Browsing by Author "Barreto, Andrew D."

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Methodological issues for designing and conducting a multicenter, international clinical trial in Acute Stroke: Experience from ARTSS-2 trial
(2015-09-01)
Rahbar, Mohammad H.
;
Dickerson, Aisha S.
;
Cai, Chunyan
;
Pedroza, Claudia
;
Hessabi, Manouchehr
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 Fisher\'s 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. (C) 2015 Elsevier Inc. All rights reserved.
Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke)
(2017-06-01)
Barreto, Andrew D.
;
Ford, Gary A.
;
Shen, Loren
;
Pedroza, Claudia
;
Tyson, Jon
Background and Purpose-We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients. Methods-Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 mu g/kg bolus) followed by infusion of either 1 (low dose) or 3 mu g/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0). Results-Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively. Conclusions-In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated.