In a phase 2a trial of patients with moderate to severe Crohn's disease who had failed treatment with tumor necrosis factor antagonists, 8 and 24 weeks of treatment with MEDI2070 were associated with clinical improvement. ClinicalTrials.gov ID: NCT01714726.
Objectives Genotype-specific associations between hepatitis C virus (HCV) and insulin resistance (IR) have been described, but a causal relationship remains unclear. This study investigated the association between a sustained virological response (SVR) and IR after chronic HCV therapy. Methods 2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 were enrolled in two phase 3 trials of albinterferon alpha-2b versus pegylated interferon alpha-2a for 48 or 24 weeks, respectively. IR was measured before treatment and 12 weeks after treatment using homeostasis model assessment (HOMA)-IR. Results Paired HOMA-IR measurements were available in 1038 non-diabetic patients (497 with genotype 1; 541 with genotype 2/3). At baseline the prevalence of HOMA-IR >3 was greater in patients with genotype 1 than 2/3 (33% vs 27%; p=0.048). There was a significant reduction in the prevalence of IR in patients with genotype 1 achieving SVR (δ 10%; p<0.001), but not in genotype 1 non-responders or those with genotype 2/3. Multivariate analysis indicated that SVR was associated with a significant reduction in mean HOMA-IR in patients with genotype 1 (p=0.004), but not in those with genotype 2/3, which was independent of body mass index, alanine transaminase, γ-glutamyl transpeptidase and lipid level changes. Conclusions SVR is associated with a reduction in HOMA-IR in patients with HCV genotype 1 but not in those with genotype 2/3. Genotype 1 may have a direct effect on the development of IR, independent of host metabolic factors, and may be partially reversed by viral eradication.
Assessing goodness-of-fit in logistic regression models can be problematic, in that commonly used deviance or Pearson chi-square statistics do not have approximate chi-square distributions, under the null hypothesis of no lack of fit, when continuous covariates are modelled. We present two easy to implement test statistics similar to the deviance and Pearson chi-square tests that are appropriate when continuous covariates are present. The methodology uses an approach similar to that incorporated by the Hosmer and Lemeshow goodness-of-fit test in that observations are classified into distinct groups according to fitted probabilities, allowing sufficient cell sizes for chi-square testing. The major difference is that the proposed tests perform this grouping within the cross-classification of all categorical covariates in the model and, in some situations, allow for a more powerful assessment of where model predicted and observed counts may differ. A variety of simulations are performed comparing the proposed tests to the Hosmer-Lemeshow test.
The efficacy and safety of albinterferon alfa-2b (alb-IFN), a novel recombinant protein consisting of interferon alfa-2b genetically fused to human albumin, was evaluated in a phase 2b, open-label study of patients with genotype 1, chronic hepatitis C. In all, 458 IFN-alfa treatment-naïve patients were randomized to 48-week treatment with peginterferon alfa (PEG-IFN␣)-2a 180 g one time per week (qwk), or alb-IFN 900 or 1,200 g once every two weeks (q2wk), or 1,200 g once every four weeks (q4wk), administered subcutaneously, plus weight-based oral ribavirin 1,000 or 1,200 mg/day. Hepatitis C virus RNA was measured by real-time polymerase chain reaction (limit of detection: 10 IU/mL). The primary efficacy endpoint was sustained virologic response (hepatitis C virus RNA <10 IU/mL 24 weeks after the end of treatment). By intentionto-treat analysis, sustained virologic response rates were 58.5% (69/118) with alb-IFN 900 g q2wk, 55.5% (61/110) with 1,200 g q2wk, and 50.9% (59/116) with 1,200 g q4wk, and 57.9% (66/114) with PEG-IFN␣-2a (P ؍ 0.64 for overall test). Discontinuation rates due to adverse events were 9.3% with alb-IFN 900 g q2wk, 18.2% with 1,200 g q2wk and 12.1% with 1,200 g q4wk, and 6.1% with PEG-IFN␣-2a (P ؍ 0.04). Hematologic reductions were lowest in the q4wk group and comparable across other groups. At week 12, mean treatmentassociated missed workdays were significantly lower with alb-IFN 900 g q2wk versus PEG-IFN␣-2a (1.1 versus 4.3 days; P ؍ 0.006). Conclusion: Alb-IFN administered q2wk or q4wk may offer comparable efficacy, with an improved dosing schedule, compared with PEG-IFN␣-2a. (HEPATOLOGY 2008;48:407-417.) Abbreviations: AE, adverse event; ANC, absolute neutrophil count; CHC, chronic hepatitis C; CI, confidence interval; EVR12, early virologic response at week 12; HCV, hepatitis C virus; HRQOL, IFN␣, interferon alfa; LOD, limit of detection; LOQ, limit of quantitation; peginterferon alfa; qwk, one time per week; q2wk, once every two weeks; q4wk, once every four weeks; RBV, ribavirin; RVR4, rapid virologic response at week 4; SVR, sustained virologic response; ULN, upper limit of normal. From the 1 J.W. Frankfurt, Germany; 2 University of British Columbia, Vancouver, Canada; Paris, France; 4 Monash University Medical School, Victoria, Australia;5 University of Alberta, Edmonton, Canada; 6 Hadassah University, Jerusalem, Israel;7 Medical University of Bialystok, Poland; Romania; Prague, Czech Republic;10 University of Manitoba, Winnipeg, Canada; 11 Human Genome Sciences Inc., Rockville, MD;and 12 Division of Gastroenterology, Duke Clinical Research Institute, Durham, NC. Received February 21, 2008; accepted April 25, 2008. Supported by Human Genome Sciences Inc., Rockville, MD, and Novartis Pharma AG, Basel, Switzerland (S.Z., E.M.Y., Y.B., S.P., V.G.B., D.S., R.F., V.R., M.G., K.K., J.G.M. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail: zeuzem@em.uni-frankfurt.de; fax: 49-(0)69-6301-6448. Copyright © 2008 [3][4][5][6][7][8] Approximately 70% ...
It is well documented that the commonly used Pearson chi-square and deviance statistics are not adequate for assessing goodness-of-fit in logistic regression models when continuous covariates are modelled. In recent years, several methods have been proposed which address this shortcoming in the binary logistic regression setting or assess model fit differently. However, these techniques have typically not been extended to the ordinal response setting and few techniques exist to assess model fit in that case. We present the modified Pearson chi-square and deviance tests that are appropriate for assessing goodness-of-fit in ordinal response models when both categorical and continuous covariates are present. The methods have good power to detect omitted interaction terms and reasonable power to detect failure of the proportional odds assumption or modelling the wrong functional form of a continuous covariate. These tests also provide immediate information as to where a model may not fit well. In addition, the methods are simple to understand and implement, and are non-specific. That is, they do not require prespecification of a type of lack-of-fit to detect.
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