Hari Indupuru

CLOTBUST-Hands Free Pilot Safety Study of a Novel Operator-Independent Ultrasound Device in Patients With Acute Ischemic Stroke

Background and Purpose— The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health–sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion. Methods— All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days. Results— Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5–29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%–64%) complete and 2 of 20 (10%; 95% confidence interval, 1%–32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%–82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%–49) patients had a modified Rankin scale of 0 to 1. Conclusions— Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: CLOTBUST-HF NCT01240356.

Methodological issues for designing and conducting a multicenter, international clinical trial in Acute Stroke: Experience from ARTSS-2 trial

BACKGROUND We describe innovations in the study design and the efficient data coordination of a randomized multicenter trial of Argatroban in Combination with Recombinant Tissue Plasminogen Activator for Acute Stroke (ARTSS-2). METHODS ARTSS-2 is a 3-arm, multisite/multiregional randomized controlled trials (RCTs) of two doses of Argatroban injection (low, high) in combination with recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke patients and rt-PA alone. We developed a covariate adaptive randomization program that balanced the study arms with respect to study site as well as hemorrhage after thrombolysis (HAT) score and presence of distal internal carotid artery occlusion (DICAO). We used simulation studies to validate performance of the randomization program before making any adaptations during the trial. For the first 90 patients enrolled in ARTSS-2, we evaluated performance of our randomization program using chi-square tests of homogeneity or extended Fishers exact test. We also designed a four-step partly Bayesian safety stopping rule for low and high dose Argatroban arms. RESULTS Homogeneity of the study arms was confirmed with respect to distribution of study site (UK sites vs. US sites, P=0.98), HAT score (0-2 vs. 3-5, P=1.0), and DICAO (N/A vs. No vs. Yes, P=0.97). Our stopping thresholds for safety of low and high dose Argatroban were not crossed. Despite challenges, data quality was assured. CONCLUSIONS We recommend adaptive designs for randomization and Bayesian safety stopping rules for multisite Phase I/II RCTs for maintaining additional flexibility. Efficient data coordination could lead to improved data quality.

Telemedicine-guided remote enrollment of patients into an acute stroke trial

Enrollment into acute stroke clinical trials is limited to experienced tertiary centers with emergency research infrastructure. Feasibility of remote enrollment via telemedicine into an acute thrombolytic clinical trial has never been demonstrated.

Comparison Between a Standardized Questionnaire and Expert Clinicians for Capacity Assessment in Stroke Clinical Trials

Research into treatments for acute strokes has dramatically increased in the last decade. Accordingly, the need for testing through randomized clinical trials has also increased. Because of the unique combination of factors that are common in acute stroke–related research, including narrow treatment windows, ethical concerns regarding research with acute stroke populations, and capacity for informed consent, stroke clinical trial enrollment levels have remained stagnant. Given the devastating consequences of acute stroke, researchers are intensifying their efforts to recruit and enroll larger sample sizes in clinical trials.1 Capacity to consent to medical treatment or medical research is closely related to cognitive functioning, which is frequently impaired in stroke.2 Medical decision-making capacity (MDC) requires the ability to understand and appreciate diagnostic, treatment, and research information and risks and ability to express a choice that is based on adequate reasoning. The treating physician is responsible for the assessment of a patient’s decision-making capacity and clinically estimate their patient’s ability to provide informed consent.3 Many physicians request additional consultative assistance to assess cognitive capacity for consent from psychiatry or neuropsychology, which are considered to be the clinical gold standards4 or they perform standardized capacity questionnaires to aid the assessment of capacity.5,6 One such tool, the aid-to-capacity evaluation (ACE) had 80% to 89% agreement with expert clinicians in 1 study and inter-rater reliability reported as ĸ=0.79 for medical hospitalized patients.7,8 The ACE has been validated and found to be one of the best available instruments to assist clinicians in making judgments on MDC.4 It is designed to be used by trained nonclinicians and takes ≈10 minutes to perform.4 For patients who lack capacity medical decisions are deferred to a surrogate decision maker. Surrogate decision makers in acute stroke are able to accurately predict …