Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion: In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov (NCT04217551, 2019-12-30).

Anemia From Inflammation After Intracerebral Hemorrhage and Relationships With Outcome.

BACKGROUND: Baseline anemia is associated with poor intracerebral hemorrhage (ICH) outcomes. However, underlying drivers for anemia and whether anemia development after ICH impacts clinical outcomes are unknown. We hypothesized that inflammation drives anemia development after ICH and assessed their relationship to outcomes. METHODS AND RESULTS: Patients with serial hemoglobin and iron biomarker concentrations from the HIDEF (High-Dose Deferoxamine in Intracerebral Hemorrhage) trial were analyzed. Adjusted linear mixed models assessed laboratory changes over time. Of 42 patients, significant decrements in hemoglobin occurred with anemia increasing from 19% to 45% by day 5. Anemia of inflammation iron biomarker criteria was met in 88%. A separate cohort of 521 patients with ICH with more granular serial hemoglobin and long-term neurological outcome data was also investigated. Separate regression models assessed whether (1) systemic inflammatory response syndrome (SIRS) scores related to hemoglobin changes over time and (2) hemoglobin changes related to poor 90-day outcome. In this cohort, anemia prevalence increased from 30% to 71% within 2 days of admission yet persisted beyond this time. Elevated systemic inflammatory response syndrome was associated with greater hemoglobin decrements over time (adjusted parameter estimate: -0.27 [95% CI, -0.37 to -0.17]) and greater hemoglobin decrements were associated with poor outcomes (adjusted odds ratio per 1 g/dL increase, 0.76 [95% CI, 0.62-0.93]) independent to inflammation and ICH severity. CONCLUSIONS: We identified novel findings that acute anemia development after ICH is common, rapid, and related to inflammation. Because anemia development is associated with poor outcomes, further work is required to clarify if anemia, or its underlying drivers, are modifiable treatment targets that can improve ICH outcomes. REGISTRATION: https://www.clinicaltrials.gov Unique identifier: NCT01662895.

Clinicians' approach to predicting post-cardiac arrest outcomes for patients enrolled in a United States clinical trial.

PURPOSE: Perceived poor prognosis can lead to withdrawal of life-sustaining therapies (WLST) in patients who might otherwise recover. We characterized clinicians' approach to post-arrest prognostication in a multicenter clinical trial. METHODS: Semi-structured interviews were conducted with clinicians who treated a comatose post-cardiac arrest patient enrolled in the Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (ICECAP) trial (NCT04217551). Two authors independently analyzed each interview using inductive and deductive coding. The clinician reported how they arrived at a prognosis for the specific patient. We summarized the frequency with which clinicians reported using objective diagnostics to formulate their prognosis, and compared the reported approaches to established guidelines. Each respondent provided demographic information and described local neuroprognostication practices. RESULTS: We interviewed 30 clinicians at 19 US hospitals. Most claimed adherence to local hospital neuroprognostication protocols (n = 19). Prognostication led to WLST for perceived poor neurological prognosis in 15/30 patients, of whom most showed inconsistencies with guidelines or trial recommendations, respectively. In 10/15 WLST cases, clinicians reported relying on multimodal testing. A prevalent theme was the use of "clinical gestalt," defined as prognosticating based on a patient's overall appearance or a subjective impression in the absence of objective data. Many clinicians (21/30) reported using clinical gestalt for initial prognostication, with 9/21 expressing high confidence initially. CONCLUSION: Clinicians in our study state they follow neuroprognostication guidelines in general but often do not do so in actual practice. They reported clinical gestalt frequently informed early, highly confident prognostic judgments, and few objective tests changed initial impressions. Subjective prognostication may undermine well-designed trials.

Cognitive Outcome after Acute Spontaneous Intracerebral Hemorrhage: Analysis of the iDEF Randomized Trial.

INTRODUCTION: The impact of intracerebral hemorrhage (ICH) on cognition and the determinants of cognitive recovery early after ICH remain elusive. In this post hoc analysis of the intracerebral hemorrhage deferoxamine (iDEF) trial, we examined the trajectories of cognitive impairment and the determinants of early cognitive recovery after ICH. METHODS: We examined baseline factors associated with a 90-day cognitive outcome and constructed generalized linear mixed models to examine the trajectory of cognitive function over time among iDEF participants. Cognition was measured by the Montreal Cognitive Assessment (MoCA) scores on days 7, 30, and 90. RESULTS: 291 were available for analysis under the trial's modified intention-to-treat definition (38% female, mean age 60.3 ± 12.0 years, median NIHSS 13, IQR 8-18). The median baseline ICH volume was 12.9 IQR (6.4-26.0) mL; 59 (20%) of the ICH cases were lobar, 120 (41%) had intraventricular extension. There was an overall significant increase in total MOCA score with time (p < 0.0001). Total MOCA score increased by an estimated 3.9 points (95% CI: 3.1, 4.7) between the day 7 and day 30 assessments and by an additional 2.9 points (95% CI: 2.2, 3.6) between the day 30 and day 90 assessments. Despite the overall improvement, 134 of 205 (65%) patients with an available 90-day MoCA score remained cognitively impaired with a score <26 on day 90. Older age, higher NIHSS score, baseline ICH volume, intraventricular hemorrhage, and perihematoma edema had an adjusted negative impact on cognitive recovery. CONCLUSIONS: Although ICH survivors exhibit significant improvement of cognitive status over the first 3 months, cognitive performance remains impaired in the majority of patients. Among factors independently associated with worse cognitive recovery, higher baseline ICH, intraventricular blood and perihematomal edema volumes, are potential therapeutic targets that merit further exploration.

Rationale and Design of the Statins Use in Intracerebral Hemorrhage Patients (SATURN) Trial.

INTRODUCTION: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life. METHODS: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE. CONCLUSION: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins.

Blood Pressure Management After Endovascular Therapy for Acute Ischemic Stroke: The BEST-II Randomized Clinical Trial.

Importance: The effects of moderate systolic blood pressure (SBP) lowering after successful recanalization with endovascular therapy for acute ischemic stroke are uncertain. Objective: To determine the futility of lower SBP targets after endovascular therapy (<140 mm Hg or 160 mm Hg) compared with a higher target (≤180 mm Hg). Design, Setting, and Participants: Randomized, open-label, blinded end point, phase 2, futility clinical trial that enrolled 120 patients with acute ischemic stroke who had undergone successful endovascular therapy at 3 US comprehensive stroke centers from January 2020 to March 2022 (final follow-up, June 2022). Intervention: After undergoing endovascular therapy, participants were randomized to 1 of 3 SBP targets: 40 to less than 140 mm Hg, 40 to less than 160 mm Hg, and 40 to 180 mm Hg or less (guideline recommended) group, initiated within 60 minutes of recanalization and maintained for 24 hours. Main Outcomes and Measures: Prespecified multiple primary outcomes for the primary futility analysis were follow-up infarct volume measured at 36 (±12) hours and utility-weighted modified Rankin Scale (mRS) score (range, 0 [worst] to 1 [best]) at 90 (±14) days. Linear regression models were used to test the harm-futility boundaries of a 10-mL increase (slope of 0.5) in the follow-up infarct volume or a 0.10 decrease (slope of -0.005) in the utility-weighted mRS score with each 20-mm Hg SBP target reduction after endovascular therapy (1-sided α = .05). Additional prespecified futility criterion was a less than 25% predicted probability of success for a future 2-group, superiority trial comparing SBP targets of the low- and mid-thresholds with the high-threshold (maximum sample size, 1500 with respect to the utility-weighted mRS score outcome). Results: Among 120 patients randomized (mean [SD] age, 69.6 [14.5] years; 69 females [58%]), 113 (94.2%) completed the trial. The mean follow-up infarct volume was 32.4 mL (95% CI, 18.0 to 46.7 mL) for the less than 140-mm Hg group, 50.7 mL (95% CI, 33.7 to 67.7 mL), for the less than 160-mm Hg group, and 46.4 mL (95% CI, 24.5 to 68.2 mL) for the 180-mm Hg or less group. The mean utility-weighted mRS score was 0.51 (95% CI, 0.38 to 0.63) for the less than 140-mm Hg group, 0.47 (95% CI, 0.35 to 0.60) for the less than 160-mm Hg group, and 0.58 (95% CI, 0.46 to 0.71) for the high-target group. The slope of the follow-up infarct volume for each mm Hg decrease in the SBP target, adjusted for the baseline Alberta Stroke Program Early CT score, was -0.29 (95% CI, -0.81 to ∞; futility P = .99). The slope of the utility-weighted mRS score for each mm Hg decrease in the SBP target after endovascular therapy, adjusted for baseline utility-weighted mRS score, was -0.0019 (95% CI, -∞ to 0.0017; futility P = .93). Comparing the high-target SBP group with the lower-target groups, the predicted probability of success for a future trial was 25% for the less than 140-mm Hg group and 14% for the 160-mm Hg group. Conclusions and Relevance: Among patients with acute ischemic stroke, lower SBP targets less than either 140 mm Hg or 160 mm Hg after successful endovascular therapy did not meet prespecified criteria for futility compared with an SBP target of 180 mm Hg or less. However, the findings suggested a low probability of benefit from lower SBP targets after endovascular therapy if tested in a future larger trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04116112.

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.

Statistical assessment of the prognostic and the predictive value of biomarkers-A biomarker assessment framework with applications to traumatic brain injury biomarker studies.

Studies that investigate the performance of prognostic and predictive biomarkers are commonplace in medicine. Evaluating the performance of biomarkers is challenging in traumatic brain injury (TBI) and other conditions when both the time factor (i.e. time from injury to biomarker measurement) and different levels or doses of treatments are in play. Such factors need to be accounted for when assessing the biomarker's performance in relation to a clinical outcome. The Hyperbaric Oxygen in Brain Injury Treatment (HOBIT) trial, a phase II randomized control clinical trial seeks to determine the dose of hyperbaric oxygen therapy (HBOT) for treating severe TBI that has the highest likelihood of demonstrating efficacy in a phase III trial. Hyperbaric Oxygen in Brain Injury Treatment will study up to 200 participants with severe TBI. This paper discusses the statistical approaches to assess the prognostic and predictive performance of the biomarkers studied in this trial, where prognosis refers to the association between a biomarker and the clinical outcome while the predictiveness refers to the ability of the biomarker to identify patient subgroups that benefit from therapy. Analyses based on initial biomarker levels accounting for different levels of HBOT and other baseline clinical characteristics, and analyses of longitudinal changes in biomarker levels are discussed from a statistical point of view. Methods for combining biomarkers that are of complementary nature are also considered and the relevant algorithms are illustrated in detail along with an extensive simulation study that assesses the performance of the statistical methods. Even though the discussed approaches are motivated by the HOBIT trial, their applications are broader. They can be applied in studies assessing the predictiveness and prognostic ability of biomarkers in relation to a well-defined therapeutic intervention and clinical outcome.

Early Signs of Elevated Intracranial Pressure on Computed Tomography Correlate With Measured Intracranial Pressure in the Intensive Care Unit and Six-Month Outcome After Moderate to Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Early triage and treatment after TBI have been shown to improve outcome. Identifying patients at risk for increased intracranial pressure (ICP) via baseline computed tomography (CT) , however, has not been validated previously in a prospective dataset. We hypothesized that acute CT findings of elevated ICP, combined with direct ICP measurement, hold prognostic value in terms of six-month patient outcome after TBI. Data were obtained from the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECTIII) multi-center clinical trial. Baseline CT scans for 881 participants were individually reviewed by a blinded central neuroradiologist. Five signs of elevated ICP were measured (sulcal obliteration, lateral ventricle compression, third ventricle compression, midline shift, and herniation). Associations between signs of increased ICP and outcomes (six-month functional outcome and death) were assessed. Secondary analyses of 354 patients with recorded ICP monitoring data available explored the relationships between hemorrhage phenotype/anatomic location, sustained ICP ≥20 mm Hg, and surgical intervention(s). Univariate and multi-variate logistic/linear regressions were performed; p < 0.05 is defined as statistically significant. Imaging characteristics associated with ICP in this cohort include sulcal obliteration (p = 0.029) and third ventricular compression (p = 0.039). Univariate regression analyses indicated that increasing combinations of the five defined signs of elevated ICP were associated with death, poor functional outcome, and time to death. There was also an increased likelihood of death if patients required craniotomy (odds ratio [OR] = 4.318, 95% confidence interval [1.330-16.030]) or hemicraniectomy (OR = 2.993 [1.109-8.482]). On multi-variate regression analyses, hemorrhage location was associated with death (posterior fossa, OR = 3.208 [1.120-9.188] and basal ganglia, OR = 3.079 [1.178-8.077]). Volume of hemorrhage >30 cc was also associated with increased death, OR = 3.702 [1.575-8.956]). The proportion of patient hours with sustained ICP ≥20 mm Hg, and maximum ICP ≥20 mm Hg were also directly correlated with increased death (OR = 6 4.99 [7.731-635.51]; and OR = 1.025 [1.004-1.047]), but not with functional outcome. Poor functional outcome was predicted by concurrent presence of all five radiographic signs of elevated ICP (OR = 4.44 [1.514-14.183]) and presence of frontal lobe (OR = 2.951 [1.265-7.067]), subarachnoid (OR = 2.231 [1.067-4.717]), or intraventricular (OR = 2.249 [1.159-4.508]) hemorrhage. Time to death was modulated by total patient days of elevated ICP ≥20 mm Hg (effect size = 3.424 [1.500, 5.439]) in the first two weeks of hospitalization. Sulcal obliteration and third ventricular compression, radiographic signs of elevated ICP, were significantly associated with measurements of ICP ≥20 mm Hg. These radiographic biomarkers were significantly associated with patient outcome. There is potential utility of ICP-related imaging variables in triage and prognostication for patients after moderate-severe TBI.

Optimal Randomization Designs for Large Multicenter Clinical Trials: From the National Institutes of Health Stroke Trials Network Funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke Experience.

From 2016 to 2021, the National Institutes of Health Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke initiated ten multicenter randomized controlled clinical trials. Optimal subject randomization designs are demanded with 4 critical properties: (1) protection of treatment assignment randomness, (2) achievement of the desired treatment allocation ratio, (3) balancing of baseline covariates, and (4) ease of implementation. For acute stroke trials, it is necessary to minimize the time between eligibility assessment and treatment initiation. This article reviews the randomization designs for 3 trials currently enrolling in Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke, the SATURN (Statins in Intracerebral Hemorrhage Trial), the MOST (Multiarm Optimization of Stroke Thrombolysis Trial), and the FASTEST (Recombinant Factor VIIa for Hemorrhagic Stroke Trial). Randomization methods utilized in these trials include minimal sufficient balance, block urn design, big stick design, and step-forward randomization. Their advantages and limitations are reviewed and compared with traditional stratified permuted block design and minimization.

COVID-19 convalescent plasma boosts early antibody titer and does not influence the adaptive immune response.

Multiple randomized, controlled clinical trials have yielded discordant results regarding the efficacy of convalescent plasma in outpatients, with some showing an approximately 2-fold reduction in risk and others showing no effect. We quantified binding and neutralizing antibody levels in 492 of the 511 participants from the Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) of a single unit of COVID-19 convalescent plasma (CCP) versus saline infusion. In a subset of 70 participants, peripheral blood mononuclear cells were obtained to define the evolution of B and T cell responses through day 30. Binding and neutralizing antibody responses were approximately 2-fold higher 1 hour after infusion in recipients of CCP compared with saline plus multivitamin, but levels achieved by the native immune system by day 15 were almost 10-fold higher than those seen immediately after CCP administration. Infusion of CCP did not block generation of the host antibody response or skew B or T cell phenotype or maturation. Activated CD4+ and CD8+ T cells were associated with more severe disease outcome. These data show that CCP leads to a measurable boost in anti-SARS-CoV-2 antibodies but that the boost is modest and may not be sufficient to alter disease course.

Decentralized research technology use in multicenter clinical research studies based at U.S. academic research centers.

Introduction: During the COVID-19 pandemic, research organizations accelerated adoption of technologies that enable remote participation. Now, there's a pressing need to evaluate current decentralization practices and develop appropriate research, education, and operations infrastructure. The purpose of this study was to examine current adoption of decentralization technologies in a sample of clinical research studies conducted by academic research organizations (AROs). Methods: The setting was three data coordinating centers in the U.S. These centers initiated coordination of 44 clinical research studies during or after 2020, with national recruitment and enrollment, and entailing coordination between one and one hundred sites. We determined the decentralization technologies used in these studies. Results: We obtained data for 44/44 (100%) trials coordinated by the three centers. Three technologies have been adopted across nearly all studies (98-100%): eIRB, eSource, and Clinical Trial Management Systems. Commonly used technologies included e-Signature (32/44, 73%), Online Payments Portals (26/44, 59%), ePROs (23/44, 53%), Interactive Response Technology (22/44, 50%), Telemedicine (19/44, 43%), and eConsent (18/44, 41%). Wearables (7/44,16%) and Online Recruitment Portals (5/44,11%) were less common. Rarely utilized technologies included Direct-to-Patient Portals (1/44, 2%) and Home Health Nurse Portals (1/44, 2%). Conclusions: All studies incorporated some type of decentralization technology, with more extensive adoption than found in previous research. However, adoption may be strongly influenced by institution-specific IT and informatics infrastructure and support. There are inherent needs, responsibilities, and challenges when incorporating decentralization technology into a research study, and AROs must ensure that infrastructure and informatics staff are adequate.

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.

White matter hyperintensity progression is associated with incident probable dementia or mild cognitive impairment.

BACKGROUND: White matter hyperintensity (WMH) on brain MRI is associated with developing dementia or mild cognitive impairment (MCI), but WMH progression over time has not been fully investigated as an independent risk factor. METHODS: We performed a post hoc analysis of the Systolic Blood Pressure Intervention Trial - Memory and Cognition in Decreased Hypertension (SPRINT MIND) trial. The primary outcome was incident probable dementia or MCI (dementia/MCI) before the follow-up MRI at 48 months from enrolment. The primary predictor was WMH progression, defined as the Z score difference between the follow-up and baseline WMH volumes. The secondary predictor was a binary WMH progression threshold (≥1.4 mL vs <1.4 mL). RESULTS: Among the 433 included patients, 33 (7.6%) developed dementia/MCI. There were 156 (36.0%) patients who met the WMH progression threshold of ≥1.4 mL, in whom the rate of dementia/MCI was 12.8% (20/156) vs 4.7% (13/277) of patients with <1.4 mL WMH progression (p=0.002). In multivariable logistic regression, the Z score of WMH progression was associated with dementia/MCI (OR 1.51, 95% CI 1.12 to 2.04, p=0.007) as was the WMH progression threshold of ≥1.4 mL (OR 2.89, 95% CI 1.23 to 6.81, p=0.015). CONCLUSIONS: In this post hoc analysis of SPRINT MIND, WMH progression over 48 months was associated with the development of probable dementia or MCI.

Prolonged Automated Robotic TCD Monitoring in Acute Severe TBI: Study Design and Rationale.

BACKGROUND: Transcranial Doppler ultrasonography (TCD) is a portable, bedside, noninvasive diagnostic tool used for the real-time assessment of cerebral hemodynamics. Despite the evident utility of TCD and the ability of this technique to function as a stethoscope to the brain, its use has been limited to specialized centers because of the dearth of technical and clinical expertise required to acquire and interpret the cerebrovascular parameters. Additionally, the conventional pragmatic episodic TCD monitoring protocols lack dynamic real-time feedback to guide time-critical clinical interventions. Fortunately, with the recent advent of automated robotic TCD technology in conjunction with the automated software for TCD data processing, we now have the technology to automatically acquire TCD data and obtain clinically relevant information in real-time. By obviating the need for highly trained clinical personnel, this technology shows great promise toward a future of widespread noninvasive monitoring to guide clinical care in patients with acute brain injury. METHODS: Here, we describe a proposal for a prospective observational multicenter clinical trial to evaluate the safety and feasibility of prolonged automated robotic TCD monitoring in patients with severe acute traumatic brain injury (TBI). We will enroll patients with severe non-penetrating TBI with concomitant invasive multimodal monitoring including, intracranial pressure, brain tissue oxygenation, and brain temperature monitoring as part of standard of care in centers with varying degrees of TCD availability and experience. Additionally, we propose to evaluate the correlation of pertinent TCD-based cerebral autoregulation indices such as the critical closing pressure, and the pressure reactivity index with the brain tissue oxygenation values obtained invasively. CONCLUSIONS: The overarching goal of this study is to establish safety and feasibility of prolonged automated TCD monitoring for patients with TBI in the intensive care unit and identify clinically meaningful and pragmatic noninvasive targets for future interventions.

Brain Oxygen Optimization in Severe Traumatic Brain Injury (BOOST-3): a multicentre, randomised, blinded-endpoint, comparative effectiveness study of brain tissue oxygen and intracranial pressure monitoring versus intracranial pressure alone.

INTRODUCTION: Management of traumatic brain injury (TBI) includes invasive monitoring to prevent secondary brain injuries. Intracranial pressure (ICP) monitor is the main measurement used to that intent but cerebral hypoxia can occur despite normal ICP. This study will assess whether the addition of a brain tissue oxygenation (PbtO2) monitor prevents more secondary injuries that will translate into improved functional outcome. METHODS AND ANALYSIS: Multicentre, randomised, blinded-endpoint comparative effectiveness study enrolling 1094 patients with severe TBI monitored with both ICP and PbtO2. Patients will be randomised to medical management guided by ICP alone (treating team blinded to PbtO2 values) or both ICP and PbtO2. Management is protocolised according to international guidelines in a tiered approach fashion to maintain ICP <22 mm Hg and PbtO2 >20 mm Hg. ICP and PbtO2 will be continuously recorded for a minimum of 5 days. The primary outcome measure is the Glasgow Outcome Scale-Extended performed at 180 (±30) days by a blinded central examiner. Favourable outcome is defined according to a sliding dichotomy where the definition of favourable outcome varies according to baseline severity. Severity will be defined according to the probability of poor outcome predicted by the IMPACT core model. A large battery of secondary outcomes including granular neuropsychological and quality of life measures will be performed. ETHICS AND DISSEMINATION: This has been approved by Advarra Ethics Committee (Pro00030585). Results will be presented at scientific meetings and published in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03754114).

The Experiences and Needs of Families of Comatose Patients After Cardiac Arrest and Severe Neurotrauma: The Perspectives of National Key Stakeholders During a National Institutes of Health-Funded Workshop.

OBJECTIVES: Severe acute brain injury (SABI) from cardiac arrest and traumatic brain injury happens suddenly and unexpectedly, carrying high potential for lifelong disability with substantial prognostic uncertainty. Comprehensive assessments of family experiences and support needs after SABI are lacking. Our objective is to elicit "on-the-ground" perspectives about the experiences and needs of families of patients with SABI. DESIGN: Two-phase qualitative study of families and multidisciplinary U.S. healthcare professionals (mHCPs) with expertise in SABI: Phase 1 included semistructured interviews to generate formative findings; phase 2 entailed facilitated discussions to confirm and expand initial findings. SETTING: Phase 1: academic medical center; phase 2: virtual workshop. SUBJECTS: Phase 1 included seven family members and 12 mHCPs. Phase 2 included nationally recruited stakeholders (17 family members and 12 mHCPs). INTERVENTION: None. MEASUREMENTS AND RESULTS: We explored: 1) what are families' needs in the first 48 hours? 2) How are these needs addressed? and 3) How can hospitals better meet these needs? Qualitative analysis included inductive and deductive approaches guided by a conceptual ecological model. Four major needs were identified: 1) challenges in coping with uncertainty in early prognostication, 2) inattention to physical needs of family, 3) deficits in compassionate and consistent communication, and 4) need for engagement with families as stakeholders in improving future practices. Participants' recommendations included: 1) ways to communicate more clearly and consistently, 2) better assistance with navigating resources and access to places for families to care for themselves, and 3) opportunities for families to remain connected with their loved ones, social support networks, and the clinical team. CONCLUSIONS: Stakeholders identified novel insights regarding families' experiences during the hospitalization of comatose SABI patients and factors that can contribute to improved decision-making and physical/emotional outcomes. Interventions to address these unmet needs are promising targets to improve outcomes.

Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial.

BACKGROUND: There are limited data on the trajectory of recovery and long-term functional outcomes after intracerebral hemorrhage (ICH). Most ICH trials have conventionally assessed outcomes at 3 months following the footsteps of ischemic stroke. The i-DEF trial (Intracerebral Hemorrhage Deferoxamine Trial) assessed modified Rankin Scale (mRS) longitudinally at prespecified time points from day 7 through the end of the 6-month follow-up period. We evaluated the trajectory of mRS among trial participants and examined the effect of deferoxamine on this trajectory. METHODS: We performed a post hoc analysis of the i-DEF trial, a multicenter, randomized, placebo-controlled, double-blind, futility-design, phase 2 clinical trial, based on the actual treatment received. Favorable outcome was defined as mRS score of 0-2. A generalized linear mixed model was used to evaluate the outcome trajectory over time, as well as whether the trajectory was altered by deferoxamine, after adjustments for randomization variables, presence of intraventricular hemorrhage, and ICH location. RESULTS: A total of 291 subjects were included in analysis (145 placebo and 146 deferoxamine). The proportion of patients with mRS score of 0-2 continually increased from day 7 to 180 in both groups (interaction P<0.0001 for time in main effects model), but treatment with deferoxamine favorably altered the trajectory (interaction P=0.0010). Between day 90 and 180, the deferoxamine group improved (P=0.0001), whereas there was not significant improvement in the placebo arm (P=0.3005). CONCLUSIONS: A large proportion of patients continue to improve up to 6 months after ICH. Future ICH trials should assess outcomes past 90 days for a minimum of 6 months. In i-DEF, treatment with deferoxamine seemed to accelerate and alter the trajectory of recovery as assessed by mRS. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02175225.

National Institutes of Health Stroke Scale as an Outcome in Stroke Research: Value of ANCOVA Over Analyzing Change From Baseline.

National Institutes of Health Stroke Scale (NIHSS), measured a few hours to days after stroke onset, is an attractive outcome measure for stroke research. NIHSS at the time of presentation (baseline NIHSS) strongly predicts the follow-up NIHSS. Because of the need to account for the baseline NIHSS in the analysis of follow-up NIHSS as an outcome measure, a common and intuitive approach is to define study outcome as the change in NIHSS from baseline to follow-up (ΔNIHSS). However, this approach has important limitations. Analyzing ΔNIHSS implies a very strong assumption about the relationship between baseline and follow-up NIHSS that is unlikely to be satisfied, drawing into question the validity of the resulting statistical analysis. This reduces the precision of the estimates of treatment effects and the power of clinical trials that use this approach to analysis. ANCOVA allows for the analysis of follow-up NIHSS as the dependent variable while adjusting for baseline NIHSS as a covariate in the model and addresses several challenges of using ΔNIHSS outcome using simple bivariate comparisons (eg, a t test, Wilcoxon rank-sum, linear regression without adjustment for baseline) for stroke research. In this article, we use clinical trial simulations to illustrate that variability in NIHSS outcome is less when follow-up NIHSS is adjusted for baseline compared to ΔNIHSS and how a reduction in this variability improves the power. We outline additional, important clinical and statistical arguments to support the superiority of ANCOVA using the final measurement of the NIHSS adjusted for baseline over, and caution against using, the simple bivariate comparison of absolute NIHSS change (ie, delta).