Zinpentraxin Alfa for Idiopathic Pulmonary Fibrosis: The Randomized Phase III STARSCAPE Trial.

Rationale: A phase II trial reported clinical benefit over 28 weeks in patients with idiopathic pulmonary fibrosis (IPF) who received zinpentraxin alfa. Objectives: To investigate the efficacy and safety of zinpentraxin alfa in patients with IPF in a phase III trial. Methods: This 52-week phase III, double-blind, placebo-controlled, pivotal trial was conducted at 275 sites in 29 countries. Patients with IPF were randomized 1:1 to intravenous placebo or zinpentraxin alfa 10 mg/kg every 4 weeks. The primary endpoint was absolute change from baseline to Week 52 in FVC. Secondary endpoints included absolute change from baseline to Week 52 in percent predicted FVC and 6-minute walk distance. Safety was monitored via adverse events. Post hoc analysis of the phase II and phase III data explored changes in FVC and their impact on the efficacy results. Measurements and Main Results: Of 664 randomized patients, 333 were assigned to placebo and 331 to zinpentraxin alfa. Four of the 664 randomized patients were never administered study drug. The trial was terminated early after a prespecified futility analysis that demonstrated no treatment benefit of zinpentraxin alfa over placebo. In the final analysis, absolute change from baseline to Week 52 in FVC was similar between placebo and zinpentraxin alfa (-214.89 ml and -235.72 ml; P = 0.5420); there were no apparent treatment effects on secondary endpoints. Overall, 72.3% and 74.6% of patients receiving placebo and zinpentraxin alfa, respectively, experienced one or more adverse events. Post hoc analysis revealed that extreme FVC decline in two placebo-treated patients resulted in the clinical benefit of zinpentraxin alfa reported by phase II. Conclusions: Zinpentraxin alfa treatment did not benefit patients with IPF over placebo. Learnings from this program may help improve decision making around trials in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04552899).

Liver transplantation for acute liver failure and acute-on-chronic liver failure.

Acute liver failure (ALF) and acute-on-chronic liver (ACLF) are distinct phenotypes of liver failure and, thus, need to be compared and contrasted for appropriate management. There has been a significant improvement in the outcomes of these patients undergoing liver transplantation (LT). Survival post-LT for ALF and ACLF ranges between 90% and 95% and 80% and 90% at 1 year, futility criteria have been described in both ALF and ACLF where organ failures define survival. Plasma exchange and continuous renal replacement therapy may serve as bridging therapies. Identifying the futility of LT is as necessary as the utility of LT in patients with ALF and ACLF. The role of regenerative therapies such as granulocyte colony-stimulating factors in ACLF and hepatocyte and xenotransplantation in both conditions remains uncertain. Measures to increase the donor pool through increasing deceased donor transplants in Asian countries, living donations in Western countries, auxiliary liver transplants, and ABO-incompatible liver transplants are necessary to improve the survival of these patients. In this review, we discuss the similarities and differences in clinical characteristics and the timing and outcomes of LT for ALF and ACLF, briefly highlighting the role of bridging therapies and providing an overview of recent advances in the management of ALF and ACLF.

Bayesian hierarchical modeling in interim futility analysis for two parallel clinical trials.

Incorporating interim analysis into a trial design is gaining popularity in the field of confirmatory clinical trials, where two studies may be conducted in parallel (ie, twin studies) in order to provide substantial evidence per the requirement of FDA guidance. Interim futility analysis provides a chance to check for the "disaster" scenario when the treatment has a high probability to be not more efficacious than the control. Therefore, it is an efficient tool to mitigate risk of running a complete and expansive trial under such scenario. There is no agreement among trial designers that interim analysis should be based on individual study data or pooled data under the twin study scenario. In fact, it is a dilemma for most scientists when specifying the interim analysis strategy at the design stage as the true treatment effects of the twin studies are unknown no matter how similar they are intended to be. To address the issue, we developed a Bayesian hierarchical modeling method to allow dynamic data borrowing between twin studies and demonstrated a favorable characteristic of the new method over the separate and pooled analyses. We evaluated a wide spectrum of the heterogeneity hyperparameters and visualized its critical impact on the Bayesian model's characteristic. Based on the evaluation, we made a suggestion on the heterogeneity hyperparameter selection independent of any a priori knowledge. We also applied our method to a case study where predictive powers of different methods are compared.

Confidence intervals for odds ratio from multistage randomized phase II trials.

A multi-stage randomized trial design can significantly improve efficiency by allowing early termination of the trial when the experimental arm exhibits either low or high efficacy compared to the control arm during the study. However, proper inference methods are necessary because the underlying distribution of the target statistic changes due to the multi-stage structure. This article focuses on multi-stage randomized phase II trials with a dichotomous outcome, such as treatment response, and proposes exact conditional confidence intervals for the odds ratio. The usual single-stage confidence intervals are invalid when used in multi-stage trials. To address this issue, we propose a linear ordering of all possible outcomes. This ordering is conditioned on the total number of responders in each stage and utilizes the exact conditional distribution function of the outcomes. This approach enables the estimation of an exact confidence interval accounting for the multi-stage designs.

Development and Validation of Futility of Resuscitation Measure in Older Adult Trauma Patients.

INTRODUCTION: This study aimed to develop and validate Futility of Resuscitation Measure (FoRM) for predicting the futility of resuscitation among older adult trauma patients. METHODS: This is a retrospective analysis of the American College of Surgeons-Trauma Quality Improvement Program database (2017-2018) (derivation cohort) and American College of Surgeons level I trauma center database (2017-2022) (validation cohort). We included all severely injured (injury severity score >15) older adult (aged ≥60 y) trauma patients. Patients were stratified into decades of age. Injury characteristics (severe traumatic brain injury [Glasgow Coma Scale ≤ 8], traumatic brain injury midline shift), physiologic parameters (lowest in-hospital systolic blood pressure [≤1 h], prehospital cardiac arrest), and interventions employed (4-h packed red blood cell transfusions, emergency department resuscitative thoracotomy, resuscitative endovascular balloon occlusion of the aorta, emergency laparotomy [≤2 h], early vasopressor requirement [≤6 h], and craniectomy) were identified. Regression coefficient-based weighted scoring system was developed using the Schneeweiss method and subsequently validated using institutional database. RESULTS: A total of 5562 patients in derivation cohort and 873 in validation cohort were identified. Mortality was 31% in the derivation cohort and FoRM had excellent discriminative power to predict mortality (area under the receiver operator characteristic = 0.860; 95% confidence interval [0.847-0.872], P < 0.001). Patients with a FoRM score of >16 had a less than 10% chance of survival, while those with a FoRM score of >20 had a less than 5% chance of survival. In validation cohort, mortality rate was 17% and FoRM had good discriminative power (area under the receiver operator characteristic = 0.76; 95% confidence interval [0.71-0.80], P < 0.001). CONCLUSIONS: FoRM can reliably identify the risk of futile resuscitation among older adult patients admitted to our level I trauma center.

Identifying Factors Associated With Code Status Changes After Emergency General Surgery.

INTRODUCTION: Surgical emergencies are time sensitive. Identifying patients who may benefit from preoperative goals of care discussions is critical to ensuring that operative intervention aligns with the patient's values. We sought to identify patient factors associated with acute changes in a patient's goals using code status change (CSC) as proxy. METHODS: A retrospective analysis of single-institution data for patients undergoing urgent laparotomy was performed. Patients were stratified based on whether a postoperative CSC occurred. Parametric, nonparametric, and regression analyses were used to identify variables associated with CSC. RESULTS: Of 484 patients, 13.8% (n = 67) had a postoperative CSC. Patients with postoperative CSC were older (65 versus 60 years, P < 0.001). Odds of CSC were significantly higher in patients who were transferred between facilities (odds ratio [OR] 2.1), had a higher Charlson Comorbidity Index (3-4: OR 3.9, 5+: OR 6.8), and had a higher quick sequential organ failure assessment score (2: OR 5.0; 3: OR 38.7). Patients with anemia (OR 1.9) and active cancer (OR 3.0) had higher odds of CSC. CONCLUSIONS: Timely intervention in emergency general surgery may result in high-risk interventions and subsequent complications that do not align with a patient's goals and values. Our analysis identified a subset of patients who undergo surgery and have a postoperative CSC leading to transition to comfort-focused care. In these patients, a pause in clinical momentum may help ensure operative intervention remains goal concordant.

Optimal futility stopping boundaries for binary endpoints.

BACKGROUND: Group sequential designs incorporating the option to stop for futility at the time point of an interim analysis can save time and resources. Thereby, the choice of the futility boundary importantly impacts the design's resulting performance characteristics, including the power and probability to correctly or wrongly stop for futility. Several authors contributed to the topic of selecting good futility boundaries. For binary endpoints, Simon's designs (Control Clin Trials 10:1-10, 1989) are commonly used two-stage designs for single-arm phase II studies incorporating futility stopping. However, Simon's optimal design frequently yields an undesirably high probability of falsely declaring futility after the first stage, and in Simon's minimax design often a high proportion of the planned sample size is already evaluated at the interim analysis leaving only limited benefit in case of an early stop. METHODS: This work focuses on the optimality criteria introduced by Schüler et al. (BMC Med Res Methodol 17:119, 2017) and extends their approach to binary endpoints in single-arm phase II studies. An algorithm for deriving optimized futility boundaries is introduced, and the performance of study designs implementing this concept of optimal futility boundaries is compared to the common Simon's minimax and optimal designs, as well as modified versions of these designs by Kim et al. (Oncotarget 10:4255-61, 2019). RESULTS: The introduced optimized futility boundaries aim to maximize the probability of correctly stopping for futility in case of small or opposite effects while also setting constraints on the time point of the interim analysis, the power loss, and the probability of stopping the study wrongly, i.e. stopping the study even though the treatment effect shows promise. Overall, the operating characteristics, such as maximum sample size and expected sample size, are comparable to those of the classical and modified Simon's designs and sometimes better. Unlike Simon's designs, which have binding stopping rules, the optimized futility boundaries proposed here are not adjusted to exhaust the full targeted nominal significance level and are thus still valid for non-binding applications. CONCLUSIONS: The choice of the futility boundary and the time point of the interim analysis have a major impact on the properties of the study design. Therefore, they should be thoroughly investigated at the planning stage. The introduced method of selecting optimal futility boundaries provides a more flexible alternative to Simon's designs with non-binding stopping rules. The probability of wrongly stopping for futility is minimized and the optimized futility boundaries don't exhibit the unfavorable properties of an undesirably high probability of falsely declaring futility or a high proportion of the planned sample evaluated at the interim time point.

The BAR Score Predicts and Stratifies Outcomes Following Liver Retransplantation: Insights From a Retrospective Cohort Study.

Liver retransplantation (reLT) yields poorer outcomes than primary liver transplantation, necessitating careful patient selection to avoid futile reLT. We conducted a retrospective analysis to assess reLT outcomes and identify associated risk factors. All adult patients who underwent a first reLT at the Medical University of Innsbruck from 2000 to 2021 (N = 111) were included. Graft- and patient survival were assessed via Kaplan-Meier plots and log-rank tests. Uni- and multivariate analyses were performed to identify independent predictors of graft loss. Five-year graft- and patient survival rates were 64.9% and 67.6%, respectively. The balance of risk (BAR) score was found to correlate with and be predictive of graft loss and patient death. The BAR score also predicted sepsis (AUC 0.676) and major complications (AUC 0.720). Multivariate Cox regression analysis identified sepsis [HR 5.179 (95% CI 2.575-10.417), p < 0.001] as the most significant independent risk factor for graft loss. At a cutoff of 18 points, the 5 year graft survival rate fell below 50%. The BAR score, a simple and easy to use score available at the time of organ acceptance, predicts and stratifies clinically relevant outcomes following reLT and may aid in clinical decision-making.

Slowed canonical progress in large fields of science.

In many academic fields, the number of papers published each year has increased significantly over time. Policy measures aim to increase the quantity of scientists, research funding, and scientific output, which is measured by the number of papers produced. These quantitative metrics determine the career trajectories of scholars and evaluations of academic departments, institutions, and nations. Whether and how these increases in the numbers of scientists and papers translate into advances in knowledge is unclear, however. Here, we first lay out a theoretical argument for why too many papers published each year in a field can lead to stagnation rather than advance. The deluge of new papers may deprive reviewers and readers the cognitive slack required to fully recognize and understand novel ideas. Competition among many new ideas may prevent the gradual accumulation of focused attention on a promising new idea. Then, we show data supporting the predictions of this theory. When the number of papers published per year in a scientific field grows large, citations flow disproportionately to already well-cited papers; the list of most-cited papers ossifies; new papers are unlikely to ever become highly cited, and when they do, it is not through a gradual, cumulative process of attention gathering; and newly published papers become unlikely to disrupt existing work. These findings suggest that the progress of large scientific fields may be slowed, trapped in existing canon. Policy measures shifting how scientific work is produced, disseminated, consumed, and rewarded may be called for to push fields into new, more fertile areas of study.

Estimation of the odds ratio from multi-stage randomized trials.

A multi-stage design for a randomized trial is to allow early termination of the study when the experimental arm is found to have low or high efficacy compared to the control during the study. In such a trial, an early stopping rule results in bias in the maximum likelihood estimator of the treatment effect. We consider multi-stage randomized trials on a dichotomous outcome, such as treatment response, and investigate the estimation of the odds ratio. Typically, randomized phase II cancer clinical trials have two-stage designs with small sample sizes, which makes the estimation of odds ratio more challenging. In this paper, we evaluate several existing estimation methods of odds ratio and propose bias-corrected estimators for randomized multi-stage trials, including randomized phase II cancer clinical trials. Through numerical studies, the proposed estimators are shown to have a smaller bias and a smaller mean squared error overall.

Futility Interim Analysis Based on Probability of Success Using a Surrogate Endpoint.

In clinical trials with time-to-event data, the evaluation of treatment efficacy can be a long and complex process, especially when considering long-term primary endpoints. Using surrogate endpoints to correlate the primary endpoint has become a common practice to accelerate decision-making. Moreover, the ethical need to minimize sample size and the practical need to optimize available resources have encouraged the scientific community to develop methodologies that leverage historical data. Relying on the general theory of group sequential design and using a Bayesian framework, the methodology described in this paper exploits a documented historical relationship between a clinical "final" endpoint and a surrogate endpoint to build an informative prior for the primary endpoint, using surrogate data from an early interim analysis of the clinical trial. The predictive probability of success of the trial is then used to define a futility-stopping rule. The methodology demonstrates substantial enhancements in trial operating characteristics when there is a good agreement between current and historical data. Furthermore, incorporating a robust approach that combines the surrogate prior with a vague component mitigates the impact of the minor prior-data conflicts while maintaining acceptable performance even in the presence of significant prior-data conflicts. The proposed methodology was applied to design a Phase III clinical trial in metastatic colorectal cancer, with overall survival as the primary endpoint and progression-free survival as the surrogate endpoint.

Beta spending function based on conditional power in group sequential design.

Conditional power (CP) serves as a widely utilized approach for futility monitoring in group sequential designs. However, adopting the CP methods may lead to inadequate control of the type II error rate at the desired level. In this study, we introduce a flexible beta spending function tailored to regulate the type II error rate while employing CP based on a predetermined standardized effect size for futility monitoring (a so-called CP-beta spending function). This function delineates the expenditure of type II error rate across the entirety of the trial. Unlike other existing beta spending functions, the CP-beta spending function seamlessly incorporates beta spending concept into the CP framework, facilitating precise stagewise control of the type II error rate during futility monitoring. In addition, the stopping boundaries derived from the CP-beta spending function can be calculated via integration akin to other traditional beta spending function methods. Furthermore, the proposed CP-beta spending function accommodates various thresholds on the CP-scale at different stages of the trial, ensuring its adaptability across different information time scenarios. These attributes render the CP-beta spending function competitive among other forms of beta spending functions, making it applicable to any trials in group sequential designs with straightforward implementation. Both simulation study and example from an acute ischemic stroke trial demonstrate that the proposed method accurately captures expected power, even when the initially determined sample size does not consider futility stopping, and exhibits a good performance in maintaining overall type I error rates for evident futility.

Futile therapeutic nursing interventions in adult intensive care: A descriptive study.

Background: Despite the progress made in recent decades on the phenomenon of futility in adult intensive care, recognizing it during clinical care practice remains a complex and sensitive process, during which questions are often raised for which concrete answers are difficult to find. Aims: To analyze the frequency with which futile nursing interventions are implemented in critically ill patients admitted to adult intensive care in specific situations and how often futile autonomous and interdependent nursing interventions are implemented in the same population, as perceived by adult intensive care nurses. Research design: Cross-sectional, quantitative, and descriptive study, which employed a questionnaire constructed specifically for this research to assess the perception of therapeutic futility in nursing in adult intensive care. Following an evaluation of the psychometric properties, the questionnaire was made available in an electronic format on the EUSurvey platform between August and October 2024. The data was analyzed between November 2023 and March 2024 using the statistical software packages SPSS and R. Participants and research context: A simple random sample of nurses working in level II and level III intensive care units in Portugal. Ethical considerations: Research ethical approvals were obtained, and the participants provided informed consent. Findings/results: Four hundred and fourteen valid questionnaires were obtained. The results allow the identification of thirty-three statistically significant associations, the inference of intervals for the mean and median for the perception of futility of nursing interventions with a 95% confidence interval, and enable the hierarchization of nursing interventions implemented in critically ill patients admitted to adult intensive care units according to the nurses' perception of their futility. Conclusion: There is a balance in nurses' perception of the futility of their interventions in the specific situations analyzed. There is statistically significant evidence that interdependent nursing interventions are, in general, more frequently perceived as futile when compared to autonomous nursing interventions.

Withdrawal/Withholding of Life-Sustaining Therapies: Limitation of Therapeutic Effort in the Intensive Care Unit.

Background/Objectives: The change in critically ill patients makes limitation of therapeutic effort (LTE) a widespread practice when therapeutic goals cannot be achieved. We aimed to describe the application of LTE in a post-surgical Intensive Care Unit (ICU), analyze the measures used, the characteristics of the patients, and their evolution. Methods: Retrospective observational study, including all patients to whom LTE was applied in a postsurgical ICU between January 2021 and December 2022. The LTE defined were brain death, withdrawal of measures, and withholding. Withholding limitations included orders for no cardiopulmonary resuscitation, no orotracheal intubation, no reintubation, no tracheostomy, no renal replacement therapies, and no vasoactive support. Patient and ICU admission data were related to the applied LTE. Results: Of the 2056 admitted, LTE protocols were applied to 106 patients. The prevalence of LTE in the ICU was 5.1%. Data were analyzed in 80 patients. A total of 91.2% of patients had been admitted in an emergency situation, and 56.2% had been admitted after surgery. The most widespread limitation was treatment withholding (83.8%) compared to withdrawal (13.8%). No differences were found regarding who made the decision and the type of limitation employed. However, patients with the limitation of no intubation had a longer stay (p = 0.025). Additionally, the order of not starting or increasing vasopressor support resulted in a longer hospital stay (p = 0.007) and a significantly longer stay until death (p = 0.044). Conclusions: LTE is a frequent measure in critically ill patient management and is less common in the postoperative setting. The most widespread measure was withholding, with the do-not-resuscitate order being the most common. The decision was made mainly by the medical team and the family, respecting the wishes of the patients. A joint patient-centered approach should be made in these decisions to avoid futile treatment and ensure end-of-life comfort.

Ethical Considerations in Pediatric Surgery.

Pediatric surgeons need to learn to give as much importance to the ethical approach as they have been giving to the systemic methodology in their clinical approach all along. The law of the land and the governmental rules also need to be kept in mind before deciding the final solution. They need to always put medical problems in the background of ethical context, reach a few solutions keeping in mind the available resources, and apply the best solution in the interest of their pediatric patients.

EASL Clinical Practice Guidelines on acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF), which was described relatively recently (2013), is a severe form of acutely decompensated cirrhosis characterised by the existence of organ system failure(s) and a high risk of short-term mortality. ACLF is caused by an excessive systemic inflammatory response triggered by precipitants that are clinically apparent (e.g., proven microbial infection with sepsis, severe alcohol-related hepatitis) or not. Since the description of ACLF, some important studies have suggested that patients with ACLF may benefit from liver transplantation and because of this, should be urgently stabilised for transplantation by receiving appropriate treatment of identified precipitants, and full general management, including support of organ systems in the intensive care unit (ICU). The objective of the present Clinical Practice Guidelines is to provide recommendations to help clinicians recognise ACLF, make triage decisions (ICU vs. no ICU), identify and manage acute precipitants, identify organ systems that require support or replacement, define potential criteria for futility of intensive care, and identify potential indications for liver transplantation. Based on an in-depth review of the relevant literature, we provide recommendations to navigate clinical dilemmas followed by supporting text. The recommendations are graded according to the Oxford Centre for Evidence-Based Medicine system and categorised as 'weak' or 'strong'. We aim to provide the best available evidence to aid the clinical decision-making process in the management of patients with ACLF.

Improving the efficiency of clinical trials in multiple sclerosis.

BACKGROUND: Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a high degree of success. However, these designs limit the types of questions that can be addressed, and the time and cost required. Moreover, trials involving people with progressive multiple sclerosis (MS) have been less successful. OBJECTIVE: The objective of this paper is to discuss complex innovative trial designs, intermediate and composite outcomes and to improve the efficiency of trial design in MS and broaden questions that can be addressed, particularly as applied to progressive MS. METHODS: We held an international workshop with experts in clinical trial design. RESULTS: Recommendations include increasing the use of complex innovative designs, developing biomarkers to enrich progressive MS trial populations, prioritize intermediate outcomes for further development that target therapeutic mechanisms of action other than peripherally mediated inflammation, investigate acceptability to people with MS of data linkage for studying long-term outcomes of clinical trials, use Bayesian designs to potentially reduce sample sizes required for pediatric trials, and provide sustained funding for platform trials and registries that can support pragmatic trials. CONCLUSION: Novel trial designs and further development of intermediate outcomes may improve clinical trial efficiency in MS and address novel therapeutic questions.

Prevalence, reasons, and timing of decisions to withhold/withdraw life-sustaining therapy for out-of-hospital cardiac arrest patients with extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is rapidly becoming a common treatment strategy for patients with refractory cardiac arrest. Despite its benefits, ECPR raises a variety of ethical concerns when the treatment is discontinued. There is little information about the decision to withhold/withdraw life-sustaining therapy (WLST) for out-of-hospital cardiac arrest (OHCA) patients after ECPR. METHODS: We conducted a secondary analysis of data from the SAVE-J II study, a retrospective, multicenter study of ECPR in Japan. Adult patients who underwent ECPR for OHCA with medical causes were included. The prevalence, reasons, and timing of WLST decisions were recorded. Outcomes of patients with or without WLST decisions were compared. Further, factors associated with WLST decisions were examined. RESULTS: We included 1660 patients in the analysis; 510 (30.7%) had WLST decisions. The number of WLST decisions was the highest on the first day and WSLT decisions were made a median of two days after ICU admission. Reasons for WLST were perceived unfavorable neurological prognosis (300/510 [58.8%]), perceived unfavorable cardiac/pulmonary prognosis (105/510 [20.5%]), inability to maintain extracorporeal cardiopulmonary support (71/510 [13.9%]), complications (10/510 [1.9%]), exacerbation of comorbidity before cardiac arrest (7/510 [1.3%]), and others. Patients with WLST had lower 30-day survival (WLST vs. no-WLST: 36/506 [7.1%] vs. 386/1140 [33.8%], p < 0.001). Primary cerebral disorders as cause of cardiac arrest and higher severity of illness at intensive care unit admission were associated with WLST decisions. CONCLUSION: For approximately one-third of ECPR/OHCA patients, WLST was decided during admission, mainly because of perceived unfavorable neurological prognoses. Decisions and neurological assessments for ECPR/OHCA patients need further analysis.

Premature termination of clinical trials in Spain: reasons, characteristics, and opportunities to improve.

PURPOSE: The aim of this study is to determine the rate of prematurely terminated clinical trials (CTs) and describe primary reasons and characteristics, and suggest strategies to improve. METHODS: We performed a retrospective, observational, cross-sectional study including all CTs registered in the Spanish Registry of Clinical Studies (REec) from January 1, 2013 to November 31, 2021. A descriptive analysis of reasons for premature termination was made. To assess characteristics associated with a premature termination, the relative risks (RR) with a 95% confidence interval were calculated. RESULTS: In total, 21% (718) of CT were prematurely terminated. Reasons for premature termination included patient recruitment issues in 25% (179) of cases, efficacy or futility problems in 18% (132), and commercial or strategic decisions from the sponsor in 12% (87). Characteristics significantly associated with an increased risk of premature termination included the following: presence of placebo (RR 2.08); multiple study sites (RR 1.32); pediatric and geriatric populations (RR 1.29 children; RR 1.47 preschoolers; RR 1.92 newborns; RR 1.27 > 64 years of age). In addition, circumstances such as investigations in phase II (RR 1.21), of cancer (RR 1.37), and of digestive pathology (RR 1.65) were also associated with increased risk of premature termination. CONCLUSION: Recruitment of the study subjects in a CT must be meticulous and account for age of participants. In addition, CT study sites should be evaluated to ensure they have appropriate resources and the desired patient population. Based on intermediate analyses, CT protocols should describe the criteria to terminate a study due to futility. These approaches are essential to avoid harm to participants, ensure internal validity of studies, and improve the use of resources in CT development.

Terminal anorexia nervosa cannot currently be identified.

OBJECTIVE: To review the recent literature on the proposed entity of "terminal anorexia nervosa." METHOD: Review of recent literature on the concept of "terminal AN" as well as past and supporting work. RESULTS: The cases and proposed definitions are reviewed, as is the growing literature on this topic. Problems exist with predicting outcomes and thus, determining futility, as well as about capacity for decision-making. DISCUSSION: To make decisions about treatment futility, the existing database for predicting AN course and treatment response must expand greatly. In addition, while decisional capacity is central to the debate, its determination may be unusually complex in this situation. The gaps identified point to extensive needs for future research, but they also indicate that the concept of "terminal AN" cannot be defined at present and should not be used. PUBLIC SIGNIFICANCE: Anorexia nervosa is challenging to treat, and it often lasts for years. There is debate about whether palliative care or medical aid in dying should be considered. Identifying who has a terminal case of AN is important for this question, but we have limited ability to predict a given individual's outcome at present, and there are concerns about the ability of those with AN to make treatment decisions. This means the concept of "terminal AN" should not currently be used.