Compare trial: Updated data
Authors: Marcelo O. Silva
Journal: Journal of Hepatology (2008)

In 2006, our article "A randomised trial to compare the pharmacokinetic, pharmacodynamic and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE)," which was an 8-week comparison of peginterferon alfa-2a and peginterferon alfa-2b, was published in the Journal of Hepatology[[1]Silva M. Poo J. Wagner F. Jackson M. Cutler D. Grace M. et al.A randomised trial to compare the pharmacokinetic, pharmacodynamic, and antiviral effects of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE).J Hepatol. 2006; 45: 204-213Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar]. In COMPARE and other Schering-Plough-supported trials, Schering-Plough used a proprietary quantitative TaqMan PCR assay to quantify hepatitis C virus (HCV)-RNA levels. In early 2007, Schering-Plough discovered that, in some instances, this assay yielded incorrect HCV-RNA levels. The COMPARE study was affected by the assay inaccuracies, and certain samples from patients enrolled in these studies required reanalysis. Samples identified as having been measured incorrectly have since been reanalyzed, and we can confirm that the overall conclusions reported in our published article remain unchanged. Although the overall conclusions of this publication remain unchanged, some of the data were adjusted. Briefly, all values presented in Table 3 in the article were adjusted slightly; however, the adjustments did not result in any change in the statistical significance between peginterferon alfa-2a and peginterferon alfa-2b. The reanalysis data indicate that the average decrease in HCV-RNA and the mean maximum decrease in HCV-RNA are significantly greater among patients receiving peginterferon alfa-2b than among those receiving peginterferon alfa-2a at week 1 (P < .05 for both comparisons) and week 4 (P < .0001 for both comparisons). In addition, at week 4, the number of patients receiving peginterferon alfa-2a is reduced from 18 to 17, and the number receiving peginterferon alfa-2b is reduced from 18 to 16. Peginterferon alfa-2a versus peginterferon alfa-2b data did not change, but correlation coefficients and probabilities for the week 8 carry-forward response (W8cfresp) data for cyclin D, IP10, ISG15, ISG54, perforin, PKR, signal transducer and activator of transcription (STAT)-1, STAT-2, and 2′5′ OAS were affected (Table 4 in the article). For each of these transcripts, the reanalysis indicated a reduced Spearman correlation coefficient compared with the original data. Similar changes were noted for the W8cfresp data in Table 5 in the article, resulting in a reduced correlation coefficient for principle component (Prin) 1 and Prin2, an increased correlation coefficient for Prin3, and a negative correlation at Prin4 and Prin5 compared with the original data. The reanalysis indicated that the differences in gene transcript levels between responders and non-responders for inducible protein 10 (IP10) and RNA-dependent protein kinase (PKR) (maximum fold increase from baseline; Cmax) and IP10, PKR, and interferon-stimulated gene (ISG) 54 (area under the curve; AUC) remained statistically significant (P < .05) (Table 2 in the article). The differences in ISG15, 2′5′ oligoadenylate synthetase (OAS), and ISG54 (Cmax) and ISG15 and 2′5′ OAS (AUC) between responders and non-responders that were statistically significant in the original analysis were no longer significant (Table 2 in the article). All the data presented in Figs. 4A and B in the article were slightly affected. For peginterferon alfa-2a, the difference in mean AUC of IP10 between responders and non-responders remained statistically significant; however, for peginterferon alfa-2b, the difference in mean AUC for ISG54 between responders and non-responders failed to reach statistical significance using the reanalysis data (Fig. 4A). In the reanalysis, a patient previously considered a responder was reclassified as a non-responder: in the reanalysis, 9 of 14 patients were responders and 5 were non-responders (Fig. 4B in the article). Data presented in Fig. 5 in the article were slightly affected; however, the mean maximal log10 change in HCV-RNA from baseline remained significantly greater among patients receiving peginterferon alfa-2b than among those receiving peginterferon alfa-2a at week 1 and week 4 (P < .05) for both comparisons. Finally, the data presented in Fig. 6 in the article were also slightly affected; however, the rate of decline in HCV-RNA during the 8 weeks of treatment remained significantly greater among patients receiving peginterferon alfa-2b than among patients receiving peginterferon alfa-2a. As stated, the adjustments noted above did not change the overall conclusions reported in our published article. However, we believe that full disclosure of the assay inaccuracies, the subsequent reanalysis, and results of the reanalysis were imperative to communicate to the medical community. Download . (NaN MB) Help with files Supplementary data