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Great expectations have been set around the clinical potential of regenerative and reparative medicine in the treatment of cardiovascular diseases [i.e. in particular, heart failure (HF)]. Initial excitement, spurred by encouraging preclinical data, resulted in a rapid translation into clinical research. The sobering outcome of the resulting clinical trials suggests that preclinical testing may have been insufficient to predict clinical outcome. A number of barriers for clinical translation include the inherent variability of the biological products and difficulties to develop potency and quality assays, insufficient rigour of the preclinical research and reproducibility of the results, manufacturing challenges, and scientific irregularities reported in the last years. The failure to achieve clinical success led to an increased scrutiny and scepticism as to the clinical readiness of stem cells and gene therapy products among clinicians, industry stakeholders, and funding bodies. The present impasse has attracted the attention of some of the most active research groups in the field, which were then summoned to analyse the position of the field and tasked to develop a strategy, to re-visit the undoubtedly promising future of cardiovascular regenerative and reparative medicine, based on lessons learned over the past two decades. During the scientific retreat of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine (CARE) in November 2018, the most relevant and timely research aspects in regenerative and/or reparative medicine were presented and critically discussed, with the aim to lay out a strategy for the future development of the field. We report herein the main ideas and conclusions of that meeting. [ABSTRACT FROM AUTHOR]

Objectives: Digitised patient-reported outcome may be beneficial for physicians and patients. The Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ) can only be completed with paper and pencil (pJHEQ). We newly developed a web version of the JHEQ (wJHEQ). This study aimed to determine whether the scores obtained with the wJHEQ are equivalent to those from the pJHEQ, how much the wJHEQ would decrease missing answers, and which JHEQ the participants preferred to use. Methods: To measure equivalence between the pJHEQ and wJHEQ, we evaluated the mean score difference for each subscale (pain, movement, mental) and Visual Analogue Scale (VAS; satisfaction, right hip pain, left hip pain) and then assessed the intraclass correlation coefficients (ICC) between the two scores. ICC values ≥0.75 were defined as excellent agreement. We used Bland-Altman analysis to assess level of agreement between the values of the two questionnaires. We compared the number of incomplete forms and amount of missing data between the two questionnaires. We investigated ease of use by asking the participants which format was easier to use. Results: This study comprised 113 patients (mean age 58.1 years, 81% female) with hip disease. Mean score differences for each subscale between the wJHEQ and pJHEQ were not significantly different. The values of ICC for each subscale and each VAS were all >0.75. All 113 participants completed the wJHEQ questionnaire, whereas nine patients did not complete the pJHEQ form. There was a significant statistical difference between the completion rate of the wJHEQ and that of the pJHEQ (p = .0017). Fifty-seven participants (55%) preferred the wJHEQ, whereas 33 participants (32%) preferred the pJHEQ. Conclusion: The wJHEQ was found to be equivalent to the original pJHEQ. The wJHEQ significantly decreased the numbers of missing answers and incomplete forms. The participants felt ease of use was nearly equivalent. The wJHEQ might help facilitate more complete assessments in clinical trials and research. [ABSTRACT FROM AUTHOR]

The proportion of patients with at least minimal improvement in TIS was significantly greater for those who received IVIG relative to placebo. A similar issue of emphasis on patients with muscle involvement arises in using TIS as the primary outcome measure. These results led to US Food and Drug Administration (FDA) approval of IVIG use in treating DM. [Extracted from the article]

Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge. [ABSTRACT FROM AUTHOR]

Modulation of vessel growth holds great promise for treatment of cardiovascular disease. Strategies to promote vascularization can potentially restore function in ischaemic tissues. On the other hand, plaque neovascularization has been shown to associate with vulnerable plaque phenotypes and adverse events. The current lack of clinical success in regulating vascularization illustrates the complexity of the vascularization process, which involves a delicate balance between pro- and anti-angiogenic regulators and effectors. This is compounded by limitations in the models used to study vascularization that do not reflect the eventual clinical target population. Nevertheless, there is a large body of evidence that validate the importance of angiogenesis as a therapeutic concept. The overall aim of this Position Paper of the ESC Working Group of Atherosclerosis and Vascular biology is to provide guidance for the next steps to be taken from pre-clinical studies on vascularization towards clinical application. To this end, the current state of knowledge in terms of therapeutic strategies for targeting vascularization in post-ischaemic disease is reviewed and discussed. A consensus statement is provided on how to optimize vascularization studies for the identification of suitable targets, the use of animal models of disease, and the analysis of novel delivery methods. [ABSTRACT FROM AUTHOR]

Conceptualizing tobacco dependence as a chronic relapsing condition suggests the need to use analytic strategies that reflect that premise. However, clinical trials for smoking cessation typically define the primary endpoint as a measure of abstinence at a single timepoint distal to the intervention, typically 3–12 months. This reinforces the concept of tobacco outcomes as a dichotomous state—one is, or is not, abstinent. Fortunately, there are several approaches available to handle longitudinal data that reflect the relapsing and remitting nature of tobacco use during treatment studies. In this paper, sponsored by the Society for Research on Nicotine and Tobacco's Treatment Research Network, we present an introductory overview of these techniques and their application in smoking cessation clinical trials. Topics discussed include models to examine abstinence outcomes (eg, trajectory models of abstinence, models for transitions in smoking behavior, models for time to event), models that examine reductions in tobacco use, and models to examine joint outcomes (eg, examining changes in the use of more than one tobacco product). Finally, we discuss three additional relevant topics (ie, heterogeneity of effects, handling missing data, and power and sample size) and provide summary information about the type of model that can be used based on the type of data collected and the focus of the study. We encourage investigators to familiarize themselves with these techniques and use them in the analysis of data from clinical trials of smoking cessation treatment. Implications Clinical trials of tobacco dependence treatment typically measure abstinence 3–12 months after participant enrollment. However, because smoking is a chronic relapsing condition, these measures of intervention success may not accurately reflect the common trajectories of tobacco abstinence and relapse. Several analytical techniques facilitate this type of outcome modeling. This paper is meant to be an introduction to these concepts and techniques to the global nicotine and tobacco research community including which techniques can be used for different research questions with visual summaries of which types of models can be used for different types of data and research questions. [ABSTRACT FROM AUTHOR]

Biostatistics plays a pivotal role in developing, interpreting and drawing conclusions from clinical, biological and epidemiological data. However, the improper application of statistical methods can lead to erroneous conclusions and misinterpretations. This paper provides a comprehensive examination of the most frequent mistakes encountered in the biostatistical analysis process. We identified and elucidated 10 common errors in biostatistical analysis. These include using the wrong metric to describe data, misinterpreting P -values, misinterpreting the 95% confidence interval, misinterpreting the hazard ratio as an index of prognostic accuracy, ignoring the sample size calculation, misinterpreting analysis by strata in randomized clinical trials, confusing correlation and causation, misunderstanding confounders and mediators, inadequately codifying variables during the data collection, and bias arising when group membership is attributed on the basis of future exposure in retrospective studies. We discuss the implications of these errors and propose some practical strategies to mitigate their impact. By raising awareness of these pitfalls, this paper aims to enhance the rigor and reproducibility of biostatistical analyses, thereby fostering more robust and reliable biomedical research findings. [ABSTRACT FROM AUTHOR]

It is becoming increasingly popular to elicit informative priors on the basis of historical data. Popular existing priors, including the power prior, commensurate prior, and robust meta-analytic predictive prior, provide blanket discounting. Thus, if only a subset of participants in the historical data are exchangeable with the current data, these priors may not be appropriate. In order to combat this issue, propensity score approaches have been proposed. However, these approaches are only concerned with the covariate distribution, whereas exchangeability is typically assessed with parameters pertaining to the outcome. In this paper, we introduce the latent exchangeability prior (LEAP), where observations in the historical data are classified into exchangeable and non-exchangeable groups. The LEAP discounts the historical data by identifying the most relevant subjects from the historical data. We compare our proposed approach against alternative approaches in simulations and present a case study using our proposed prior to augment a control arm in a phase 3 clinical trial in plaque psoriasis with an unbalanced randomization scheme. [ABSTRACT FROM AUTHOR]

There is a critical need for new pathways to develop antibacterial agents to treat life-threatening infections caused by highly resistant bacteria. Traditionally, antibacterial agents have been studied in noninferiority clinical trials that focus on one site of infection (eg, pneumonia, intra-abdominal infection). Conduct of superiority trials for infections caused by highly antibiotic-resistant bacteria represents a new, and as yet, untested paradigm for antibacterial drug development. We sought to define feasible trial designs of antibacterial agents that could enable conduct of superiority and organism-specific clinical trials. These recommendations are the results of several years of active dialogue among the white paper's drafters as well as external collaborators and regulatory officials. Our goal is to facilitate conduct of new types of antibacterial clinical trials to enable development and ultimately approval of critically needed new antibacterial agents. [ABSTRACT FROM AUTHOR]

The author discusses the article "Meta-Analysis for Surrogacy: Accelerated Failure Time (AFT) Models and Semi-Competing Risks Modeling," by D. Ghosh et al. He focuses on some issues raised by the methodology for trial-level surrogacy used in the paper. He restricts attention to oncology trials as their illustrative application is in oncology. He also argues on the recommendation by the authors not to use composite time-to-event endpoints in the trial.

Competing risks data are commonly encountered in randomized clinical trials and observational studies. This paper considers the situation where the ending statuses of competing events have different clinical interpretations and/or are of simultaneous interest. In clinical trials, often more than one competing event has meaningful clinical interpretations even though the trial effects of different events could be different or even opposite to each other. In this paper, we develop estimation procedures and inferential properties for the joint use of multiple cumulative incidence functions (CIFs). Additionally, by incorporating longitudinal marker information, we develop estimation and inference procedures for weighted CIFs and related metrics. The proposed methods are applied to a COVID‐19 in‐patient treatment clinical trial, where the outcomes of COVID‐19 hospitalization are either death or discharge from the hospital, two competing events with completely different clinical implications. [ABSTRACT FROM AUTHOR]

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program's goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science. [ABSTRACT FROM AUTHOR]

The article presents the recommended design features of future clinical trials of antibacterial agents for community-acquired pneumonia (CAP). The efficaciousness of new antibiotics for the treatment of CAP has been assessed and compared with that of established antibiotics in noninferiority clinical trials. But the U.S. Food and Drug Administration is reassessing the appropriateness of a noninferiority trial design for CAP. Based on the pertinent data, there is a definitive and substantial treatment effect of antibiotic therapy for CAP. The evidence supporting a treatment effect of antibiotics includes higher mortality rates among patients with CAP, immediate decline in the mortality due to CAP, higher rates of treatment failure among patients infected with organisms and many others.

We provide commentary on the paper by Willi Maurer, Frank Bretz, and Xiaolei Xun entitled, "Optimal test procedures for multiple hypotheses controlling for the familywise expected loss." The authors provide an excellent discussion of the multiplicity problem in clinical trials and propose a novel approach based on a decision‐theoretic framework that incorporates loss functions that can vary across multiple hypotheses in a family. We provide some considerations for the practical use of the authors' proposed methods as well as some alternative methods that may also be of interest in this setting. [ABSTRACT FROM AUTHOR]

Multistate process data are common in studies of chronic diseases such as cancer. These data are ideal for precision medicine purposes as they can be leveraged to improve more refined health outcomes, compared to standard survival outcomes, as well as incorporate patient preferences regarding quantity versus quality of life. However, there are currently no methods for the estimation of optimal individualized treatment rules with such data. In this paper, we propose a nonparametric outcome weighted learning approach for this problem in randomized clinical trial settings. The theoretical properties of the proposed methods, including Fisher consistency and asymptotic normality of the estimated expected outcome under the estimated optimal individualized treatment rule, are rigorously established. A consistent closed‐form variance estimator is provided and methodology for the calculation of simultaneous confidence intervals is proposed. Simulation studies show that the proposed methodology and inference procedures work well even with small‐sample sizes and high rates of right censoring. The methodology is illustrated using data from a randomized clinical trial on the treatment of metastatic squamous‐cell carcinoma of the head and neck. [ABSTRACT FROM AUTHOR]

Recurrent events are often important endpoints in randomized clinical trials. For example, the number of recurrent disease‐related hospitalizations may be considered as a clinically meaningful endpoint in cardiovascular studies. In some settings, the recurrent event process may be terminated by an event such as death, which makes it more challenging to define and estimate a causal treatment effect on recurrent event endpoints. In this paper, we focus on the principal stratum estimand, where the treatment effect of interest on recurrent events is defined among subjects who would be alive regardless of the assigned treatment. For the estimation of the principal stratum effect in randomized clinical trials, we propose a Bayesian approach based on a joint model of the recurrent event and death processes with a frailty term accounting for within‐subject correlation. We also present Bayesian posterior predictive check procedures for assessing the model fit. The proposed approaches are demonstrated in the randomized Phase III chronic heart failure trial PARAGON‐HF (NCT01920711). [ABSTRACT FROM AUTHOR]

Aims There has been an increased interest in studying the association between microbial communities and different diseases and in discovering microbiome biomarkers. This association is pivotal to discover such biomarkers. In this paper, we present a unified modelling approach that can be used to detect and develop microbiome biomarkers for different clinical responses of interest at different levels of the microbiome ecosystem. Methods and results We extended the methodology rooted in the information theory and joint modelling approaches for the evaluation of surrogate endpoints in randomized clinical trials to the high-dimensional microbiome setting. The unified modelling approach introduced in this paper allows for detecting biomarkers associated with a clinical response of interest, adjusting for the intervention applied to the subjects. For some microbiome features, the association is driven by the treatment, while for others, the association reflects the correlation between the microbiome biomarker and the clinical response of interest. Conclusions The results have demonstrated that biomarkers can be identified at different levels of the microbiome phylogenetic tree using various measures as biomarkers. [ABSTRACT FROM AUTHOR]

Despite progress in antimicrobial drug development, a critical need persists for new, feasible pathways to develop antibacterial agents to treat people infected with drug-resistant bacteria. Infections due to resistant gram-negative bacilli continue to cause unacceptable morbidity and mortality rates. Antibacterial agents have been historically studied in noninferiority clinical trials that focus on a single site of infection (eg, complicated urinary tract infections, intra-abdominal infections), yet these designs may not be optimal, and often are not feasible, for study of infections caused by drug-resistant bacteria. Over the past several years, multiple stakeholders have worked to develop consensus regarding paths forward with a goal of facilitating timely conduct of antimicrobial development. Here we advocate for a novel and pragmatic approach and, toward this end, present feasible trial designs for antibacterial agents that could enable conduct of narrow-spectrum, organism-specific clinical trials and ultimately approval of critically needed new antibacterial agents. [ABSTRACT FROM AUTHOR]

Pronounced disparities exist in detecting and treating breast cancer in women with disabilities, leading to cancer detection at advanced stages. This paper provides an overview of disparities for women with disabilities related to breast cancer screening and care, primarily focusing on clinically significant mobility disabilities. Current care gaps include screening barriers related to accessibility and inequitable treatment options, with race and ethnicity, socioeconomic status, geographic location, and disability severity factors mediating the disparities for this population. The reasons for these disparities are myriad and stem from both system-level deficiencies and individual-level clinician bias. Although structural changes are warranted, individual healthcare professionals must also be incorporated into the requisite change. Intersectionality is critical to disparities and inequities and should be central to any discussion of strategies for improving care for people with disabilities, many of whom have intersectional identities. Efforts to reduce screening rate disparities for breast cancer in women with mobility-related disabilities should start with improving accessibility through removing structural barriers, establishing comprehensive accessibility standards, and addressing healthcare professional bias. Future interventional studies are needed to implement and assess the value of programs to improve breast cancer screening rates in women with disabilities. Increasing the representation of women with disabilities in clinical trials may provide another avenue for reducing treatment disparities because these trials often provide breakthrough treatment to women with cancer diagnosed at later stages. Ultimately, attention to the specific needs of patients with disabilities should be improved across the United States to promote inclusive and effective cancer screening and treatment. [ABSTRACT FROM AUTHOR]

When there is a predictive biomarker, enrichment can focus the clinical trial on a benefiting subpopulation. We describe a two‐stage enrichment design, in which the first stage is designed to efficiently estimate a threshold and the second stage is a "phase III‐like" trial on the enriched population. The goal of this paper is to explore design issues: sample size in Stages 1 and 2, and re‐estimation of the Stage 2 sample size following Stage 1. By treating these as separate trials, we can gain insight into how the predictive nature of the biomarker specifically impacts the sample size. We also show that failure to adequately estimate the threshold can have disastrous consequences in the second stage. While any bivariate model could be used, we assume a continuous outcome and continuous biomarker, described by a bivariate normal model. The correlation coefficient between the outcome and biomarker is the key to understanding the behavior of the design, both for predictive and prognostic biomarkers. Through a series of simulations we illustrate the impact of model misspecification, consequences of poor threshold estimation, and requisite sample sizes that depend on the predictive nature of the biomarker. Such insight should be helpful in understanding and designing enrichment trials. [ABSTRACT FROM AUTHOR]

The existing methods for subgroup analysis can be roughly divided into two categories: finite mixture models (FMM) and regularization methods with an ℓ1‐type penalty. In this paper, by introducing the group centers and ℓ2‐type penalty in the loss function, we propose a novel center‐augmented regularization (CAR) method; this method can be regarded as a unification of the regularization method and FMM and hence exhibits higher efficiency and robustness and simpler computations than the existing methods. In particular, its computational complexity is reduced from the O(n2)$O(n^2)$ of the conventional pairwise‐penalty method to only O(nK)$O(nK)$, where n is the sample size and K is the number of subgroups. The asymptotic normality of CAR is established, and the convergence of the algorithm is proven. CAR is applied to a dataset from a multicenter clinical trial, Buprenorphine in the Treatment of Opiate Dependence; a larger R2 is produced and three additional significant variables are identified compared to those of the existing methods. [ABSTRACT FROM AUTHOR]

Randomized clinical trials with time‐to‐event endpoints are frequently stopped after a prespecified number of events has been observed. This practice leads to dependent data and nonrandom censoring, which can in general not be solved by conditioning on the underlying baseline information. In case of staggered study entry, matters are complicated substantially. The present paper demonstrates that the study design at hand entails general independent censoring in the counting process sense, provided that the analysis is based on study time information only. To illustrate that the filtrations must not use abundant information, we simulated data of event‐driven trials and evaluated them by means of Cox regression models with covariates for the calendar times. The Breslow curves of the cumulative baseline hazard showed considerable deviations, which implies that the analysis is disturbed by conditioning on the calendar time variables. A second simulation study further revealed that Efron's classical bootstrap, unlike the (martingale‐based) wild bootstrap, may lead to biased results in the given setting, as the assumption of random censoring is violated. This is exemplified by an analysis of data on immunotherapy in patients with advanced, previously treated nonsmall cell lung cancer. [ABSTRACT FROM AUTHOR]

In 2005, an applied theatre community outreach programme was launched to address low levels of HIV/AIDS awareness among farm workers in the Cape Winelands of South Africa. In cooperation with HIV testing organizations, the Lucky , the Hero mini-musical promoted regular HIV testing, condom use and acceptance of people living with HIV until being retired in 2017. Applying principles of the health belief model to interview data collected in 2015 from former Lucky, the Hero participants, this paper examines the effectiveness of the theatre production to achieve the behavioural outcomes of (i) encouraging regular HIV testing and ongoing awareness of HIV serostatus, and (ii) reducing AIDS-related social stigma. The findings suggest that the interventions were successful in persuading participants to know their HIV status immediately following the shows, as well as potentially contributing to a reduction of community-based external social stigma. However, the interventions were unable to maintain engagement with these behavioural outcomes in the years following the performances, resulting in low adherence to regular HIV testing and inconsistent condom use. Additionally, ongoing social and structural barriers to regular HIV testing and the potential for self-imposed HIV-related stigma were highlighted during the discussions. While applied theatre can be an effective avenue for HIV awareness and prevention, the paper demonstrates the importance of creating and maintaining strong community networks to support continued engagement with health-related behavioural outcomes. [ABSTRACT FROM AUTHOR]

The discussions of our paper provide insights into the practical considerations of the latent exchangeability prior while also highlighting further extensions. In this rejoinder, we briefly summarize the discussions and provide comments. [ABSTRACT FROM AUTHOR]

Jeffries et al. (2018) investigated testing for a treatment difference in the setting of a randomized clinical trial with a single outcome measured longitudinally over a series of common follow‐up times while adjusting for covariates. That paper examined the null hypothesis of no difference at any follow‐up time versus the alternative of a difference for at least one follow‐up time. We extend those results here by considering multivariate outcome measurements, where each individual outcome is examined at common follow‐up times. We consider the case where there is interest in first testing for a treatment difference in a global function of the outcomes (e.g., weighted average or sum) with subsequent interest in examining the individual outcomes, should the global function show a treatment difference. Testing is conducted for each follow‐up time and may be performed in the setting of a group sequential trial. Testing procedures are developed to determine follow‐up times for which a global treatment difference exists and which individual combinations of outcome and follow‐up time show evidence of a difference while controlling for multiplicity in outcomes, follow‐up, and interim analyses. These approaches are examined in a study evaluating the effects of tissue plasminogen activator on longitudinally obtained stroke severity measurements. [ABSTRACT FROM AUTHOR]

Temporal changes exist in clinical trials. Over time, shifts in patients' characteristics, trial conduct, and other features of a clinical trial may occur. In typical randomized clinical trials, temporal effects, that is, the impact of temporal changes on clinical outcomes and study analysis, are largely mitigated by randomization and usually need not be explicitly addressed. However, temporal effects can be a serious obstacle for conducting clinical trials with complex designs, including the adaptive platform trials that are gaining popularity in recent medical product development. In this paper, we introduce a Bayesian robust prior for mitigating temporal effects based on a hidden Markov model, and propose a particle filtering algorithm for computation. We conduct simulation studies to evaluate the performance of the proposed method and provide illustration examples based on trials of Ebola virus disease therapeutics and hemostat in vascular surgery. [ABSTRACT FROM AUTHOR]

Identifying effective and valid surrogate markers to make inference about a treatment effect on long‐term outcomes is an important step in improving the efficiency of clinical trials. Replacing a long‐term outcome with short‐term and/or cheaper surrogate markers can potentially shorten study duration and reduce trial costs. There is sizable statistical literature on methods to quantify the effectiveness of a single surrogate marker. Both parametric and nonparametric approaches have been well developed for different outcome types. However, when there are multiple markers available, methods for combining markers to construct a composite marker with improved surrogacy remain limited. In this paper, building on top of the optimal transformation framework of Wang et al. (2020), we propose a novel calibrated model fusion approach to optimally combine multiple markers to improve surrogacy. Specifically, we obtain two initial estimates of optimal composite scores of the markers based on two sets of models with one set approximating the underlying data distribution and the other directly approximating the optimal transformation function. We then estimate an optimal calibrated combination of the two estimated scores which ensures both validity of the final combined score and optimality with respect to the proportion of treatment effect explained by the final combined score. This approach is unique in that it identifies an optimal combination of the multiple surrogates without strictly relying on parametric assumptions while borrowing modeling strategies to avoid fully nonparametric estimation which is subject to the curse of dimensionality. Our identified optimal transformation can also be used to directly quantify the surrogacy of this identified combined score. Theoretical properties of the proposed estimators are derived, and the finite sample performance of the proposed method is evaluated through simulation studies. We further illustrate the proposed method using data from the Diabetes Prevention Program study. [ABSTRACT FROM AUTHOR]

Background Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective. Methods A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021. Results Of 2838 articles screened, 276 were reviewed in full. A total of 15 046 challenged participants were described in 308 studies that met inclusion criteria; 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies that reported on SAEs, 0.2% of participants experienced at least 1 challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. Eighty percent of studies published after 2010 were registered in a trials database. Conclusions HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Following cardiac surgery, postoperative cognitive decline (POCD) is a common complication that can impair the quality of life and increase mortality. The aim of this study was to investigate whether early postoperative cognitive training can decrease POCD after cardiac surgery. METHODS The study was a multi-centred, two-arm, randomized (1:1 ratio), controlled trial involving older patients undergoing elective heart valve surgery with extracorporeal circulation. Recruitment took place at the Department of Cardiac Surgery of the Kerckhoff-Clinic in Bad Nauheim (Germany) and the University-Hospital in Giessen (Germany). The patients were randomized to either a paper-and-pencil-based cognitive training group or a standard rehabilitation care control group. The cognitive training started 1 week after surgery and lasted about 3 weeks until discharge from rehabilitation. To detect POCD, neuropsychological functions were assessed prior to surgery, upon discharge from rehabilitation (primary outcome), and 3 months after discharge (secondary outcome). Data were primarily analysed in a per-protocol fashion. RESULTS The frequency of POCD at discharge from rehabilitation (training group, n  = 37; control group, n  = 44) was 50% in the control group and 19% in the training group (χ2[1] = 8.45, P  = 0.004; odds ratio = 4.29, 95% confidence interval [1.56–11.80]). Three months after the cognitive training (training group, n  = 33; control group, n  = 34), POCD frequency was 29% in the control group and 6% in the training group (χ2[1] = 6.21, P  = 0.013; odds ratio = 6.46, 95% confidence interval [1.29–32.28]). CONCLUSIONS Since our cognitive training showed beneficial effects, it could be a promising method to prevent POCD. [ABSTRACT FROM AUTHOR]

Background: Tissue adhesive, adhesive tape, and sutures are used to close surgical incisions. However, it is unclear which produces the best results in children, and whether combination wound closure is better than sutures alone. Methods: In this parallel randomised controlled trial (ANZCTR: ACTRN12617000158369), children (aged 18 years or less) undergoing elective general surgical or urological procedures were randomized to skin closure with sutures alone, sutures and adhesive tape, or sutures and tissue adhesive. Participants were assessed 2 weeks, 6 weeks, and more than 6 months after operation. Outcomes included wound cosmesis (clinician- and parent-rated) assessed using four validated scales, parental satisfaction, and wound complication rates. Results: 295 patients (333 wounds) were recruited and 277 patients (314 wounds) were included in the analysis. Tissue adhesive wounds had poorer cosmesis at 6 weeks: median 10-point VAS score 7.7 with sutures alone, 7.5 with adhesive tape, and 7.0 with tissue adhesive (P=0.014). Respective median scores on a 100-point VAS were 80.0, 77.2, and 73.8 (P=0.010). This difference was not sustained at over 6 months. There was no difference in parent-rated wound cosmesis at 6 weeks (P=0.690) and more than 6 months (P=0.167): median score 9.0 with sutures alone, 10.0 with adhesive tape, and 10.0 with tissue adhesive at both stages. Parental satisfaction was similar at all points, with a median score of 5 (very satisfied) for all groups. There was one instance of wound dehiscence in the tissue adhesive group and no wound infections. Conclusion: Short-term wound cosmesis was poorer with tissue adhesive although it is unclear whether this difference is sustained in the long-term. There were no differences between techniques for the study outcomes. [ABSTRACT FROM AUTHOR]

Although Boorse's and Wakefield's accounts of health are generally regarded as competing ones, they are in fact so only if they are aimed at the same concept. Some remarks made by Boorse and Wakefield, however, leave it unclear whether they are. On one possible interpretation, Boorse's account aims at analysing a theoretical concept of abnormality, which ought to be distinguished from a more clinical or therapeutic concept, whereas Wakefield's account aims at analysing a clinical or therapeutic concept. The debate between Boorse and Wakefield would then either be merely terminological, or would boil down to whether Boorse is correct to assert the existence of a theoretical concept of abnormality which ought to be distinguished from a clinical or therapeutic one. This paper aims to clarify what is at stake between Boorse and Wakefield, by maintaining that their accounts are most plausibly interpreted as both being aimed towards a theoretical concept of abnormality. [ABSTRACT FROM AUTHOR]

Primary cicatricial alopecia (PCA), also known as scarring alopecia, comprises a diverse group of hair disorders that cause permanent destruction of the pilosebaceous unit, resulting in disappearance of the follicular ostia. Lichen planopilaris (LPP) is a subtype of primary lymphocytic cicatricial alopecia. There is an urgent need to identify novel molecules that successfully target specific pathogenic pathways in LPP to inhibit and reverse disease progression. Recent studies into LPP pathogenesis have discovered that follicular stem cells undergo epithelial–mesenchymal transition (EMT). We sought to identify drugs that target molecules involved in EMT to repurpose these drugs for treatment of LPP. We identified 8 molecules and 15 drugs that target these EMT molecules. Only four of these drugs (pioglitazone, tofacitinib, barcitinib and apremilast) have been reported in individual cases or case series of patients with LPP and controlled studies are missing. We describe each drug and mechanism of action target EMT in detail. Although previous studies have demonstrated the efficacy of EMT inhibitors in anticancer therapy, there are, to our knowledge, no studies using EMT‐attenuating drugs for the treatment of LPP. The treatment molecules discussed in this paper provide a new platform for clinical studies and controlled trials in LPP. [ABSTRACT FROM AUTHOR]

Summary: This study summarizes the use, since its inception, of the Cutaneous Lupus Disease Area and Severity Index (CLASI) as an outcome measure in clinical studies. We systematically searched the MEDLINE, PubMed, EMBASE and Cochrane databases for papers including the term 'cutaneous lupus disease area and severity index' and its abbreviations up to August 2017, identifying 205 abstracts. Following shortlisting, two independent physicians critically reviewed 71 papers for data extraction. We found that a limited number of high‐quality studies used the CLASI scoring as an outcome measure. We concluded that further validation is necessary to identify the effectiveness of the CLASI in the assessment of cutaneous lupus erythematosus subtypes. The use of standardized core patient‐ and physician‐reported outcome measures may reduce heterogeneity and allow comparisons between patients enrolled in clinical trials. This would improve the relevance within clinical practice, where the use of CLASI is currently limited. [ABSTRACT FROM AUTHOR]

This article discusses the importance of appropriate statistical analysis and reporting in randomized clinical trial (RCT) reports. The British Journal of Dermatology (BJD) has implemented initiatives to enhance the quality of published papers, including more detailed statistical guidelines and a dedicated statistics section in the editorial team. The article presents an analysis of 55 RCT reports submitted to the BJD, focusing on the statistical concerns raised during the peer review process. The analysis reveals that some reports had no statistical comments, while others were rejected due to major statistical concerns. Issues included flaws in study design, analysis and reporting, and interpretations not supported by the study results. The majority of manuscripts were considered unsuitable for publication without revision, but authors were given the opportunity to make changes. The article emphasizes the importance of adhering to BJD guidelines for reporting RCT results to enhance clarity and understanding. [Extracted from the article]

In this paper we bring together ethnographic research carried out during two clinical prevention trials to explore identities, relations and political imaginations that were brought to life by these different technologies. We highlight the ways in which critical anthropological engagement in clinical trials can help us radically reconsider the parameters and standards of medical research. In the paper we analyse the very different circumstances that made these two trials possible, highlighting the different temporalities and politics of HIV and Ebola as epidemics. We then describe four themes revealed by ethnographic research with participants and their communities but mediated by the specific sociopolitical contexts in which the trials were taking place. In both countries we found materiality and notions of exchange to be important to participants' understanding of the value of medical research and their role within it. These dynamics were governed through social relations and moral economies that also underpinned challenges to Western notions of research ethics. The clinical trials offered a language to express both disaffection and disillusionment with the political status quo (often through rumours and anxieties) while at the same time setting the foundations for alternative visions of citizenship. Attached to these were expressions of 'uncertainty and hope' steeped in locally distinctive notions of destiny and expectations of the future. [ABSTRACT FROM AUTHOR]

We examined the importance of understanding and incorporating cultural context within Aotearoa/New Zealand when engaging in clinical research and practice. This paper reports on the qualitative findings of a mixed methods study aimed at determining what effect a cardiac risk reduction exercise and lifestyle management programme, embedded within a kaupapa Māori methodological approach, had on Māori participants. This methodology saw participants able to redevelop a western model cardiac risk reduction programme by introducing a Māori worldview. Our study revealed how the kaupapa Māori approach empowered participants to examine and evaluate not only their own health and lifestyle choices, but those of family and the wider community. Combining biomedical and kaupapa Māori components into the programme was found to benefit participants' mental, physical, spiritual and family well-being. [ABSTRACT FROM AUTHOR]

Background Older people experience multiple barriers to enrolment in clinical trials. Caregivers play an important role in supporting patients with Parkinson's disease. Understanding the experiences of patients and caregivers who participate in trials is important to inform the design of future studies and identify problems with recruitment and retention. Objective To systematically review and synthesize qualitative studies exploring the experiences of participating in clinical trials from the perspectives of patients with Parkinson's disease and their caregivers. Methods Two reviewers independently searched the following databases: MEDLINE, Embase, PsycInfo, Cochrane, and CINAHL. The reference lists of all selected papers were screened for additional studies. Articles meeting predefined eligibility criteria were included in the synthesis. Methodological quality of each study was assessed using the Critical Appraisal Skills Programme (CASP) Qualitative Checklist. Included study findings were synthesized using the principles of thematic analysis. Results Eleven studies were included. Five key themes were identified: positive experiences of participating in research, assessment completion, motivators, enablers, and barriers. Positive experiences of participating in studies were linked to social interaction with other patients, building trust with the researchers, and expertise of the research team. Conclusions This review supports literature highlighting the important role of caregivers in supporting patients with Parkinson's disease. Future studies are needed to further examine their perspectives on participating in research. [ABSTRACT FROM AUTHOR]

Ulipristal acetate (UPA) is a medical treatment for uterine fibroids and was authorized for surgical pre-treatment in 2012 after the conduct of the PEARL I and II randomized controlled trials and for intermittent treatment after the observational PEARL III and IV trials. However, UPA came into disrepute due to its temporary suspension in 2017 and 2020 because of an apparent association with liver injury. This clinical opinion paper aims to review the process of marketing authorization and implementation of UPA, in order to provide all involved stakeholders with recommendations for the introduction of future drugs. Before marketing authorization, the European Medicines Agency (EMA) states that Phase III registration trials should evaluate relevant outcomes in a representative population, while comparing to gold-standard treatment. This review shows that the representativeness of the study populations in all PEARL trials was limited, surgical outcomes were not evaluated and intermittent treatment was assessed without comparative groups. Implementation into clinical practice was extensive, with 900 000 prescribed treatment cycles in 5 years in Europe and Canada combined. Extremely high costs are involved in developing and evaluating pre-marketing studies in new drugs, influencing trial design and relevance of chosen outcomes, thereby impeding clinical applicability. It is vitally important that the marketing implementation after authorization is regulated in such way that necessary evidence is generated before widespread prescription of a new drug. All stakeholders, from pharmaceutical companies to authorizing bodies, governmental funding bodies and medical professionals should be aware of their role and take responsibility for their part in this process. [ABSTRACT FROM AUTHOR]

Background: Changes in tobacco products, use patterns, and assessment technology in the last 15 years led the Society for Research on Nicotine and Tobacco (SRNT) Treatment Research Network to call for an update to the 2003 SRNT recommendations for assessing abstinence in clinical trials of smoking cessation interventions.Methods: The SRNT Treatment Research Network convened a group of investigators with decades of experience in conducting tobacco treatment clinical trials. To arrive at the updated recommendations, the authors reviewed the recommendations of the prior SRNT Workgroup as well as current literature. Ten additional experts in the field provided feedback on this paper and these recommendations.Results: With respect to defining abstinence, the authors recommend: (1) continuing to use the definition of no use of combustible tobacco products (regardless of use of noncombustible tobacco products [e.g., snus] and alternative products [e.g., e-cigarettes]) and collecting additional data to permit alternate abstinence definitions; (2) no use of combustible or smokeless tobacco products; and (3) no use of combustible or smokeless tobacco products or alternative products, as appropriate for the research question being addressed. The authors also recommend reporting point prevalence and prolonged abstinence at multiple timepoints (end of treatment, ≥3 months after the end of treatment, and ≥6 months postquit or posttreatment initiation).Conclusions: Defining abstinence requires specification of which products a user must abstain from using, the type of abstinence (i.e., point prevalence or continuous), and the duration of abstinence. These recommendations are intended to serve as guidelines for investigators as they collect the necessary data to accurately describe participants' abstinence during smoking cessation clinical trials.Implications: This paper provides updated recommendations for defining abstinence in the context of smoking cessation treatment clinical trials. [ABSTRACT FROM AUTHOR]

Background and Objectives Many investigators of Alzheimer's disease and related dementias (AD/ADRD) are unfamiliar with the embedded pragmatic clinical trials (ePCTs) and the indispensable pilot phase preceding ePCTs. This paper provides a much-needed example for such a pilot phase and discusses implementation barriers and additional infrastructure and implementation strategies developed in preparation for a nationwide AD/ADRD ePCT. Research Design and Methods Two pilot trials were conducted in 2 hospices sequentially to refine and test Aliviado Dementia Care—Hospice Edition, a complex quality improvement intervention for advanced dementia symptom management. Readiness for the subsequent full-scale ePCT was assessed by three milestones: ≥80% training completion rate ("feasibility"), ≥80% posttraining survey respondents indicating intention for practice changes ("applicability"), and at least 1 Aliviado care plan/assessment instrument administered in ≥75% of dementia patients admitted to home hospice within 1-month posttraining ("fidelity"). Results Participants included 72 interdisciplinary team members and 11 patients with AD/ADRD across the pilots. Feasibility, applicability, and fidelity outcomes (92%, 93%, and 100%, respectively) all surpassed the preestablished milestones (80%, 80%, and 75%). Main implementation challenges were related to hospice staff turnover, integration of the Aliviado toolbox materials within the electronic health records, and hospices' limited research experience and infrastructure. Discussion and Implications This pilot phase demonstrated feasibility, applicability, and fidelity required to proceed to the full-scale ePCT. Our study findings and discussions of additional infrastructure and implementation strategies developed following the pilot phase can inform researchers and clinicians interested in conducting AD/ADRD-related pilot studies for ePTCs or quality improvement initiatives. Clinical Trials Registration Number NCT03681119 [ABSTRACT FROM AUTHOR]

The use of probiotics to improve health via the modulation of gut microbiota has gained wide attention. The growing volume of investigations of probiotic microorganisms and commercialized probiotic products has created the need for a database to organize the health-promoting functions driven by probiotics reported in academic articles, clinical trials and patents. We constructed ProBioQuest to collect up-to-date literature related to probiotics from PubMed.gov, ClinicalTrials.gov and PatentsView. More than 2.8 million articles have been collected. Automated information technology-assisted procedures enabled us to collect the data continuously, providing the most up-to-date information. Statistical functions and semantic analyses are provided on the website as an advanced search engine, which contributes to the semantic tool of this database for information search and analyses. The semantic analytical output provides categorized search results and functions to enhance further analysis. A keyword bank is included which can display multiple tables of contents. Users can select keywords from different displayed categories to achieve easily filtered searches. Additional information on the searched items can be browsed via the link-out function. ProBioQuest is not only useful to scientists and health professionals but also to dietary supplement manufacturers and the general public. In this paper, the method we used to build this database-web system is described. Applications of ProBioQuest for several literature-based analyses of probiotics are included as examples of the various uses of this search engine. ProBioQuest can be accessed free of charge at http://kwanlab.bio.cuhk.edu.hk/PBQ/. Database URL http://kwanlab.bio.cuhk.edu.hk/PBQ/ [ABSTRACT FROM AUTHOR]

The utilization of surrogate markers offers the opportunity to reduce the length of required follow‐up time and/or costs of a randomized trial examining the effectiveness of an intervention or treatment. There are many available methods for evaluating the utility of a single surrogate marker including both parametric and nonparametric approaches. However, as the dimension of the surrogate marker increases, a completely nonparametric procedure becomes infeasible due to the curse of dimensionality. In this paper, we define a quantity to assess the value of multiple surrogate markers in a time‐to‐event outcome setting and propose a robust estimation approach for censored data. We focus on surrogate markers that are measured at some landmark time, t0, which occurs earlier than the end of the study. Our approach is based on a dimension reduction procedure with an option to incorporate weights to guard against potential misspecification of the working model, resulting in three different proposed estimators, two of which can be shown to be double robust. We examine the finite sample performance of the estimators under various scenarios using a simulation study. We illustrate the estimation and inference procedures using data from the Diabetes Prevention Program (DPP) to examine multiple potential surrogate markers for diabetes. [ABSTRACT FROM AUTHOR]

Summary: Background: Frontal fibrosing alopecia (FFA) has become one of the most common causes of cicatricial alopecia worldwide. However, there is a lack of clear aetiology and robust clinical trial evidence for the efficacy and safety of agents currently used for treatment. Objectives: To enable data to be collected worldwide on FFA using common criteria and assessment methods. Methods: A multicentre, international group of experts in hair loss was convened by email to create consensus recommendations for clinical trials. Consensus was defined at > 90% agreement on each recommended part of these guidelines. Results: Standardized diagnostic criteria, severity rating, staging, and investigator and patient assessment of scalp hair loss and other clinical features of FFA were created. Conclusions: These guidelines should allow the collection of reliable aggregate data on FFA and advance efforts in both clinical and basic research to close knowledge gaps in this condition. What is already known about this topic? Frontal fibrosing alopecia (FFA) is a common psychologically debilitating progressive type of hair loss without a clear aetiology or treatments vetted by well‐controlled clinical trials. What does this study add? This paper provides methods for collecting meaningful data on FFA in clinical trials, databases and registries across the globe.These guidelines will promote clinical and basic research on well‐defined populations of patients affected with FFA and provide the means to assess the efficacy and safety of individual treatments. Linked Comment: M. Kinoshita‐Ise. Br J Dermatol 2021; 185: 1092–1093. Plain language summary available online [ABSTRACT FROM AUTHOR]

The number of operations that surgeons have previously performed is associated with their patients' outcomes. However, this association may not be causal, because previous studies have often been cross-sectional and their analyses have not considered time-varying confounding or positivity violations. In this paper, using the example of surgeons who perform coronary artery bypass grafting, we describe (hypothetical) target trials for estimation of the causal effect of the surgeons' operative volumes on patient mortality. We then demonstrate how to emulate these target trials using data from US Medicare claims and provide effect estimates. Our target trial emulations suggest that interventions on physicians' volume of coronary artery bypass grafting operations have little effect on patient mortality. The target trial framework highlights key assumptions and draws attention to areas of bias in previous observational analyses that deviated from their implicit target trials. The principles of the presented methodology may be adapted to other scenarios of substantive interest in health services research. [ABSTRACT FROM AUTHOR]

The article comments on the paper "Unpublished Clinical Trials of Common Rheumatic Diseases" by C. Pedersen and colleagues. Topics discussed include the examination of randomized clinical trials (RCTs) from the ClinicalTrials.gov database, the importance of publishing negative-result RCTs in Sjogren's syndrome and lupus, and reasons for the lack of publication of RCTs.

Introduction: Smoking rates are alarmingly high among young people experiencing homelessness (YEH), yet there are no evidence-based cessation programs for this population. This paper presents results from a pilot evaluation of a text messaging-based smoking cessation treatment, as an adjunct to brief group cessation counseling, to improve abstinence rates among 18-25-year-old smokers experiencing homelessness. The goal of this study was to estimate effect sizes for a larger trial and it was not powered to detect group differences.Aims and Methods: YEH smokers who had a working cell phone with them at recruitment were randomized to receive a group counseling session, nicotine patches, and written material on quitting (n = 37) or a similar program that also included a 6-week automated text messaging intervention (TMI) to provide ongoing support for quitting (n = 40). Smoking outcomes were evaluated through a 90-day follow-up.Results: Seven-day point prevalence abstinence at 90-day follow-up was higher in the TMI condition than standard condition (17.50% vs. 8.11%, respectively; Cohen's h = .37); however, the 90-day continuous abstinence rate was not statistically different from zero in either condition. Reductions in the number of days smoked in the past 30 days from baseline to follow-up were greater in the TMI condition than the standard condition (-14.24 vs. -8.62, respectively; Cohen's d = .49).Conclusions: Adding a 6-week TMI support to a brief group counseling and pharmacotherapy protocol holds promise for smoking reduction and abstinence among YEH smokers. Results indicate that further development and evaluation of the TMI in this population is warranted.Trial Registration: ClinicalTrials.gov Identifier NCT03874585. Registered March 14, 2019, https://clinicaltrials.gov/ct2/show/record/NCT03874585.Implications: This is the first study to evaluate the feasibility of using a text messaging-based intervention (TMI) for behavior change with 18-25 year olds experiencing homelessness, and more specifically, the first to test a TMI to provide ongoing support for smoking cessation. Small to medium effect sizes for the TMI are promising in terms of implementing a TMI using participants' own cell phones, as well as the efficacy of this approach as an adjunct to standard care (brief group counseling and pharmacotherapy) for smoking cessation among YEH. [ABSTRACT FROM AUTHOR]

Summary: Curcuma and its derivatives are associated with anti‐inflammatory and antioxidant activities in the skin. They exhibit beneficial effects in wound healing and prevention of chronic ultraviolet B damage and may prevent facial redness such as rosacea and flushing. This review aims to provide an up‐to‐date and rigorous synthesis of studies that demonstrated the clinical efficacy of curcuminoids in the skin. We evaluated studies published in the MEDLINE–PubMed/PMC (National Library of Medicine) databases, and followed Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines for this review. This search included papers published in the past 10 years in controlled clinical trials, double‐blind and randomized controlled studies, and case studies. The search resulted in 12 studies published in the past 10 years. Curcuma species (Curcuma longa and Curcuma aeruginosa) and curcumin were found to produce various dermatological effects, including influencing antioxidant and anti‐inflammatory processes in the production of hyaluronan, increasing skin moisture, and reducing axillary hair growth. Curcuma was also found to reduce thickness, erythema, pruritus, burning and pain in psoriasis lesions and to improve radiodermatitis lesions. Our review results show that Curcuma species may play a role in skin health management and may exhibit various dermatological effects, thus it could be a new therapeutic arsenal for dermatology professionals. Nevertheless, more clinical trials should be conducted with humans to establish the optimum delivery method and dosages for different dermatological conditions. Click here for the corresponding questions to this CME article. [ABSTRACT FROM AUTHOR]

Covariate‐adaptive randomization (CAR) is widely used in clinical trials to balance treatment allocation over covariates. Over the past decade, significant progress has been made on the theoretical properties of covariate‐adaptive design and associated inference. However, most results are established under the assumption that the covariates are correctly measured. In practice, measurement error is inevitable, resulting in misclassification for discrete covariates. When covariate misclassification is present in a clinical trial conducted using CAR, the impact is twofold: it impairs the intended covariate balance, and raises concerns over the validity of test procedures. In this paper, we consider the impact of misclassification on covariate‐adaptive randomized trials from the perspectives of both design and inference. We derive the asymptotic normality, and thereby the convergence rate, of the imbalance of the true covariates for a general family of covariate‐adaptive randomization methods, and show that a superior covariate balance can still be attained compared to complete randomization. We also show that the two sample t‐test is conservative, with a reduced Type I error, but that this can be corrected using a bootstrap method. Moreover, if the misclassified covariates are adjusted in the model used for analysis, the test maintains its nominal Type I error, with an increased power. Our results support the use of covariate‐adaptive randomization in clinical trials, even when the covariates are subject to misclassification. [ABSTRACT FROM AUTHOR]