Biological Age, Chronological Age and Survival in Pulmonary Fibrosis: A Causal Mediation Analysis.

RATIONALE: Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. OBJECTIVES: To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. METHODS: Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis (IPF) discovery cohort. Proteins mediating this relationship after adjustment for false discovery were advanced for testing in an independent ILD validation cohort and explored in a chronic obstructive pulmonary disease (COPD) cohort. A proteomic-based measure of biological age was constructed and survival analysis performed assessing the impact of biological age and peripheral blood telomere length on the chronological age-survival relationship. RESULTS: Twenty-two proteins mediated the chronological age-survival relationship after adjustment for false discovery in the IPF discovery cohort (n=874), with nineteen remaining significant mediators of this relationship in the ILD validation cohort (n=983) and one mediating this relationship in the COPD cohort. Latent transforming growth factor beta binding protein 2 and ectodysplasin A2 receptor showed the strongest mediation across cohorts. A proteomic measure of biological age completely attenuated the chronological age-survival association and better discriminated survival than chronological age. Results were robust to adjustment for peripheral blood telomere length, which did not mediate the chronological age-survival relationship. CONCLUSIONS: Molecular measures of aging completely mediate the relationship between chronological age and survival, suggesting that chronological age has no direct effect on ILD survival.

Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Study.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease, which causes progressive cough, exertional dyspnea, impaired quality of life and death. OBJECTIVES: Bexotegrast (PLN 74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. METHODS: This Phase 2a, multicenter, clinical trial, randomized participants with IPF to receive oral, once daily bexotegrast 40 mg, 80 mg, 160 mg, 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in forced vital capacity (FVC); quantitative lung fibrosis (QLF) extent (%) and changes from baseline in fibrosis-related biomarkers. MEASUREMENTS AND MAIN RESULTS: Bexotegrast was well tolerated with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Bexotegrast treated participants experienced a reduction in FVC decline over 12 weeks vs. placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging and a decrease in fibrosis-associated biomarkers was observed with bexotegrast vs. placebo. CONCLUSIONS: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT04396756. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Deep Learning Classification of Usual Interstitial Pneumonia Predicts Outcomes.

Rationale: Computed tomography (CT) enables noninvasive diagnosis of usual interstitial pneumonia (UIP), but enhanced image analyses are needed to overcome the limitations of visual assessment. Objectives: Apply multiple instance learning (MIL) to develop an explainable deep learning algorithm for prediction of UIP from CT and validate its performance in independent cohorts. Methods: We trained an MIL algorithm using a pooled dataset (n = 2,143) and tested it in three independent populations: data from a prior publication (n = 127), a single-institution clinical cohort (n = 239), and a national registry of patients with pulmonary fibrosis (n = 979). We tested UIP classification performance using receiver operating characteristic analysis, with histologic UIP as ground truth. Cox proportional hazards and linear mixed-effects models were used to examine associations between MIL predictions and survival or longitudinal FVC. Measurements and Main Results: In two cohorts with biopsy data, MIL improved accuracy for histologic UIP (area under the curve, 0.77 [n = 127] and 0.79 [n = 239]) compared with visual assessment (area under the curve, 0.65 and 0.71). In cohorts with survival data, MIL-UIP classifications were significant for mortality (n = 239, mortality to April 2021: unadjusted hazard ratio, 3.1; 95% confidence interval [CI], 1.96-4.91; P < 0.001; and n = 979, mortality to July 2022: unadjusted hazard ratio, 3.64; 95% CI, 2.66-4.97; P < 0.001). Individuals classified as UIP positive by the algorithm had a significantly greater annual decline in FVC than those classified as UIP negative (-88 ml/yr vs. -45 ml/yr; n = 979; P < 0.01), adjusting for extent of lung fibrosis. Conclusions: Computerized assessment using MIL identifies clinically significant features of UIP on CT. Such a method could improve confidence in radiologic assessment of patients with interstitial lung disease, potentially enabling earlier and more precise diagnosis.

Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Effects of nintedanib on symptoms in patients with progressive pulmonary fibrosis.

BACKGROUND: Dyspnoea and cough can have a profound impact on the lives of patients with pulmonary fibrosis. We investigated the effects of nintedanib on the symptoms and impact of pulmonary fibrosis in patients with progressive pulmonary fibrosis (PPF) in the INBUILD trial using the Living with Pulmonary Fibrosis (L-PF) questionnaire. METHODS: Patients had a fibrosing interstitial lung disease (ILD) (other than idiopathic pulmonary fibrosis) of >10% extent on high-resolution computed tomography (HRCT) and met criteria for ILD progression within the prior 24 months. Patients were randomised 1:1 to receive nintedanib or placebo. Changes in L-PF questionnaire scores from baseline to week 52 were assessed using mixed models for repeated measures. RESULTS: In total, 663 patients were treated. Compared with placebo, there were significantly smaller increases (worsenings) in adjusted mean L-PF questionnaire total (0.5 versus 5.1), symptoms (1.3 versus 5.3), dyspnoea (4.3 versus 7.8) and fatigue (0.7 versus 4.0) scores in the nintedanib group at week 52. L-PF questionnaire cough score decreased in the nintedanib group and increased in the placebo group (-1.8 versus 4.3). L-PF questionnaire impacts score decreased slightly in the nintedanib group and increased in the placebo group (-0.2 versus 4.6). Similar findings were observed in patients with a usual interstitial pneumonia-like fibrotic pattern on HRCT and in patients with other fibrotic patterns on HRCT. CONCLUSION: Based on changes in L-PF questionnaire scores, nintedanib reduced worsening of dyspnoea, fatigue and cough and the impacts of ILD over 52 weeks in patients with PPF.

Proteomic Biomarkers of Survival in Idiopathic Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) causes progressive lung scarring and high mortality. Reliable and accurate prognostic biomarkers are urgently needed. OBJECTIVE: To identify and validate circulating protein biomarkers of IPF survival. METHODS: High-throughput proteomic data were generated using prospectively collected plasma samples from patients with IPF from the Pulmonary Fibrosis Foundation Patient Registry (discovery cohort) and the Universities of California-Davis, Chicago, and Virginia (validation cohort). Proteins associated with three-year transplant-free survival (TFS) were identified using multivariable Cox proportional hazards regression. Those associated with TFS after adjustment for false discovery in the discovery cohort were advanced for testing in the validation cohort, with proteins maintaining TFS association with consistent effect direction considered validated. After combining cohorts, functional analyses were performed, and machine learning used to derive a proteomic signature of TFS. MAIN RESULTS: Of 2921 proteins tested in the discovery cohort (n=871), 231 were associated with differential TFS. Of these, 140 maintained TFS association with consistent effect direction in the validation cohort (n=355). After combining cohorts, validated proteins with strongest TFS association were latent-transforming growth factor beta-binding protein 2 (HR 2.43, 95% CI 2.09-2.82), collagen alpha-1(XXIV) chain (HR 2.21; 95% CI 1.86-2.39) and keratin 19 (HR 1.60; 95% CI 1.47-1.74). In decision curve analysis, a proteomic signature of TFS outperformed a similarly derived clinical prediction model. CONCLUSIONS: In largest proteomic investigation of IPF outcomes performed to date, we identified and validated 140 protein biomarkers of TFS. These results shed important light on potential drivers of IPF progression.

Nintedanib in children and adolescents with fibrosing interstitial lung diseases.

BACKGROUND: Childhood interstitial lung disease (ILD) comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. METHODS: Patients aged 6-17 years with fibrosing ILD on high-resolution computed tomography and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks and then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary end-points were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. RESULTS: 26 patients received nintedanib and 13 patients received placebo. The geometric mean (geometric coefficient of variation) AUCτ,ss for nintedanib was 175 µg·h·L-1 (85.1%) in patients aged 6-11 years and 160 µg·h·L-1 (82.7%) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean±se changes in percentage predicted forced vital capacity at week 24 were 0.3±1.3% in the nintedanib group and -0.9±1.8% in the placebo group. CONCLUSIONS: In children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

Progressive pulmonary fibrosis: an expert group consensus statement.

This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate initial diagnosis being of paramount importance in ensuring appropriate initial management. Equally, case-by-case decisions on monitoring and management are essential, given the varying presentations of F-ILDs and the varying rates of progression. The value of diagnostic tests in risk stratification at presentation and, separately, the importance of a logical monitoring strategy, tailored to manage the risk of progression, are also stressed. The term "progressive pulmonary fibrosis" (PPF) exactly describes the entity that clinicians often face in practice. The importance of using antifibrotic therapy early in PPF (once initial management has failed to prevent progression) is increasingly supported by evidence. Artificial intelligence software for high-resolution computed tomography analysis, although an exciting tool for the future, awaits validation. Guidance is provided on pulmonary rehabilitation, oxygen and the use of non-invasive ventilation focused specifically on the needs of ILD patients with progressive disease. PPF should be differentiated from acute deterioration due to drug-induced lung toxicity or other forms of acute exacerbations. Referral criteria for a lung transplant are discussed and applied to patient needs in severe diseases where transplantation is not realistic, either due to access limitations or transplantation contraindications. In conclusion, expert group consensus guidance is provided on the diagnosis, treatment and monitoring of F-ILDs with specific focus on the recognition of PPF and the management of pulmonary fibrosis progressing despite initial management.

Expert consensus on the management of systemic sclerosis-associated interstitial lung disease.

BACKGROUND: Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting for 20-40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD. METHODS: A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from - 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤ - 2.5 or ≥ + 2.5 with a standard deviation not crossing zero. RESULTS: Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants. CONCLUSIONS: This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need.

B7H3 expression and significance in idiopathic pulmonary fibrosis.

The clinical significance of B7H3 (CD276) and its cleavage product soluble B7H3 (sB7H3) in idiopathic pulmonary fibrosis (IPF) is unknown. Mounting evidence suggests the potential utility of peripheral blood myeloid cell enumeration to predict disease outcome and indicate active lung disease. Here we hypothesized that sB7H3 is involved in regulation of circulating myeloid cells in pulmonary fibrosis. In support of this possibility, both plasma sB7H3 and B7H3+ cells were elevated in IPF patient blood samples, which correlated negatively with lung function. To analyze its function, the effects of sB7H3 on naïve or bleomycin-treated mice were examined. The results revealed that sB7H3 injection induced an influx of myeloid-derived suppressor cells (MDSCs) and Ccl2 expression in lung tissue of naïve mice, accompanied by enhanced overall inflammation. Additionally, sB7H3 caused accumulation of MDSCs in bone marrow with increased expression of inflammatory cytokines. Notably, in vitro assays revealed chemotaxis of MDSCs to sB7H3, which was dependent on TLT-2 (TREML2), a putative receptor for sB7H3. Thus, increased circulating sB7H3 and/or B7H3+ cells in IPF patient blood samples correlated with lung function decline and potential immunosuppressive status. The correlation of sB7H3 with deterioration of lung function might be due to its ability to enhance inflammation and recruitment of MDSCs into the lung and their expansion in the bone marrow, and thus potentially contribute to IPF exacerbation. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Phase 2B Study of Inhaled RVT-1601 for Chronic Cough in Idiopathic Pulmonary Fibrosis: A Multicenter, Randomized, Placebo-controlled Study (SCENIC Trial).

Rationale: Chronic cough remains a major and often debilitating symptom for patients with idiopathic pulmonary fibrosis (IPF). In a phase 2A study, inhaled RVT-1601 (cromolyn sodium) reduced daytime cough and 24-hour average cough counts in patients with IPF. Objectives: To determine the efficacy, safety, and optimal dose of inhaled RVT-1601 for the treatment of chronic cough in patients with IPF. Methods: In this multicenter, randomized, placebo-controlled phase 2B study, patients with IPF and chronic cough for ⩾8 weeks were randomized (1:1:1:1) to receive 10, 40, and 80 mg RVT-1601 three times daily or placebo for 12 weeks. The primary endpoint was change from baseline to end of treatment in log-transformed 24-hour cough count. Key secondary endpoints were change from baseline in cough severity and cough-specific quality of life. Safety was monitored throughout the study. Measurements and Main Results: The study was prematurely terminated owing to the impact of the coronavirus disease (COVID-19) pandemic. Overall, 108 patients (mean age 71.0 years, 62.9% males) received RVT-1601 10 mg (n = 29), 40 mg (n = 25), 80 mg (n = 27), or matching placebo (n = 27); 61.1% (n = 66) completed double-blind treatment. No statistically significant difference was observed in the least-square mean change from baseline in log-transformed 24-hour average cough count, cough severity, and cough-specific quality of life score between the RVT-1601 groups and the placebo group. The mean percentage change from baseline in 24-hour average cough count was 27.7% in the placebo group. Treatment was generally well tolerated. Conclusions: Treatment with inhaled RVT-1601 (10, 40, and 80 mg three times a day) did not provide benefit over placebo for the treatment of chronic cough in patients with IPF.

Integrating Clinical Probability into the Diagnostic Approach to Idiopathic Pulmonary Fibrosis: An International Working Group Perspective.

Background: When considering the diagnosis of idiopathic pulmonary fibrosis (IPF), experienced clinicians integrate clinical features that help to differentiate IPF from other fibrosing interstitial lung diseases, thus generating a "pre-test" probability of IPF. The aim of this international working group perspective was to summarize these features using a tabulated approach similar to chest HRCT and histopathologic patterns reported in the international guidelines for the diagnosis of IPF, and to help formally incorporate these clinical likelihoods into diagnostic reasoning to facilitate the diagnosis of IPF. Methods: The committee group identified factors that influence the clinical likelihood of a diagnosis of IPF, which was categorized as a pre-test clinical probability of IPF into "high" (70-100%), "intermediate" (30-70%), or "low" (0-30%). After integration of radiological and histopathological features, the post-test probability of diagnosis was categorized into "definite" (90-100%), "high confidence" (70-89%), "low confidence" (51-69%), or "low" (0-50%) probability of IPF. Findings: A conceptual Bayesian framework was created, integrating the clinical likelihood of IPF ("pre-test probability of IPF") with the HRCT pattern, the histopathology pattern when available, and/or the pattern of observed disease behavior, into a "post-test probability of IPF." The diagnostic probability of IPF was expressed using an adapted diagnostic ontology for fibrotic interstitial lung diseases. Interpretation: The present approach will help incorporate the clinical judgment into the diagnosis of IPF, thus facilitating the application of IPF diagnostic guidelines and, ultimately improving diagnostic confidence and reducing the need for invasive diagnostic techniques.

Syndrome of Combined Pulmonary Fibrosis and Emphysema: An Official ATS/ERS/JRS/ALAT Research Statement.

Background: The presence of emphysema is relatively common in patients with fibrotic interstitial lung disease. This has been designated combined pulmonary fibrosis and emphysema (CPFE). The lack of consensus over definitions and diagnostic criteria has limited CPFE research. Goals: The objectives of this task force were to review the terminology, definition, characteristics, pathophysiology, and research priorities of CPFE and to explore whether CPFE is a syndrome. Methods: This research statement was developed by a committee including 19 pulmonologists, 5 radiologists, 3 pathologists, 2 methodologists, and 2 patient representatives. The final document was supported by a focused systematic review that identified and summarized all recent publications related to CPFE. Results: This task force identified that patients with CPFE are predominantly male, with a history of smoking, severe dyspnea, relatively preserved airflow rates and lung volumes on spirometry, severely impaired DlCO, exertional hypoxemia, frequent pulmonary hypertension, and a dismal prognosis. The committee proposes to identify CPFE as a syndrome, given the clustering of pulmonary fibrosis and emphysema, shared pathogenetic pathways, unique considerations related to disease progression, increased risk of complications (pulmonary hypertension, lung cancer, and/or mortality), and implications for clinical trial design. There are varying features of interstitial lung disease and emphysema in CPFE. The committee offers a research definition and classification criteria and proposes that studies on CPFE include a comprehensive description of radiologic and, when available, pathological patterns, including some recently described patterns such as smoking-related interstitial fibrosis. Conclusions: This statement delineates the syndrome of CPFE and highlights research priorities.

Nintedanib in Progressive Fibrosing Interstitial Lung Diseases.

BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown. METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern. RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group. CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).

Nintedanib in progressive interstitial lung diseases: data from the whole INBUILD trial.

BACKGROUND: The primary analysis of the INBUILD trial showed that in subjects with progressive fibrosing interstitial lung diseases (ILDs), nintedanib slowed the decline in forced vital capacity (FVC) over 52 weeks. We report the effects of nintedanib on ILD progression over the whole trial. METHODS: Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice, were randomised to receive nintedanib or placebo. Subjects continued on blinded randomised treatment until all subjects had completed the trial. Over the whole trial, mean±sd exposure to trial medication was 15.6±7.2 and 16.8±5.8 months in the nintedanib and placebo groups, respectively. RESULTS: In the nintedanib (n=332) and placebo (n=331) groups, respectively, the proportions of subjects who had ILD progression (absolute decline in FVC ≥10% predicted) or died were 40.4% and 54.7% in the overall population (hazard ratio (HR) 0.66, 95% CI 0.53-0.83; p=0.0003) and 43.7% and 55.8% among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT) (HR 0.69, 95% CI 0.53-0.91; p=0.009). In the nintedanib and placebo groups, respectively, the proportions who had an acute exacerbation of ILD or died were 13.9% and 19.6% in the overall population (HR 0.67, 95% CI 0.46-0.98; p=0.04) and 15.0% and 22.8% among subjects with a UIP-like fibrotic pattern on HRCT (HR 0.62, 95% CI 0.39-0.97; p=0.03). CONCLUSION: Based on data from the whole INBUILD trial, nintedanib reduced the risk of events indicating ILD progression.

Effects of nintedanib by inclusion criteria for progression of interstitial lung disease.

BACKGROUND: The INBUILD trial investigated nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs). We investigated the decline in forced vital capacity (FVC) in subgroups based on the inclusion criteria for ILD progression. METHODS: Subjects had a fibrosing ILD other than idiopathic pulmonary fibrosis and met the following criteria for ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice: Group A, relative decline in FVC ≥10% predicted; Group B, relative decline in FVC ≥5-<10% predicted with worsened respiratory symptoms and/or increased extent of fibrosis on high-resolution computed tomography (HRCT); Group C, worsened respiratory symptoms and increased extent of fibrosis on HRCT only. RESULTS: In the placebo group, the rates of FVC decline over 52 weeks in Groups A, B and C, respectively, were -241.9, -133.1 and -115.3 mL per year in the overall population (p=0.0002 for subgroup-by-time interaction) and -288.9, -156.2 and -100.1 mL per year among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on HRCT (p=0.0005 for subgroup-by-time interaction). Nintedanib had a greater absolute effect on reducing the rate of FVC decline in Group A than in Group B or C. However, the relative effect of nintedanib versus placebo was consistent across the subgroups (p>0.05 for heterogeneity). CONCLUSIONS: The inclusion criteria used in the INBUILD trial, based on FVC decline or worsening of symptoms and extent of fibrosis on HRCT, were effective at identifying patients with progressive fibrosing ILDs. Nintedanib reduced the rate of decline in FVC across the subgroups based on the inclusion criteria related to ILD progression.

Predictors of mortality in subjects with progressive fibrosing interstitial lung diseases.

BACKGROUND AND OBJECTIVE: Demographic and clinical variables, measured at baseline or over time, have been associated with mortality in subjects with progressive fibrosing interstitial lung diseases (ILDs). We used data from the INPULSIS trials in subjects with idiopathic pulmonary fibrosis (IPF) and the INBUILD trial in subjects with other progressive fibrosing ILDs to assess relationships between demographic/clinical variables and mortality. METHODS: The relationships between baseline variables and time-varying covariates and time to death over 52 weeks were analysed using pooled data from the INPULSIS trials and, separately, the INBUILD trial using a Cox proportional hazards model. RESULTS: Over 52 weeks, 68/1061 (6.4%) and 33/663 (5.0%) subjects died in the INPULSIS and INBUILD trials, respectively. In the INPULSIS trials, a relative decline in forced vital capacity (FVC) >10% predicted within 12 months (hazard ratio [HR] 3.77) and age (HR 1.03 per 1-year increase) were associated with increased risk of mortality, while baseline FVC % predicted (HR 0.97 per 1-unit increase) and diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (HR 0.77 per 1-unit increase) were associated with lower risk. In the INBUILD trial, a relative decline in FVC >10% predicted within 12 months (HR 2.60) and a usual interstitial pneumonia-like fibrotic pattern on HRCT (HR 2.98) were associated with increased risk of mortality, while baseline DLCO % predicted (HR 0.95 per 1-unit increase) was associated with lower risk. CONCLUSION: These data support similarity in the course of lung injury between IPF and other progressive fibrosing ILDs and the value of FVC decline as a predictor of mortality.

Association of Circulating Proteins with Death or Lung Transplant in Patients with Idiopathic Pulmonary Fibrosis in the IPF-PRO Registry Cohort.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics (1305 proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or < 0.5, corrected p ≤ 0.05). In multivariable analyses, a set of 4 clinical measures and 47 unique proteins predicted the probability of respiratory death or lung transplant with an optimism-corrected C-index of 0.76. Our results suggest that select circulating proteins strongly associate with the risk of mortality in patients with IPF and confer information independent of clinical measures.

Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial. METHODS: The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC. DISCUSSION: The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920.