The Design of Nested Adaptive Clinical Trials of Multiple Organ Dysfunction Syndrome Children in a Single Study
John M. VanBuren, Mark Hall, Athena F. Zuppa, Peter M. Mourani, Joseph Carcillo, J. Michael Dean, Kevin Watt, Richard Holubkov- Critical Care and Intensive Care Medicine
- Pediatrics, Perinatology and Child Health
OBJECTIVES:
Describe the statistical design of the Personalized Immunomodulation in Sepsis-induced Multiple Organ Dysfunction Syndrome (MODS) (PRECISE) study.
DESIGN:
Children with sepsis-induced MODS undergo real-time immune testing followed by assignment to an immunophenotype-specific study cohort. Interventional cohorts include the granulocyte macrophage-colony stimulating factor (GM-CSF) for the Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS (GRACE)-2 trial, which uses the drug GM-CSF (or placebo) to reverse immunoparalysis; and the Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS (TRIPS) trial, which uses the drug anakinra (or placebo) to reverse systemic inflammation. Both trials have adaptive components and use a statistical framework in which frequent data monitoring assesses futility and efficacy, allowing potentially earlier stopping than traditional approaches. Prespecified simulation-based stopping boundaries are customized to each trial to preserve an overall one-sided type I error rate. The TRIPS trial also uses response-adaptive randomization, updating randomization allocation proportions to favor active arms that appear more efficacious based on accumulating data.
SETTING:
Twenty-four U.S. academic PICUs
PATIENTS:
Septic children with specific immunologic derangements during ongoing dysfunction of at least two organs.
INTERVENTIONS:
The GRACE-2 trial compares GM-CSF and placebo in children with immunoparalysis. The TRIPS trial compares four different doses of anakinra to placebo in children with moderate to severe systemic inflammation.
MEASUREMENTS AND MAIN RESULTS:
Both trials assess primary efficacy using the sum of the daily pediatric logistic organ dysfunction-2 score over 28 days. Ranked summed scores, with mortality assigned the worst possible value, are compared between arms using the Wilcoxon Rank Sum test (GRACE-2) and a dose-response curve (TRIPS). We present simulation-based operating characteristics under several scenarios to demonstrate the behavior of the adaptive design.
CONCLUSIONS:
The adaptive design incorporates innovative statistical features that allow for multiple active arms to be compared with placebo based on a child’s personal immunophenotype. The design increases power and provides optimal operating characteristics compared with traditional conservative methods.