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 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.
Division of Clinical and Translational Sciences, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX 77030, USA; Division of Epidemiology, Human Genetics, and Environmental Sciences (EHGES), University of Texas School of Public Health at Houston, Houston, TX 77030, USA; Biostatistics/Epidemiology/Research Design (BERD) Component, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Mohammad.H.Rahbar@uth.tmc.edu.
Mohammad H
MH
Rahbar
Biostatistics/Epidemiology/Research Design (BERD) Component, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Aisha.S.Dickerson@uth.tmc.edu.
Aisha S
AS
Dickerson
Division of Clinical and Translational Sciences, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX 77030, USA; Biostatistics/Epidemiology/Research Design (BERD) Component, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Chunyan.Cai@uth.tmc.edu.
Chunyan
C
Cai
Center for Clinical Research and Evidence-Based Medicine, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Claudia.Pedroza@uth.tmc.edu.
Claudia
C
Pedroza
Biostatistics/Epidemiology/Research Design (BERD) Component, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Manouchehr.Hessabi@uth.tmc.edu.
Manouchehr
M
Hessabi
Department of Neurology, Stroke Program, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Loren.Shen@uth.tmc.edu.
Loren
L
Shen
Biostatistics/Epidemiology/Research Design (BERD) Component, Center for Clinical and Translational Sciences (CCTS), University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: Renga.Pandurengan@uth.tmc.edu.
Renganayaki
R
Pandurengan
Department of Neurology, Stroke Program, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Amber.Nicole.M.Jacobs@uth.tmc.edu.
Amber Nicole M
ANM
Jacobs
Department of Neurology, Stroke Program, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Hari.Kishan.R.Indupuru@uth.tmc.edu.
Hari
H
Indupuru
Department of Neurology, Stroke Program, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Melvin.Sline@uth.tmc.edu.
Melvin R
MR
Sline
Department of Management, Policy & Community Health, University of Texas School of Public Health at Houston, Houston, TX 77030, USA. Electronic address: Rigoberto.I.Delgado@uth.tmc.edu.
Rigoberto I
RI
Delgado
Newcastle Clinical Trials Unit (NCTU), Newcastle University, Newcastle upon Tyne NE2 4AE, United Kingdom. Electronic address: claire.macdonald@newcastle.ac.uk.
Claire
C
Macdonald
Newcastle Clinical Trials Unit (NCTU), Newcastle University, Newcastle upon Tyne NE2 4AE, United Kingdom; Oxford Academic Health Science Network, Magdalen Centre North, Oxford Science Park, OX4 4GA, United Kingdom. Electronic address: gary.ford@ouh.nhs.uk.
Gary A
GA
Ford
Clinical Innovation and Research Institute, Memorial Hermann Hospital, Houston, TX 77030, USA. Electronic address: James.C.Grotta@uth.tmc.edu.
James C
JC
Grotta
Department of Neurology, Stroke Program, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Andrew.D.Barreto@uth.tmc.edu.
Andrew D
AD
Barreto
Acute Stroke; Adaptive design; Argatroban; Bayesian methods; Data quality assurance; Multisite randomized clinical trials