© 2019, Springer Nature Limited. The name of an author, Alex John London, has been corrected.

A central question in the assessment of benefit/harm of new treatments is: how does the average outcome on the new treatment (the factual) compare to the average outcome had patients received no treatment or a different treatment known to be effective (the counterfactual)? Randomized controlled trials (RCTs) are the standard for comparing the factual with the counterfactual. Recent developments necessitate and enable a new way of determining the counterfactual for some new medicines. For select situations, we propose a new framework for evidence generation, which we call “threshold‐crossing.” This framework leverages the wealth of information that is becoming available from completed RCTs and from real world data sources. Relying on formalized procedures, information gleaned from these data is used to estimate the counterfactual, enabling efficacy assessment of new drugs. We propose future (research) activities to enable “threshold‐crossing” for carefully selected products and indications in which RCTs are not feasible.

We sought to simultaneously confirm that substantial recovery at day 1 and day 7 after acute ischaemic stroke onset is associated with subsequent neurological deterioration in patients of the Acute Stroke Therapy by Inhibition of Neutrophils randomized clinical trial. Substantial recovery was assessed by improvement in the National Institutes of Health Stroke Score (NIHSS). Neurological deterioration was defined as any stroke event or NIHSS worsening from recovery assessment to day 90. After adjusting for age, t‐PA and day 1 NIHSS, there was a non‐significant tendency of substantial (pre‐specified as 75%) recovery at day 1 to be associated with later deterioration [odds ratio (OR) 2.47; 95% CI, 0.95–6.50]. The corresponding OR for substantial (pre‐defined as 65%) recovery at day 7 was 1.84 (0.85–3.96). Other thresholds for recovery were significantly associated with later deterioration: >50%, 80%, 90% and 100% for day 1 and >50%, 60%, 70%, 90% and 100% for day 7. The effect of recovery at day 1 was more important than that of later recovery. This study confirms the association between recovery and subsequent neurological deterioration and is the first to indicate the greater importance of acute recovery at day 1 in comparison with later recovery.

Section Editors: Marc Fisher MD Antoni Davalos MD More than 74 000 patients with acute ischemic stroke have been randomized into clinical trials over the past 35 years to investigate new therapies.1 Only one treatment, thrombolysis with recombinant tissue plasminogen activator, has emerged from these investigations.2 Efforts to establish acute neuroprotectant therapies have yet to succeed.3,4Have we squandered our resources? Has methodological rigidity delayed development of a new treatment or prolonged investigation of an ineffective therapy? Here we present a flexible and more efficient approach to clinical trial design and analysis. We have the potential to improve the use of scarce patient resources and to accelerate development of promising agents.In medical practice, we respond to a patient if a dosage seems inadequate by either changing the dosage or switching to another medication. We cautiously change treatment after reviewing new evidence: side effects, intractable symptoms, and poor adherence. We might express our estimate of how much the change may improve the patient’s condition in terms of probability. We repeat this process every time we update the treatment plan in light of new important information. Why not take the same approach to clinical trials?The proposed approach to the design and conduct of clinical trials uses Bayesian methods that make careful use of high-quality available past (prior) evidence to refine the inference from accumulating evidence in the ongoing clinical trial. This approach may: (1) enhance investigation of single agents or combination therapies; (2) make earlier and more reliable choices of dose for use in pivotal trials; (3) accelerate the progression from phase II into phase III trials all the way to a potentially seamless switch; and (4) treat trial participants more effectively by adaptively allocating more resources to therapies that are performing well while reducing support for …

BACKGROUND AND PURPOSE:UK-279,276, a recombinant glycoprotein, binds selectively to the CD11b/CD18 integrin on neutrophils and has the potential to modulate the neuroinflammation associated with acute stroke. After preclinical evidence of neuroprotection, UK-279,276 has entered clinical development. The purposes of this study were to evaluate the safety and tolerability of UK-279,276 and to examine its pharmacokinetics and pharmacodynamics (binding to neutrophil CD11b) in patients with acute stroke.METHODS:This was a multicenter, double-blind, dose-escalation study in 176 patients randomized to a single intravenous dose of UK-279,276 (6 cohorts: 0.06, 0.1, 0.2, 0.5, 1.0, 1.5 mg/kg) or placebo (3:1 randomization within each cohort) within 12 hours of stroke onset.RESULTS:Age and stroke severity were well balanced across groups, with a mean age of 70 years (range, 39 to 92 years) and moderate baseline stroke severity (mean Scandinavian Stroke Scale score, 36.5 to 43.2; mean National Institutes of Health Stroke Scale score, 6.3 to 8.5). UK-279,276 was well tolerated at doses up to 1.5 mg/kg. There was no evidence of a relationship between dose of UK-279,276 and adverse events or clinical chemistry or hematology laboratory tests, or of an increased incidence of infection-related adverse events with the study drug. A dose-dependent UK-279,276-specific IgG antibody response was observed in patients treated with the 1.0- and 1.5-mg/kg doses. UK-279,276 displayed nonlinear pharmacokinetics across the dose range investigated. The duration of CD11b saturation was dose dependent, with >80% saturation achieved for at least 7 days after treatment with UK-279,276 1.0 and 1.5 mg/kg.CONCLUSIONS:UK-279,276 was well tolerated in acute stroke patients at single doses up to 1.5 mg/kg. Further clinical investigation of UK-279,276 is ongoing.

Background and Purpose— UK-279,276 (neutrophil inhibitory factor) reduced infarct volume in a rat middle cerebral artery occlusion reperfusion model. ASTIN (Acute Stroke Therapy by Inhibition of Neutrophils) was an adaptive phase 2 dose-response–finding, proof-of-concept study to establish whether UK-279,276 improves recovery in acute ischemic stroke. The prime objective was to determine the dose that gave a clinically relevant effect in patients. Methods— A Bayesian sequential design with real-time efficacy data capture and continuous reassessment of the dose response allowed double-blind, randomized, adaptive allocation to 1 of 15 doses (dose range, 10 to 120 mg) or placebo and early termination for efficacy or futility. The primary end point was change from baseline to day 90 on the Scandinavian Stroke Scale (ΔSSS), adjusted for baseline SSS, aiming for a 3-point additional mean recovery above placebo. Results— Nine hundred sixty-six acute stroke patients (887 ischemic, 204 cotreated with intravenous tissue plasminogen activator; mean baseline SSS score, 28; range, 10 to 40) were treated within 6 hours of symptom onset. Mean ΔSSS was approximately +17 points of improvement on SSS for the overall evaluable population. There was no treatment effect for UK-279,276 (posterior probability of futility, 0.89). The trial was stopped early for futility. Post hoc analysis indicated a mean 1.6-point additional improvement on ΔSSS in the tissue plasminogen activator–treated subset (credible interval=0.5, 2.6). UK-279,276 was generally well tolerated, with no increased incidence of infections. Conclusions— UK-279,276 did not improve recovery in acute ischemic stroke patients but was devoid of serious side effects. The adaptive design facilitated early termination for futility.

The development of therapies for acute ischemic stroke has achieved a few notable successes and, unfortunately, many unsuccessful efforts. Many valuable lessons for the future assessment of new acute stroke therapies can be gleaned from the positive and negative prior trials. Phase T and II trials must be carefully designed and implemented to derive relevant, valuable information needed to proceed to phase III trials with promising interventions. The phase III trial should evaluate drug efficacy in an appropriately targeted stroke population evaluated by a meaningful and reliable outcome measure. Combinations of various types-of stroke therapies will likely be increasingly assessed in future trials that are designed and implemented by cooperative: efforts between the pharmaceutical industry, government agencies, academic advisors and clinical investigators.:The chances for future success in demonstrating efficacy with:acute stroke therapies will be enhanced by Carefully conceive, scientifically based clinical trials; The recommendations contained in this document may help to focus attention on how to achieve the goal of developing an expanding number of a effective and safe acute stroke therapies.

It is widely agreed that visuospatial orienting attention depends on a network of frontal and parietal areas in the right hemisphere. It is thought that the visuospatial orienting role of the right parietal lobe is related to its role in the production of overt eye movements. The experiments reported here test the possibility that other parietal regions may be important for directing attention in relation to response modalities other than eye movement. Specifically, we used positron emission tomography (PET) to test the hypothesis that a 'left' parietal area, the supramarginal gyrus, is important for attention in relation to limb movements (Rushworth et al., 1997; Rushworth, Ellison, & Walsh, in press). We have referred to this process as 'motor attention' to distinguish it from orienting attention. In one condition subjects spent most of the scanning period covertly attending to 'left' hand movements that they were about to make. Activity in this first condition was compared with a second condition with identical stimuli and movement responses but lacking motor attention periods. Comparison of the conditions revealed that motor attention-related activity was almost exclusively restricted to the 'left' hemisphere despite the fact that subjects only ever made ipsilateral, left-hand responses. Left parietal activity was prominent in this comparison, within the parietal lobe the critical region for motor attention was the supramarginal gyrus and the adjacent anterior intraparietal sulcus (AIP), a region anterior to the posterior parietal cortex identified with orienting attention. In a second part of the experiment we compared a condition in which subjects covertly rehearsed verbal responses with a condition in which they made verbal responses immediately without rehearsal. A comparison of the two conditions revealed verbal rehearsal-related activity in several anterior left hemisphere areas including Broca's area. The lack of verbal rehearsal-related activity in the left supra-marginal gyrus confirms that this area plays a direct role in motor attention that cannot be attributed to any strategy of verbal mediation. The results also provide evidence concerning the importance of ventral premotor (PMv) and Broca's area in motor attention and language processes.

PET was used to study cerebral dominance for the selection of action. In one condition the subjects moved one of two fingers depending on the cue presented (choice reaction time), and in another they moved the same finger whatever the cue (simple reaction time). There was also a baseline condition in which cues were shown but no movements were made. A conjunction analysis was performed to reveal those areas which were more activated for the choice versus simple reaction time, irrespective of whether the right or left hand was used. The activations were in prefrontal, premotor and intraparietal areas, and they were all in the left hemisphere. Thus, while there were activations in the right hemisphere for the choice versus simple reaction time task when the subjects used their left (contralateral) hand, there were activations in left prefrontal, premotor and parietal areas whether the right (contralateral) or left (ipsilateral) hands were used. It is argued that the results suggest that the left hemisphere is dominant not only for speech but also for action in general.

OBJECTIVE:To investigate the etiology of mirror movements in patients with X-linked Kallmann's syndrome (xKS) through statistical analysis of pooled white matter data from structural MR images. BACKGROUND:Mirror movements occur in 85% of xKS patients. Previous electrophysiologic studies have suggested an abnormal ipsilateral corticospinal tract projection in xKS patients exhibiting mirror movements. However, an alternative hypothesis has proposed a functional lack of transcallosal inhibitory fibers. METHODS:T1-weighted brain scans were normalized into stereotaxic space with segregation of gray and white matter to allow comparison of pooled white matter data on a voxel-by-voxel basis using SPM-96 software. Nine xKS patients were compared with two age-matched groups of nonmirroring individuals: nine patients with autosomal Kallmann's syndrome (aKS) and nine age-matched normal (healthy) men. RESULTS:Hypertrophy of the corpus callosum was found in both Kallmann's syndrome groups: the anterior and midsection in xKS, and the genu and posterior section in aKS. Bilateral hypertrophy of the corticospinal tract was found only in the group of xKS patients exhibiting mirror movements. SPM analysis was validated by an independent region of interest analysis of corpus callosum size. CONCLUSION:Although morphometry on its own cannot determine the cause of mirror movements, the specific finding of a hypertrophied corticospinal tract in xKS is consistent with electrophysiologic evidence suggesting that mirror movements in xKS result from abnormal development of the ipsilateral corticospinal tract fibers.

Autism is a biological disorder which affects social cognition, and understanding brain abnormalities of the former will elucidate the brain basis of the latter. We report structural MRI data on 15 high-functioning individuals with autistic disorder. A voxel-based whole brain analysis identified grey matter differences in an amygdala centered system relative to 15 age- and IQ-matched controls. Decreases of grey matter were found in anterior parts of this system (right paracingulate sulcus, left inferior frontal gyrus). Increases were found in posterior parts (amygdala/peri-amygdaloid cortex, middle temporal gyrus, inferior temporal gyrus), and in regions of the cerebellum. These structures are implicated in social cognition by animal, imaging and histopathological studies. This study therefore provides converging evidence of the physiological basis of social cognition.

Anticipatory anxiety is a complex combination of a future-oriented cognitive state, negative affect, and autonomic arousal. A dual-task paradigm of anticipation of electric shocks and a motor-learning task was used to examine the changes in neural patterns of activation associated with modulation of the cognitive state in anxiety by a distracting motor task. We used positron emission tomography (PET) and15O-water to measure regional cerebral blood flow (rcbf) in 10 healthy male volunteers. A 2 × 2 factorial design-(shock vs no shock) × (low vs high distraction) was used with three scans per condition. Twelve PET scans were performed on each subject. In six of these scans, subjects were given electric shocks. In all scans, subjects also simultaneously performed a motor repetition (low distraction) or learning (high distraction) task. Galvanic skin conductance (GSR), Spielberger State and Trait Anxiety Inventory (STAI), and self-report data were also collected. In comparisons between the shock and no-shock conditions, the main finding was of increased rcbf in the left insula (−38,8,8) (z=4.85,P<0.05 corrected) and a homologous area in the right insula at a lower threshold (z=3.20,P=0.001 uncorrected). Other areas activated were the right superior temporal sulcus, left fusiform, and left anterior cingulate. Using the STAI-state scores as a covariate of interest, significant correlations with rCBF were seen in the left orbitofrontal cortex, left insula, and left anterior cingulate cortex. There was no significant distraction effect as measured by the STAI, self-report, GSR response or interactional analysis of the PET data. These findings support the role of paralimbic structures as neural substrates of anticipatory anxiety. The failure to demonstrate behavioral and neurophysiological changes with the distractor task may reflect the modest increases in anxiety with the shock, the relatively simple distractor task, and small sample size.

Objective: To investigate the etiology of mirror movements in patients with X-linked Kallmann’s syndrome (xKS) through statistical analysis of pooled white matter data from structural MR images. Background: Mirror movements occur in 85% of xKS patients. Previous electrophysiologic studies have suggested an abnormal ipsilateral corticospinal tract projection in xKS patients exhibiting mirror movements. However, an alternative hypothesis has proposed a functional lack of transcallosal inhibitory fibers. Methods: T1-weighted brain scans were normalized into stereotaxic space with segregation of gray and white matter to allow comparison of pooled white matter data on a voxel-by-voxel basis using SPM-96 software. Nine xKS patients were compared with two age-matched groups of nonmirroring individuals: nine patients with autosomal Kallmann’s syndrome (aKS) and nine age-matched normal (healthy) men. Results: Hypertrophy of the corpus callosum was found in both Kallmann’s syndrome groups: the anterior and midsection in xKS, and the genu and posterior section in aKS. Bilateral hypertrophy of the corticospinal tract was found only in the group of xKS patients exhibiting mirror movements. SPM analysis was validated by an independent region of interest analysis of corpus callosum size. Conclusion: Although morphometry on its own cannot determine the cause of mirror movements, the specific finding of a hypertrophied corticospinal tract in xKS is consistent with electrophysiologic evidence suggesting that mirror movements in xKS result from abnormal development of the ipsilateral corticospinal tract fibers.

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