Clinical trial simulation to optimize trial design for fludarabine dosing strategies in allogeneic hematopoietic cell transplantation Journal Article
| Authors: | Langenhorst, J. B.; Dorlo, T. P. C.; van Kesteren, C.; van Maarseveen, E. M.; Nierkens, S.; de Witte, M. A.; Boelens, J. J.; Huitema, A. D. R. |
| Article Title: | Clinical trial simulation to optimize trial design for fludarabine dosing strategies in allogeneic hematopoietic cell transplantation |
| Abstract: | Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation, suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be warranted, but should be sufficiently powered for a relevant end point, while still feasible to enroll. To find the optimal design, we simulated RCTs comparing current practice (160 mg/m2) to either covariate-based or therapeutic drug monitoring (TDM)-guided dosing with potential outcomes being nonrelapse mortality (NRM), graft failure, or relapse, and ultimately overall survival (covering all three aforementioned outcomes). The inclusion in each treatment arm (n) required to achieve 80% power was calculated for all combinations of end points and dosing comparisons. The trial requiring the lowest n for sufficient power compared TDM-guided dosing to current practice with NRM as primary outcome (n = 70, NRM decreasing from 21% to 5.7%). We conclude that a superiority trial is feasible. © 2020 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics. |
| Keywords: | adult; clinical article; controlled study; treatment outcome; overall survival; fludarabine; mortality; sensitivity analysis; randomized controlled trial; risk factor; body mass; graft failure; allogeneic hematopoietic stem cell transplantation; computer simulation; drug monitoring; predictive value; creatinine clearance; lung transplantation; randomized controlled trial (topic); study design; body surface; estimated glomerular filtration rate; human; male; female; priority journal; article; allometry |
| Journal Title: | CPT: Pharmacometrics and Systems Pharmacology |
| Volume: | 9 |
| Issue: | 5 |
| ISSN: | 2163-8306 |
| Publisher: | John Wiley & Sons, Inc. |
| Date Published: | 2020-05-01 |
| Start Page: | 272 |
| End Page: | 281 |
| Language: | English |
| DOI: | 10.1002/psp4.12486 |
| PUBMED: | 31957334 |
| PROVIDER: | scopus |
| PMCID: | PMC7239337 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2020 -- Source: Scopus |
