Protocol for a Multicenter, Prospective, Observational Pilot Study on the Implementation of Resource-Stratified Algorithms for the Treatment of Severe Traumatic Brain Injury Across Four Treatment Phases: Prehospital, Emergency Department, Neurosurgery, and Intensive Care Unit.

BACKGROUND: Severe traumatic brain injury (sTBI) is a public health issue with great disparity among low- and middle-income countries where the implementation of evidence-based guidelines is challenging because resources are often unavailable. A consensus process including experts in the prehospital, emergency department, neurosurgery, and intensive care unit took place in Colombia to develop a set of stratified protocols called BOOTStraP, targeting resource-poor environments, but it has not been systematically implemented and tested. OBJECTIVE: To identify the facilitators of, and barriers to, collecting data about patients with sTBI and to implement a stratified protocol across the treatment phases of prehospital, emergency department, neurosurgery, and intensive care unit in low-resource settings. We also aim to identify a possible association between adherence to these protocols and outcomes for these patients. METHODS: A prospective, observational, before and after, pilot study will be performed in three phases as follows: before implementation, implementation, and after implementation. The BOOTStraP protocols will be implemented in three Colombian centers. EXPECTED OUTCOMES: We expect to find numerous barriers during the implementation phase. We also expect moderate adherence to the protocols. However, we expect to find an increase in the survival rate to hospital discharge and an improvement in neurological outcomes at discharge. DISCUSSION: This pilot study will serve as a first step to identify variables that are critical to successful implementation, to be considered for the design of a future large-scale international study to measure the effectiveness of resource-based protocols and to improve outcomes from sTBI.

Optimizing subgroup selection in two-stage adaptive enrichment and umbrella designs.

We design two-stage confirmatory clinical trials that use adaptation to find the subgroup of patients who will benefit from a new treatment, testing for a treatment effect in each of two disjoint subgroups. Our proposal allows aspects of the trial, such as recruitment probabilities of each group, to be altered at an interim analysis. We use the conditional error rate approach to implement these adaptations with protection of overall error rates. Applying a Bayesian decision-theoretic framework, we optimize design parameters by maximizing a utility function that takes the population prevalence of the subgroups into account. We show results for traditional trials with familywise error rate control (using a closed testing procedure) as well as for umbrella trials in which only the per-comparison type 1 error rate is controlled. We present numerical examples to illustrate the optimization process and the effectiveness of the proposed designs.

Delayed treatment effects, treatment switching and heterogeneous patient populations: How to design and analyze RCTs in oncology.

In the analysis of survival times, the logrank test and the Cox model have been established as key tools, which do not require specific distributional assumptions. Under the assumption of proportional hazards, they are efficient and their results can be interpreted unambiguously. However, delayed treatment effects, disease progression, treatment switchers or the presence of subgroups with differential treatment effects may challenge the assumption of proportional hazards. In practice, weighted logrank tests emphasizing either early, intermediate or late event times via an appropriate weighting function may be used to accommodate for an expected pattern of non-proportionality. We model these sources of non-proportional hazards via a mixture of survival functions with piecewise constant hazard. The model is then applied to study the power of unweighted and weighted log-rank tests, as well as maximum tests allowing different time dependent weights. Simulation results suggest a robust performance of maximum tests across different scenarios, with little loss in power compared to the most powerful among the considered weighting schemes and huge power gain compared to unfavorable weights. The actual sources of non-proportional hazards are not obvious from resulting populationwise survival functions, highlighting the importance of detailed simulations in the planning phase of a trial when assuming non-proportional hazards.We provide the required tools in a software package, allowing to model data generating processes under complex non-proportional hazard scenarios, to simulate data from these models and to perform the weighted logrank tests.

A critical review of graphics for subgroup analyses in clinical trials.

Subgroup analyses are a routine part of clinical trials to investigate whether treatment effects are homogeneous across the study population. Graphical approaches play a key role in subgroup analyses to visualise effect sizes of subgroups, to aid the identification of groups that respond differentially, and to communicate the results to a wider audience. Many existing approaches do not capture the core information and are prone to lead to a misinterpretation of the subgroup effects. In this work, we critically appraise existing visualisation techniques, propose useful extensions to increase their utility and attempt to develop an effective visualisation approach. We focus on forest plots, UpSet plots, Galbraith plots, subpopulation treatment effect pattern plot, and contour plots, and comment on other approaches whose utility is more limited. We illustrate the methods using data from a prostate cancer study.

Electrical Stimulation of the Greater Auricular Nerve to Reduce Postoperative Atrial Fibrillation.

BACKGROUND: Postoperative atrial fibrillation (POAF) occurs in up to 40% of patients undergoing cardiac surgery. Invasive stimulation of the vagal nerve previously demonstrated a reduced risk of POAF. Therefore, we examined the antiarrhythmic and anti-inflammatory effects of noninvasive low-level transcutaneous electrical stimulation (LLTS) of the greater auricular nerve in a pilot trial including patients undergoing cardiac surgery. METHODS: Patients were randomized into a sham (n=20) or a treatment group (n=20) for LLTS. After cardiac surgery, electrodes were applied in the triangular fossa of the ear. Stimulation (amplitude 1 mA, frequency 1 Hz for 40 minutes, followed by a 20 minutes break) was performed for up to 2 weeks after cardiac surgery. Heart rhythm was recorded continuously using an ECG during the observation period. CRP (C-reactive protein) and IL (interleukin)-6 plasma concentrations were measured immediately after surgery as well as on day 2 and 7 postsurgery. RESULTS: Patients receiving LLTS had a significantly reduced occurrence of POAF (4 of 20) when compared with controls (11 of 20, P=0.022) during a similar mean Holter recording period. The median duration of POAF was comparable between the treatment and the control group (878 [249; 1660] minutes versus 489 [148; 1775] minutes; P=0.661). No effect of LLTS on CRP or IL-6 levels was detectable. CONCLUSIONS: LLTS of the greater auricular nerve may be a potential therapy for POAF. We demonstrated the feasibility to conduct a randomized trial of neurostimulation as an outlay for a multisite clinical trial.

The Assessment of Quality Attributes for Biosimilars: a Statistical Perspective on Current Practice and a Proposal.

Establishing comparability of the originator and its biosimilar at the structural and functional level, by analyzing so-called quality attributes, is an important step in biosimilar development. The statistical assessment of quality attributes is currently in the focus of attention because both the FDA and the EMA are working on regulatory documents for advising companies on the use of statistical approaches for strengthening their comparability claim. In this paper, we first discuss "comparable" and "not comparable" settings and propose a shift away from the usual comparison of the mean values: we argue that two products can be considered comparable if the range of the originator fully covers the range of the biosimilar. We then introduce a novel statistical testing procedure (the "tail-test") and compare the operating characteristics of the proposed approach with approaches currently used in practice. In contrast to the currently used approaches, we note that our proposed methodology is compatible with the proposed understanding of comparability and has, compared to other frequently applied range-based approaches, the advantage of being a formal statistical testing procedure which controls the patient's risk and has reasonable large-sample properties.

Subgroup identification in clinical trials via the predicted individual treatment effect.

Identifying subgroups of treatment responders through the different phases of clinical trials has the potential to increase success in drug development. Recent developments in subgroup analysis consider subgroups that are defined in terms of the predicted individual treatment effect, i.e. the difference between the predicted outcome under treatment and the predicted outcome under control for each individual, which in turn may depend on multiple biomarkers. In this work, we study the properties of different modelling strategies to estimate the predicted individual treatment effect. We explore linear models and compare different estimation methods, such as maximum likelihood and the Lasso with and without randomized response. For the latter, we implement confidence intervals based on the selective inference framework to account for the model selection stage. We illustrate the methods in a dataset of a treatment for Alzheimer disease (normal response) and in a dataset of a treatment for prostate cancer (survival outcome). We also evaluate via simulations the performance of using the predicted individual treatment effect to identify subgroups where a novel treatment leads to better outcomes compared to a control treatment.

Intensive care treatments associated with favorable discharge outcomes in Argentine children with severe traumatic brain injury: For the South American Guideline Adherence Group.

OBJECTIVE: Little is known about the critical care management of children with traumatic brain injury (TBI) in low middle income countries. We aimed to identify indicators of intensive care unit (ICU) treatments associated with favorable outcomes in Argentine children with severe TBI. METHODS: We conducted a secondary analysis of data from patients previously enrolled in a prospective seven center study of children with severe TBI who were admitted to an ICU in one of the seven study centers. Severe TBI was defined by head AIS ≥ 3, head CT with traumatic lesion, and admission GCS < 9. Seven indicators of best practice TBI care were examined. The primary outcome was discharge Pediatric Cerebral Performance Category Scale [PCPC] and Pediatric Overall Performance category Scale [POPC]. We also examined variation in ICU care and in-patient mortality. RESULTS: Of the 117 children, 67% were male and 7.5 (4.3) years on average, 92% had isolated TBI. Hypotension (54%) was more common than hypoxia (28%) and clinical or radiographic signs of high intracranial pressure (ICP) were observed in 92%. Yet, ICP monitoring occurred in 60% and hyperosmolar therapy was used in only 36%. Adherence to indicators of best TBI practice ranged from 55.6% to 83.7% across the seven centers and adherence was associated with favorable discharge PCPC (aRR 0.98; 95% CI [0.96, 0.99]), and POPC (aRR 0.98; 95% CI [0.96, 0.99]). Compared to patients whose adherence rates were below 65%, patients whose adherence rates were higher between 75%-100% had better discharge PCPC (aRR 0.28; 95% CI [0.10, 0.83]) and POPC (aRR 0.32; 95% CI [0.15, 0.73]. Two indicators were associated with favorable discharge PCPC: Avoidance of hypoxia (aRR 0.46; 95% CI [0.23, 0.93]), and Nutrition started in 72 hours (aRR 0.45; 95% CI [0.21, 0.99]). Avoiding hypoxia was also associated with favorable discharge POPC (aRR 0.47; 95% CI [0.22, 0.99]). CONCLUSION: There is variation in Argentine ICU practice in the care of children with severe TBI. Second insults are common and hyperosmolar therapy use is uncommon. Adherence to best practice TBI care by avoiding hypoxia and providing timely nutrition were associated with significantly favorable discharge outcomes. Implementing strategies that prevent hypoxia and facilitate early nutrition in the ICUs are urgently needed to improve pediatric TBI outcomes.

Benchmarking Prehospital and Emergency Department Care for Argentine Children with Traumatic Brain Injury: For the South American Guideline Adherence Group.

OBJECTIVE: There is little information on the type of early care provided to children with traumatic brain injury (TBI) in low middle income countries. We benchmarked early prehospital [PH] and emergency department [ED] pediatric TBI care in Argentina. METHODS: We conducted a secondary analysis of data from patients previously enrolled in a prospective seven center study of children with TBI. Eligible participants were patients 0-18 years, and had diagnosis of TBI (admission Glasgow Coma scale score [GCS] < 13 or with GCS 14-15 and abnormal head CT scan within 48 hours of admission, and head AIS > 0). Outcomes were transport type, transport time, PH and ED adherence to best practice, and discharge Pediatric Cerebral Performance Category Scale (PCPC) and Pediatric Overall Performance category Scale (POPC). RESULTS: Of the 366 children, mean age was 8.7 (5.0) years, 58% were male, 90% had isolated TBI and 45.4% were transported by private vehicle. 50 (34.7%) of the 144 children with severe TBI (39.3% of all TBI patients) were transported by private vehicle. Most (267; 73%) patients received initial TBI care at an index hospital prior to study center admission, including children with severe (81.9%) TBI. Transport times were shorter for those patients who were directly transported by ambulance to study center than for the whole cohort (1.4 vs.5.5 hours). Ambulance blood pressure data were recorded in 30.9%. ED guideline adherence rate was higher than PH guideline adherence rate (84.8% vs. 26.4%). For patients directly transferred from scene to study trauma centers, longer transport time was associated with worse discharge outcome (PCPC aOR 1.10 [1.04, 1.18] and (POPC aOR 1.10 [1.04, 1.18]). There was no relationship between PH or ED TBI guideline adherence rate and discharge POPC and PCPC. CONCLUSION: This study benchmarks early pediatric TBI care in Argentina and shows that many critically injured children with TBI do not receive timely or best practice PH care, that PH guideline adherence rate is low and that longer transport time was associated with poor discharge outcomes for patients with direct transfer status. There is an urgent need to improve the early care of children with TBI in Argentina, especially timely transportation to a hospital.

Postdischarge Care of Pediatric Traumatic Brain Injury in Argentina: A Multicenter Randomized Controlled Trial.

OBJECTIVE: To develop, in partnership with families of children with traumatic brain injury, a postdischarge intervention that is effective, simple, and sustainable. DESIGN: Randomized Controlled Trial. SETTING: Seven Level 1 Pediatric Trauma Centers in Argentina. PATIENTS: Persons less than 19 years of age admitted to one of the study hospitals with a diagnosis of severe, moderate, or complicated mild traumatic brain injury and were discharged alive. INTERVENTIONS: Patients were randomly assigned to either the intervention or standard care group. A specially trained Community Resource Coordinator was assigned to each family in the intervention group. We hypothesized that children with severe, moderate, and complicated mild traumatic brain injury who received the intervention would have significantly better functional outcomes at 6 months post discharge than those who received standard care. We further hypothesized that there would be a direct correlation between patient outcome and measures of family function. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was a composite measured at 6 months post injury. There were 308 patients included in the study (61% men). Forty-four percent sustained a complicated mild traumatic brain injury, 18% moderate, and 38% severe. Sixty-five percent of the patients were 8 years old or younger, and over 70% were transported to the hospital without ambulance assistance. There was no significant difference between groups on the primary outcome measure. There was a statistically significant correlation between the primary outcome measure and the scores on the Family Impact Module of the Pediatric Quality of Life Inventory (ρ = 0.57; p < 0.0001). Children with better outcomes lived with families reporting better function at 6 months post injury. CONCLUSIONS: Although no significant effect of the intervention was demonstrated, this study represents the first conducted in Latin America that documents the complete course of treatment for pediatric patients with traumatic brain injury spanning hospital transport through hospital care and into the postdischarge setting.