Early phase and adaptive design clinical trials in rheumatoid arthritis: a systematic review of early phase trials

Abstract

Objective: Adaptive designs can enable highly sophisticated and efficient early phase trials, but the clinical inference from these trials is surrounded by complexity, and currently there is a paucity but steadily increasing amount of use of these designs in all fields of medicine. We aim to review early phase trials in RA to discover those that have used adaptive designs and benchmark trial characteristics.

Methods: From an OVID search for journal articles reporting the results of early phase trials in rheumatology, 35 studies were found, with 9 subsequently excluded; 11 were added from manual searches and 19 from searching the references. Study characteristics were extracted from the 56 papers (describing 62 trials), including the number of arms, number of patients, the primary outcome and when it was measured.

Result: One early phase trial using an adaptive design was found. The benchmark early phase trial in RA is a phase II double-blinded randomized trial, with four arms (one control and three intervention), each with 34 patients, and ACR20 measured at 16 weeks as the primary outcome.

Conclusion: The one adaptive design reviewed here, and a simulation study found in the search, both indicate that adaptive designs can be applied to early phase trials in RA. We have described the benchmark, which the efficiency of early phase trials using an adaptive design needs to exceed. These efficient designs could drive down numbers required, time for data collection and thus cost. Changes have been suggested, but more needs to be done.

Keywords: adaptive design; early phase trial; rheumatoid arthritis; systematic review.

Fig. 1

Flow of numbers of papers (and numbers of trials described) throughout the different search phases

Fig. 2

Forest plot of dichotomous outcomes (ACR20, ACR50, modified Paulus approach, Paulus20 and 50% decrease in swollen joint count from baseline) mPa: Paulus approach (see supplementary material, available at Rheumatology Advances in Practice online for detail); P20: Paulus20; SJC50: 50% decrease in swollen joint count from baseline. Numbers in brackets are [Search Number].[Intervention Number], as noted in the supplementary material, available at Rheumatology Advances in Practice online.

Fig. 3

Forest plot of continuous outcomes (DAS28) Number in brackets are [Search Number].[Intervention Number], as noted in the supplementary material, available at Rheumatology Advances in Practice online.