Evaluating the use of hierarchical composite endpoints in pediatric cancer supportive care clinical trials: Illustrative examples from two multi-center phase-III randomized clinical trials.
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PURPOSE: Pediatric supportive care trials frequently rely on analyses of multiple clinically relevant outcomes, posing challenges for overall trial interpretation. Hierarchical composite endpoints (HCEs) rank relevant outcomes by prespecified clinical importance and offer potential advantages such as harmonizing trial conclusions. METHODS: We reanalyzed two randomized supportive care trials utilizing post-hoc HCE, each conducted through the Children's Oncology Group. ACCL0934 evaluated levofloxacin for prevention of bloodstream infection (BSI) in patients with acute leukemia (AL) or undergoing hematopoietic cell transplant (HCT) and was chosen because of observed multidimensional benefits of levofloxacin. ACCL0431 evaluated sodium thiosulfate (STS) for prevention of cisplatin-induced hearing loss. ACCL0431 analyses were performed for overall and localized disease subgroups, chosen due to conflicting effect directionality on hearing vs survival by cohort. We estimated treatment effects on HCEs using win-odds ratios (WO). For ACCL0934, the primary HCE included death, severe infection, BSI, and neutropenic fever. For ACCL0431, the HCE included death, relapse/progression, and hearing loss. RESULTS: In ACCL0934, levofloxacin reduced BSI incidence, but only with corresponding p-value <0.05 in the AL cohort (22% vs 43% on control; P =0.003; HCT: 11% versus 17% on control; P= 0.06). Using HCE reanalysis, the estimated win-odds achieved statistical significance in both cohorts (AL: WO=1.74, P= 0.002; HCT: WO=1.28, P= 0.031). In ACCL0431, HCE analyses resulted in an estimated null effect (WO=1) in the overall cohort but resulted in beneficial effects (WO>1) for analyses of the localized cohort. CONCLUSION: HCEs can provide a harmonized framework for interpreting complex supportive care trials by integrating outcomes of varying clinical importance. These post-hoc analyses should not be used to reinterpret either trial but motivate consideration of prospective use of HCE going forward.