Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points: A systematic review.

No systematic review of trial designs in patients with relapsing multiple sclerosis (RMS) was reported. This systematic review was conducted on the trial designs and primary end points (PEs) of phase II and III trials intended to modify the natural course of the disease in patients with RMS. The purpose of the study is to explore trends/topics and discussion points in clinical trial design and PE, comparing them to regulatory guidelines and expert recommendations. Three trial registration systems, ClinicalTrials.gov, the EU Clinical Trials Register, and the Japan Registry of Clinical Trials, were used and 60 trials were evaluated. The dominant clinical trial design was a randomized controlled parallel-arms trial and other details were as follows: in adult phase III confirmatory trials (n = 32), active-controlled double-blind trial (DBT) (53%) and active-controlled open-label assessor-masking trial (16%); in adult phase II dose-finding trials (n = 9), placebo- and active-controlled DBT (44%), placebo-controlled DBT (22%), and placebo-controlled add-on DBT (22%); and in pediatric phase III confirmatory trials (n = 8), active-controlled DBT (38%) and active-controlled open-label non-masking trial (25%). The most common PEs were as follows: in adult confirmatory trials, annual relapse rate (ARR) (56%) and no evidence of disease activity-3 (NEDA-3) (13%); in adult dose-finding trials, the cumulative number of T1 gadolinium-enhancing lesions (56%), combined unique active lesions (22%), and overall disability response score (22%); and in pediatric confirmatory trials, ARR (38%) and time to first relapse (25%). It was suggested that some parts of the regulatory guidelines and expert recommendations need to be revised.

Considerations for using potential surrogate endpoints in cancer screening trials.

The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.

Analysis of core outcome set reporting in coronary intervention trials.

BACKGROUND: This paper will focus on outcome reporting within percutaneous coronary intervention (PCI) trials. A core outcome set (COS) is a standardised set of outcomes that are recommended to be reported in every clinical trial. Using a COS can help to ensure that all relevant outcomes are consistently reported across clinical trials. In 2018, the European Society of Cardiology outlined the only COS published for PCI trials. METHODS: We searched the literature for all randomised controlled trials published between 2014 and 2022. PCI trials included were late-phase trials and must investigate coronary intervention. The primary outcome was the proportion of trials that reported all of the COS-defined outcomes within their publication as either a primary, secondary or safety endpoint. The secondary outcomes included; the number of primary outcomes reported per study, the proportion of studies which use patient and public involvement (PPI) during trial design, outcome variability and outcome consistency. RESULTS: 9580 trials were screened and 115 studies met inclusion/exclusion criteria. Our study demonstrated that 55% (34/62) of PCI trials used a COS when it was available, compared with 40% (21/53) before the availability of a PCI COS set, p=0.121. Fewer primary outcomes were reported after the implementation of the COS, 2 compared with 2.3, p=0.014. There was no difference in the use of PPI between either group. There was a higher level of variability in outcomes reported before the availability of the COS, while the consistency of outcome reporting remained similar. CONCLUSION: The use of a COS in PCI trials is low. This study provides evidence that there still is a lack of awareness of the COS among those who design clinical trials. We also presented the inconsistency and heterogenicity in reporting clinical trial outcomes. Finally, there was a clear lack of PPI utilisation in PCI trials.

Protocol for the development of a core outcome set and reporting guidelines for locoregional treatment in neoadjuvant systemic breast cancer treatment trials: the PRECEDENT project.

INTRODUCTION: Neoadjuvant systemic anticancer therapy (neoSACT) is increasingly used in the treatment of early breast cancer. Response to therapy is prognostic and allows locoregional and adjuvant systemic treatments to be tailored to minimise morbidity and optimise oncological outcomes and quality of life. Accurate information about locoregional treatments following neoSACT is vital to allow the translation of downstaging benefits into practice and facilitate meaningful interpretation of oncological outcomes, particularly locoregional recurrence. Reporting of locoregional treatments in neoSACT studies, however, is currently poor. The development of a core outcome set (COS) and reporting guidelines is one strategy by which this may be improved. METHODS AND ANALYSIS: A COS for reporting locoregional treatment (surgery and radiotherapy) in neoSACT trials will be developed in accordance with Core Outcome Measures in Effectiveness Trials (COMET) and Core Outcome Set-Standards for Development guidelines. Reporting guidance will be developed concurrently.The project will have three phases: (1) generation of a long list of relevant outcome domains and reporting items from a systematic review of published neoSACT studies and interviews with key stakeholders. Identified items and domains will be categorised and formatted into Delphi consensus questionnaire items. (2) At least two rounds of an international online Delphi survey in which at least 250 key stakeholders (surgeons/oncologists/radiologists/pathologists/trialists/methodologists) will score the importance of reporting each outcome. (3) A consensus meeting with key stakeholders to discuss and agree the final COS and reporting guidance. ETHICS AND DISSEMINATION: Ethical approval for the consensus process will be obtained from the Queen's University Belfast Faculty Ethics Committee. The COS/reporting guidelines will be presented at international meetings and published in peer-reviewed journals. Dissemination materials will be produced in collaboration with our steering group and patient advocates so the results can be shared widely. REGISTRATION: The study has been prospectively registered on the COMET website (https://www.comet-initiative.org/Studies/Details/2854).

In-Depth Retinal Sensitivity Assessment With the MP3 Type S Microperimeter: A Methods Study.

Purpose: Retinal sensitivity is frequently listed as an end point in clinical trials, often with long working practices. The purpose of this methods study was to provide a new workflow and reduced test time for in-depth characterization of retinal sensitivity. Methods: A workflow for the MP3-S microperimeter with detailed functional characterization of the retina under photopic, mesopic, and scotopic conditions was evaluated. Grids of 32 and 28 test positions for photopic/mesopic and scotopic, respectively, were tested in 12 healthy individuals and compared with an established 68-point grid for test time, mean sensitivity (MS), and bivariate contour ellipse area (BCEA). Results: The mean test time (range; ±SD) was 10.5 minutes (8.4-14.9; ±2.0) in the 68-point grid and 4.3 minutes (3.8-5.0; ±0.4) in the 32-point grid, which was significantly different (P < 0.0001). The mean of difference in test time (±SD; 95% confidence interval) was 6.1 minutes (±2.0; 4.6-7.6). MS and BCEA were significantly correlated between grids (r = 0.89 and 0.74; P = 0.0005 and 0.014, respectively). Mean test time of subjects who underwent the full protocol (n = 4) was 2.15 hours. Conclusions: The protocol suggested herein appears highly feasible with in-depth characterization of retinal function under different testing conditions and in a short test time. Translational Relevance: The protocol described herein allows for characterization of the retina under different testing conditions and in a short test time, which is relevant due to its potential for patient prognostication and follow-up in clinical settings and also given its increasing role as a clinical trial end point.

Methodological challenges in the development of endpoints for myelofibrosis clinical trials.

Myelofibrosis is a myeloid neoplasm characterised by the presence of JAK2, CALR, or MPL mutations (with a 90% mutation frequency) and trilineage myeloid proliferation with prominent megakaryocyte atypia. People with myelofibrosis have a lower survival rate and poorer quality of life than healthy individuals. Therapy for myelofibrosis uses Janus kinase inhibitors, which reduce splenomegaly and alleviate symptoms. Regulatory approvals for Janus kinase inhibitors have focused on this dual endpoint. In this Viewpoint, we discuss the validity of using spleen reduction as a surrogate endpoint for the disease-modifying activity of candidate drugs for myelofibrosis. We suggest alternative endpoints addressing unmet patient needs, including progression-free survival and overall survival. Moreover, we highlight the importance of selecting a core set of crucial outcomes with which we can individualise clinical decision making and standardise reporting of clinical trials results. We propose selecting patient-reported outcomes and anaemia response. We also suggest integrating economic considerations in the process of evaluating new drugs for myelofibrosis.

Assessing 'response' to the low-FODMAP diet in irritable bowel syndrome: Should we be reporting harder primary endpoints?

BACKGROUND & AIMS: The low-FODMAP diet (LFD) has become almost synonymous with IBS care, yet the challenges associated with this rigorous therapeutic approach are often underacknowledged. Despite positive outcomes in RCTs, comparator groups frequently exhibit substantial response rates, raising questions about the definition of 'response'. Whilst the assessment of response in drug trials has evolved to utilize the more stringent FDA/EMA primary clinical endpoints, trials of the LFD have not yet followed. The aim of this article is to opine whether the current approach to the measurement of clinical response to the LFD in clinical trials should be reconsidered. METHODS: A comprehensive literature review of LFD clinical trials from the past decade was conducted, focusing on recorded response metrics for primary clinical endpoints. RESULTS: While response definitions vary, the 50-point IBS-SSS delta emerged as the predominant metric. Notably, no trials to date have adopted the more stringent primary clinical endpoints used in drug trials. Other response measures included binary response metrics (such as 'adequate clinical response'), changes in visual analogue scales or stool form/output, reductions in abdominal pain, as well as changes the magnitude of the IBS-SSS delta. Whether these metrics correspond to a clinically meaningful improvement for the patient is less clear, and as such aligning patient-clinician expectations can be challenging. CONCLUSIONS: A paradigm shift in the conceptualization of 'response' coupled with an emphasis on harder clinical endpoints in the context of clinical trials may serve to better justify the trade-off between symptom-improvement and the inherent challenges associated with this burdensome therapeutic approach.

Optimal allocation strategies in platform trials with continuous endpoints.

Platform trials are randomized clinical trials that allow simultaneous comparison of multiple interventions, usually against a common control. Arms to test experimental interventions may enter and leave the platform over time. This implies that the number of experimental intervention arms in the trial may change as the trial progresses. Determining optimal allocation rates to allocate patients to the treatment and control arms in platform trials is challenging because the optimal allocation depends on the number of arms in the platform and the latter typically varies over time. In addition, the optimal allocation depends on the analysis strategy used and the optimality criteria considered. In this article, we derive optimal treatment allocation rates for platform trials with shared controls, assuming that a stratified estimation and a testing procedure based on a regression model are used to adjust for time trends. We consider both, analysis using concurrent controls only as well as analysis methods using concurrent and non-concurrent controls and assume that the total sample size is fixed. The objective function to be minimized is the maximum of the variances of the effect estimators. We show that the optimal solution depends on the entry time of the arms in the trial and, in general, does not correspond to the square root of k allocation rule used in classical multi-arm trials. We illustrate the optimal allocation and evaluate the power and type 1 error rate compared to trials using one-to-one and square root of k allocations by means of a case study.

Study protocol: a core outcome set for perioperative exercise clinical effectiveness trials for lung cancer patients.

BACKGROUND: Outcome assessment in perioperative exercise trials for lung cancer is heterogeneous, often omitting those that are important and patient-relevant. This heterogeneity hinders the synthesis of evidence. To address this issue, a core outcome set, an agreed-upon standardized set of outcomes to be measured and reported, is required to reduce heterogeneity among outcome measurements. This study protocol describes the methodology, aiming to develop a core outcome set for perioperative exercise intervention trials for lung cancer in clinical practice. METHODS: The project will follow the standard methodology recommended by the Core Outcome Measures in Effectiveness Trials (COMET) initiative, which is divided into four steps. Stage I: Conducting a scoping review of outcomes reported in clinical trials and protocols to develop a list of potential outcome domains. Stage II: Conducting semi-structured interviews to obtain important outcomes for patients. Stage III: Choosing the most important outcomes by conducting two rounds of the Delphi exercise. Stage IV: Achieving a consensus in a face-to-face meeting to discuss the final core outcome set. DISCUSSION: This is the first project identified for the core outcome set of perioperative exercise trials in lung cancer, which will enhance the quality, comparability, and usability of future trials and positively impact perioperative exercise and the care of patients with lung cancer. TRIALS REGISTRATION: Core Outcome Measurement in Effectiveness Trials (COMET) Initiative database registration: https://www.comet-initiative.org/Studies/Details/2091.

Use of win time for ordered composite endpoints in clinical trials.

Consider the choice of outcome for overall treatment benefit in a clinical trial which measures the first time to each of several clinical events. We describe several new variants of the win ratio that incorporate the time spent in each clinical state over the common follow-up, where clinical state means the worst clinical event that has occurred by that time. One version allows restriction so that death during follow-up is most important, while time spent in other clinical states is still accounted for. Three other variants are described; one is based on the average pairwise win time, one creates a continuous outcome for each participant based on expected win times against a reference distribution and another that uses the estimated distributions of clinical state to compare the treatment arms. Finally, a combination testing approach is described to give robust power for detecting treatment benefit across a broad range of alternatives. These new methods are designed to be closer to the overall treatment benefit/harm from a patient's perspective, compared to the ordinary win ratio. The new methods are compared to the composite event approach and the ordinary win ratio. Simulations show that when overall treatment benefit on death is substantial, the variants based on either the participants' expected win times (EWTs) against a reference distribution or estimated clinical state distributions have substantially higher power than either the pairwise comparison or composite event methods. The methods are illustrated by re-analysis of the trial heart failure: a controlled trial investigating outcomes of exercise training.

The Finkelstein-Schoenfeld Test: A Note on Some Overlooked Issues Concerning Power.

In this note, we express our viewpoint regarding power considerations, via simulation studies, in clinical study design using hierarchical composite endpoint and Finkelstein-Schoenfeld test.

Development of a Core Outcome Set for Dysphagia Interventions in Parkinson's disease (COS-DIP): study protocol.

INTRODUCTION: Current clinical trials on swallowing disorders (dysphagia) in Parkinson's disease (PD) apply a high variety of outcomes and different outcome measures making comparative effectiveness research challenging. Furthermore, views of patients and dysphagia clinicians when selecting trial outcomes have not been considered in the past, thus study results may have little importance to them. This study aims to develop an agreed standardised Core Outcome Set for Dysphagia Interventions in Parkinson's disease (COS-DIP), systematically measured and reported as a minimum for all clinical trials. It will also comprise guidance on outcome definitions, outcome measures and time points of measurement. METHODS AND ANALYSIS: The COS-DIP development will comprise five stages following established methodology: (1) a recent scoping review on all applied outcomes, their definitions, methods and time points of measurement in clinical trials in dysphagia in PD, (2) online surveys and focus groups with clinicians, patients, caregivers and family members to identify outcomes that are important to them, (3) an identified list of outcomes based on results of stage 1 and 2, (4) three round online Delphi survey with up to 200 key stakeholders to determine core outcomes and (5) two online consensus meetings with up to 40 representative key stakeholders to agree on all outcomes, definitions, methods and time points of measurement in the final COS-DIP. ETHICS AND DISSEMINATION: Full ethical approval was obtained from the Research Ethics Committee, School of Linguistic, Speech and Communication Sciences, Trinity College Dublin, on 15 May 2023 (HT27). Dissemination of the COS-DIP will be enhanced through presentations at (inter-) national conferences and through peer-reviewed, open access publications of related manuscripts. Lay and professional information sheets and infographics will be circulated through relevant patient and professional organisations and networks. TRIAL REGISTRATION NUMBER: The COS-DIP study was registered prospectively with the Core Outcome Measures in Effectiveness Trials (COMET) database on 24 September 2021 (www.comet-initiative.org/Studies/Details/1942).

An information-theoretic approach for the assessment of a continuous outcome as a surrogate for a binary true endpoint based on causal inference: Application to vaccine evaluation.

Within the causal association paradigm, a method is proposed to assess the validity of a continuous outcome as a surrogate for a binary true endpoint. The methodology is based on a previously introduced information-theoretic definition of surrogacy and has two main steps. In the first step, a new model is proposed to describe the joint distribution of the potential outcomes associated with the putative surrogate and the true endpoint of interest. The identifiability issues inherent to this type of models are handled via sensitivity analysis. In the second step, a metric of surrogacy new to this setting, the so-called individual causal association is presented. The methodology is studied in detail using theoretical considerations, some simulations, and data from a randomized clinical trial evaluating an inactivated quadrivalent influenza vaccine. A user-friendly R package Surrogate is provided to carry out the evaluation exercise.

Surrogate endpoints: a key concept in clinical epidemiology.

Surrogate endpoints are biomarkers or intermediate outcomes that are used as substitutes for clinical outcomes of interest, often to expedite research or decision-making. In contrast, patient-important (or patient-centered) outcomes are health outcomes that are of direct relevance and importance to patients themselves; clinical trials may have measured the impact of the intervention on other endpoints related to, but different from, those of primary importance to patients. This article aims to elaborate on the use and understanding of surrogate endpoints. There should be a well-understood and scientifically grounded relationship between the surrogate (replacement) and the patient-important (target) endpoint it is intended to represent. It should be biologically plausible that changes in the surrogate will consistently and predictably reflect changes in the patient-important endpoint. The surrogate endpoint should show a threshold effect, meaning that a specific change (or state) in the surrogate with an intervention (relative to the comparator) is associated with a predictable (change in the) patient-important outcome. This helps establish a meaningful cutoff or target for the treatment effect on the surrogate endpoint. While surrogate endpoints offer advantages in certain situations, it is important to remember that their use requires careful validation to ensure they reliably predict the true clinical outcome. The validity of "surrogate endpoints" should be supported by robust scientific evidence and rigorous evaluation before these can be considered and labeled as surrogate endpoints.

Development of a core outcome set for cardiovascular diabetology: a methodological framework.

Background: Cardiovascular diabetology is an emergent field focusing on all aspects of diabetes/cardiovascular interrelationship and metabolic syndrome. High-quality evidence needs to be provided to determine the efficacy and safety of interventions in cardiovascular diabetology. The heterogeneity of outcomes among trials limits the comparison of results, and some outcomes are not always meaningful to end-users. The cardiovascular diabetology core outcome set (COS) study aims to develop a COS of interventions for cardiovascular diabetology. In this paper, we introduce the methodological framework for developing the COS. Methods: The COS development will include the following steps: (a) establish the COS groups of stakeholders, including international steering committee, Delphi survey group, and consensus meeting group; (b) systematic reviews of outcomes used in trials of cardiovascular diabetology; (c) semistructured interview of stakeholders for outcomes of cardiovascular diabetology; (d) generate a list of candidate outcomes and determine the original outcome pool; (e) Delphi survey with stakeholders of cardiovascular diabetology to select potential core outcomes; and (f) review and endorse the cardiovascular diabetology COS by expert consensus meeting. Conclusions: This current study reports the methodological framework to develop a COS in cardiovascular diabetology and will provide evidence for the future development of COS in cardiovascular diabetology.

Increasing confidence in new approach methodologies for inhalation risk assessment with multiple end point assays using 5-day repeated exposure to 1,3-dichloropropene.

New Approach Methodologies (NAMs) are being widely used to reduce, refine, and replace, animal use in studying toxicology. For respiratory toxicology, this includes both in silico and in vitro alternatives to replace traditional in vivo inhalation studies. 1,3-Dichloropropene (1,3-DCP) is a volatile organic compound that is widely used in agriculture as a pre-planting fumigant. Short-term exposure of humans to 1,3-DCP can result in mucous membrane irritation, chest pain, headache, and dizziness. In our previous work, we exposed differentiated cells representing different parts of the respiratory epithelium to 1,3-DCP vapor, measured cytotoxicity, and did In Vitro to In Vivo Extrapolation (IVIVE). We have extended our previous study with 1,3-DCP vapors by conducting transcriptomics on acutely exposed nasal cultures and have implemented a separate 5-day repeated exposure with multiple endpoints to gain further molecular insight into our model. MucilAir™ Nasal cell culture models, representing the nasal epithelium, were exposed to six sub-cytotoxic concentrations of 1,3-DCP vapor at the air-liquid interface, and the nasal cultures were analyzed by different methodologies, including histology, transcriptomics, and glutathione (GSH) -depletion assays. We observed the dose-dependent effect of 1,3-DCP in terms of differential gene expression, change in cellular morphology from pseudostratified columnar epithelium to squamous epithelium, and depletion of GSH in MucilAir™ nasal cultures. The MucilAir™ nasal cultures were also exposed to 3 concentrations of 1,3-DCP using repeated exposure 4 h per day for 5 days and the histological analyses indicated changes in cellular morphology and a decrease in ciliated bodies and an increase in apoptotic bodies, with increasing concentrations of 1,3-DCP. Altogether, our results suggest that sub-cytotoxic exposures to 1,3-DCP lead to several molecular and cellular perturbations, providing significant insight into the mode-of-action (MoA) of 1,3-DCP using an innovative NAM model.

Generalized Pairwise Comparisons to Assess Treatment Effects: JACC Review Topic of the Week.

A time-to-first-event composite endpoint analysis has well-known shortcomings in evaluating a treatment effect in cardiovascular clinical trials. It does not fully describe the clinical benefit of therapy because the severity of the events, events repeated over time, and clinically relevant nonsurvival outcomes cannot be considered. The generalized pairwise comparisons (GPC) method adds flexibility in defining the primary endpoint by including any number and type of outcomes that best capture the clinical benefit of a therapy as compared with standard of care. Clinically important outcomes, including bleeding severity, number of interventions, and quality of life, can easily be integrated in a single analysis. The treatment effect in GPC can be expressed by the net treatment benefit, the success odds, or the win ratio. This review provides guidance on the use of GPC and the choice of treatment effect measures for the analysis and reporting of cardiovascular trials.

A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry-selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer's Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aß42, tTau, and pTau181) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.