Background Small open label pilot trials generate important information on tolerability, toxicity, pharmacokinetics, and antigenicity in the early phase investigation of new compounds in the treatment of rheumatoid arthritis (RA). However, because the standard disease activity measures (DAMs), such as the disease activity score in 28 joints (DAS28) have a major subjective component, the efficacy data acquired in such trials is generally felt to be much less reliable than that obtained in blinded trials. Incorporating more objective DAMs, and performing them in a blinded fashion, might enhance the validity of efficacy data in such an early clinical setting.
One possible disease activity measure to fulfill this role would be an ultrasound power Doppler joint count (UPD) which has been shown to correlate with conventional clinical measures1.
Objectives To determine whether the blinded use of a truncated (low joint count) UPD in an early phase RA trial correlates with other DAMs in the trial and contributes to validation of efficacy of the drug.
Methods The results of an open label trial in which Staph Protein A (PRTX-100, Protalex Inc.) was given to patients with active RA has been previously reported2. Standard disease activity measurements were obtained. In addition, an UPD was performed utilizing a truncated methodology in which three sites at the dorsal wrist and three dorsal metacarpal sites were analyzed bilaterally for a total of twelve sites studied. There were a total of 117 UPDs performed on eleven patients. UPD were acquired in less than five minutes per study. These UPDs were stored digitally and subsequently read in duplicate in a blinded fashion after completion of the study by the investigator (CW). Each joint site was subjectively scored from 0 (normal) to 3 (severe) with a possible total score of 0 -36 Intra-observer reliability was determined by two-way random intra-class correlations (ICC). Significant changes of UPD and clinical DAMs from baseline to single time points were assessed by the Wilcoxon signed rank test and correlations were performed by the Spearman's rho test (p). Effect size was determined by standardized mean difference (SMD).
Clinical assessments and UPDs were obtained weekly for the first month, then monthly for five more months.
Results Intra-observer UPD score reproducibility was high (ICC =0.886). Significant reductions (p<0.05) in UPD and the DAS28 were found at day 22 and on all subsequent visits. Correlations between UPD and DAMs total scores were moderate to strong. However, the total differences from baseline and visits did not correlate, except for CRP (n=67 p=0.471, p<0.001). Also, some individual time points showed differences such as baseline vs day 196 (see table). SRMs for both UPD and DAMs were high, but higher for the DAS28 (1.00–2.16) than for the UPD (0.83–1.10).
Conclusions The use of a truncated UPD in this small open label trial was feasible, reproducibly read, and significantly correlated with conventional disease activity measure.
The inclusion of UPD in this open label pilot trial adds validation to the efficacy data.
D'Agostino, M. Ann Rheum Dis doi:10.1136/annrheumdis-2015–207709.
Wiesenhutter, C Ann Rheum Dis 2016;75:1019 doi:10.1136/annrheumdis-2016-eular.2540.
Acknowledgements C. Wiesenhutter Grant/research support from Protalex Inc.
Disclosure of Interest None declared