Real-world observational cohort study of treatment patterns and safety outcomes of infliximab biosimilar CT-P13 for the treatment of inflammatory bowel disease (CONNECT-IBD)

The objective of this non-interventional, observational prospective cohort study (CONNECT-IBD) was to assess the use of CT-P13 (Inflectra®) in the treatment of patients with Crohn’s disease (CD) and ulcerative colitis (UC) in the context of treatment with reference infliximab (IFX; Remicade®). Patients (recruited April 2015 to October 2018) at 150 sites across 13 European countries were followed for up to 2 years. Primary outcomes were safety, population characteristics, and drug utilization patterns. Secondary outcomes included clinical assessment of disease activity. Data were analyzed descriptively. Overall, 2543 patients (CD, n = 1676; UC, n = 867) were included. In the CT-P13 cohort (n = 1522), median disease duration was 63 (0–579) months and 30% of patients were IFX naïve; median duration of prior IFX treatment was 5 months. During the observation period, median duration of drug exposure was 14 (0–28) months. 41% of patients reported 912 all-causality treatment-emergent adverse events (TEAEs); 24% experienced treatment-related TEAEs. Most TEAEs were of mild-to-moderate severity. Treatment-emergent serious adverse events were reported by 17% of patients. Safety information for CT-P13 in this large study was consistent with the known safety profile for IFX and did not alter the established benefit-risk profile of CT-P13.</p

Predictive Factors for Sustained Virological Response after Treatment with Pegylated Interferon α-2a and Ribavirin in Patients Infected with HCV Genotypes 2 and 3

<div><p>Background</p><p>Previous trials have often defined genotype 2 and 3 patients as an “easy to treat” group and guidelines recommend similar management.</p><p>Aims</p><p>The present study looks for differences between the two genotypes and analyzes predictive factors for SVR.</p><p>Methods</p><p>Prospective, community-based cohort study involving 421 physicians throughout Germany. The analysis includes 2,347 patients with untreated chronic HCV genotype 2 (n = 391) and 3 (n = 1,956) infection treated with PEG-IFN α-2a plus ribavirin between August 2007 and July 2012.</p><p>Results</p><p>When compared with genotype 2 patients, those with genotype 3 were younger, had a shorter duration of infection, lower values of total cholesterol, LDL cholesterol and BMI, a higher frequency of drug use as infection mode and male gender (p<0.0001, respectively), and a higher APRI score (p<0.005). SVR was higher in genotype 2 when compared with genotype 3 (64.7% vs. 56.9%, p = 0.004). By multivariate analysis of genotype 2 patients, low baseline γ -GT and RVR predicted SVR. In genotype 3 age ≤45 years, cholesterol>130 mg/dl, a low APRI score, and a γ-GT ≥3-times ULN, RVR, and RBV starting dose were associated with SVR by multivariate analysis.</p><p>Conclusions</p><p>The present study corroborates that liver fibrosis is more pronounced in genotype 3 vs. 2. SVR is higher in genotype 2 versus genotype 3 partly because of follow-up problems in genotype 3 patients, in particular in those infected by drug use. Thus, subgroups of genotype 3 patients have adherence problems and need special attention also because they often have significant liver fibrosis.</p><p>Trial Registration</p><p>Verband Forschender Arzneimittelhersteller e.V., Berlin, Germany <a href="http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb" target="_blank">ML21645</a> ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT02106156" target="_blank">NCT02106156</a></p></div

Main characteristics of patients infected with GT2 and GT3.

<p># alcohol abuse was assessed by judgement of the physician.</p><p>* only patients who were treated at least for 4 weeks and in whom RVR was correctly determined (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0107592#s2" target="_blank">Methods</a> for further details).</p><p>** only patients who were treated at least for 12 weeks and in whom EVR was correctly determined (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0107592#s2" target="_blank">Methods</a> for further details).</p><p>Main characteristics of patients infected with GT2 and GT3.</p

SVR versus mode of infection in GT2 and GT3 patients.

<p>(multiple answers allowed; differences between modes of infections in GT2 versus GT3 were tested for significance by Fisher's exact χ²-test without correcting for multiple testing).</p><p>SVR versus mode of infection in GT2 and GT3 patients.</p

Univariate analysis of variables for prediction of SVR in GT2 and GT3.

<p>* OR  =  Odds Ratio; CI  =  Confidence interval.</p><p>** With a planned treatment end or with treatment discontinuation for virological failure or adverse events.</p><p># By univariate analysis baseline thrombocytes and GOT were also significant in GT3 in predicting SVR; in GT2 these variables were not significant. Since the APRI score which combines these two variables had a higher predictive value when compared with the two single variables only the APRI score was used for further analyses.</p><p>Univariate analysis of variables for prediction of SVR in GT2 and GT3.</p

Main characteristics of patients infected with GT2 and GT3 (Mean).

<p>Main characteristics of patients infected with GT2 and GT3 (Mean).</p

BMI and baseline cholesterol versus gender.

<p>BMI and baseline cholesterol versus gender.</p

Enrichment of alleles discovered in AJ exome sequencing project.

<p><b>A)</b> Histogram of estimated log enrichment statistic, defined as the log of the bias corrected odds ratio comparing the allele frequency in AJ population to the maximum allele frequency estimated from NFE, AFR, and AMR populations in ExAC. For each histogram bin we show a bar plot of the expected number of alleles belonging to the two groups we analyzed: 1) enriched (green) and 2) not enriched (white). <b>B)</b> Bar plots of estimated percentage of alleles belonging to the two groups we analyzed for all protein-coding (ALL), synonymous (SYN), protein-altering (PRA), and protein-truncating variants (PTV). An estimate of 34% of protein-coding alleles observed in AJ have a mean shift of 15-fold increased odds of the alternate allele compared to other reference populations. This observation is supported by the property that compared to intergenic variants, coding variants tend to be younger for a given frequency and the more pathogenic a variant, the younger it is, therefore tending to be population specific[<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007329#pgen.1007329.ref013" target="_blank">13</a>].</p

AJ individuals have higher CD polygenic risk score than NJ controls.

<p>NJ: non-Jewish; AJ: Ashkenazi Jewish; CD: Crohn’s disease; PRS: polygenic risk score. <b>A</b>) Density plot of CD polygenic risk scores in 454 AJ (green) and 35,007 NJ(purple)controls. AJ controls have higher CD polygenic risk score than NJ controls (0.97 s.d. higher, p<10⁻¹⁶). <b>B</b>) Density plot of CD polygenic risk scores in 1,938 AJ (green) and 20,652 NJ CD (purple) cases (0.54 s.d. higher, p<10⁻¹⁶). For both density plots the scores have been scaled to NJ controls, thus resulting in an NJ control PRS density of mean equal to 0 and variance equal to 1 (see Online Methods). <b>C</b>) Ranked (decreasing order) CD associated variants by estimated contribution to the differences in genetic risk between AJ and NJ. Associated variants with estimated contribution greater than or equal to 0.01, computed as 2 log(odds ratio) (AJ frequency—NJ frequency), assuming additive effects on the log scale, are highlighted in green. Associated variants with estimated contribution less than or equal to -0.01 are highlighted in purple. Forward slashes represent a break in variants highlighted.</p

Forty-eight ClinVar “pathogenic” alleles enriched in AJ.

<p>HGVS and Gene is the allele nomenclature in ClinVar and gene symbol, respectively. Enrichment odds ratio corresponds to the bias corrected comparison of allele frequency in AJ (AJ AF) to maximum frequency among three population groups (max EXAC AF): 1) NFE; 2) AMR; and 3) AFR. Curated trait is based on the trait description in the Online Mendelian Inheritance in Man (OMIM) and is independent of effect size as a Crohn’s risk allele. Inheritance corresponds to the inheritance description in OMIM (AR: autosomal recessive, AD: autosomal dominant, risk factor: not specified genetic risk factor). Alleles are sorted in decreasing order by AJ AF.</p