Abstract
PurposeMissing scores complicate analysis of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) because patients with and without missing scores may systematically differ. We focus on optimal analysis methods for incomplete PRO-CTCAE items, with application to two randomized, double-blind, placebo-controlled, phase III trials.MethodsIn Alliance A091105 and COMET-2, patients completed PRO-CTCAE items before randomization and several times post-randomization (N = 64 and 107, respectively). For each trial, we conducted between-arm comparisons on the PRO-CTCAE via complete-case two-sample t-tests, mixed modeling with contrast, and multiple imputation followed by two-sample t-tests. Because interest lies in whether CTCAE grades can inform missing PRO-CTCAE scores, we performed multiple imputation with and without CTCAE grades as auxiliary variables to assess the added benefit of including them in the imputation model relative to only including PRO-CTCAE scores across all cycles.ResultsPRO-CTCAE completion rates ranged from 100.0 to 71.4% and 100.0 to 77.1% across time in A091105 and COMET-2, respectively. In both trials, mixed modeling and multiple imputation provided the most similar estimates of the average treatment effects. Including CTCAE grades in the imputation model did not consistently narrow confidence intervals of the average treatment effects because correlations for the same PRO-CTCAE item between different cycles were generally stronger than correlations between each PRO-CTCAE item and its corresponding CTCAE grade at the same cycle.ConclusionFor between-arm comparisons, mixed modeling and multiple imputation are informative techniques for handling missing PRO-CTCAE scores. CTCAE grades do not provide added benefit for informing missing PRO-CTCAE scores. ClinicalTrials.gov Identifiers: NCT02066181 (Alliance A091105); NCT01522443 (COMET-2).
Highlights
Safety and treatment tolerability have historically been assessed solely by clinicians via the Common Terminology Criteria for Adverse Events (CTCAE)
We conduct between-arm comparisons within each trial while comparing the following strategies for addressing missing PRO-CTCAE scores: complete-case two-sample t-test, mixed modeling with contrast, and multiple imputation followed by a two-sample t-test
Between-arm comparisons on the PRO-CTCAE at week 122 were conducted using the following strategies: completecase two-sample t-test, mixed modeling with contrast, and multiple imputation followed by a two-sample t-test
Summary
Safety and treatment tolerability have historically been assessed solely by clinicians via the Common Terminology Criteria for Adverse Events (CTCAE). This paper focuses on analysis of the PRO-CTCAE when some patients’ responses are missing (Alliance A151912), with application to 2 randomized, double-blind, placebo-controlled, phase III trials: Alliance A091105 and COMET-2. We applied various methods for comparing patient-reported symptoms across treatment arms while addressing missing PRO-CTCAE responses. This paper focuses on optimal analysis methods for incomplete PRO-CTCAE items (Alliance A151912), with application to 2 randomized, double-blind, placebo-controlled, phase III trials: Alliance A091105 and COMET-2. To incorporate the patient perspective into assessments of symptomatic adverse events, the National Cancer Institute contracted development of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) [1]. The National Cancer Institute recommends reporting patients’ PROCTCAE scores in conjunction with clinicians’ CTCAE grades to improve the evaluation of symptomatic adverse
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