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

Lookup NU author(s): Claire Macdonald, Professor Gary Ford


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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.

Publication metadata

Author(s): Rahbar MH, Dickerson AS, Cai CY, Pedroza C, Hessabi M, Shen L, Pandurengan R, Jacobs ANM, Indupuru H, Sline MR, Delgado RI, Macdonald C, Ford GA, Grotta JC, Barreto AD

Publication type: Article

Publication status: Published

Journal: Contemporary Clinical Trials

Year: 2015

Volume: 44

Pages: 139-148

Print publication date: 01/09/2015

Online publication date: 13/08/2015

Acceptance date: 08/08/2015

ISSN (print): 1551-7144

ISSN (electronic): 1559-2030

Publisher: Elsevier


DOI: 10.1016/j.cct.2015.08.007


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Funder referenceFunder name
Harold and Dianne Farb Stroke Fund
Biostatistics/Epidemiology/Research Design (BERD) component of the Center for Clinical and Translational Sciences (CCTS)
National Center for Advancing Translational Sciences (NCATS)
KL2 RR0224149NIH Centers for Translational Science Award (NIH-CTSA)
P50NS044227National Institute of Neurological Disorders and Stroke (NINDS)
UL1 RR024148NIH Centers for Translational Science Award (NIH-CTSA)
UL1 TR000371National Center for Research Resources (NCRR)