Endpoints In Clinical Trials Research Articles

Dynamics of Liver Stiffness Measurement and Clinical Course of Primary Biliary Cholangitis

Background & aimsIn primary biliary cholangitis (PBC), static liver stiffness measurement (LSM) has proven prognostic value. However, the added prognostic value of LSM time course in this disease remains uncertain. MethodsWe conducted an international retrospective cohort study among PBC patients treated with ursodeoxycholic acid (UDCA) and followed by vibration-controlled transient elastography (VCTE) between 2003 and 2022. Using joint modeling, the association of LSM trajectory and the incidence of serious clinical events (SCE), defined as cirrhosis complications, liver transplantation (LT) or death, was quantified using the hazard ratio (HR) and its confidence interval (CI). ResultsA total of 6,362 LSMs were performed in 3,078 patients (2,007 on UDCA alone; 13% with cirrhosis), in whom 316 SCE occurred over 14,445 person-years (median follow-up, 4.2 years; incidence rate, 21.9 per 1,000 person-years). LSM progressed in 59% of patients (mean 0.39 kPa/year). After adjusting for prognostic factors at baseline, including LSM, any relative change in LSM was associated with a significant variation in SCE risk (p<0.001). For example, the adjusted HRs (95% CI) associated with a 20% annual variation in LSM were 2.13 (1.89 – 2.45) for the increase and 0.40 (0.33 – 0.46) for the decrease. The association between LSM trajectory and SCE risk persisted regardless of treatment response or duration, when patients with cirrhosis were excluded, and when only death or LT was considered. ConclusionsTracking longitudinal changes in LSM using VCTE provides valuable insights into PBC prognosis, offering a robust predictive measure for the risk of SCE. LSM could be used as a clinically relevant surrogate endpoint in PBC clinical trials.

Incorporating the perspectives of participants and research coordinators on home spirometry into clinical trial design: The example of the OUTREACH study

BackgroundWe undertook a human-centered design approach to design the OUTREACH study of home spirometry as a CF clinical trial endpoint. We conducted a qualitative needs assessment to elicit the perspectives of people with CF (PwCF) and research coordinators (RCs) about home spirometry in the research setting and co-produced written and video home spirometry instructions in partnership with representatives from these stakeholder groups. MethodsWe conducted 7 focus groups of PwCF (N = 27), caregivers of children with CF (N = 6), or RCs (N = 24) to elicit current experiences, barriers and facilitators of home spirometry across 6 target areas, followed by discussion and prioritization. The co-production team, composed of 3 PwCF, 3 RCs and study team members created written and video training materials. ResultsWhile most PwCF and caregivers found home spirometry convenient, many experienced technical barriers, reported a “learning curve”, and expressed uncertainty about the quality and reliability of measurements. Major barriers identified by RCs included tailoring participant training to individual needs, scheduling remote coaching, and performing effective coaching remotely. Participants offered age-specific recommendations in key domains: training materials and procedures, remote coaching, monitoring progress and maintaining engagement. Co-produced training materials included handouts and videos on how to perform spirometry, and troubleshooting, cleaning, and maintaining home spirometers. ConclusionsThe OUTREACH design was improved by incorporating results of the needs assessment. The home spirometry training materials are freely available for public use. We hope our results and materials can help to inform the design and success of remote clinical trials of the future.

Using multiple primary endpoints in clinical trials with a focus on heart failure

Using multiple primary endpoints in clinical trials with a focus on heart failure

Developing a fit-for-purpose composite symptom score as a symptom burden endpoint for clinical trials in patients with malignant pleural mesothelioma

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92–0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79–0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

Inter-reader reproducibility of a radiographic grading system for usual interstitial pneumonitis validates its use as a surrogate endpoint in clinical trials

AbstractBackgroundThe primary purpose of this study was to assess the interreader reliability of a grading system for UIP based on the quantification of normal lung. This grading system considers each of the following lung regions: right upper and middle lobes, right lower lobe, left upper lobe, and left lower lobe. Each is assigned a grade based on the following: 0: 0% normal lung; 1: 1–49% normal lung; 2: 50–74% normal lung; 3: 75–89% normal lung; 4: 90–99% normal lung; 5: 100% normal lung. The secondary purpose was to compare the grades rendered by non-cardiothoracic subspecialty trained radiologists to grades established by cardiothoracic radiologists, which were considered the gold standard.MethodsChest CT images of patients were obtained by searching the radiology record system for the terms “usual interstitial pneumonia” and “UIP”. Each case was confirmed by radiologist review; pathology was not assessed given the small fraction of cases that underwent biopsy due to the high risk of complications in patients with fibrotic lung disease. Two cardiothoracic radiologists evaluated each CT and reached a consensus grade. Two different radiologists who were not subspecialty trained in cardiothoracic radiology independently graded each case. Spearman correlation analysis was performed to compare the two reader's grades as well as each reader's grade independently to the gold standard score.ResultsOur analysis demonstrated a strongly positive statistically significant interreader correlation coefficient (RS) = 0.7062, P &lt; 0.001. Our analysis of each reader compared to the gold standard demonstrated an Rs = 0.77559, P &lt; 0.001 and an RS = 0.69958, P &lt; 0.001 for readers 1 and 2, respectively, both representing statistically significant strongly positive correlations.ConclusionsThese results demonstrate strong interreader reproducibility and show that radiologists without subspecialty training in cardiothoracic radiology render grades that correlate strongly with those given by cardiothoracic radiologists. These findings support the use of this grading system for UIP both to monitor clinical progression and as a surrogate endpoint for antifibrotic drug trials.

Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae.

Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints. 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms. Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms. We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC.

A Vector Theory of Assessing Clinical Trials: An Application to Bioequivalence.

A novel idea is introduced regarding the statistical comparisons of endpoints in clinical trials. Currently, the (dis)similarity of measured endpoints is not assessed. Instead, statistical analysis is directly applied, which can lead to multiplicity issues, reduced statistical power, and the recruitment of more subjects. The Vector-Based Comparison (VBC) approach originates from vector algebra and considers clinical endpoints as "vectors". In the general case of N clinical endpoints, a Cartesian coordinate system is defined, and the most important primary endpoint (E1) is set. Following an explicitly defined procedure, the pairwise relationships of the remaining N-1 endpoints with E1 are estimated, and the N-1 endpoints are decomposed into axes perpendicular to E1. The angle between vectors provides insight into the level of dependency between variables. Vectors that are perpendicular to each other are considered independent, and only these are used in the statistical analysis. In this work, VBC is applied to bioequivalence studies of three anti-hypertensive drugs: amlodipine, irbesartan, and hydrochlorothiazide. The results suggest that VBC is a reproducible, easily applicable method allowing for the discrimination and utilization of the endpoint component expressing different attributes. All clinical characteristics are assessed with increased statistical power, without inflation of type I error.

PROpwr: a Shiny R application to analyze patient-reported outcomes data and estimate power

ABSTRACT Patient Reported Outcomes (PROs) are widely used in quality of life (QOL) studies, health outcomes research, and clinical trials. The importance of PRO has been advocated by health authorities. We propose this R shiny web application, PROpwr, that estimates power for two-arm clinical trials with PRO measures as endpoints using Item Response Theory (GRM: Graded Response Model) and simulations. PROpwr also supports the analysis of PRO data for convenience of estimating the effect size. There are seven function tabs in PROpwr: Frequentist Analysis, Bayesian Analysis, GRM power, T-test Power Given Sample Size, T-test Sample Size Given Power, Download, and References. PROpwr is user-friendly with point-and-click functions. PROpwr can assist researchers to analyze and calculate power and sample size for PRO endpoints in clinical trials without prior programming knowledge.

Preferences and perceptions of 617 migraine patients on acute and preventive migraine treatment attributes and clinical trial endpoints

ABSTRACT Background To identify the preferences and perceptions of migraine patients for acute and preventive treatment options and to investigate which treatment outcomes are the most important. Design and Methods The authors performed a choice-format survey in a cohort of migraine patients from Greece and Cyprus. A self-administered questionnaire developed in collaboration with the Greek Society of Migraine Patients was used. Results Questionnaires were collected from 617 migraine patients. Efficacy was preferred over safety as the single most important parameter, both in acute and preventive treatment. When analyzing single outcomes, patients prioritized a complete pain remission at 1-hour post-dose for acute therapies. Regarding migraine prevention, a 75% reduction in frequency, intensity of pain, accompanying symptoms and acute medication intake were considered as most important. Conversely, outcomes routinely used in clinical trials, namely complete or partial pain remission at 2-hours post-dose for acute treatment and 50% or 30% reduction in migraine frequency for prevention, were not deemed particularly relevant. Tablet formulation was mostly preferred, both in acute and preventive treatment. Conclusion: Listening to patients’ needs may add a piece of the puzzle that is generally missing in clinical practice and often explains the lack of adherence in both acute and preventative anti-migraine therapies.

Heart failure patients' perspectives on treatment outcomes and unmet medical needs: A qualitative preference study.

Decision-makers still predominantly focus on the perspective of non-patient stakeholders, which may deviate from the unique perspective of heart failure (HF) patients. To enhance patient-centred decision-making, there is a need for more patient-based evidence derived directly from the patients themselves. Hence, this study aimed to understand (i) HF patients' unmet medical needs and preferred treatment outcomes; (ii) patients' risk tolerance; and (iii) their information needs, uncertainties and satisfaction towards HF treatment. This qualitative patient preference study consisted of a literature review with a systematic search strategy and semi-structured interviews with HF patients, analysed using the framework method. During the interviews, patients were asked to rank a predefined list of disease and treatment-related characteristics informed by the literature review and were able to spontaneously raise additional characteristics. The study included 14 Belgian HF patients (age range: 58-79, mean age: 72). (i) Regarding their unmet medical needs, HF patients reported that the most important unmet medical needs were shortness of breath and fatigue, as they negatively impact their quality of life (QoL) and independence. In the ranking exercise, patients prioritized improvements in QoL over improvements in life expectancy, whereby the following characteristics received the highest cumulative score: (1) independence, (2) shortness of breath, (3) impaired renal function, (4) survival, (5) fatigue, (6) risk of hospitalization and (7) communication with and between physicians. Patients most often spontaneously raise characteristics related to the general care process. Mechanism of action, route of administration, dose frequency and weight fluctuations scored among the least important characteristics. (ii) Regarding patients' risk tolerance towards HF treatment, some of the patients expressed zero tolerance for side effects, as they had not yet experienced any discomfort caused by the treatment or disease. (iii) Regarding their information needs, patients voiced their desire to receive practical and comprehensible advice orally from their physician because they highly value individualized treatment decision-making. Patients also expressed uncertainties regarding whether the experienced effects were due to their treatment, disease, ageing or other comorbidities. This study shows that, besides increasing life expectancy, HF patients prioritize improvements in symptoms and side effects reducing their QoL and independence, such as shortness of breath and fatigue. The patient-relevant characteristics identified in this study, from the perspective of HF patients themselves, may be useful to inform clinical trial endpoint selection and guide downstream drug development, evaluation and clinical decision-making towards addressing the unmet medical needs and treatment outcomes of importance to HF patients.

Motor assessment of X-linked dystonia parkinsonism via machine-learning-based analysis of wearable sensor data

X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. We performed wearable sensor-based analyses in XDP participants to quantitatively characterize disease phenomenology as a potential clinical trial endpoint. Wearable sensor data was collected from 10 symptomatic XDP patients and 3 healthy controls during a standardized examination. Disease severity was assessed with the Unified Parkinson’s Disease Rating Scale Part 3 (MDS-UPDRS) and Burke-Fahn-Marsden dystonia scale (BFM). We collected sensor data during the performance of specific MDS-UPDRS/BFM upper- and lower-limb motor tasks, and derived data features suitable to estimate clinical scores using machine learning (ML). XDP patients were at varying stages of disease and clinical severity. ML-based algorithms estimated MDS-UPDRS scores (parkinsonism) and dystonia-specific data features with a high degree of accuracy. Gait spatio-temporal parameters had high discriminatory power in differentiating XDP patients with different MDS-UPDRS scores from controls, XDP freezing of gait, and dystonic/non-dystonic gait. These analyses suggest the feasibility of using wearable sensor data for deriving reliable clinical score estimates associated with both parkinsonian and dystonic features in a complex, combined movement disorder and the utility of motion sensors in quantifying clinical examination.

Towards a lifelong personalized brain health program: empowering individuals to define, pursue, and monitor meaningful outcomes.

Incorporating person-centered outcomes into clinical trials for neurodegenerative diseases has been challenging due to a deficiency in quantitative measures. Meanwhile, the integration of personally meaningful treatment targets in clinical practice remains qualitative, failing to truly inform evaluations, therapeutic interventions and longitudinal monitoring and support. We discuss the current advances and future directions in capturing individualized brain health outcomes and present an approach to integrate person-centered outcome in a scalable manner. Our approach stems from the evidence-based electronic Person-Specific Outcome Measure (ePSOM) program which prompts an individual to define personally meaningful treatment priorities and report level of confidence in managing items that matter to the individual the most (e.g., "Do I feel confident in my ability to contribute to a conversation?"). Deployed either as a single version (person only) or a dyad version (person and care partner), our proposed tool could be used as an endpoint in clinical trials, offering proof of meaningful intervention benefits and in clinical practice, by establishing an anchor for the therapeutic objectives sought by the individual.

Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope® Diagnostic System (MMDx).

There is a major unmet need for improved accuracy and precision in the assessment of transplant rejection and tissue injury. Diagnoses relying on histologic and visual assessments demonstrate significant variation between expert observers (as represented by low kappa values) and have limited ability to assess many biological processes that produce little histologic changes, for example, acute injury. Consensus rules and guidelines for histologic diagnosis are useful but may have errors. Risks of over- or under-treatment can be serious: many therapies for transplant rejection or primary diseases are expensive and carry risk for significant adverse effects. Improved diagnostic methods could alleviate healthcare costs by reducing treatment errors, increase treatment efficacy, and serve as useful endpoints for clinical trials of new agents that can improve outcomes. Molecular diagnostic assessments using microarrays combined with machine learning algorithms for interpretation have shown promise for increasing diagnostic precision via probabilistic assessments, recalibrating standard of care diagnostic methods, clarifying ambiguous cases, and identifying potentially missed cases of rejection. This review describes the development and application of the Molecular Microscope® Diagnostic System (MMDx), and discusses the history and reasoning behind many common methods, statistical practices, and computational decisions employed to ensure that MMDx scores are as accurate and precise as possible. MMDx provides insights on disease processes and highly reproducible results from a comparatively small amount of tissue and constitutes a general approach that is useful in many areas of medicine, including kidney, heart, lung, and liver transplants, with the possibility of extrapolating lessons for understanding native organ disease states.

The randomized study of enteral nutrition with rapid versus conventional administration in acute stroke patients; the protocol of rapid EN trial.

Enteral nutrition is beneficial for stroke patients with oral intake difficulties. However, it is time consuming and may interfere with routine medical care. Therefore, there is a clinical benefit if enteral nutrition can be safely administered in a short time. Although our retrospective study showed the safety of rapid administration, it remains unclear whether rapid administration of enteral nutrition is as safe as conventional administration. The randomized study of Enteral Nutrition with Rapid versus conventional administration in acute stroke patients (Rapid EN trial) aims to clarify the safety of rapid feeding of enteral nutrition compared with conventional feeding. This is an investigator-initiated, multicenter, prospective, randomized, open-label, blinded end-point clinical trial. Eligible criteria include acute stroke patients who have difficulty with oral intake defined as severe altered consciousness (Japan Coma Scale 10-300) or modified water swallowing test <4. The target enrollment is 700 patients, with 350 patients receiving rapid enteral nutrition at a rate of 100 mL in 5 min (Rapid EN group) and 350 patients receiving conventional enteral nutrition at a rate of 100 mL in 30 min (Conventional EN group). The primary outcome is the incidence of one or more complications of vomiting or diarrhea or pneumonia within 7 days would be non-inferior in the rapid EN group compared to the conventional EN group. Secondary outcomes were total time spent on enteral nutrition within 7 days from enteral nutrition, the incidence of vomiting, diarrhea and pneumonia within 3 or 7 days, and the rate of favorable clinical outcome. Since no previous reports have focused on the speed of administration, we felt it was necessary to prove the safety of rapid administration. If this study shows positive results, it will not only benefit patients, but also reduce the burden of medical care. We believe this study is novel and will be useful in clinical practice. https://rctportal.niph.go.jp/s/detail/um?trial_id=UMIN000046610 Identifier UMIN000046610.

Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials.

Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

CO129 Novel Endpoints in Chronic Kidney Disease (CKD): Trends in the Use of eGFR Slope and Proteinuria As Efficacy Endpoints in Clinical Trials

CO129 Novel Endpoints in Chronic Kidney Disease (CKD): Trends in the Use of eGFR Slope and Proteinuria As Efficacy Endpoints in Clinical Trials

EPS4.07 Validation of home spirometry as a CF clinical trial endpoint: results of the OUTREACH study

EPS4.07 Validation of home spirometry as a CF clinical trial endpoint: results of the OUTREACH study

(Re-) Defining "Successful Aging" as the Endpoint in Clinical Trials? Current Methods, Challenges, and Emerging Solutions.

"Successful aging" as defined in Rowe & Kahn's model aims to include the major domains of aging under a single overarching concept. From here the question arises how "successful aging" itself can be implemented as an endpoint in clinical research in a way that it is compliant to methodological regulatory framework and recommendations as formulated, for example, by the FDA. This article discusses from an applied perspective approaches and examples of how "successful aging" as a multi domain concept can be put into measurement practice. Narrative literature review. Existing methods of merging insights from, e.g., functional, social, and cognitive outcomes, can fail to perform under conditions of extreme heterogeneity, as often present in samples of older adults. In research on rare diseases, the methodological approach of a Multi Domain Responder Index (MDRI) has been proposed to handle heterogeneity. MDRIs may also provide a solution to combine aging outcomes from different domains into a single "successful aging" endpoint. However, strict measurement criteria will need to be fulfilled to find acceptance in decision making and validated meaningful change thresholds are a critical prerequisite. Gerontology can spearhead methodological approaches of handling multidimensional measurement under heterogeneity by validating a "successful aging" MDRI suitable for use as an endpoint in clinical research.

Spliced-Leader RNA as a Dynamic Marker for Monitoring Viable Leishmania Parasites During and After Treatment.

Accurate detection of viable Leishmania parasites is critical for evaluating visceral leishmaniasis (VL) treatment response at an early timepoint. We compared the decay of kinetoplast DNA (kDNA) and spliced-leader RNA (SL-RNA) in vitro, in vivo, and in a VL patient cohort. An optimized combination of blood preservation and nucleic acid extraction improved efficiency for both targets. SL-RNA degraded more rapidly during treatment than kDNA, and correlated better with microscopic examination. SL-RNA quantitative polymerase chain reaction emerges as a superior method for dynamic monitoring of viable Leishmania parasites. It enables individualized treatment monitoring for improved prognoses and has potential as an early surrogate endpoint in clinical trials.

Advanced MRI Techniques: Diagnosis and Follow-Up of Multiple Sclerosis.

Brain and spinal cord imaging plays a pivotal role in aiding clinicians with the diagnosis and monitoring of multiple sclerosis. Nevertheless, the significance of magnetic resonance imaging in MS extends beyond its clinical utility. Advanced imaging modalities have facilitated the in vivo detection of various components of MS pathogenesis, and, in recent years, MRI biomarkers have been utilized to assess the response of patients with relapsing-remitting MS to the available treatments. Similarly, MRI indicators of neurodegeneration demonstrate potential as primary and secondary endpoints in clinical trials targeting progressive phenotypes. This review aims to provide an overview of the latest advancements in brain and spinal cord neuroimaging in MS.