Two-stage approach based on zone and dose findings for two-agent combination Phase I/II trials

<p>In Phase I/II trials for a combination therapy of two agents, we ideally want to explore as many dose combinations as possible with limited sample size in Phase I and to reduce the number of untried dose combinations before moving to Phase II. Efficient collection of toxicity data in Phase I would eventually improve the accuracy of optimal dose combination identification in Phase II. In this paper, we develop a novel dose-finding method based on efficacy and toxicity outcomes for two-agent combination Phase I/II trials. We propose a “zone-finding stage” that determines the most admissible toxicity zone on the dose combination matrix and subsequently select the dose combination allocated to the next patient from that zone in Phase I. Upon completion of this zone-finding stage, we allocate the next patient to the dose combination determined by adaptive randomization of the admissible toxicity and efficacy dose combinations in Phase II. Simulation studies demonstrated the utility of the proposed zone-finding stage and proved that the operating characteristic of the proposed method was no worse than the existing method. The sensitivity of the proposed method, as well as the operating characteristic of this method when the efficacy outcome is delayed, was also examined.</p

Additional file 2: of Effect of subcutaneous tocilizumab treatment on work/housework status in biologic-naĂŻve rheumatoid arthritis patients using inverse probability of treatment weighting: FIRST ACT-SC study

Overall baseline demographic and clinical characteristics of each group in the modified intention-to-treat set (unadjusted, adjusted). (DOCX 25 kb

Additional file 1: of Effect of subcutaneous tocilizumab treatment on work/housework status in biologic-naĂŻve rheumatoid arthritis patients using inverse probability of treatment weighting: FIRST ACT-SC study

Baseline demographic and clinical characteristics of patients in each group adjusted using inverse probability of treatment weighting in the modified intention-to-treat set (paid worker, house worker). (DOCX 22 kb