Developing a conceptual model of symptoms and impacts in progressive fibrosing interstitial lung disease to evaluate patient-reported outcome measures.

Background: An understanding of the experience of patients with progressive fibrosing interstitial lung disease (PF-ILD) is needed to select appropriate patient-reported outcome measures (PROMs) to evaluate treatment effect in clinical trials. Methods: A systematic literature review was conducted to develop a preliminary conceptual model of the symptoms experienced by patients with PF-ILD and the impacts the disease has on them. An online survey and consensus meetings were then conducted with 12-14 stakeholders (patients, clinicians, regulatory and payer advisors) to refine the conceptual model and critically appraise how key concepts should be measured by PROMs. PROMs assessed included Living with Idiopathic Pulmonary Fibrosis, Living with Pulmonary Fibrosis, the King's Brief Interstitial Lung Disease questionnaire, Cough and Sputum Assessment Questionnaire, Evaluating Respiratory Symptoms, Leicester Cough Questionnaire, Functional Assessment of Chronic Illness Therapy (Dyspnoea/Fatigue) and St George's Respiratory Questionnaire for Idiopathic Pulmonary Fibrosis. Results: The literature review identified 36 signs/symptoms and 43 impacts directly or indirectly related to pulmonary aspects of PF-ILD. The most relevant symptoms identified by participants included shortness of breath on exertion, fatigue and cough; relevant impacts included effects on physical functioning, activities of daily living and emotional wellbeing. These are presented in a conceptual model. Consensus opinion was that existing PROMs need further modification and validation before use in clinical trials. Conclusions: The conceptual model improves understanding of the symptoms and impacts that living with PF-ILD has on patients' wellbeing. It can help to inform the choice of PROMs in clinical trials and highlight aspects to assess in the clinical care of patients with PF-ILD.

The psychometric properties of the King's Brief Interstitial Lung Disease questionnaire and thresholds for meaningful treatment response in patients with progressive fibrosing interstitial lung diseases.

BACKGROUND: There is a lack of fully validated patient-reported outcome measures for progressive fibrosing interstitial lung disease (ILD). We aimed to validate the King's Brief Interstitial Lung Disease (K-BILD) questionnaire for measuring health-related quality of life (HRQoL) in these patients. We also aimed to estimate the meaningful change threshold for interpreting stabilisation of HRQoL as a clinical end-point in progressive fibrosing ILD, where the current goal of treatment is disease stability and slowing progression. METHODS: This analysis evaluated data from 663 patients with progressive fibrosing ILD other than idiopathic pulmonary fibrosis from the INBUILD trial. Validation of the measurement properties was assessed for internal consistency, test-retest reliability, construct validity, known-groups validity and responsiveness. We calculated meaningful change thresholds for treatment response using anchor-based (within-patient) and distribution-based methods. RESULTS: K-BILD had strong internal consistency (Cronbach's α was 0.94 for total score, 0.88 for breathlessness and activities, 0.91 for psychological, and 0.79 for chest symptoms). The test-retest reliability intraclass correlation coefficient was 0.74 for K-BILD total score. K-BILD demonstrated weak correlations with forced vital capacity (FVC) percent predicted. Known-groups validity showed significant differences in K-BILD scores for patient groups with different disease severity based on use of supplemental oxygen or baseline FVC % pred (≤70% or >70%). We estimated a meaningful change threshold of ≥ -2 units for K-BILD total score for defining patients who remain stable/improved versus those with progressive deterioration. CONCLUSIONS: Our results validate K-BILD as a tool for assessing HRQoL in patients with progressive fibrosing ILD and set a meaningful change threshold of ≥ -2 units for K-BILD total score.

The Living with Pulmonary Fibrosis questionnaire in progressive fibrosing interstitial lung disease.

The Living with Idiopathic Pulmonary Fibrosis (L-IPF) questionnaire was developed with substantial input from patients with idiopathic pulmonary fibrosis (IPF) to assess symptoms and health-related quality of life (HRQoL). Because IPF is the prototypical chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype, we expanded applicability of the L-IPF by deleting the word "idiopathic", creating the L-PF (Living with Pulmonary Fibrosis) questionnaire, and then assessed its relevance among patients with progressive fibrosing ILDs in one-to-one interviews. Patients in the USA and Germany with any progressive fibrosing ILD other than IPF were asked about their disease and symptoms, completed the 44-item L-PF questionnaire (comprising two modules that assess symptoms and impacts of disease) and then answered a series of debriefing questions. Interviews were recorded, transcribed and coded for qualitative content analysis. 20 patients were interviewed, but time constraints meant not all were asked about all items. The most frequent diagnoses were rheumatoid arthritis-associated ILD (25%) and mixed connective tissue disease-associated ILD (20%). Almost all patients endorsed the symptoms assessed by the L-PF: shortness of breath (19 out of 20 patients), cough (19 out of 20) and fatigue (18 out of 20). Most patients endorsed impacts of progressive fibrosing ILD on activities of daily living, physical well-being, sleep, emotional well-being, and social aspects of their lives. Most patients had an overall positive impression of the Symptoms module and understood items as intended. All seven patients asked understood the items of the Impacts module. The L-PF contains concepts relevant and important to patients with progressive fibrosing ILD, and items are understood as intended.

Health-related quality of life and symptoms in patients with IPF treated with nintedanib: analyses of patient-reported outcomes from the INPULSIS® trials.

BACKGROUND: In the Phase III INPULSIS® trials, treatment of patients with idiopathic pulmonary fibrosis (IPF) with nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) versus placebo, consistent with slowing disease progression. However, nintedanib was not associated with a benefit in health-related quality of life (HRQoL) assessed using the St George's respiratory questionnaire (SGRQ). We aimed to further examine the impact of IPF progression on HRQoL and symptoms, and to explore the effect of nintedanib on HRQoL in patients from the INPULSIS® trials stratified by clinical factors associated with disease progression. METHODS: Patient-reported outcome (PRO) data from the INPULSIS® trials were included in three post hoc analyses. Two analyses used the pooled data set to examine PRO changes from baseline to week 52 according to 1) decline in FVC and 2) occurrence of acute exacerbations. In the third analysis, patients were stratified based on clinical indicators of disease progression (gender, age and physiology [GAP] stage; FVC % predicted; diffusing capacity of the lung for carbon monoxide [DLCO] % predicted; composite physiologic index [CPI]; and SGRQ total score) at baseline; median change from baseline was measured at 52 weeks and treatment groups were compared using the Wilcoxon two-sample test. RESULTS: Data from 1061 patients (638 nintedanib, 423 placebo) were analyzed. Greater categorical decline from baseline in FVC % predicted over 52 weeks was associated with significant worsening of HRQoL and symptoms across all PRO measures. Acute exacerbations were associated with deterioration in HRQoL and worsened symptoms. In general, patients with advanced disease at baseline (defined as GAP II/III, FVC ≤ 80%, DLCO ≤ 40%, CPI >  45, or SGRQ > 40) experienced greater deterioration in PROs than patients with less-advanced disease. Among patients with advanced disease, compared with placebo, nintedanib slowed deterioration in several PROs; benefit was most apparent on the SGRQ (total and activity scores). CONCLUSIONS: In patients with advanced IPF, compared with placebo, nintedanib slowed deterioration in HRQoL and symptoms as assessed by several PROs. HRQoL measures have a higher responsiveness to change in advanced disease and may lack sensitivity to capture change in patients with less-advanced IPF.

Supramolecular iron cylinder with unprecedented DNA binding is a potent cytostatic and apoptotic agent without exhibiting genotoxicity.

The supramolecular iron cylinder, [Fe(2)L(3)]Cl(4) (L = C(25)H(20)N(4)), shows unprecedented DNA binding in vitro, inducing intramolecular DNA coiling and also targeting Y-shaped DNA junctions. We investigated its effects on proliferation and survival in both tumor and normal cell lines. Iron cylinder reduced mitochondrial activity of cultures with potency similar to cisplatin, inhibited the cell cycle, and increased cell death by apoptosis. Associated with this, we observed a lowering of the association of propidium iodide with cellular DNA consistent with an observed competitive displacement of PI from naked DNA by cylinders. Importantly, and in contrast to existing anticancer drugs such as cisplatin, the iron cylinder [Fe(2)L(3)](4+) was not genotoxic. In summary, the design of metal complexes such as [Fe(2)L(3)](4+) with potential anticancer properties in the absence of genotoxicity may represent a significant step toward therapeutic advancement.