Search Results (134)

Clinical trials in nephrology have historically been hindered by significant challenges, including slow disease progression, patient heterogeneity, and recruitment difficulties. While recent therapeutic breakthroughs have transformed care, they have also created a ‘paradox of success’ by lowering baseline event rates, further complicating traditional trial designs. We hypothesize that integrating innovative trial methodologies with advanced computational tools is essential for overcoming these hurdles and accelerating therapeutic development in kidney disease. This narrative review synthesizes the literature on persistent challenges in nephrology trials and explores methodological innovations. It investigates the transformative impact of computational tools, specifically Artificial Intelligence (AI), techniques like Augmented Reality (AR) and Conditional Tabular Generative Adversarial Networks (CTGANs), in silico clinical trials (ISCTs) and Digital Health Technologies across the research lifecycle. Key methodological innovations include adaptive designs, pragmatic trials, real-world evidence, and validated surrogate endpoints. AI offers transformative potential in optimizing trial design, accelerating patient stratification, and enabling complex data analysis, while AR can improve procedural accuracy, and CTGANs can augment scarce datasets. ISCTs provide complementary capabilities for simulating drug effects and optimizing designs using virtual patient cohorts. The future of clinical research in nephrology lies in the synergistic convergence of methodological and computational innovation. This integrated approach offers a pathway for conducting more efficient, precise, and patient-centric trials, provided that critical barriers related to data quality, model validation, regulatory acceptance, and ethical implementation are addressed. Full article

Many applications in health research involve the analysis of multivariate distributions of random variables. In this paper, we review the basic theory of copulas to illustrate their advantages in deriving a joint distribution from given marginal distributions, with a specific focus on bivariate cases. Particular attention is given to the Archimedean family of copulas, which includes widely used functions such as Clayton and Gumbel–Hougaard, characterized by a single association parameter and a relatively simple structure. This work differs from previous reviews by providing a focused overview of applied studies in biomedical research that have employed Archimedean copulas, due to their flexibility in modeling a wide range of dependence structures. Their ease of use and ability to accommodate rotated forms make them suitable for various biomedical applications, including those involving survival data. We briefly present the most commonly used methods for estimation and model selection of copula’s functions, with the purpose of introducing these tools within the broader framework. Several recent examples in the health literature, and an original example of a pediatric study, demonstrate the applicability of Archimedean copulas and suggest that this approach, although still not widely adopted, can be useful in many biomedical research settings. Full article

The designs of clinical trials of drugs for rare diseases are challenged by health technology assessment organisations and payers. Phase II pivotal studies, single-arm or open-label designs, the extensive use of non-final endpoints, and the limited use of patient-reported outcomes (PROs) are the main points of contention. The evidence on the actual design of these trials is limited, but corroborates the concerns of the above. Our aim is to scrutinise whether the design of pivotal studies of drugs for rare diseases to be launched into the Italian market by 2026 present similar issues. The drugs and the relevant pivotal studies were retrieved from Biomedtracker and US and European clinical trial databases. We identified 154 new drugs for rare diseases. Single-arm designs account for 36% of trials. Almost 50% of randomised control trials (RCTs) are designed using an active comparator and 61% are double-blinded. Primary endpoints are mostly (82%) surrogate. A total of 59% of studies include PROs. Our findings were partially expected (e.g., extensive use of surrogate endpoints) and partially not (e.g., RCTs and an active comparator), considering previous studies on the same topic. Having more head-to-head studies may reduce uncertainty concerning evidence at market launch, but different issues persist, including the still limited role of PROs. Full article

Background: Pathological complete response (pCR) serves as a prognostic surrogate endpoint for long-term clinical outcomes in breast cancer patients receiving neoadjuvant systemic therapy (NAST). This study aims to develop and evaluate machine learning-based biomarkers for predicting pCR and recurrence-free survival (RFS). Methods: This retrospective monocentric study included 235 women (mean age 46 ± 11 years) with non-metastatic breast cancer treated with NAST. We developed various machine learning models using clinical features (age, genetic mutations, TNM stage, hormonal receptor expression, HER2 status, and histological grade), along with morphological features (size, T2 signal, and surrounding edema) and radiomics data extracted from pre-treatment MRI. Patients were divided into training and test groups with different MRI models. A customized machine learning pipeline was implemented to handle these diverse data types, consisting of feature selection and classification components. Results: The models demonstrated superior prediction ability using radiomics features, with the best model achieving an AUC of 0.72. Subgroup analysis revealed optimal performance in triple-negative breast cancer (AUC of 0.80) and HER2-positive subgroups (AUC of 0.65). Conclusion: Machine learning models incorporating clinical, qualitative, and radiomics data from pre-treatment MRI can effectively predict pCR in breast cancer patients receiving NAST, particularly among triple-negative and HER2-positive breast cancer subgroups. Full article

Over the past four decades, cardioprotective research has revealed an extraordinary complexity of cellular and molecular mechanisms capable of mitigating ischemia/reperfusion injury (IRI). Among these, ischemic conditioning has emerged as one of the most influential discoveries: brief episodes of ischemia followed by reperfusion activate protective programs that reduce myocardial damage. These effects can be elicited locally (pre- or postconditioning) or remotely (remote conditioning), acting mainly through paracrine signaling and mitochondria-linked kinase pathways, with both early and delayed windows of protection. We have contributed to clarifying the roles of mitochondria, oxidative stress, prosurvival kinases, connexins, extracellular vesicles, and sterile inflammation, particularly via activation of the NLRP3 inflammasome. Despite robust preclinical evidence, clinical translation of these approaches has remained disappointing. The challenges largely stem from experimental models that poorly reflect real-world clinical settings—such as advanced age, comorbidities, and multidrug therapy—as well as the reliance on surrogate endpoints that do not reliably predict clinical outcomes. Nevertheless, interest in multi-target protective strategies remains strong. New lines of investigation are focusing on emerging mediators—such as gasotransmitters, extracellular vesicles, and endogenous peptides—as well as targeted modulation of inflammatory responses. Future perspectives point toward personalized cardioprotection tailored to patient metabolic and immune profiles, with special attention to high-risk populations in whom IRI continues to represent a major clinical challenge. Full article

Background: Telemonitoring aimed at detecting subclinical heart failure and facilitating medication up-titration offers a promising approach to reducing heart failure hospitalizations. Our team has recently developed a non-invasive metric called “respiratory stability time (RST)”, which quantifies respiratory instability, a surrogate marker of subclinical worsening heart failure. A decrease in RST below 20 s predicts the onset of worsening heart failure within 28 days. However, the clinical utility of RST-guided management in reducing mortality and heart failure hospitalizations remains uncertain. Methods: The Innovative Tele-Monitoring Environment To Halt Ongoing Deterioration of Heart Failure-III (ITMETHOD-HF-III) is a non-blinded, interventional, multicenter, single-arm study. Eighty heart failure patients with a history of at least two prior hospitalizations for heart failure will be enrolled. After validating the robustness of RST measurements, participants will be monitored for 1.5 years through daily RST measurements. Mandatory up-titration of heart failure medications will be started if RST values decrease below 20 s for two consecutive days or decrease progressively below 30 s over 10–90 days from RST values above 45 s maintained for over 1 month, irrespective of the presence of heart failure signs/symptoms. Medication adjustment will continue until RST exceeds 30 s. The study will compare a composite endpoint of heart failure hospitalization and cardiac death between the present RST-guided group and a historical control group from the ITMETHOD-HF-II trial, in which management was based on patients’ symptoms. Results: We anticipate that the precent ITMETHOD-HF-III study will demonstrate that mandatory, RST-guided heart failure management significantly reduces the incidence of the primary composite endpoint—heart failure hospitalization and cardiac death—compared with symptom-guided standard care in the historical control group (ITMETHOD-HF-II). Conclusions: The ITMETHOD-HF-III study aims to demonstrate the clinical efficacy of RST-guided management in reducing heart failure hospitalization rates and cardiac mortality by enabling early detection of subclinical heart failure and facilitating timely medication adjustments, irrespective of heart failure signs/symptoms. If successful, RST-guided management could establish a new standard for telemonitoring heart failure patients in outpatient settings. Full article

Background: Locally acting gastrointestinal (GI) drugs present challenges for generic drug development because traditional bioequivalence measures, which rely on systemic drug levels, do not reflect local efficacy. This review examines regulatory guidelines for establishing therapeutic equivalence for such drugs, using rifaximin—a minimally absorbed, gut-localized antibiotic—as a case study. Methods: We reviewed bioequivalence guidelines from the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA), along with the literature on rifaximin’s biopharmaceutical and clinical properties, to identify strategies and challenges for establishing equivalence for locally acting GI drugs. Results: Rifaximin exemplifies the limitations of standard bioequivalence methods: as a Biopharmaceutics Classification System (BCS) class IV drug with minimal absorption and low solubility, in vitro dissolution may not predict local drug availability. Clinical endpoint trials (e.g., traveler’s diarrhea, hepatic encephalopathy, IBS-D) are resource-intensive and insensitive to formulation differences. Pharmacokinetic (PK) studies in healthy volunteers show low, variable plasma levels, which may inaccurately discriminate between formulations. The EMA requires evidence of non-saturable absorption to accept PK data, a difficult-to-establish but potentially irrelevant criterion. Differences between FDA and EMA approaches highlight a lack of harmonization, complicating global generic development. Conclusions: A tailored, multifaceted approach is needed to demonstrate bioequivalence for GI-localized drugs like rifaximin. This case underscores the need for more sensitive surrogate methods (e.g. advanced in vitro or pharmacodynamic models) and flexible regulatory criteria. Harmonization across international guidelines and innovative bioequivalence study designs are key to facilitating the approval of safe and effective generic alternatives in this drug class. Full article

Operable non-small cell lung cancer (NSCLC) has been traditionally managed with surgical resection, often followed by adjuvant chemotherapy with or without radiotherapy. However, disease recurrence still occurs approximately 50% of the time. Most recently, (neo) adjuvant/perioperative systemic therapy has evolved to include checkpoint inhibitor therapy and targeted therapies that have proved successful in advanced disease settings. We provide a comprehensive review of the trials investigating neoadjuvant, adjuvant, and perioperative systemic therapies in resectable lung cancer, including a discussion on surrogate survival endpoints. We review the management of N2 disease, the utility of circulating tumor DNA (ctDNA) in determining the risk and benefit from systemic therapy in operable NSCLC, as well as future directions of investigation. Full article

Background/Objectives: Patients suffering from inflammatory bowel diseases (IBDs) undergoing treatment with anti-TNF antibodies mount a diminished humoral immune response to vaccination against SARS-CoV-2 compared to healthy controls. The characterization of variant-specific immune responses is particularly warranted among immunosuppressed patients, where reduced responses may necessitate further medical interventions. Methods: This pilot study investigated the humoral immune response of vaccinated IBD patients on anti-TNF medication and a comparable group of healthy individuals against the viral variants Alpha, Beta, Gamma, Delta, and Omicron BA.1 and BA.5. While total IgG antibodies targeting the receptor binding site of the spike protein of SARS-CoV-2 were quantified using a chemiluminescence microparticle immunoassay (CMIA), their potential neutralizing capacity was determined using commercial and variant-specific in-house surrogate virus neutralization tests (sVNTs) against a variant-specific in-house VSV-pseudotyped virus neutralization test (pVNT) as the gold standard. Results: Employing variant-specific assays recapitulated the immune escape functions of virus variants. Conspicuously, antibody reactivity against Alpha and Omicron BA.1 and BA.5 was strikingly poor in IBD patient sera post-initial vaccination compared to healthy individuals. A comparison of the diagnostic performance of assays with the pVNT revealed that identification of patients with inadequate humoral responses by CMIA and sVNT may require adjustments to cut-off values and end-point titration of sera. Following adaptation of cut-off values, patient sera exhibited reduced reactivity against all tested variants. The assay panel used substantiated the impact of anti-TNF therapy in IBD patients as to reduced strength, function, and breadth of the immune response to several SARS-CoV-2 variants. The immune response measured following the second vaccination was comparable to the antibody response observed in healthy individuals following the first vaccination. Conclusion: Variant-specific sVNTs and pVNTs have the potential to serve as valuable tools for evaluating the efficacy of adapted vaccines and to inform clinical interventions in the care of immunosuppressed patients. Anti-TNF-treated individuals with antibody levels below the optimized CMIA threshold should be considered for early booster vaccination and/or close immunological monitoring. Full article

Heart failure (HF) remains a global health burden with high morbidity and mortality, despite significant pharmacological advances. Vitamin D deficiency (VDD) is commonly observed in HF patients and may exacerbate disease progression through various pathophysiological mechanisms, including activation of the renin–angiotensin–aldosterone system, inflammation, oxidative stress, and impaired calcium homeostasis. While vitamin D (VD) supplementation may positively influence surrogate markers in selected patient groups—particularly those with reduced ejection fraction or severe vitamin D deficiency—its effect on primary endpoints such as mortality or HF-related hospitalization varies significantly across studies and patient populations. As a result, while VD supplementation may benefit VD-deficient HF patients, current evidence does not support routine administration across the whole HF population. It is still a matter of debate whether VDD belongs to prognostic markers of worse outcomes in HF or is instead their potential cause. Therefore, the clinical utility of VD in HF management remains underexplored. This review aims to assess the evidence regarding vitamin D status and its supplementation in the context of HF, with a focus on different HF phenotypes: reduced (HFrEF), mildly reduced (HFmrEF), and preserved ejection fraction (HFpEF). The aim is to synthesize findings from novel observational studies, randomized controlled trials, and meta-analyses that shed light onto this intricate relationship and may be valuable in everyday clinical practice. Full article

The extracellular matrix (ECM) is a major driver of tumorigenesis, yet its role in cancer prevention has received relatively little attention. Here, we discuss studies linking the ECM to cancer initiation with an emphasis on ECM stiffness and remodeling, pericytes, and hyaluronan (hyaluronic acid). We then share our thoughts on how an ECM viewpoint could lead to new insights and directions in cancer-prevention research. Topics discussed include mouse experiments, clinical studies, risk factors, biomarkers for risk prediction or the early detection of cancer, surrogate endpoints, and targets for preventive interventions. Full article

Background/Objective: Objective response rate (ORR) is a surrogate endpoint frequently employed in early-phase clinical trials of anticancer agents for the treatment of solid tumors. Assessments of ORR by local investigators tend to be influenced by subjective factors, and blinded independent central review (BICR) is recommended by regulatory agencies in order to detect evaluation bias. The objective of this analysis was to compare BICR-assessed vs. investigator-assessed ORRs in pivotal trials of cancer drugs recently approved by the United States Food and Drug Administration (FDA) for solid tumor indications. Methods: The FDA’s Novel Drug Approvals reports were reviewed to identify cancer therapies approved for solid tumor indications between 1 January 2020 and 30 June 2024. Among therapies with ORR as a primary endpoint in pivotal trials, and for which both BICR- and investigator-assessed ORRs were available, a pooled analysis was conducted to compare these ORRs (using the Mantel–Haenszel method). A correlation analysis was also performed to evaluate the concordance between ORR assessments. Results: A total of 20 anticancer agents met the criteria for inclusion in this analysis, each supported by a single pivotal trial. Comparing BICR- and investigator-assessed ORRs in a pooled analysis did not identify any significant difference between the two assessments overall: OR = 0.98 (95% CI: 0.87–1.11), p = 0.75, and I² = 0%. The correlation analysis also revealed a high level of concordance between BICR- and investigator-assessed ORRs, with r = 0.96 (p < 0.05). Conclusions: This study found no evidence of evaluation bias in the assessment of ORR among registrational trials supporting recent FDA approvals of anticancer agents for solid tumor indications. Full article

Understanding the relationship between the Objective Response Rate (ORR) and survival outcomes, notably Progression-Free Survival (PFS) and Overall Survival (OS), is relevant for assessing the efficacy of regimens in oncology. We evaluate the relationship between ORR, PFS and OS in immuno-oncology (IO) trials. Data from 68 clinical trials submitted to the FDA were evaluated, examining immunotherapy regimens, notably immune checkpoint inhibitors such as anti-programmed death (ligand)-1 [anti-PD-(L)1], cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors and combination therapies [e.g., IO + IO, anti-PD-L1 + chemotherapy, anti-PD-L1 + CTLA-4, anti-PD-L1 + TKI (tyrosine kinase inhibitors)]. Studies were included based on their reporting of ORR, PFS, and OS. Of the 68 clinical trials reviewed, 55 were included in the analysis. The correlation between ORR and PFS was moderate across most immunotherapy regimens, indicating that ORR can serve as a useful predictor of short-term disease control. However, the correlation between ORR and OS was weaker, especially in trials including combination therapies, indicating that ORR alone may not reliably predict long-term survival outcomes. ORR predicts PFS better in first-line treatment but declines in later lines and remains a weak OS predictor overall. Differing degrees of correlation between ORR and survival metrics, particularly across treatment lines and combinations, are observed. While ORR can serve as a surrogate marker for PFS in IO trials, its utility in predicting OS is restricted and the interpretation of the relationship between ORR and PFS or OS is a key limitation. Rather, a decline in PFS with increasing ORR may reflect trial differences rather than a direct relationship. Future analyses should adopt better methodologies to capture these dynamics and focus on improving surrogate endpoints for immunotherapy to improve clinical trial design and patient outcomes. Full article

Grape seed procyanidin extract (GSE) is widely used to promote cardiovascular health and has purported anti-inflammatory properties. Chronic inflammation in the lungs caused by environmental toxins such as tobacco smoking plays a pivotal role in lung cancer development. In a modified phase I lung cancer chemoprevention study conducted in heavy active and former smokers using leucoselect phytosome (LP), a standardized grape seed procyanidin extract complexed with soy phospholipids to enhance bioavailability, three months of LP treatment favorably modulated a variety of surrogate endpoint biomarkers, including markers of cell proliferation. In this correlative study, we further analyzed the effects of LP on cytochrome P450 3A4 (CYP3A4) activities by comparing the endogenous conversions of cortisol and cortisone to 6-beta-hydroxycortisol and 6-beta-hydroxycortisone, respectively, before and after LP treatment and the anti-inflammatory effects of LP in the lung microenvironment of these participants by comparing a profile of inflammatory cytokines and chemokines in matched pre- and post-treatment bronchoalveolar lavage (BAL) fluids. LP treatment did not significantly alter CYP3A4 activity, and three months of LP treatment significantly decreased tumor necrosis factor (TNF), C-C Motif Chemokine Ligand 3 (CCL3) and granzyme B in BAL fluids. Furthermore, post-LP-treatment BAL fluids significantly reduced migration/invasion of various human lung neoplastic cells in vitro. Our findings support the anti-inflammatory effects of GSE/LP in the lung microenvironment and its potential utility for reducing cancerizing forces, as well as driving forces for other common respiratory diseases such as chronic obstructive pulmonary disease and asthma, in the lungs of heavy former and active smokers. Full article

IgA nephropathy (IgAN), first described in 1968, is one of the most common forms of glomerulonephritis and can progress to end-stage kidney disease (ESKD) in 25 to 30 percent of patients within 20 to 25 years from the onset. It is histologically characterized by mesangial proliferation with prominent IgA deposition. The prognosis may be difficult to predict, but important risk factors for disease progression of kidney disease have been recognized: usually proteinuria above 0.75–1 g/day with or without hematuria, hypertension, high-risk histologic features (such as crescent formation, immune deposits in the capillary loops, mesangial deposits, glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular disease), and a reduced Glomerular Filtration Rate (GFR). In the absence of reliable specific biomarkers, current standards of care are addressed to decrease proteinuria, as a surrogate endpoint, and control blood pressure. For a long time, corticosteroids have been considered the only cure for proteinuric patients or those at risk of progression to ESKF; however, unfortunately, like other immunosuppressive agents, they are burdened with high collateral risks. Therefore, optimal treatment remains a challenge, even if, to date, clinicians have many more options available. Here, we will review the main therapies proposed, such as the stronghold of RAAS inhibition and the use of SGLT2 inhibitors; it is expected that ongoing clinical trials may find other therapies, apart from corticosteroids, that may help improve treatment, including both immunosuppressive monoclonal antibodies and other strategies. At the current time, there are no disease-specific therapies available for IgAN, because no largescale RCTs have demonstrated a reduction in mortality or in major adverse kidney or cardiovascular events with any therapy. Full article