Standard Clinical Endpoints Research Articles

Automatic International Hidradenitis Suppurativa Severity Score System (AIHS4): A novel tool to assess the severity of hidradenitis suppurativa using artificial intelligence.

Hidradenitis suppurativa (HS) is a painful chronic inflammatory skin disease that affects up to 4% of the European adult population. International Hidradenitis Suppurativa Severity Score System (IHS4) is a dynamic scoring tool that was developed to be incorporated into the doctor's daily clinical practice and clinical studies. This helps measure disease severity and guides the therapeutic strategy. However, IHS4 assessment is a time-consuming and manual process, with high inter-observer variability and high dependence on the observer's expertise. We introduce the Automatic International Hidradenitis Suppurativa Severity Score System (AIHS4), an automatic equivalent of IHS4 that deploys a deep learning model for lesion detection, called Legit.Health-IHS4net, based on the YOLOv5 architecture. AIHS4 was trained on Legit.Health-HS-IHS4, a collection of HS images manually annotated by six specialists and processed by a novel knowledge unification algorithm. Our results show that, with the current dataset size, our tool assesses the severity of HS cases with a performance comparable to that of the most expert physician. Furthermore, the model can be implemented into CADx systems to support doctors in their clinical practice and act as a new endpoint in clinical trials. Our work proves the potential usefulness of artificial intelligence in the practice of evidence-based dermatology: models trained on the consensus of large clinical boards have the potential to empower dermatologists in their daily practice and replace current standard clinical endpoints.

High-density electroanatomic activation mapping to guide slow pathway modification in patients with persistent left superior vena cava

Slow pathway (SP) mapping and modification can be challenging in patients with persistent left superior vena cava (PLSVC) due to anatomic variance of the Koch triangle (KT) and coronary sinus (CS) dilation. Studies using detailed 3-dimensional (3D) electroanatomic mapping (EAM) to investigate conduction characteristics and guide ablation targets in this condition are lacking. The purpose of this study was to describe a novel technique of SP mapping and ablation in sinus rhythm using 3D EAM in patients with PLSVC after validation in a cohort with normal CS anatomy. Seven patients with PLSVC and dual atrioventricular (AV) nodal physiology who underwent SP modification with the use of 3D EAM were included. Twenty-one normal heart patients with AV nodal reentrant tachycardias formed the validation group. High-resolution, ultra-high-density local activation timing mapping of the right atrial septum and proximal CS in sinus rhythm was performed. SP ablation targets were consistently identified by an area in the right atrial septum with the latest activation time and multicomponent atrial electrogram adjacent to a region with isochronal crowding (deceleration zone). In PLSVC patients, these targets were located at or within 1 cm of the midanterior CS ostium. Ablation in this area led to successful SP modification, reaching standard clinical endpoints with a median of 43 seconds of radiofrequency energy or 14 minutes of cryoablation without complications. High-resolution activation mapping of the KT in sinus rhythm can facilitate localization and safe SP ablation in patients with PLSVC.

Association of Days Alive and at Home at Day 90 After Intensive Care Unit Admission With Long-term Survival and Functional Status Among Mechanically Ventilated Patients

Many conventional end points in randomized clinical trials of interventions for critically ill patients do not account for patient-centered concerns such as time at home, physical function, and quality of life after critical illness. To establish whether days alive and at home at day 90 (DAAH90) is associated with long-term survival and functional outcomes in mechanically ventilated patients. The RECOVER prospective cohort study was conducted from February 2007 to March 2014, using data from 10 intensive care units (ICUs) in Canada. Patients were included in the baseline cohort if they were aged 16 years or older and underwent invasive mechanical ventilation for 7 or more days. The follow-up cohort analyzed here comprised RECOVER patients who were alive and had functional outcomes ascertained at 3, 6, and 12 months. Secondary data analysis occurred from July 2021 to August 2022. Composite of survival and days alive and at home at day 90 after ICU admission (DAAH90). Functional outcomes at 3, 6, and 12 months were evaluated with the Functional Independence Measure (FIM), the 6-Minute Walk Test (6MWT), the Medical Research Council (MRC) Scale for Muscle Strength, and the 36-Item Short Form Health Survey physical component summary (SF-36 PCS). Mortality was evaluated at 1 year from ICU admission. Ordinal logistic regression was used to describe the association between DAAH90 tertiles and outcomes. Cox proportional hazards regression models were used to examine the independent association of DAAH90 tertiles with mortality. The baseline cohort comprised 463 patients. Their median age was 58 years (IQR, 47-68 years), and 278 patients (60.0%) were men. In these patients, Charlson Comorbidity Index score, Acute Physiology and Chronic Health Evaluation II score, ICU intervention (eg, kidney replacement therapy or tracheostomy), and ICU length of stay were independently associated with lower DAAH90. The follow-up cohort comprised 292 patients. Their median age was 57 years (IQR, 46-65 years), and 169 patients (57.9%) were men. Among patients who survived to day 90, lower DAAH90 was associated with higher mortality at 1 year after ICU admission (tertile 1 vs tertile 3: adjusted hazard ratio [HR], 0.18 [95% CI, 0.07-0.43]; P < .001). At 3 months of follow-up, lower DAAH90 was independently associated with lower median scores on the FIM (tertile 1 vs tertile 3, 76 [IQR, 46.2-101] vs 121 [IQR, 112-124.2]; P = .04), 6MWT (tertile 1 vs tertile 3, 98 [IQR, 0-239] vs 402 [IQR, 300-494]; P < .001), MRC (tertile 1 vs tertile 3, 48 [IQR, 32-54] vs 58 [IQR, 51-60]; P < .001), and SF-36 PCS (tertile 1 vs tertile 3, 30 [IQR, 22-38] vs 37 [IQR, 31-47]; P = .001) measures. Among patients who survived to 12 months, being in tertile 3 vs tertile 1 for DAAH90 was associated with higher FIM score at 12 months (estimate, 22.4 [95% CI, 14.8-30.0]; P < .001), but this association was not present for ventilator-free days (estimate, 6.0 [95% CI, -2.2 to 14.1]; P = .15) or ICU-free days (estimate, 5.9 [95% CI, -2.1 to 13.8]; P = .15) at day 28. In this study, lower DAAH90 was associated with greater long-term mortality risk and worse functional outcomes among patients who survived to day 90. These findings suggest that the DAAH90 end point reflects long-term functional status better than standard clinical end points in ICU studies and may serve as a patient-centered end point in future clinical trials.

Clinical Benefit Associated with Biomarker Changes Indicative of Disease Modification in Patients with Myelofibrosis Treated with the BET Inhibitor Pelabresib As Monotherapy or in Combination with Ruxolitinib

Bromodomain and extraterminal domain (BET) proteins play a key role in the regulation of neoplastic myeloproliferation and proinflammatory cytokine production in myelofibrosis (MF). Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100). In the ongoing Phase 2 MANIFEST study (NCT02158858) (Kremyanskaya M, et al. Blood 2021;138:141) PELA is being evaluated as monotherapy in ruxolitinib (RUX)-intolerant, ineligible or refractory patients (pts) with MF (Arm 1) and in combination with RUX as an 'add-on' in pts with MF with suboptimal response to RUX (Arm 2) or in JAK inhibitor (JAKi)-naïve pts with MF (Arm 3). Assessment of ≥35% spleen volume reduction (SVR35) and ≥50% total symptom score reduction (TSS50) are standard clinical trial endpoints to evaluate disease response in MF. However, SVR35 and TSS50 do not fully reflect underlying disease improvement, and additional approaches are needed to understand what constitutes disease modification in MF (Pemmaraju N, et al. Cancer 2022;128:2420-2432) and to provide better insight into the mechanisms of novel drugs in development, such as PELA. Here we report results in pts enrolled in MANIFEST from exploratory analyses of treatment-induced changes at Week 24 in a range of biomarkers that are suggestive of disease modification (≥1 grade improvements in bone marrow fibrosis [BMF], reduction of Janus Kinase 2 V617F [JAK2V617F] variant allele frequency [VAF] in blood, improvements in hemoglobin and increased distance of CD61+ megakaryocytic [MK] cells in bone marrow ['declustering']) with respect to the clinical outcomes of SVR35 and TSS50. We previously demonstrated (Mascarenhas J, et al. HemaSphere 2022;6:99-100) that the increase in distance in MK cells correlated with SVR35 responses. Table 1 shows a summary of SVR35 and TSS50 response rates and changes in biomarkers associated with potential disease modification observed in the MANIFEST study in each study arm. Of note, with PELA monotherapy, 30% (7/23) of pts in a RUX-resistant/intolerant population (Arm 1) showed ≥1 grade improvement in BMF. Additional changes indicating biologic effect of PELA included declustering of MK cells (increase in distance of ≥15%) observed in 46% (5/11) of pts. Similar or better results were observed in pts treated with PELA/RUX combination. Changes in these markers of potential disease modification were associated with SVR35 and TSS50 endpoint responses. In evaluable pts with available data, splenic responses at Week 24 across the three arms were associated with ≥1 grade reduced BMF (in 18/43 pts, 42%), increased MK distance (in 20/26 pts, 77%, median change +34%) and JAK2V617F VAF reductions (in 41/50 pts, 82%, median change -13%). Of TSS50 responders at Week 24 with available data, 36% (16/44) showed ≥1 grade improvements in BMF; 71% (20/28) had an increase in MK distance (median change +22.3%); and 64% achieved reductions in JAK2V617F VAF (30/47, median change -8%). In JAKi-naïve pts (Arm 3), 68% (57/84) achieved SVR35 at Week 24; among these patients with available data, 38% (12/32) improved BMF ≥1 grade; 74% (14/19, median change +19.7%) increased MK distance; and 83% (34/41, median change -18%) reduced JAK2V617F VAF (any level of improvement). TSS50 was observed in 56% (46/82) of JAKi-naïve pts; among these patients with available data, improvements in ≥1 grade BMF, MK distance and JAK2V617F VAF (any level of improvement) were observed in 46% (11/24), 75% (12/16, median change +24%) and 78% (18/23, median change -14.3%) of pts, respectively. In nonresponders, changes in biomarkers were consistently smaller. Our data indicate differences in the association of individual markers of potential disease modification with SVR35 and TSS50. While reduction in JAK2V617F VAF and increase in MK distance appear to be associated with SVR35, a high incidence of BMF improvements were also observed in Arm 3 TSS50 responders. Extended multivariable, longitudinal, biomarker analyses for association with time-to-event endpoints (eg duration of splenic response) will be presented with a new data cutoff with the objective to investigate potential disease-modifying activity of PELA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Use of Digital Health Technology in Heart Failure and Diabetes: a Scoping Review.

Use of digital health technologies (DHT) in chronic disease management is rising. We aim to evaluate the impact of DHT on clinical outcomes from randomized controlled trials (RCTs) of patients with heart failure (HF) and diabetes mellitus (DM). Electronic databases were searched for DHT RCTs in patients with HF and DM until February 2021. Patient characteristics and outcomes were analyzed. One published (N = 519) and 6 registered (N = 3423) eligible studies were identified, with one study exclusively including HF and DM patients. Median DHT monitoring was 12 months, with six studies using mobile platforms as their key exposure. Clinical outcomes included quality-of-life or self-care surveys (n = 1 each), physical activity metrics, changes in biomarkers, and other clinical endpoints (n = 3). Limited data exist on RCTs evaluating DHT in patients with concomitant HF and DM. Further work should define standardized clinical endpoints and platforms that can manage patients with multiple comorbidities.Graphical abstract

Assessing the safety of bioactive ingredients in infant formula that affect the immune system: recommendations from an expert panel

Bioactive ingredients for infant formula have been sought to reduce disparities in health outcomes between breastfed and formula-fed infants. Traditional food safety methodologies have limited ability to assess some bioactive ingredients. It is difficult to assess the effects of nutrition on the infant immune system because of coincident developmental adaptations to birth, establishment of the microbiome and introduction to solid foods, and perinatal environmental factors. An expert panel was convened to review information on immune system development published since the 2004 Institute of Medicine report on evaluating the safety of new infant formula ingredients and to recommend measurements that demonstrate the safety of bioactive ingredients intended for that use. Panel members participated in a 2-d virtual symposium in November 2020 and in follow-up discussions throughout early 2021. Key topics included identification of immune system endpoints from nutritional intervention studies, effects of human milk feeding and human milk substances on infant health outcomes, ontologic development of the infant immune system, and microbial influences on tolerance. The panel explored how "nonnormal" conditions such as preterm birth, allergy, and genetic disorders could help define developmental immune markers for healthy term infants. With consideration of breastfed infants as a reference, ensuring proper control groups, and attention to numerous potential confounders, the panel recommended a set of standard clinical endpoints including growth, response to vaccination, infection and other adverse effects related to inflammation, and allergy and atopic diseases. It compiled a set of candidate markers to characterize stereotypical patterns of immune system development during infancy, but absence of reference ranges, variability in methods and populations, and unreliability of individual markers to predict disease prevented the panel from including many markers as safety endpoints. The panel's findings and recommendations are applicable for industry, regulatory, and academic settings, and will inform safety assessments for immunomodulatory ingredients in foods besides infant formula.

POSB268 Landscape Review Exploring Acceptability of Oncology Surrogate Endpoints By NICE (England), CADTH (Canada), and PBAC (Australia) from 2010 to 2021

Many health technology assessment (HTA) agencies still consider OS to be the gold standard clinical endpoint. However, as mature OS data are often not available for early stage oncology technology appraisals (TAs), manufacturers may provide supporting evidence of correlation between surrogate endpoints (SEs) and OS to strengthen submissions. This study aims to understand the inclusion of SEs in TAs and HTA agencies’ perception of these.

Assessing duration of breakthrough chemotherapy-induced nausea and vomiting (CINV): A pooled study analysis of NEPA versus aprepitant.

12091 Background: The historical standard clinical trial endpoint for preventing chemotherapy-induced nausea and vomiting (CINV) has been assessment of complete response (CR: no emesis and no rescue medication use) over five days. Recent evaluations focused on the duration of breakthrough CINV suggest that long duration of CINV results in more lost work time and impaired activity and is also a strong predictor for CINV in subsequent cycles. A recent pooled analysis of three similarly designed registration trials of NEPA, a fixed oral combination NK1 receptor antagonist (RA) (netupitant)/5-HT3RA (palonosetron), showed significantly higher CR rates during the delayed phase (≥24-120h) for NEPA compared to an aprepitant (APR) regimen. In this post-hoc analysis, we evaluated the extent and duration of breakthrough CINV in these pooled studies. Methods: Chemotherapy-naïve patients who received cisplatin-based chemotherapy and antiemetic prophylaxis of either a single dose of NEPA plus dexamethasone (DEX) or a 3-day APR/5-HT3 RA/DEX regimen from three randomized, double-blind pivotal trials were included. Patients without a CR were defined as treatment failures. Extent of CINV was evaluated using proportions of patients with treatment failure, emesis, and significant nausea (defined as &gt;25 mm on a 100 mm visual analog scale). Over the 5-day overall phase, duration was categorized as 1-2, and ≥3 days. Pearson’s chi-square test was employed to compare risks between treatments for each duration category in each of the previously mentioned endpoints. Results: Among all 621 NEPA and 576 APR patients, a significantly greater proportion of APR patients experienced treatment failure, emesis, and significant nausea for ≥3 days. Specifically, among patients with treatment failure, 31% (41/134) who received NEPA and 43% (61/143) who received APR experienced breakthrough CINV for ≥3 days. Conclusions: Expanding on data suggesting single-day NEPA is more effective than 3-day APR in preventing delayed CINV, NEPA is also more effective in minimizing the extent and duration of CINV in patients with breakthrough emesis and nausea.[Table: see text]

How to RESPOND to Modern Challenges for People Living with HIV: A Profile for a New Cohort Consortium.

Background: the International Cohort Consortium of Infectious Disease (RESPOND) is a collaboration dedicated to research on HIV and other infectious diseases. Methods: RESPOND is a flexible organization, with several independent substudies operating under one shared governance. HIV-related variables, including full antiretroviral therapy (ART) history, are collected annually for all participants and merged with substudy specific data into a shared data pool. Incident clinical events are reported using standardized forms. Prospective follow-up started 1/10/17 (enrolment) with retrospective data collected back to 01/01/12. Results: Overall, 17 cohorts from Europe and Australia provided data on 26,258 people living with HIV (PLWH). The majority (43.3%) of the population were white, with men-sex-with-men accounting for 43.3% of the risk for HIV acquisition. The median age was 48 years (IQR 40–56) and 5.2% and 25.5% were known to be co-infected with hepatitis B or C. While 5.3% were ART-naïve, the median duration on ART was 10.1 years (4.8–17.6), with 89.5% having a VL <200 copies/mL and the median CD4 count being 621 cells/µL (438–830). Malignancies (n = 361) and cardiovascular disease (n = 168) were the predominant reported clinical events. Conclusion: RESPOND’s large, diverse study population and standardized clinical endpoints puts the consortium in a unique position to respond to the diverse modern challenges for PLWH.

When to use probiotics in luminal gastrointestinal disorders?

With the growing popularity and commercialization of probiotics, it is important to understand the implications of existing randomized controlled trials and their applicability in the clinical setting to treat luminal gastrointestinal diseases. Probiotics may be useful in the prevention of antibiotic-associated diarrhea, prevention of Clostridioides difficile infection and eradication of Helicobacter pylori. Some evidence supports the use of probiotics in the treatment of ulcerative colitis, prevention and treatment of pouchitis and irritable bowel syndrome. Caution has to be exercised in immunocompromised and critically ill individuals. New society guidelines do not encourage probiotic use in gastrointestinal disorders with the exception of premature infants to prevent necrotizing enterocolitis. Despite burgeoning body of literature and wide acceptance by the public, a thorough understanding of efficacy and safety of probiotics is lacking. Uniform dosage, standardized clinical end points, personalization based on host microbial profile and longer duration of follow-up on the research front may help in the future in appropriate positioning of probiotics in health and disease.

Window of Opportunity trials for biomarker discovery in breast cancer.

Window of Opportunity (WOO) studies have gain their place in current clinical and translational research in breast cancer patients. This review provides current information and future applications of this specific type of research. So far, WOO trials in breast cancer patients have demonstrated their utility in breast cancer research as: first they allow administering a treatment for a short period of time to treatment-naïve patients whose tumors have not developed mechanisms of resistance or heterogeneity because of previous therapies. Second, it brings a unique opportunity for translational research providing easy access to tumor tissue in order to evaluate antitumor effect from initial biopsy and from surgical resection specimen. They provide the perfect scenario for biomarker discovery and validation in an efficient and timely manner and valuable information about drug pharmacodynamics. Several issues need to be contemplated when designing and performing this type of trials including choice of a biological surrogate endpoint of efficacy as standard clinical activity endpoints are not feasible. Despite some limitations like the absence of information about secondary mechanisms of resistance, WOO trials represent an important support for drug development and biomarker discovery in breast cancer patients.

Early prediction of phenotypic severity in Citrullinemia Type 1

ObjectiveCitrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild‐to‐moderate or asymptomatic disease course. Since the phenotypic severity has not been predictable early during the disease course so far, we aimed to design a reliable disease prediction model.MethodsWe used a newly established mammalian biallelic expression system to determine residual enzymatic activity of argininosuccinate synthetase 1 (ASS1; OMIM #215700) in 71 individuals with CTLN1, representing 48 ASS1 gene variants and 50 different, mostly compound heterozygous combinations in total. Residual enzymatic ASS1 activity was correlated to standardized biochemical and clinical endpoints available from the UCDC and E‐IMD databases.ResultsResidual enzymatic ASS1 activity correlates with peak plasma ammonium and L‐citrulline concentrations at initial presentation. Individuals with 8% of residual enzymatic ASS1 activity or less had more frequent and more severe hyperammonemic events and lower cognitive function than those above 8%, highlighting that residual enzymatic ASS1 activity allows reliable severity prediction. Noteworthy, empiric clinical practice of affected individuals is in line with the predicted disease severity supporting the notion of a risk stratification‐based guidance of therapeutic decision‐making based on residual enzymatic ASS1 activity in the future.InterpretationResidual enzymatic ASS1 activity reliably predicts the phenotypic severity in CTLN1. We propose a new severity‐adjusted classification system for individuals with CTLN1 based on the activity results of the newly established biallelic expression system.

Neurocognitive evaluation in older adult patients affected by glioma

BackgroundGlioblastoma (GBM) has an increasing incidence and dismal prognosis in older adults. This study evaluated neurocognitive status of an older adult population with GBM and its correlation with clinical and demographical variables. MethodsEach patient underwent an extended neuropsychological evaluation by means of a battery of standardized tests describing eight cognitive domains: global function; verbal learning; short- and long-term memory (LTM); executive functions (EFs); abstract reasoning (AR); attention; and visuo-constructional abilities (CA). ResultsWe assessed 79 patients with GBM (median age: 74 years). Out of this initial sample, a subgroup of seventeen patients with six-month median time underwent a follow-up test session. 46 out of the 79 patients (58.2%) presented multi-domain cognitive impairment, 24 patients (30.3%) showed single-domain cognitive impairment and only seven (9%) showed no cognitive impairment. Kaplan Meier estimator showed that patients with AR deficit had a poorer prognosis in terms of progression-free survival and overall survival (p < .001). At the multivariate analysis AR (deficit vs non; hazard ratio (HR) = 5.07, 95%; confidence interval (CI): 1.91–13.46; p < .001) was correlated with disease progression and overall survival, AR (deficit vs non; HR = 7.24, 95% CI: 2.58–20.32; p < .001).Eight out of seventeen patients who underwent follow-up test session showed cognitive improvement, five resulted in further deterioration, and four patients remained stable. LTM, EF, and CA were the most affected functions at follow-up, while verbal learning was the most improved one in patients with cognitive improvement. ConclusionsCognitive functioning evaluation should be included among the standard clinical endpoints in the treatment of older adult neuro-oncology patients.

Robust identification of molecular phenotypes using semi-supervised learning

BackgroundModern molecular profiling techniques are yielding vast amounts of data from patient samples that could be utilized with machine learning methods to provide important biological insights and improvements in patient outcomes. Unsupervised methods have been successfully used to identify molecularly-defined disease subtypes. However, these approaches do not take advantage of potential additional clinical outcome information. Supervised methods can be implemented when training classes are apparent (e.g., responders or non-responders to treatment). However, training classes can be difficult to define when assessing relative benefit of one therapy over another using gold standard clinical endpoints, since it is often not clear how much benefit each individual patient receives.ResultsWe introduce an iterative approach to binary classification tasks based on the simultaneous refinement of training class labels and classifiers towards self-consistency. As training labels are refined during the process, the method is well suited to cases where training class definitions are not obvious or noisy. Clinical data, including time-to-event endpoints, can be incorporated into the approach to enable the iterative refinement to identify molecular phenotypes associated with a particular clinical variable. Using synthetic data, we show how this approach can be used to increase the accuracy of identification of outcome-related phenotypes and their associated molecular attributes. Further, we demonstrate that the advantages of the method persist in real world genomic datasets, allowing the reliable identification of molecular phenotypes and estimation of their association with outcome that generalizes to validation datasets. We show that at convergence of the iterative refinement, there is a consistent incorporation of the molecular data into the classifier yielding the molecular phenotype and that this allows a robust identification of associated attributes and the underlying biological processes.ConclusionsThe consistent incorporation of the structure of the molecular data into the classifier helps to minimize overfitting and facilitates not only good generalization of classification and molecular phenotypes, but also reliable identification of biologically relevant features and elucidation of underlying biological processes.

Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by progressive loss of spinal and cortical motor neurons, leading to muscular atrophy, respiratory failure, and ultimately death. There is no known cure, and the clinical benefit of the two drugs approved to treat ALS remains unclear. Novel disease-modifying therapeutics that are able to modulate the disease course are desperately needed. Our objective was to evaluate the efficacy and tolerability of Elysium Health’s candidate drug EH301 in people with ALS (PALS). Methods: This was a single-center, prospective, double-blind, randomized, placebo-controlled pilot study. Thirty-two PALS were recruited thanks to the collaboration of the Spanish Foundation for ALS Research (FUNDELA). Study participants were randomized to receive either EH301 or placebo and underwent evaluation for 4 months. Differences between EH301 and placebo-treated participants were evaluated based on standard clinical endpoints, including the revised ALS functional rating scale (ALSFRS-R), forced vital capacity (FVC), and the Medical Research Council (MRC) grading scale. Results: Compared to placebo, participants treated with EH301 demonstrated significant improvements in the ALSFRS-R score, pulmonary function, muscular strength, and in skeletal muscle/fat weight ratio. EH301 was shown to significantly slow the progression of ALS relative to placebo, and even showed improvements in several key outcome measures compared with baseline. Conclusions: This study provides evidence in support of the disease-modifying effects of EH301 for the treatment of ALS.Trial registration: ClinicalTrials.gov identifier: NCT03489200.

Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology

BackgroundAs increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification.MethodsThe endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research.ResultsMost respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1–10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets.ConclusionThe structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue.

Development of standard clinical endpoints for use in dengue interventional trials.

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials.

FDA Regulatory Perspectives for Studies on Hemodialysis Vascular Access.

In an effort to foster innovation and new product development, the American Society of Nephrology and the US Food and Drug Administration partnered to form the Kidney Health Initiative in 2012. Part of the Kidney Health Initiative's mission is to foster development of therapies by creating a collaborative environment where the US Food and Drug Administration and the greater nephrology community can interact to optimize product evaluation. This particular Kidney Health Initiative project focused on products related to hemodialysis vascular access, with the goal of clarifying appropriate trial end points that could subsequently inform clinical, regulatory, and coverage decisions. Both the lack of common definitions and the lack of consensus on trial end points have been viewed as barriers to innovation in this area. Toward this end, the Kidney Health Initiative convened teams of expert stakeholders to address these issues for each major vascular access category (arteriovenous grafts, arteriovenous fistulas, and central venous catheters), and each team provided recommendations. This commentary provides an overview of the US Food and Drug Administration centers that regulate hemodialysis vascular access and certain laws and regulations that affect these products as well as our perspectives on some of the issues raised and end points proposed by the Kidney Health Initiative teams. The standardized definitions and clinical trial end points proposed by the teams represent an important step forward to improve innovation in this area.

Transcatheter Aortic Valve Implantation versus Surgical Aortic Valve Replacement: Meta-Analysis of Clinical Outcomes and Cost-Effectiveness.

Transcatheter aortic valve implantation (TAVI) has emerged as a feasible alternative treatment to conventional surgical aortic valve replacement (AVR) for high-risk patients with aortic stenosis. The present systematic review aimed to assess the comparative clinical and cost-effectiveness outcomes of TAVI versus AVR, and meta-analyse standardized clinical endpoints. An electronic search was conducted on 9 online databases to identify all relevant studies. Eligible studies had to report on either periprocedural mortality or incremental cost-effectiveness ratio (ICER) to be included for analysis. The systematic review identified 24 studies that reported on comparative clinical outcomes, including three randomized controlled trials and ten matched observational studies involving 7906 patients. Meta-analysis demonstrated no significant differences in regards to mortality, stroke, myocardial infarction or acute renal failure. Patients who underwent TAVI were more likely to experience major vascular complications or arrhythmias requiring permanent pacemaker insertion. Patients who underwent AVR were more likely to experience major bleeding. Eleven analyses from 7 economic studies reported on ICER. Six analyses defined TAVI to be low value, 2 analyses defined TAVI to be intermediate value, and three analyses defined TAVI to be high value. The present study demonstrated no significant differences in regards to mortality or stroke between the two therapeutic procedures. However, the cost-effectiveness and long-term efficacy of TAVI may require further investigation. Technological improvement and increased experience may broaden the clinical indication for TAVI for low-intermediate risk patients in the future.

Overall survival in non-small cell lung cancer-what is clinically meaningful?

The development of molecularly targeted therapies [tyrosine kinase inhibitors (TKIs) and monoclonal antibodies] has significantly improved outcomes for patients with advanced or metastatic non-small cell lung cancer (NSCLC) resulting in improved progression-free survival (PFS), overall survival (OS) and quality of life (QoL). In addition, targeting the immune axis (CTLA-4, PD-1/PD-L1) has also shown promising results. Major goals of almost all clinical trials based on histology and molecular markers for NSCLC patients are improvements of OS and QoL. However, in the majority of these trials only small incremental improvements in OS were seen. Food and Drug Administration (FDA) and other health authorities have recommended to consider OS to be the standard clinical benefit endpoint that should be used to establish the efficacy of a treatment for NSCLC patients, however, the question remains what is clinically meaningful and how can this outcome be measured. According to suggestions of the American Society of Clinical Oncology (ASCO) Cancer Research Committee a relative improvement in median OS of at least 20% (3-4 months) is regarded to define a clinically meaningful improvement in outcome of NSCLC patients. However, this should not diminish PFS as a valid endpoint since a PFS improvement can also result in a meaningful palliation (e.g., painful bone metastases). Other factors (e.g., QoL) may also be involved to measure and to define the clinical importance of a given trial result. Using the "Quality-adjusted Time Without Symptoms of Toxicity" (Q-TWiST) analysis method it has been demonstrated that a clinically important and meaningful difference for Q-TWiST is 10-15% of OS in a study. Trials that are designed with less ambitious goals, however, may still be of benefit to individual NSCLC patients if the trial endpoints are met. Since there is no single factor which will make a trial clinically meaningful, these recommendations, however, are not intended to set standards for regulatory approval or insurance coverage but rather to encourage patients and investigators to demand more from clinical trials.