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Proposing a novel composite score as an outcome measure in a Phase II/III clinical trial with application to Type II Diabetes

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Background: In the complex disease, type II diabetes mellitus (T2DM), to study the effect of an intervention, using a single endpoint, such as glycated hemoglobin (HbA1c), and without stratified block randomization may not be justified. Diabetic drugs may be toxic. Hence toxicity monitoring during a clinical trial is an important consideration. Methods: In this article, we suggest conducting separate clinical trials for moderately (6.5% ≤ HbA1c < 7.5%) and severely (HbA1c ≥7.5%) diabetic patients to reduce heterogeneity due to disease burden at and baseline and expecting different responses withing each cohort, we propose a novel composite score for a Phase II/III clinical trial for testing therapeutic interventions in diabetic patients, and present sample size calculations required to conduct such a clinical trial. The composite score incorporates multiple outcomes together into a binary measure, based on HbA1c, which has not been used before in any of the clinical trials designed for diabetes. We also present the toxicity monitoring rules for the two diabetic populations. Results: We expect to recruit higher number of patients for the moderately diabetic group than for the severely diabetic group. Using one or two interim analyses does not significantly change the required sample size Conclusions: For the moderately diabetic patient group, an allocation ratio of 1:1 is advised and for the severely diabetic patient group, an allocation ratio of 1:2 is advised with a greater number of patients recruited on the experimental treatment arm. Since clinical trials for T2DM are carried out over longer periods of time, we suggest using O’Brien-Fleming (OBF) alpha-spending function with two interim analyses.


composite score, Phase II/III clinical trial, type II diabetes mellitus, Interim analysis, continuous toxicity monitoring, sample size