N A Goldenberg1,2, T Abshire3,4, P J Blatchford5, L Z Fenton6, J L Halperin7, W R Hiatt8,9, C M Kessler10, J M Kittelson5, M J Manco-Johnson11, A C Spyropoulos12, P G Steg13, N V Stence5, A G G Turpie14,15, S Schulman14,15. 1. All Children's Research Institute, All Children's Hospital Johns Hopkins Medicine, St Petersburg, FL, USA. 2. Departments of Pediatrics and Medicine, Divisions of Hematology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 3. Department of Pediatrics, Section of Hematology/Oncology/BMT, Medical College of Wisconsin, Milwaukee, WI, USA. 4. BloodCenter of Wisconsin, Milwaukee, WI, USA. 5. Department of Biostatistics, School of Public Health, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA. 6. Department of Pediatric Radiology, School of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA. 7. The Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 8. Department of Medicine, Division of Cardiology, School of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA. 9. CPC Clinical Research, Aurora, CO, USA. 10. Department of Medicine, Division of Hematology, Georgetown University School of Medicine, Washington, DC, USA. 11. Department of Pediatrics, Section of Hematology/Oncology/BMT, and Hemophilia and Thrombosis Center, School of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA. 12. Department of Medicine, Division of Hematology, Hofstra North Shore - Long Island Jewish School of Medicine, Manhasset, NY, USA. 13. Department of Cardiology, Département Hospitalo-Universitaire FIRE (Fibrosis-Inflammation-REmodelling), University Paris-Diderot, Paris, France. 14. Department of Medicine, McMaster University, Hamilton, ON, Canada. 15. Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.
Abstract
BACKGROUND: Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS: The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design. RESULTS: No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%). CONCLUSIONS: The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT.
RCT Entities:
BACKGROUND: Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS: The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design. RESULTS: No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%). CONCLUSIONS: The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT.
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Authors: Neil A Goldenberg; John M Kittelson; Thomas C Abshire; Marc Bonaca; James F Casella; Rita A Dale; Jonathan L Halperin; Frances Hamblin; Craig M Kessler; Marilyn J Manco-Johnson; Robert F Sidonio; Alex C Spyropoulos; P Gabriel Steg; Alexander G G Turpie; Sam Schulman Journal: JAMA Date: 2022-01-11 Impact factor: 157.335
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