The Design of Nested Adaptive Clinical Trials of Multiple Organ Dysfunction Syndrome Children in a Single Study.

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.