Improved mortality analysis in early-phase dose-ranging clinical trials for emergency medical diseases using Bayesian time-to-event models with active comparators.

Emergency medical diseases (EMDs) are the leading cause of death worldwide. A time-to-death analysis is needed to accurately identify the risks and describe the pattern of an EMD because the mortality rate can peak early and then decline. Dose-ranging Phase II clinical trials are essential for developing new therapies for EMDs. However, most dose-finding trials do not analyze mortality as a time-to-event endpoint. We propose three Bayesian dose-response time-to-event models for a secondary mortality analysis of a clinical trial: a two-group (active treatment vs control) model, a three-parameter sigmoid EMAX model, and a hierarchical EMAX model. The study also incorporates one specific active treatment as an active comparator in constructing three new models. We evaluated the performance of these six models and a very popular independent model using simulated data motivated by a randomized Phase II clinical trial focused on identifying the most effective hyperbaric oxygen dose to achieve favorable functional outcomes in patients with severe traumatic brain injury. The results show that the three-group, EMAX, and EMAX model with an active comparator produce the smallest averaged mean squared errors and smallest mean absolute biases. We provide a new approach for time-to-event analysis in early-phase dose-ranging clinical trials for EMDs. The EMAX model with an active comparator can provide valuable insights into the mortality analysis of new EMDs or other conditions that have changing risks over time. The restricted mean survival time, a function of the model's hazards, is recommended for displaying treatment effects for EMD research.

Selection of a statistical analysis method for the Glasgow Outcome Scale-Extended endpoint for estimating the probability of favorable outcome in future severe TBI clinical trials.

The Glasgow outcome scale-extended (GOS-E), an ordinal scale measure, is often selected as the endpoint for clinical trials of traumatic brain injury (TBI). Traditionally, GOS-E is analyzed as a fixed dichotomy with favorable outcome defined as GOS-E ≥ 5 and unfavorable outcome as GOS-E < 5. More recent studies have defined favorable vs unfavorable outcome utilizing a sliding dichotomy of the GOS-E that defines a favorable outcome as better than a subject's predicted prognosis at baseline. Both dichotomous approaches result in loss of statistical and clinical information. To improve on power, Yeatts et al proposed a sliding scoring of the GOS-E as the distance from the cutoff for favorable/unfavorable outcomes, and therefore used more information found in the original GOS-E to estimate the probability of favorable outcome. We used data from a published TBI trial to explore the ramifications to trial operating characteristics by analyzing the sliding scoring of the GOS-E as either dichotomous, continuous, or ordinal. We illustrated a connection between the ordinal data and time-to-event (TTE) data to allow use of Bayesian software that utilizes TTE-based modeling. The simulation results showed that the continuous method with continuity correction offers higher power and lower mean squared error for estimating the probability of favorable outcome compared to the dichotomous method, and similar power but higher precision compared to the ordinal method. Therefore, we recommended that future severe TBI clinical trials consider analyzing the sliding scoring of the GOS-E endpoint as continuous with continuity correction.

An adaptive clinical trial design to identify the target dose of tenecteplase for treatment of acute pulmonary embolism.

BACKGROUND/AIMS: Fibrinolytic therapy with tenecteplase has been proposed for patients with pulmonary embolism but the optimal dose is unknown. Higher-than-necessary dosing is likely to cause excess bleeding. We designed an adaptive clinical trial to identify the minimum and assumed safest dose of tenecteplase that maintains efficacy. METHODS: We propose a Bayesian adaptive, placebo-controlled, group-sequential dose-finding trial using response-adaptive randomization to preferentially allocate subjects to the most promising doses, dual analyses strategies (continuous and dichotomized) using a gatekeeping approach to maximize clinical impact, and interim stopping rules to efficiently address competing trial objectives. The operating characteristics of the proposed design were evaluated using Monte Carlo simulation across multiple hypothetical efficacy scenarios. RESULTS: Simulation demonstrated response-adaptive randomization can preferentially allocate subjects to doses which appear to be performing well based on interim data. Interim decision-making, including the interim evaluation of both analysis strategies with gatekeeping, allows the trial to continue enrollment when success with the dichotomized analysis strategy appears sufficiently likely and to stop enrollment and declare superiority based on the continuous analysis strategy when there is little chance of ultimately declaring superiority with the dichotomized analysis. CONCLUSION: The proposed design allows evaluation of a greater number of dose levels than would be possible with a non-adaptive design and avoids the need to choose either the continuous or the dichotomized analysis strategy for the primary endpoint.

Comparison of Bayesian vs Frequentist Adaptive Trial Design in the Stroke Hyperglycemia Insulin Network Effort Trial.

Importance: Bayesian adaptive trial design has the potential to create more efficient clinical trials. However, a barrier to the uptake of bayesian adaptive designs for confirmatory trials is limited experience with how they may perform compared with a frequentist design. Objective: To compare the performance of a bayesian and a frequentist adaptive clinical trial design. Design, Setting, and Participants: This prospective cohort study compared 2 trial designs for a completed multicenter acute stroke trial conducted within a National Institutes of Health neurologic emergencies clinical trials network, with individual patient-level data, including the timing and order of enrollments and outcome ascertainment, from 1151 patients with acute stroke and hyperglycemia randomized to receive intensive or standard insulin therapy. The implemented frequentist design had group sequential boundaries for efficacy and futility interim analyses at 90 days after randomization for 500, 700, 900, and 1100 patients. The bayesian alternative used predictive probability of trial success to govern early termination for efficacy and futility with a first interim analysis at 500 randomized patients and subsequent interims after every 100 randomizations. Main Outcomes and Measures: The main outcome was the sample size at end of study, which was defined as the sample size at which each of the studies stopped accrual of patients. Results: Data were collected from 1151 patients. As conducted, the frequentist design passed the futility boundary after 936 participants were randomized. Using the same sequence and timing of randomization and outcome data, the bayesian alternative crossed the futility boundary approximately 3 months earlier after 800 participants were randomized. Conclusions and Relevance: Both trial designs stopped for futility before reaching the planned maximum sample size. In both cases, the clinical community and patients would benefit from learning the answer to the trial's primary question earlier. The common feature across the 2 designs was frequent interim analyses to stop early for efficacy or for futility. Differences between how these analyses were implemented between the 2 trials resulted in the differences in early stopping.

Coagulation markers and functional outcome in acute ischemic stroke: Impact of intensive versus standard hyperglycemia control.

OBJECTIVE: Alterations in coagulation could mediate functional outcome in patients with hyperglycemia after acute ischemic stroke (AIS). We prospectively studied the effects of intensive versus standard glucose control on coagulation markers and their relationships to functional outcomes in patients with AIS. APPROACH: The Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial measured the coagulation biomarkers whole blood tissue factor procoagulant activity (TFPCA); plasma factors VII (FVII), VIIa (FVIIa), and VIII (FVIII); thrombin-antithrombin (TAT) complex; D-dimer; tissue factor pathway inhibitor, and plasminogen activator inhibitor-1 (PAI-1) antigen in patients enrolled in the Stroke Hyperglycemia Insulin Network Effort trial of intensive versus standard glucose control on functional outcome at 3 months after AIS. Changes in biomarkers over time (from baseline ≈12 hours after stroke onset) to 48 hours, and changes in biomarkers between treatment groups, functional outcomes, and their interaction were analyzed by two-way analysis of variance. RESULTS: A total of 125 patients were included (57 in the intensive treatment group and 68 in the standard treatment group). The overall mean age was 66 years; 42% were women. Changes from baseline to 48 hours in coagulation markers were significantly different between treatment groups for TFPCA (P = 0.02) and PAI-1 (P = .04) and FVIIa (P = .04). Increases in FVIIa and decreases in FVIII were associated with favorable functional outcomes (P = .04 and .04, respectively). In the intensive treatment group, reductions in TFPCA and FVIII and increases in FVIIa were greater in patients with favorable than unfavorable outcomes (P = .02, 0.002, 0.03, respectively). In the standard treatment group, changes in FVII were different by functional outcome (P = .006). CONCLUSIONS: Intensive glucose control induced greater alterations in coagulation biomarkers than standard treatment, and these were associated with a favorable functional outcome at 3 months after AIS.

Outcomes of Intensive Systolic Blood Pressure Reduction in Patients With Intracerebral Hemorrhage and Excessively High Initial Systolic Blood Pressure: Post Hoc Analysis of a Randomized Clinical Trial.

Importance: The safety and efficacy of intensive systolic blood pressure reduction in patients with intracerebral hemorrhage who present with systolic blood pressure greater than 220 mm Hg appears to be unknown. Objective: To evaluate the differential outcomes of intensive (goal, 110-139 mm Hg) vs standard (goal, 140-179 mm Hg) systolic blood pressure reduction in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more vs less than 220 mm Hg. Design, Setting, and Participants: This post hoc analysis of the Antihypertensive Treatment of Acute Cerebral Hemorrhage-II trial was performed in November 2019 on data from the multicenter randomized clinical trial, which was conducted between May 2011 to September 2015. Patients with intracerebral hemorrhage and initial systolic blood pressure of 180 mm Hg or more, randomized within 4.5 hours after symptom onset, were included. Interventions: Intravenous nicardipine infusion titrated to goals. Main Outcomes and Measures: Neurological deterioration and hematoma expansion within 24 hours and death or severe disability at 90 days, plus kidney adverse events and serious adverse events until day 7 or hospital discharge. Results: A total of 8532 patients were screened, and 999 individuals (mean [SD] age, 62.0 [13.1] years; 620 men [62.0%]) underwent randomization and had an initial SBP value. Among 228 participants with initial systolic blood pressures of 220 mm Hg or more, the rate of neurological deterioration within 24 hours was higher in those who underwent intensive (vs standard) systolic blood pressure reduction (15.5% vs 6.8%; relative risk, 2.28 [95% CI, 1.03-5.07]; P = .04). The rate of death and severe disability (39.0% vs 38.4%; relative risk, 1.02 [95% CI, 0.73-1.78]; P = .92) was not significantly different between the 2 groups. There was a significantly higher rate of kidney adverse events in participants randomized to intensive systolic blood pressure reduction (13.6% vs 4.2%; relative risk, 3.22 [95% CI, 1.21-8.56]; P = .01), but no difference was observed in the rate of kidney serious adverse events. Conclusions and Relevance: The higher rate of neurological deterioration within 24 hours associated with intensive treatment in patients with intracerebral hemorrhage and initial systolic blood pressure of 220 mm Hg or more, without any benefit in reducing hematoma expansion at 24 hours or death or severe disability at 90 days, warrants caution against generalization of recommendations for intensive systolic blood pressure reduction.

Sliding Scoring of the Glasgow Outcome Scale-Extended as Primary Outcome in Traumatic Brain Injury Trials.

The Glasgow Outcome Scale-Extended (GOS-E), an ordinal scale measuring global outcome, is used commonly as the primary outcome measure in clinical trials of traumatic brain injury. Analysis is often based on a dichotomization and thus has inherent statistical limitations, including loss of information related to the collapse of adjacent categories. A fixed dichotomization defines favorable outcome consistently for all subjects, whereas a sliding dichotomy tailors the definition of favorable outcome according to baseline prognosis/severity. Literature indicates that the sliding dichotomy is more statistically efficient than the fixed dichotomy; however, the sliding dichotomy still collapses categories and therefore discards information. We propose an alternative, a sliding scoring system for the GOS-E, intended to address the limitations of the sliding dichotomy. The score is assigned based on the number of levels between the achieved score and the favorable cut-point. The proposed scoring system reflects the magnitude of change, where change is defined according to each subject's baseline prognosis. Because the score is approximately continuous, statistical methods can rely on the normal distribution, both for analysis and study design. Two examples show the corresponding potential for improved power. A sliding score approach allows for quantification of the magnitude of change while still accounting for prognosis. Scientific advantages include increased power and an intuitive interpretation.

Assessment of the End Point Adjudication Process on the Results of the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial: A Secondary Analysis.

Importance: Debate continues about the value of event adjudication in clinical trials and whether independent centralized assessments improve reliability and validity of study results in masked randomized trials compared with local, investigator-assessed end points. Objective: To assess the results of the adjudicated end point process in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial by comparing end points assessed by local site investigators with centrally adjudicated end points. Design, Setting, and Participants: This is an ad hoc secondary analysis of a randomized, double-blind clinical trial comparing safety and effectiveness of clopidogrel bisulphate plus aspirin vs placebo plus aspirin. Patients received either 600 mg of clopidogrel bisulphate on day 1, then 75 mg per day through day 90 plus 50 to 325 mg of aspirin per day, or the same range of dosages of placebo plus aspirin. Investigators reported all potential end points; independent masked adjudicators were randomly assigned to review using definitions specified in the study protocol. This was a multicenter study; 269 international sites in 10 countries enrolled from May 28, 2010, to December 19, 2017. The study enrolled 4881 patients 18 years or older with transient ischemic attack or minor acute ischemic stroke within 12 hours of symptom onset and followed for 90 days from randomization; last follow-up was completed in March 2018. Main Outcomes and Measures: Independent adjudicators external to the study and masked to study treatment assignment adjudicated 467 primary and secondary effectiveness outcomes and major and minor bleeding events, including the primary composite end point, which was the risk of a composite of major ischemic events at 90 days, defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event. The primary safety end point was major hemorrhage. All components of the primary and safety outcomes were adjudicated. Results: In this secondary analysis of an international randomized clinical trial, a total of 269 sites worldwide randomized 4881 patients (median age, 65.0 years; interquartile range, 55-74 years); 55.0% were male. The primary results have been published previously. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary composite end point were 0.75 (95% CI, 0.59-0.95) for adjudicator-assessed events and 0.76 (95% CI, 0.60-0.95) for investigator-assessed events. Agreement between adjudicator and investigator assessments was 90.7%. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary safety end point were 2.32 (95% CI, 1.10-4.87) for adjudicator-assessed events and 2.58 (95% CI, 1.19-5.58) for investigator-assessed events, with an agreement rate of 77.5%. Conclusions and Relevance: Independent end point adjudication did not substantially alter estimates of the primary treatment effectiveness in the POINT trial. Trial Registration: ClinicalTrials.gov identifier: NCT00991029.

Time Course for Benefit and Risk of Clopidogrel and Aspirin After Acute Transient Ischemic Attack and Minor Ischemic Stroke.

BACKGROUND: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke [POINT] Trial), the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage in comparison to aspirin alone. METHODS: In a secondary analysis of POINT (N=4881), we assessed the time course for benefit and risk from the combination of clopidogrel and aspirin. The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction, or ischemic vascular death. The primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left-truncated models. RESULTS: Through 90 days, the rate of major ischemic events was initially high then decreased markedly, whereas the rate of major hemorrhage remained low but relatively constant throughout. With the use of a model-based approach, the optimal change point for major ischemic events was 21 days (0-21 days hazard ratio 0.65 for clopidogrel-aspirin versus aspirin; 95% CI, 0.50-0.85; P=0.0015, in comparison to 22-90 days hazard ratio, 1.38; 95% CI, 0.81-2.35; P=0.24). Models showed benefits of clopidogrel-aspirin for treatment delayed as long as 3 days after symptom onset. CONCLUSIONS: The benefit of clopidogrel-aspirin occurs predominantly within the first 21 days, and outweighs the low, but ongoing risk of major hemorrhage. When considered with the results of the CHANCE trial (Clopidogrel in High-Risk Patients With Non-disabling Cerebrovascular Events), a similar trial treating with clopidogrel-aspirin for 21 days and showing no increase in major hemorrhage, these results suggest that limiting clopidogrel-aspirin use to 21 days may maximize benefit and reduce risk after high-risk transient ischemic attack or minor ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Bayesian hierarchical EMAX model for dose-response in early phase efficacy clinical trials.

A primary goal of a phase II dose-ranging trial is to identify a correct dose before moving forward to a phase III confirmatory trial. A correct dose is one that is actually better than control. A popular model in phase II is an independent model that puts no structure on the dose-response relationship. Unfortunately, the independent model does not efficiently use information from related doses. One very successful alternate model improves power using a pre-specified dose-response structure. Past research indicates that EMAX models are broadly successful and therefore attractive for designing dose-response trials. However, there may be instances of slight risk of nonmonotone trends that need to be addressed when planning a clinical trial design. We propose to add hierarchical parameters to the EMAX model. The added layer allows information about the treatment effect in one dose to be "borrowed" when estimating the treatment effect in another dose. This is referred to as the hierarchical EMAX model. Our paper compares three different models (independent, EMAX, and hierarchical EMAX) and two different design strategies. The first design considered is Bayesian with a fixed trial design, and it has a fixed schedule for randomization. The second design is Bayesian but adaptive, and it uses response adaptive randomization. In this article, a randomized trial of patients with severe traumatic brain injury is provided as a motivating example.

Recommendations for the Establishment of Stroke Systems of Care: A 2019 Update.

In 2005, the American Stroke Association published recommendations for the establishment of stroke systems of care and in 2013 expanded on them with a statement on interactions within stroke systems of care. The aim of this policy statement is to provide a comprehensive review of the scientific evidence evaluating stroke systems of care to date and to update the American Stroke Association recommendations on the basis of improvements in stroke systems of care. Over the past decade, stroke systems of care have seen vast improvements in endovascular therapy, neurocritical care, and stroke center certification, in addition to the advent of innovations, such as telestroke and mobile stroke units, in the context of significant changes in the organization of healthcare policy in the United States. This statement provides an update to prior publications to help guide policymakers and public healthcare agencies in continually updating their stroke systems of care in light of these changes. This statement and its recommendations span primordial and primary prevention, acute stroke recognition and activation of emergency medical services, triage to appropriate facilities, designation of and treatment at stroke centers, secondary prevention at hospital discharge, and rehabilitation and recovery.

Blood Pressure-Attained Analysis of ATACH 2 Trial.

BACKGROUND AND PURPOSE: We compared the rates of death or disability, defined by modified Rankin Scale score of 4 to 6, at 3 months in patients with intracerebral hemorrhage according to post-treatment systolic blood pressure (SBP)-attained status. METHODS: We divided 1000 subjects with SBP ≥180 mm Hg who were randomized within 4.5 hours of symptom onset as follows: SBP <140 mm Hg achieved or not achieved within 2 hours; subjects in whom SBP <140 mm Hg was achieved within 2 hours were further divided: SBP <140 mm Hg for 21 to 22 hours (reduced and maintained) or SBP was ≥140 mm Hg for at least 2 hours during the period between 2 and 24 hours (reduced but not maintained). RESULTS: Compared with subjects without reduction of SBP <140 mm Hg within 2 hours, subjects with reduction and maintenance of SBP <140 mm Hg within 2 hours had a similar rate of death or disability (relative risk of 0.98; 95% confidence interval, 0.74-1.29). The rates of neurological deterioration within 24 hours were significantly higher in reduced and maintained group (10.4%; relative risk, 1.98; 95% confidence interval, 1.08-3.62) and in reduced but not maintained group (11.5%; relative risk, 2.08; 95% confidence interval, 1.15-3.75) compared with reference group. The rates of cardiac-related adverse events within 7 days were higher among subjects with reduction and maintenance of SBP <140 mmHg compared to subjects without reduction (11.2% versus 6.4%). CONCLUSIONS: No decline in death or disability but higher rates of neurological deterioration and cardiac-related adverse events were observed among intracerebral hemorrhage subjects with reduction with and without maintenance of intensive SBP goals. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01176565.

The life cycles of six multi-center adaptive clinical trials focused on neurological emergencies developed for the Advancing Regulatory Science initiative of the National Institutes of Health and US Food and Drug Administration: Case studies from the Adaptive Designs Accelerating Promising Treatments Into Trials Project.

OBJECTIVES: Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed. METHODS: To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations. RESULTS: The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies. CONCLUSION: Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early in the process appears to be associated with improved attitudes towards adaptive designs over the life cycle of clinical trial development.

A conceptual model for the development process of confirmatory adaptive clinical trials within an emergency research network.

BACKGROUND: Adaptive clinical trials use accumulating data from enrolled subjects to alter trial conduct in pre-specified ways based on quantitative decision rules. In this research, we sought to characterize the perspectives of key stakeholders during the development process of confirmatory-phase adaptive clinical trials within an emergency clinical trials network and to build a model to guide future development of adaptive clinical trials. METHODS: We used an ethnographic, qualitative approach to evaluate key stakeholders' views about the adaptive clinical trial development process. Stakeholders participated in a series of multidisciplinary meetings during the development of five adaptive clinical trials and completed a Strengths-Weaknesses-Opportunities-Threats questionnaire. In the analysis, we elucidated overarching themes across the stakeholders' responses to develop a conceptual model. RESULTS: Four major overarching themes emerged during the analysis of stakeholders' responses to questioning: the perceived statistical complexity of adaptive clinical trials and the roles of collaboration, communication, and time during the development process. Frequent and open communication and collaboration were viewed by stakeholders as critical during the development process, as were the careful management of time and logistical issues related to the complexity of planning adaptive clinical trials. CONCLUSION: The Adaptive Design Development Model illustrates how statistical complexity, time, communication, and collaboration are moderating factors in the adaptive design development process. The intensity and iterative nature of this process underscores the need for funding mechanisms for the development of novel trial proposals in academic settings.

Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage.

BACKGROUND: Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. METHODS: We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. RESULTS: Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P=0.002). CONCLUSIONS: The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565 .).

Hyperbaric oxygen brain injury treatment (HOBIT) trial: a multifactor design with response adaptive randomization and longitudinal modeling.

The goals of phase II clinical trials are to gain important information about the performance of novel treatments and decide whether to conduct a larger phase III trial. This can be complicated in cases when the phase II trial objective is to identify a novel treatment having several factors. Such multifactor treatment scenarios can be explored using fixed sample size trials. However, the alternative design could be response adaptive randomization with interim analyses and additionally, longitudinal modeling whereby more data could be used in the estimation process. This combined approach allows a quicker and more responsive adaptation to early estimates of later endpoints. Such alternative clinical trial designs are potentially more powerful, faster, and smaller than fixed randomized designs. Such designs are particularly challenging, however, because phase II trials tend to be smaller than subsequent confirmatory phase III trials. The phase II trial may need to explore a large number of treatment variations to ensure that the efficacy of optimal clinical conditions is not overlooked. Adaptive trial designs need to be carefully evaluated to understand how they will perform and to take full advantage of their potential benefits. This manuscript discusses a Bayesian response adaptive randomization design with a longitudinal model that uses a multifactor approach for predicting phase III study success via the phase II data. The approach is based on an actual clinical trial design for the hyperbaric oxygen brain injury treatment trial. Specific details of the thought process and the models informing the trial design are provided. Copyright © 2016 John Wiley & Sons, Ltd.

Reflections on the Adaptive Designs Accelerating Promising Trials Into Treatments (ADAPT-IT) Process-Findings from a Qualitative Study.

CONTEXT: The context for this study was the Adaptive Designs Advancing Promising Treatments Into Trials (ADAPT-IT) project, which aimed to incorporate flexible adaptive designs into pivotal clinical trials and to conduct an assessment of the trial development process. Little research provides guidance to academic institutions in planning adaptive trials. OBJECTIVES: The purpose of this qualitative study was to explore the perspectives and experiences of stakeholders as they reflected back about the interactive ADAPT-IT adaptive design development process, and to understand their perspectives regarding lessons learned about the design of the trials and trial development. MATERIALS AND METHODS: We conducted semi-structured interviews with ten key stakeholders and observations of the process. We employed qualitative thematic text data analysis to reduce the data into themes about the ADAPT-IT project and adaptive clinical trials. RESULTS: The qualitative analysis revealed four themes: education of the project participants, how the process evolved with participant feedback, procedures that could enhance the development of other trials, and education of the broader research community. DISCUSSION AND CONCLUSIONS: While participants became more likely to consider flexible adaptive designs, additional education is needed to both understand the adaptive methodology and articulate it when planning trials.

Clinical trialist perspectives on the ethics of adaptive clinical trials: a mixed-methods analysis.

BACKGROUND: In an adaptive clinical trial (ACT), key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts' views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to elucidate the opinions of clinical trial experts regarding their beliefs about ethical aspects of ACTs. METHODS: We used a convergent, mixed-methods design employing a 22-item ACTs beliefs survey with visual analog scales and open-ended questions and mini-focus groups. We developed a coding scheme to conduct thematic searches of textual data, depicted responses to visual analog scales on box-plot diagrams, and integrated findings thematically. Fifty-three clinical trial experts from four constituent groups participated: academic biostatisticians (n = 5); consultant biostatisticians (n = 6); academic clinicians (n = 22); and other stakeholders including patient advocacy, National Institutes of Health, and U.S. Food and Drug Administration representatives (n = 20). RESULTS: The respondents recognized potential ethical benefits of ACTs, including a higher probability of receiving an effective intervention for participants, optimizing resource utilization, and accelerating treatment discovery. Ethical challenges voiced include developing procedures so trial participants can make informed decisions about taking part in ACTs and plausible, though unlikely risks of research personnel altering enrollment patterns. CONCLUSIONS: Clinical trial experts recognize ethical advantages but also pose potential ethical challenges of ACTs. The four constituencies differ in their weighing of ACT ethical considerations based on their professional vantage points. These data suggest further discussion about the ethics of ACTs is needed to facilitate ACT planning, design and conduct, and ultimately better allow planners to weigh ethical implications of competing trial designs.

Very early administration of progesterone for acute traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS: We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS: A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).

The empirical foundations of telemedicine interventions for chronic disease management.

The telemedicine intervention in chronic disease management promises to involve patients in their own care, provides continuous monitoring by their healthcare providers, identifies early symptoms, and responds promptly to exacerbations in their illnesses. This review set out to establish the evidence from the available literature on the impact of telemedicine for the management of three chronic diseases: congestive heart failure, stroke, and chronic obstructive pulmonary disease. By design, the review focuses on a limited set of representative chronic diseases because of their current and increasing importance relative to their prevalence, associated morbidity, mortality, and cost. Furthermore, these three diseases are amenable to timely interventions and secondary prevention through telemonitoring. The preponderance of evidence from studies using rigorous research methods points to beneficial results from telemonitoring in its various manifestations, albeit with a few exceptions. Generally, the benefits include reductions in use of service: hospital admissions/re-admissions, length of hospital stay, and emergency department visits typically declined. It is important that there often were reductions in mortality. Few studies reported neutral or mixed findings.