Clinical Trial Educator program - a novel approach to accelerate enrollment in a phase III International Acute Coronary Syndrome Trial.

BACKGROUND: The conduct of current cardiovascular outcome trials requires investigation of thousands of patients at hundreds of investigator sites. Such large trials are clinically and logistically highly demanding and often tend to finish with significant delays, consequently delaying patient access to new medicines. PURPOSE: To address this issue, we designed and implemented a novel approach - a Clinical Trial Educator (CTE) program - to accelerate enrollment in the Thrombin-Receptor Antagonist for Clinical Event Reduction (TRA•CER) trial. This article analyzes the effect of this approach on the study milestones: patient recruitment, site start-up time, and recruitment rate. METHODS: Scientifically qualified and specifically trained CTEs regularly visited TRA•CER investigator sites in 18 European countries where they trained and educated investigators and site personnel to support them address recruitment challenges. Patient recruitment was assessed in absolute numbers and as recruitment rates, both in relation to CTE site visits. RESULTS: CTEs performed 2184 visits at 373 European TRA•CER sites (out of 921 global sites). Of sites visited by a CTE, significantly less remained without enrolling any patient than of sites not visited by a CTE (5.9% vs. 15.3%; p < 0.001). Sites visited within 30 days after initiation showed a significantly shortened median time to recruitment of the first patient (28 vs. 59 days with visits ≤30 or >30 days after initiation; p < 0.001). Mean patient recruitment rates were significantly higher at visited than at not-visited sites (1.13 vs. 0.89 patients per site per month, p < 0.001) and significantly increased after the first CTE site visit (from 0.70 to 1.17 patients per site per month; p < 0.001). Finally, there were fewer low-recruiting sites and more high-recruiting sites among the CTE-visited sites compared to the not-visited sites, and the mean recruitment rate at high-recruiting sites visited by CTEs was significantly higher than at high-recruiting sites without CTE visits (2.07 vs. 1.64 patients per site per month; p < 0.01). LIMITATIONS: The possibility for selection bias is inherent to this post hoc analysis of a nonrandomized data set. The European focus of the CTE program described here might add some geographical bias. Also, other activities such as investigator meetings conducted in parallel with CTE activities might have partly masked the results of our analysis. Finally, the analysis is limited to recruitment-related parameters, and the aspect of cost-effectiveness has not been quantitatively assessed. CONCLUSION: We found a significant positive association between CTE site visits and the assessed recruitment-related study milestones in the TRA•CER trial, and enrollment finished ahead of plan. We propose that a CTE program could efficiently accelerate enrollment in other clinical trials and therapeutic areas and could contribute to shortening patient access time to novel and potential lifesaving treatments in cardiovascular medicine and beyond.

Transcription under the control of nuclear Arm/beta-catenin.

The Wingless/Wnt pathway controls cell fates during animal development and regulates tissue homeostasis as well as stem cell number and differentiation in epithelia. Deregulation of Wnt signaling has been associated with cancer in humans. In the nucleus, the Wingless/Wnt signal is transmitted via the key effector protein Armadillo/beta-catenin. The recent identification and functional analysis of novel Armadillo/beta-catenin interaction partners provide new and exciting insights into the highly complex mechanism of Wingless/Wnt target gene activation.

Dissecting nuclear Wingless signalling: recruitment of the transcriptional co-activator Pygopus by a chain of adaptor proteins.

Members of the Wingless (Wg)/Wnt family of secreted glycoproteins control cell fate during embryonic development and adult homeostasis. Wnt signals regulate the expression of target genes by activating a conserved signal transduction pathway. Upon receptor activation, the signal is transmitted intracellularly by stabilization of Armadillo (Arm)/beta-catenin. Arm/beta-catenin translocates to the nucleus, interacts with DNA-binding factors of the Pangolin (Pan)/TCF/LEF class and activates transcription of target genes in cooperation with the recently identified proteins Legless/BCL9 (Lgs) and Pygopus (Pygo). Here, we analyse the mode of action of Pan, Arm, Lgs, and Pygo in Drosophila cultured cells. We provide evidence that together these four proteins form a 'chain of adaptors' linking the NH2-terminal homology domain (NHD) of Pygo to the DNA-binding domain of Pan. We show that the NHD has potent transcriptional activation capacity, which differs from that of acidic activator domains and depends on a conserved NPF tripeptide. A single point mutation within this NPF motif abolishes the transcriptional activity of the Pygo NHD in vitro and strongly reduces Wg signalling in vivo. Together, our results suggest that the transcriptional output of Wg pathway activity largely relies on a 'chain of adaptors' design to direct the Pygo NHD to Wg target promoters in an Arm-dependent manner.

Pygopus and legless provide essential transcriptional coactivator functions to armadillo/beta-catenin.

Wnt signaling controls important aspects of animal development, and its deregulation has been causally linked to cancer. Transduction of Wnt signals entails the association of beta-catenin with nuclear TCF DNA binding proteins and the subsequent activation of target genes. The transcriptional activity of Armadillo (Arm, the Drosophila beta-catenin homolog) largely depends on two recently discovered components, Legless (Lgs) and Pygopus (Pygo). Lgs functions as an adaptor between Arm/beta-catenin and Pygo, but different mechanisms have been proposed as to how Arm/beta-catenin is controlled by Lgs and Pygo. Although Lgs and Pygo were originally thought to serve as nuclear cofactors for Arm/beta-catenin to enhance its transactivation capacity, a recent analysis argued that they function instead to target Arm/beta-catenin to the nucleus. Here, we used genetic assays in cultured cells and in vivo to discriminate between the two paradigms. Regardless of the measures taken to maintain the nuclear presence of Arm/beta-catenin, a transcriptional-activation function of Pygo could not be bypassed. Our findings therefore indicate that Arm/beta-catenin depends on Lgs and Pygo primarily for its transcriptional output rather than for its nuclear import.