VOC/VOI or the presence of epitope substitutions in sotrovimab-treated participants.

Fluorescence-tagged salivary small extracellular vesicles as a nanotool in early diagnosis of Parkinson’s disease

BackgroundParkinson’s disease is generally asymptomatic at earlier stages. At an early stage, there is an extensive progression in the neuropathological hallmarks, although, at this stage, diagnosis is not possible with currently available diagnostic methods. Therefore, the pressing need is for susceptibility risk biomarkers that can aid in better diagnosis and therapeutics as well can objectively serve to measure the endpoint of disease progression. The role of small extracellular vesicles (sEV) in the progression of neurodegenerative diseases could be potent in playing a revolutionary role in biomarker discovery.MethodsIn our study, the salivary sEV were efficiently isolated by chemical precipitation combined with ultrafiltration from subjects (PD = 70, healthy controls = 26, and prodromal PD = 08), followed by antibody-based validation with CD63, CD9, GAPDH, Flotillin-1, and L1CAM. Morphological characterization of the isolated sEV through transmission electron microscopy. The quantification of sEV was achieved by fluorescence (lipid-binding dye-labeled) nanoparticle tracking analysis and antibody-based (CD63 Alexa fluor 488 tagged sEV) nanoparticle tracking analysis. The total alpha-synuclein (α-synTotal) in salivary sEVs cargo was quantified by ELISA. The disease severity staging confirmation for n = 18 clinically diagnosed Parkinson’s disease patients was done by 99mTc-TRODAT-single-photon emission computed tomography.ResultsWe observed a significant increase in total sEVs concentration in PD patients than in the healthy control (HC), where fluorescence lipid-binding dye-tagged sEV were observed to be higher in PD (p = 0.0001) than in the HC using NTA with a sensitivity of 94.34%. In the prodromal PD cases, the fluorescence lipid-binding dye-tagged sEV concentration was found to be higher (p = 0.008) than in HC. This result was validated through anti-CD63 tagged sEV (p = 0.0006) with similar sensitivity of 94.12%. We further validated our findings with the ELISA based on α-synTotal concentration in sEV, where it was observed to be higher in PD (p = 0.004) with a sensitivity of 88.24%. The caudate binding ratios in 99mTc-TRODAT-SPECT represent a positive correlation with sEV concentration (r = 0.8117 with p = 0.0112).ConclusionsIn this study, for the first time, we have found that the fluorescence-tagged sEV has the potential to screen the progression of disease with clinically acceptable sensitivity and can be a potent early detection method for PD.Graphical

Proteinuria as a Surrogate Endpoint for Disease Progression in IgA Nephropathy: Predicting Long-Term Treatment Effects of Sparsentan

IgA nephropathy (IgAN) is a rare, life-limiting disease for which there is significant unmet need. Until recently, drug development for IgAN had been impeded by the requirement for large-scale, long-term clinical trials to measure clinical outcomes. However, the recent establishment of ‘reduction in proteinuria’ as a surrogate endpoint to predict clinical outcomes in IgAN, as a basis for accelerated drug approval, has transformed the field. At the 60th European Renal Association (ERA) Congress in June 2023, two oral poster presentations focused on the use of early reduction in proteinuria as an endpoint for clinical studies in IgAN. Alex Mercer, Consultant in Clinical Drug Development at JAMCO Pharma Consulting in Stockholm, Sweden, presented data estimating the long-term clinical outcome of reductions in proteinuria (clinically meaningful extensions in time to kidney failure or death), which could help predict the future protective effect of any new intervention on kidney function. Following this, Jonathan Barratt, Mayer Professor of Renal Medicine at the University of Leicester, and Honorary Consultant Nephrologist at Leicester General Hospital, UK, described findings from the prespecified interim analysis of the Phase III PROTECT study of sparsentan (a novel dual endothelin angiotensin receptor antagonist) in IgAN, which included reduction in proteinuria as a primary endpoint. In patients with IgAN at high risk of disease progression, sparsentan produced a rapid and significant reduction in proteinuria of a level that, according to the study data presented by Mercer, would correspond to a substantially lowered risk of kidney failure or death. Long-term data to confirm this predicted clinical outcome on disease progression are anticipated.

Describing complex disease progression using joint latent class models for multivariate longitudinal markers and clinical endpoints.

Neurodegenerative diseases are characterized by numerous markers of progression and clinical endpoints. For instance, multiple system atrophy (MSA), a rare neurodegenerative synucleinopathy, is characterized by various combinations of progressive autonomic failure and motor dysfunction, and a very poor prognosis. Describing the progression of such complex and multi-dimensional diseases is particularly difficult. One has to simultaneously account for the assessment of multivariate markers over time, the occurrence of clinical endpoints, and a highly suspected heterogeneity between patients. Yet, such description is crucial for understanding the natural history of the disease, staging patients diagnosed with the disease, unravelling subphenotypes, and predicting the prognosis. Through the example of MSA progression, we show how a latent class approach modeling multiple repeated markers and clinical endpoints can help describe complex disease progression and identify subphenotypes for exploring new pathological hypotheses. The proposed joint latent class model includes class-specific multivariate mixed models to handle multivariate repeated biomarkers possibly summarized into latent dimensions and class-and-cause-specific proportional hazard models to handle time-to-event data. Maximum likelihood estimation procedure, validated through simulations is available in the lcmm R package. In the French MSA cohort comprising data of 598 patients during up to 13 years, five subphenotypes of MSA were identified that differ by the sequence and shape of biomarkers degradation, and the associated risk of death. In posterior analyses, the five subphenotypes were used to explore the association between clinical progression and external imaging and fluid biomarkers, while properly accounting for the uncertainty in the subphenotypes membership.

Interpretation of GFR slope in untreated and treated adult Fabry patients.

Nephropathy is one of the main features of Fabry disease (FD) that leads, in untreated patients with classical mutations, to end-stage renal disease (ESRD) from the third to the fifth decade of life. The availability of a specific treatment modified the natural history of FD; in particular, it was widely reported that enzyme replacement therapy (ERT) is able to slow the progression of the disease. Regarding Fabry nephropathy, several reports have documented an elevated estimated glomerular filtration rate (eGFR) slope in untreated patients as expression of a rapid disease progression towards ESRD. Otherwise, the prompt start of treatment may be beneficial in stabilizing renal function or slowing its decline. Therefore, based on data in the literature about the effects of ERT on eGFR decline and on the evidence supporting the role of eGFR slope as a surrogate endpoint for chronic kidney disease progression, we suggest, in this 'Expert Opinion', that a treatment should be defined effective when eGFR decline is <1ml/min/1.73m2/year and not effective when eGFR loss remains ≥3ml/min/1.73m2/year (≥2.5ml/min/1.73m2/year in females). Moreover, practical clinical recommendations and guidance for Fabry patients suggests that a change in treatment may be appropriate if individualized therapeutic goals are not achieved. Since a dose-dependent efficacy has been demonstrated for ERT, we suggest considering a switch to a higher dose of ERT in symptomatic adult Fabry patients (ages 18-60years) with an eGFR of 45-90ml/min/1.73m2 and treated with a stable dose of ERT for at least 1year, in which a linear negative slope of eGFR of 3ml/min/1.73m2/year for males (2.5ml/min/1.73m2/year for females) was observed.

Myopia control: short-term effect of 0.01% atropine vs. defocus incorporated multiple segment lenses—a retrospective study in European children

PurposeTo compare 0.01% atropine with DIMS spectacle lenses in the prevention of myopia progression in European children.MethodsThis was a retrospective study including data from pediatric European patients with myopia. From November 2021 to March 2022, only 0.01% atropine was prescribed because DIMS lenses were still not available in Portugal. From March to October 2022, only DIMS spectacle lenses were prescribed due to patients’ parents’ preference. Myopia progression endpoints were axial length (AL) and spherical equivalent (SE) differences between before and 6 months after treatment. AL and SE evolution were compared using a general linear model with repeated measures.ResultsThe study included 98 eyes from 50 patients: 47 in the atropine group and 51 in the DIMS group. There were no statistically significant differences between groups in terms of initial AL, initial SE, sex or age. The mean AL elongation at 6 months was 0.057 mm in the atropine group (SD = 0.118) and 0.002 mm (SD = 0.077) in the DIMS group. SE progression was − 0.098 (SD = 0.232) D in the atropine group and − 0.039 (SD = 0.105) D in the DIMS group. AL elongation was significantly lower in the DIMS lens group (p = 0.038, partial Eta2 = 0.045). There was no difference in SE progression between groups (p = 0.302, partial Eta2 = 0.011).ConclusionComparison between 0.01% atropine eyedrops and DIMS spectacle lenses for slowing the progression of myopia favored DIMS lenses in terms of AL elongation in a short-term follow-up. There was no difference in terms of SE between groups.

411-P: Extended Validation of KidneyIntelXTM in Diabetic Kidney Disease

We have previously shown that plasma TNFR1, TNFR2, and KIM-1 combined with clinical variables provides effective risk stratification for kidney outcomes in individuals with diabetic kidney disease (DKD) stages 1-3. With the recommended use of a race-free eGFR and a refinement of our progression endpoint, we sought to develop and independently validate a version 2.0 of KidneyIntelX assay in a previously untested, independent, contemporary cohort of subjects from BioMe Biobank (Mount Sinai Health System, NYC, NY). The primary outcome was a composite of ≥40% sustained decline in eGFR or kidney failure (sustained eGFR&amp;lt;15 ml/min/1.73 m2) within 5 years from enrollment. In a training cohort of 573 patients with DKD from the Penn Medicine Biobank (PMBB), 15.4% experienced the progressive decline in kidney function over a median of 3.1 years. The following features were selected in a training model utilizing optimized random forests to predict the kidney outcome: TNFR1, TNFR2, KIM-1, baseline UACR, HbA1c, and blood urea nitrogen. The external validation cohort (BioMe, n=657) had an 11.7% event rate over a median of 3.8 years. Based on risk categorization cutoffs derived from training, 57%, 35% and 8.3% of participants were classified as low, intermediate and high-risk, respectively. The cumulative event incidence probability in the low, intermediate, and high-risk groups were 5.9% (95% CI: 3.6-9.4%), 21.2% (95% CI: 15.6-28.3%) and 66.9% (95% CI:, 49.3-83.5%). The unadjusted HRs for high vs. low and intermediate vs. low were 18.4 (95% CI: 9.4 -34.6) and 4.2 (95% CI: 2.4-7.4), respectively. After adjustment for age, sex, race, baseline eGFR, uACR, SBP, and HbA1c, the adjusted HRs were 7.7 (95% CI: 3.0-19.6) and 3.7 (95% CI: 2.0-6.8), respectively. In summary, we developed and independently validated a version 2.0 KidneyIntelX with previously established biomarkers combined with selected clinical variables and demonstrated robust prediction of progressive decline in kidney function, independent of common risk factors. Disclosure G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; Renalytix, Other Relationship; Renalytix, Speaker's Bureau; Daiichi Sankyo, GlaxoSmithKline plc., Menarini Group, Stock/Shareholder; Renalytix. F.Fleming: Employee; Renalytix. M.J.Donovan: Employee; Renalytix. S.Coca: Advisory Panel; Renalytix, Bayer Inc., Boehringer Ingelheim International GmbH, Consultant; Renalytix, Nuwellis, 3ive Labs, Reprieve Cardiovascular, Vifor Pharma Management Ltd., Stock/Shareholder; Renalytix. Funding Renalytix