Mohammad H Rahbar1, Aisha S Dickerson2, Chunyan Cai3, Claudia Pedroza4, Manouchehr Hessabi5, Loren Shen6, Renganayaki Pandurengan7, Amber Nicole M Jacobs8, Hari Indupuru9, Melvin R Sline10, Rigoberto I Delgado11, Claire Macdonald12, Gary A Ford13, James C Grotta14, Andrew D Barreto15. 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. Department of Neurology, Stroke Program, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Loren.Shen@uth.tmc.edu. 7. 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. 8. 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. 9. 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. 10. Department of Neurology, Stroke Program, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Melvin.Sline@uth.tmc.edu. 11. 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. 12. Newcastle Clinical Trials Unit (NCTU), Newcastle University, Newcastle upon Tyne NE2 4AE, United Kingdom. Electronic address: claire.macdonald@newcastle.ac.uk. 13. 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. 14. Clinical Innovation and Research Institute, Memorial Hermann Hospital, Houston, TX 77030, USA. Electronic address: James.C.Grotta@uth.tmc.edu. 15. Department of Neurology, Stroke Program, University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: Andrew.D.Barreto@uth.tmc.edu.
Abstract
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.
RCT Entities:
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 strokepatients 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.
Authors: Andrew D Barreto; Gary A Ford; Loren Shen; Claudia Pedroza; Jon Tyson; Chunyan Cai; Mohammad H Rahbar; James C Grotta Journal: Stroke Date: 2017-05-15 Impact factor: 7.914
Authors: Samkeliso C Mawocha; Michael D Fetters; Laurie J Legocki; Timothy C Guetterman; Shirley Frederiksen; William G Barsan; Roger J Lewis; Donald A Berry; William J Meurer Journal: Clin Trials Date: 2017-01-31 Impact factor: 2.486