Results
Table 1. Baseline characteristics of subjects in the INSTAGE trial
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Data are n (%) or mean (SD). *Determined by the investigator based on qualitative assessment of HRCT scans. †Corrected for hemoglobin.
Changes in gene expression
- Data from 224 subjects (112 in each group) were analyzed.
- Of 60,675 genes evaluated, 42,078 had counts per million ≥0.1 in at least half the samples from either treatment group at every time point and were included in the analysis.
- After 24 weeks of treatment:
- No genes were upregulated in either treatment group. Two genes were downregulated in the nintedanib plus sildenafil group, while none was downregulated in subjects who received nintedanib alone. There were no significant differences in gene expression between treatment groups (Table 2).
Table 2. Genes downregulated at week 24 (with adjusted p≤0.05 and |log2fold change|≥0.5) in subjects treated with nintedanib plus sildenafil
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TINCR, tissue differentiation-inducing non-protein coding RNA.
- Of the nine genes downregulated after 12 weeks of nintedanib treatment in the INMARK trial, eight were downregulated at week 24 in the nintedanib plus sildenafil group of the INSTAGE trial, while one was downregulated in subjects receiving nintedanib alone in the INSTAGE trial (Table 3; Figure 1).
Table 3. Changes in expression in the INSTAGE trial of genes downregulated after 12 weeks’ treatment with nintedanib in the INMARK trial
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SHISA4, shisa family member 4; DEFA4, defensin alpha 4; OLR1, oxidized low density lipoprotein receptor 1; CEACAM6/8, carcinoembryonic antigen related cell adhesion molecule 6/8; LTF, lactotransferrin; CTSG, cathepsin G; OLFM4, olfactomedin 4; MMP8, matrix metalloproteinase 8.
Blue shading: |log2fold change|≥0.5 and unadjusted p≤0.05.
Figure 1. Expression at baseline and week 24 in the INSTAGE trial of the nine genes downregulated at week 12 in subjects treated with nintedanib in the INMARK trial
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cpm, counts per million; IQR, interquartile range.
Gene set variation analysis
- Gene set variation analysis was performed on the set of nine genes downregulated at week 12 in subjects treated with nintedanib in the INMARK trial.
- Between baseline and week 24 of the INSTAGE trial, genes in this set were positively enriched compared with genes not in this set among subjects treated with nintedanib plus sildenafil and nintedanib alone (Figure 2). The changes in enrichment scores were not significantly different between the treatment groups (p=0.63).
Figure 2. Gene set variation analysis enrichment scores in the INSTAGE trial for the set of nine genes downregulated in subjects treated with nintedanib in the INMARK trial
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Pathways analyses
- The network of these nine genes showed enrichment of genes related to neutrophil degranulation and lung damage (Figure 3).
Figure 3. Changes in gene expression at week 24 in the INSTAGE trial based on the network of nine genes downregulated in nintedanib-treated subjects in the INMARK trial
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