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.

Student-teacher relationships and sense of academic futility: Longitudinal associations among early adolescents of immigrant and non-immigrant background.

Sense of academic futility entails feelings of having no control over ones' educational success. Although mounting evidence points to its negative consequences for students' educational outcomes, less is known about its socio-contextual antecedents. Relatedly, the current study explored how fair and supportive relationships with teachers are related to the sense of academic futility and if class belonging mediates this link in a sample of adolescents with immigrant and non-immigrant backgrounds. A total of 1065 seventh-grade students (Mage = 13.12; SD = 0.42; 45% girls) from 55 classrooms completed questionnaires at two time points 1 year apart. Results of multilevel analyses indicated that fair and supportive relationships with teachers contributed to decreases in sense of academic futility at the individual but not at the classroom level. No mediation or moderation effects emerged. These findings highlight the crucial role of democratic student-teacher relationships in supporting the positive school adjustment of all students in increasingly multicultural societies.

Discordant conceptualisations of eating disorder recovery and their influence on the construct of terminality.

Eating disorders (EDs) are complex, multifaceted conditions that significantly impact quality-of-life, often co-occur with multiple medical and psychiatric diagnoses, and are associated with a high risk of medical sequelae and mortality. Fortunately, many people recover even after decades of illness, although there are different conceptualisations of recovery and understandings of how recovery is experienced. Differences in these conceptualisations influence categorisations of ED experiences (e.g., longstanding vs. short-duration EDs), prognoses, recommended treatment pathways, and research into treatment outcomes. Within recent years, the proposal of a 'terminal' illness stage for a subset of individuals with anorexia nervosa and arguments for the prescription of end-of-life pathways for such individuals has ignited debate. Semantic choices are influential in ED care, and it is critical to consider how conceptualisations of illness and recovery and power dynamics influence outcomes and the ED 'staging' discourse. Conceptually, 'terminality' interrelates with understandings of recovery, efficacy of available treatments, iatrogenic harm, and complex co-occurring diagnoses, as well as the functions of an individual's eating disorder, and the personal and symbolic meanings an individual may hold regarding suffering, self-starvation, death, health and life. Our authorship represents a wide range of lived and living experiences of EDs, treatment, and recovery, ranging from longstanding and severe EDs that may meet descriptors of a 'terminal' ED to a variety of definitions of 'recovery'. Our experiences have given rise to a shared motivation to analyse how existing discourses of terminality and recovery, as found in existing research literature and policy, may shape the conceptualisations, beliefs, and actions of individuals with EDs and the healthcare systems that seek to serve them.

Examining ethnic identity, school climate, and academic futility among minoritized students.

The present causal-comparative study examined the relation between school climate, ethnic identity, and academic futility among racially and ethnically minoritized students. The sample included 1721 racially and ethnically minoritized students identifying as Black, Asian, Latine, and Multiracial from 11 schools in the northeastern region of the United States. Regression models indicated a direct relation between the school climate subscales including School Connectedness, Safety, Character, Peer Support, Adult Support, Cultural Acceptance, Physical Environment, and Order and Discipline and academic futility for all groups in the study. Ethnic identity moderated the relation between school climate subscales and academic futility, although the impact differed across racial and ethnic groups. The present study's results highlight the similarities and differences in the educational experiences of minoritized students. The discussion provides recommendations for cultivating educational environments that are culturally affirming and informed to meet the needs of an increasingly diverse student population. Limitations and future directions are discussed.

Upstrapping to determine futility: predicting future outcomes nonparametrically from past data.

BACKGROUND: Clinical trials often involve some form of interim monitoring to determine futility before planned trial completion. While many options for interim monitoring exist (e.g., alpha-spending, conditional power), nonparametric based interim monitoring methods are also needed to account for more complex trial designs and analyses. The upstrap is one recently proposed nonparametric method that may be applied for interim monitoring. METHODS: Upstrapping is motivated by the case resampling bootstrap and involves repeatedly sampling with replacement from the interim data to simulate thousands of fully enrolled trials. The p-value is calculated for each upstrapped trial and the proportion of upstrapped trials for which the p-value criteria are met is compared with a pre-specified decision threshold. To evaluate the potential utility for upstrapping as a form of interim futility monitoring, we conducted a simulation study considering different sample sizes with several different proposed calibration strategies for the upstrap. We first compared trial rejection rates across a selection of threshold combinations to validate the upstrapping method. Then, we applied upstrapping methods to simulated clinical trial data, directly comparing their performance with more traditional alpha-spending and conditional power interim monitoring methods for futility. RESULTS: The method validation demonstrated that upstrapping is much more likely to find evidence of futility in the null scenario than the alternative across a variety of simulations settings. Our three proposed approaches for calibration of the upstrap had different strengths depending on the stopping rules used. Compared to O'Brien-Fleming group sequential methods, upstrapped approaches had type I error rates that differed by at most 1.7% and expected sample size was 2-22% lower in the null scenario, while in the alternative scenario power fluctuated between 15.7% lower and 0.2% higher and expected sample size was 0-15% lower. CONCLUSIONS: In this proof-of-concept simulation study, we evaluated the potential for upstrapping as a resampling-based method for futility monitoring in clinical trials. The trade-offs in expected sample size, power, and type I error rate control indicate that the upstrap can be calibrated to implement futility monitoring with varying degrees of aggressiveness and that performance similarities can be identified relative to considered alpha-spending and conditional power futility monitoring methods.

Defining futile and potentially avoidable interhospital trauma transfers.

PURPOSE: Interhospital transfer of critically injured patients to a major trauma service reduces preventable death in major trauma. Yet some of those transferred die without intervention. These 'futile' interhospital trauma transfers (IHTs), and other potentially avoidable IHTs place enormous stress on families of trauma victims, can delay care, and incur great cost to public health resources. This study sought to characterise these IHTs using current state guidelines for interhospital transfer. METHODS: A retrospective cohort study was conducted using our institution's trauma registry from January 2016-December 2020. All adult patients transferred to our major trauma service were analysed. Futile IHTs were defined as death or transfer to hospice care without surgical, endoscopic, or radiological intervention, and without ICU admission, within 72 h of admission. Potentially avoidable IHTs were defined as all patients discharged alive without intervention or ICU care, and secondary over-triage patients are a subset of these patients who were discharged within 72 h of admission. Patient demographics, injuries, and treatments were categorised from electronic records and analysed. RESULTS: Of 2,837 IHTs, seven (0.2 %) met criteria for futility. The majority were female, median age of 80 (IQR 85-75) and had a median Injury Severity Score (ISS) of 16 (IQR 25.5-11.5). By contrast, 1391 patients (49 %) were classified as potentially avoidable and 513 (18 %) were considered secondary over-triage. The majority were male, median age of 43 (IQR 62-28), and had a median ISS of 9 (IQR 13-4). Of these potentially avoidable IHTs, 984 (70.7 %) were discharged directly home. CONCLUSION: Futile IHTs were infrequent, however over half of all trauma patients transferred from other hospitals were discharged without tertiary-level intervention. Trauma services should consider developing systems such as telehealth to support regional general and orthopaedic surgeons to co-manage lower risk trauma, particularly minor head and minor spinal trauma patients. This could be an integral part of safely reducing potentially avoidable IHTs and their associated costs while maintaining a low rate of preventable mortality in trauma.

How Seeking Transfer Often Fails to Help Define Medically Inappropriate Treatment.

On September 1, 2023, Texas made important revisions to it its decades-old statute granting legal safe harbor immunity to physicians who withhold or withdraw life-sustaining treatment over the objection of critically ill patients' surrogate decision-makers. However, lawmakers left untouched glaring flaws in a key safeguard for patients-the transfer option. The transfer option is ethically important because, when no hospital is willing to accept the patient in transfer, that fact is taken as strong evidence that the surrogates' treatment requests fall outside accepted medical practice. But there are serious shortcomings in how the transfer option is carried out in Texas and many other states, which undermines the ethical usefulness of the process. We identify these shortcomings and recommend revisions to state statutes and professional guidelines to overcome them.

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.

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.

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.

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.

Optimal timing for an accelerated interim futility analysis incorporating real world data.

BACKGROUND: Randomized controlled trials include interim monitoring guidelines to stop early for safety, efficacy, or futility. Futility monitoring facilitates re-allocation of limited resources. However, conventional methods for interim futility monitoring require a trial to accrue nearly half of the outcome data to make a reliable early stopping decision, limiting its benefit. As early stopping for futility will not inflate type-I error, these analyses are an appealing venue for incorporating external data to improve efficiency. METHODS: We propose a Bayesian approach to futility monitoring leveraging real world data using Semi-Supervised MIXture Multi-source Exchangeability Models, which accounts for both measured and unmeasured differences between data sources. We implement futility monitoring using predictive probabilities and investigate the optimal timing with respect to the expected sample size under the null hypothesis. Because we only incorporate external data during the interim futility analysis the proposed design is not limited by type-I error inflation. RESULTS: When the external and trial data are exchangeable, the proposed method provides a roughly 70 person reduction in expected sample size under the null. Under scenarios where exchangeability does not hold, our approach still provides a 10-20 person reduction in expected sample size under the null with about 80% power. CONCLUSIONS: External data borrowing in interim futility monitoring is a promising venue to improve trial efficiency without type-I error inflation. Approaches that are acceptable to regulatory authorities and leverage the complementary strengths of real world and trial data are vital to more efficiently allocate limited resources amongst clinical trials.

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.

Factors associated with limitation of life support: Post-ICU mortality case study of a tertiary hospital.

BACKGROUND: Life-sustaining treatment limitation (LSV) is the medical act of withdrawing or not initiating measures that are considered futile in a patient's specific situation. LSV in critically ill patients remains a difficult topic to study, due to the multitude of factors that condition it. OBJECTIVE: To determine factors related to LSV in ICU in cases of post-ICU in-hospital mortality, as well as factors associated with survival after discharge from ICU. DESIGN: Retrospective longitudinal study. AMBIT: Intensive care unit of a tertiary hospital. PATIENTS: People who died in the hospitalization ward after ICU treatment between January 2014 and December 2019. INTERVENTIONS: None. This is an observational study. VARIABLES OF INTEREST: Age, sex, probability of death, type of admission, LSV in ICU, oncological disease, dependence, invasive mechanical ventilation, emergency hemodialysis, transfusion of blood products, nosocomial infection (NI), pre-ICU, intra-ICU and post-ICU stays. RESULTS: Of 114 patients who died outside the ICU, 49 had LSV registered in the ICU (42.98%). Age and stay prior to ICU admission were positively associated with LSV (OR 1,03 and 1,08, respectively). Patients without LSV had a higher post-ICU stay, while it was lower for male patients. CONCLUSIONS: Our results support that LSV established within the ICU can avoid complications commonly associated with unnecessary prolongation of stay, such as NI.

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).

Perceived potentially inappropriate treatment in the PICU: frequency, contributing factors and the distress it triggers.

Background: Potentially inappropriate treatment in critically ill adults is associated with healthcare provider distress and burnout. Knowledge regarding perceived potentially inappropriate treatment amongst pediatric healthcare providers is limited. Objectives: Determine the frequency and factors associated with potentially inappropriate treatment in critically ill children as perceived by providers, and describe the factors that providers report contribute to the distress they experience when providing treatment perceived as potentially inappropriate. Methods: Prospective observational mixed-methods study in a single tertiary level PICU conducted between March 2 and September 14, 2018. Patients 0-17 years inclusive with: (1) ≥1 organ system dysfunction (2) moderate to severe mental and physical disabilities, or (3) baseline dependence on medical technology were enrolled if they remained admitted to the PICU for ≥48 h, and were not medically fit for transfer/discharge. The frequency of perceived potentially inappropriate treatment was stratified into three groups based on degree of consensus (1, 2 or 3 providers) regarding the appropriateness of ongoing active treatment per enrolled patient. Distress was self-reported using a 100-point scale. Results: Of 374 patients admitted during the study, 133 satisfied the inclusion-exclusion criteria. Eighteen patients (unanimous - 3 patients, 2 providers - 7 patients; single provider - 8 patients) were perceived as receiving potentially inappropriate treatment; unanimous consensus was associated with 100% mortality on 3-month follow up post PICU discharge. Fifty-three percent of providers experienced distress secondary to providing treatment perceived as potentially inappropriate. Qualitative thematic analysis revealed five themes regarding factors associated with provider distress: (1) suffering including a sense of causing harm, (2) conflict, (3) quality of life, (4) resource utilization, and (5) uncertainty. Conclusions: While treatment perceived as potentially inappropriate was infrequent, provider distress was commonly observed. By identifying specific factor(s) contributing to perceived potentially inappropriate treatment and any associated provider distress, organizations can design, implement and assess targeted interventions.

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.