With the advent of high-resolution computed tomography (CT) scanners and sophisticated software programs, there are endeavors to now include objective CT-based scoring systems as endpoints for clinical trials in IPF . Previous attempts to characterize image-based disease burden have used more crude subjective scoring systems . Although it makes intuitive sense to score change in the extent of disease via high-resolution imaging, the accuracy, reproducibility and precision of these imaging modalities remain to be determined.
Patient-reported outcomes (PROs) are important constituents for any study in IPF . There are a number of quality-of-life (QOL) measures that have been employed previously in the context of clinical trials, but most of these have not been IPF-specific instruments, such as the Saint George's Respiratory Questionnaire (SGRQ), the 36-Item Short Form Health Survey (SF-36) and the San Diego shortness of breath questionnaire (SDSQ). There have been attempts to develop IPF-specific instruments that capture the global burden of the disease, and it makes intuitive sense that such instruments should be further validated and employed in future studies [34,35]. In patients with very advanced disease in which stage symptom palliation is the primary objective, the use of such instruments as primary outcome measures might make sense.
A biomarker is defined as an objectively measured indicator of a normal or abnormal biological process that may also track progression of disease and/or the response to a therapeutic intervention. There are, however, no validated biomarkers that track progression of disease in IPF, and none have yet been shown to track response to therapy. A number of serum protein biomarkers have been shown to be increased [e.g. Krebs von den Lungen 6 glycoprotein (KL-6), surfactant protein A (SPA), chemokine (C-C motif) ligand 18 (CCL 18), matrix metalloproteinase-7 (MMP-7), intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-8, vascular cell adhesion molecule-1 (VCAM-1) and S100 calcium binding protein A12 (S100A12)] or decreased (albumin) in IPF and to be predictors of survival [36–39]. However, the reproducibility of these measures and the precision of serial change in predicting subsequent outcomes have yet to be established. Beyond proteins, other serum biomarkers may be useful, including the red cell distribution width, which is readily available on routine complete blood counts and has been shown to correlate with outcomes in IPF . An increased level of brain natriuretic peptide (BNP), which may reflect the presence of underlying pulmonary hypertension or heart failure, has also been shown to be associated with worse outcomes [41–43]. BNP or pro-NT BNP levels may be useful to track as secondary endpoints in IPF studies that target the treatment of IPF-associated pulmonary hypertension. Many other cytokines and chemokines have been recently identified that are elevated as a consequence of the pathogenic cascade in IPF [44,45]. Indeed, proteomic and transcriptomic biomarkers have been identified that appear to be highly predictive of disease progression and mortality, and these may prove to be useful to stratify study participants enrolled in clinical trials [46,47▪]. However, whether serial change in any of these biomarkers ultimately proves to be a useful prognostic biomarker or study endpoint remains to be established.
There is increasing recognition of the role of pulmonary vascular changes in the clinical course of patients with IPF. The prevalence of pulmonary hypertension has been reported as ranging anywhere from 10 to 85% . The presence of pulmonary hypertension, even when mild in nature, has a strong association with subsequent outcomes. Whether treating pulmonary hypertension is a worthwhile approach and which patient phenotype to study with this form of targeted therapy also remain to be determined. Additionally, the presence of pulmonary hypertension or right-ventricular dysfunction might be important to establish during patient selection for any study in order to either stratify patients or identify a group at higher risk for disease progression and mortality.
There are many necessary components to the implementation and completion of a successful IPF trial, not least of which is the chosen endpoint. However, consensus on the best IPF endpoint for clinical trials remains elusive. Whereas mortality has come to be commonly regarded as the ‘gold standard’ endpoint in this deadly disease, the implementation and successful completion of such studies are prone to many potential pitfalls. Because of the inherent difficulties and costs of mortality studies, other endpoints need to be considered not only for earlier phase trials, but also for pivotal phase 3 studies. Event-driven studies and composites of events that capture the full spectrum of untoward outcomes represent attractive, pragmatic approaches. Finally, the investigational agent and the patient phenotype being studied are important considerations in choosing the best endpoint for any given study.
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