TY - JOUR
T1 - Methodological issues for designing and conducting a multicenter, international clinical trial in Acute Stroke
T2 - Experience from ARTSS-2 trial
AU - Rahbar, Mohammad H.
AU - Dickerson, Aisha S.
AU - Cai, Chunyan
AU - Pedroza, Claudia
AU - Hessabi, Manouchehr
AU - Shen, Loren
AU - Pandurengan, Renganayaki
AU - Jacobs, Amber Nicole M.
AU - Indupuru, Hari
AU - Sline, Melvin R.
AU - Delgado, Rigoberto I.
AU - Macdonald, Claire
AU - Ford, Gary A.
AU - Grotta, James C.
AU - Barreto, Andrew D.
N1 - Funding Information:
This research is co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) through a SPOTRIAS program grant [ P50NS044227 ] awarded to the University of Texas Health Science Center at Houston (UTHealth), a supplement from the American Recovery and Revitalization Act as well as the Harold and Dianne Farb Stroke Fund. We also acknowledge the support provided by the Biostatistics/Epidemiology/Research Design (BERD) component of the Center for Clinical and Translational Sciences (CCTS) for this project. CCTS is mainly funded by the NIH Centers for Translational Science Award (NIH CTSA) grant [ UL1 RR024148 (KL2 RR0224149 for the K12 program)], awarded to University of Texas Health Science Center at Houston in 2006 by the National Center for Research Resources (NCRR) and its renewal ( UL1 TR000371 ) by the National Center for Advancing Translational Sciences (NCATS). Glaxo-Smith-Kline (GSK) provided study medication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, Farb Stroke Fund, NCRR, or the NCATS.
Publisher Copyright:
© 2015.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - Acute Stroke
KW - Adaptive design
KW - Argatroban
KW - Bayesian methods
KW - Data quality assurance
KW - Multisite randomized clinical trials
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U2 - 10.1016/j.cct.2015.08.007
DO - 10.1016/j.cct.2015.08.007
M3 - Article
AN - SCOPUS:84939640992
SN - 1551-7144
VL - 44
SP - 139
EP - 148
JO - Contemporary Clinical Trials
JF - Contemporary Clinical Trials
ER -