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/).

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.

Quantitative interstitial lung disease scores in idiopathic inflammatory myopathies: longitudinal changes and clinical implications.

OBJECTIVES: To investigate computer-aided quantitative scores from high-resolution CT (HRCT) images and determine their longitudinal changes and clinical significance in patients with idiopathic inflammatory myopathies (IIMs)-related interstitial lung disease (IIMs-ILD). METHODS: The clinical data and HRCT images of 80 patients with IIMs who underwent serial HRCT scans at least twice were retrospectively analysed. Quantitative ILD (QILD) scores (%) were calculated as the sum of the extent of lung fibrosis, ground-glass opacity, and honeycombing. The individual time-estimated ΔQILD between two consecutive scans was derived using a linear approximation of yearly changes. RESULTS: The baseline median QILD (interquartile range) scores in the whole lung were 28.1% (19.1-43.8). The QILD was significantly correlated with forced vital capacity (r = -0.349, P = 0.002) and diffusing capacity for carbon monoxide (r = -0.381, P = 0.001). For ΔQILD between the first two scans, according to the visual ILD subtype, QILD aggravation was more frequent in patients with usual interstitial pneumonia (UIP) than non-UIP (80.0% vs 44.4%, P = 0.013). Multivariable logistic regression analyses identified UIP was significantly related to radiographic ILD progression (ΔQILD >2%, P = 0.015). Patients with higher baseline QILD scores (>28.1%) had a higher risk of lung transplantation or death (P = 0.015). In the analysis of three serial HRCT scans (n = 41), dynamic ΔQILD with four distinct patterns (improving, worsening, convex and concave) was observed. CONCLUSION: QILD changes in IIMs-ILD were dynamic, and baseline UIP patterns seemed to be related to a longitudinal progression in QILD. These may be potential imaging biomarkers for lung function, changes in ILD severity and prognosis in IIMs-ILD.

Translating AI to Clinical Practice: Overcoming Data Shift with Explainability.

To translate artificial intelligence (AI) algorithms into clinical practice requires generalizability of models to real-world data. One of the main obstacles to generalizability is data shift, a data distribution mismatch between model training and real environments. Explainable AI techniques offer tools to detect and mitigate the data shift problem and develop reliable AI for clinical practice. Most medical AI is trained with datasets gathered from limited environments, such as restricted disease populations and center-dependent acquisition conditions. The data shift that commonly exists in the limited training set often causes a significant performance decrease in the deployment environment. To develop a medical application, it is important to detect potential data shift and its impact on clinical translation. During AI training stages, from premodel analysis to in-model and post hoc explanations, explainability can play a key role in detecting model susceptibility to data shift, which is otherwise hidden because the test data have the same biased distribution as the training data. Performance-based model assessments cannot effectively distinguish the model overfitting to training data bias without enriched test sets from external environments. In the absence of such external data, explainability techniques can aid in translating AI to clinical practice as a tool to detect and mitigate potential failures due to data shift. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Long-Term Safety and Efficacy of Tocilizumab in Early Systemic Sclerosis-Interstitial Lung Disease: Open-Label Extension of a Phase 3 Randomized Controlled Trial.

Rationale: Tocilizumab, an anti-IL-6 receptor antibody, had no statistically significant effect on skin sclerosis but preserved lung function over 48 weeks in patients with early systemic sclerosis (SSc)-associated interstitial lung disease (ILD) in a phase 3 randomized controlled trial. Objectives: Assess long-term safety and efficacy of tocilizumab. Methods: Adults with diffuse cutaneous SSc for ⩽60 months and elevated acute-phase reactants, including those with ILD, received weekly placebo or tocilizumab 162 mg subcutaneously in the 48-week, double-blind period and then open-label tocilizumab from Weeks 48 to 96 (placebo-tocilizumab; continuous-tocilizumab). Measurements and Main Results: Eighty-two of 107 patients in the placebo-tocilizumab group and 85 of 105 patients in the continuous-tocilizumab group completed 96 weeks. Mean age and disease duration were 48 years and 23 months; high-resolution computed tomography revealed ILD in 61%. Mean (95% confidence interval [CI]) change in modified Rodnan skin score from baseline to week 96 was -8.4 (-10.0 to -6.8) for placebo-tocilizumab and -9.6 (-10.9 to -8.4) for continuous-tocilizumab. Mean (95% CI) change in FVC (percent predicted) from baseline to week 96 was -3.3 (-5.1 to -1.5) for placebo-tocilizumab and -0.5 (-2.4 to 1.3) for continuous-tocilizumab among completers and, in a post hoc analysis, -4.1 (-6.7 to -1.6) and -0.6 (-3.1 to 2.0), respectively, among completers with ILD (mean [95% CI] change from Weeks 48 to 96: 0.9 [-0.8 to 2.7] and -0.4 [-2.3 to 1.5], respectively). Rates per 100 patient-years of serious adverse events from Weeks 48 to 96 were 14.8 for placebo-tocilizumab and 15.8 for continuous-tocilizumab. Conclusions: Tocilizumab preserved lung function, slowing decline in FVC, in patients with SSc, including those with ILD. Long-term safety was consistent with the known safety profile of tocilizumab. Clinical trial registered with www.clinicaltrials.gov (NCT02453256).

Effect of indacaterol/glycopyrronium on ventilation and perfusion in COPD: a randomized trial.

RATIONALE: The long-acting ß2-agonist/long-acting muscarinic antagonist combination indacaterol/glycopyrronium (IND/GLY) elicits bronchodilation, improves symptoms, and reduces exacerbations in COPD. Magnetic resonance imaging (MRI) of the lung with hyperpolarized gas and gadolinium contrast enhancement enables assessment of whole lung functional responses to IND/GLY. OBJECTIVES: The primary objective was assessment of effect of IND/GLY on global ventilated lung volume (%VV) versus placebo in COPD. Lung function, regional ventilation and perfusion in response to IND/GLY were also measured. METHODS: This double-blind, randomized, placebo-controlled, crossover study assessed %VV and pulmonary perfusion in patients with moderate-to-severe COPD after 8 days of once-daily IND/GLY treatment (110/50 µg) followed by 8 days of placebo, or vice versa, using inhaled hyperpolarized 3He gas and gadolinium contrast-enhanced MRI, respectively. Lung function measures including spirometry were performed for each treatment after 8 days. MEASUREMENTS AND MAIN RESULTS: Of 31 patients randomized, 29 completed both treatment periods. IND/GLY increased global %VV versus placebo (61.73% vs. 56.73%, respectively, least squares means treatment difference: 5.00% [90% CI 1.40 to 8.60]; P = 0.025). IND/GLY improved whole lung index of ventilation volume to perfusion volume (V/Q) ratio versus placebo; 94% (90% CI 83 to 105) versus 86% (90% CI 75 to 97; P = 0.047), respectively. IND/GLY showed a trend to improve diffusing capacity for carbon monoxide (DLCO) (+ 0.66 mL/min/mmHg; P = 0.082). By Day 8, forced expiratory volume in 1 s (FEV1) was increased by 0.32 L versus placebo (90% CI 0.26 to 0.38; P < 0.0001), substantiating earlier findings and providing evidence of assay sensitivity for this trial. CONCLUSIONS: IND/GLY improved lung ventilation assessed by 3He MRI after 1 week of treatment. This observation may provide mechanistic support for the symptomatic clinical benefit shown with IND/GLY in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02634983).

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma.

BACKGROUND: Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS: We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS: In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS: Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).

The Emerging Role of Quantification of Imaging for Assessing the Severity and Disease Activity of Emphysema, Airway Disease, and Interstitial Lung Disease.

There has been an explosion of use for quantitative image analysis in the setting of lung disease due to advances in acquisition protocols and postprocessing technology, including machine and deep learning. Despite the plethora of published papers, it is important to understand which approach has clinical validation and can be used in clinical practice. This paper provides an introduction to quantitative image analysis techniques being used in the investigation of lung disease and focusses on the techniques that have a reasonable clinical validation for being used in clinical trials and patient care.

Prediction of idiopathic pulmonary fibrosis progression using early quantitative changes on CT imaging for a short term of clinical 18-24-month follow-ups.

OBJECTIVE: High-resolution computed tomography (HRCT) plays an indispensable role in the diagnosis of idiopathic pulmonary fibrosis (IPF). Due to unpredictability in progression and the short median survival of 2-5 years, it is critical to delineate the patients with rapid progression. The aim is to evaluate the predictability of IPF progression using the early quantitative changes. METHODS: Automated texture-based quantitative lung fibrosis (QLF) was calculated from the anonymized HRCT. Two datasets were collected retrospectively: (1) a pilot study of 35 subjects with three sequential scans (baseline and 6 and 12 months) to obtain a threshold, where visual assessments were stable at 6 months but worsened at 12 months; (2) 157 independent subjects to test the threshold. Landmark Cox regressions were used to compare the progression-free survival (PFS) defined by pulmonary function using the threshold from the early changes in QLF. C-indexes were reported as estimations of the concordance of prediction. RESULTS: A threshold of 4% QLF change at 6 months corresponded to the mean change that worsened on HRCT visually at 12 months from the pilot study. Using the threshold, significant differences were found in the independent dataset (hazard ratio (HZ) = 5.92, p = 0.001 by Cox model, C-index = 0.71 at the most severe lobe; and HZ = 3.22, p = 0.012, C-index = 0.68 in the whole lung). Median PFS was 11.9 months for subjects with ≥ 4% changes, whereas median PFS was greater than 18 months for subjects with < 4% changes at the most severe lobe. CONCLUSION: Early structural changes on HRCT using a quantitative score can predict progression in lung function. KEY POINTS: • Changes on HRCT using quantitative texture-based scores can play a pivotal role for providing information and an aid tool for timely management decision for patients with IPF. • Quantitative changes on HRCT of 4% or more, which matched 6-month prior changes with visual assessment of worsening, can play a pivotal role for providing prediction of clinical progression by 3-5 folds higher in the next incidence, compared with those of subjects with less than 4% changes. • Early structural changes of 4% or more in a paired HRCT scans derived by quantitative scores can predict the progression in lung function in 1-2 years in subjects with IPF, which is critical information for timely management decision for subjects with IPF where the median survival is 2 to 5 years.

Correction to: Toward clinically usable CAD for lung cancer screening with computed tomography.

The original version of this article, published on 24 July 2014, unfortunately contained a mistake. In section "Discussion," a sentence was worded incorrectly.

Components of Radiologic Progressive Disease Defined by RECIST 1.1 in Patients with Metastatic Clear Cell Renal Cell Carcinoma.

Background Progression-free survival (PFS) determined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) is the reference standard to assess efficacy of treatments in patients with clear cell renal cell carcinoma. Purpose To assess the most common components of radiologic progressive disease as defined by RECIST 1.1 in patients with clear cell renal cell carcinoma and how the progression events impact PFS. Materials and Methods This secondary analysis of the phase III METEOR trial conducted between 2013 and 2014 included patients with metastatic clear cell renal cell carcinoma, with at least one target lesion at baseline and one follow-up time point, who were determined according to RECIST 1.1 to have progressive disease. A chest, abdominal, and pelvic scan were acquired at each time point. Kruskal-Wallis analysis was used to test differences in median PFS among the RECIST 1.1 progression events. The Holm-Bonferroni method was used to compare the median PFS of the progression events for the family-wise error rate of 5% to adjust P values for multiple comparisons. Results Of the 395 patients (296 men, 98 women, and one patient with sex not reported; mean age, 61 years ± 10), 73 (18.5%) had progression due to non-target disease, 105 (26.6%) had new lesions, and 126 (31.9%) had progression of target lesions (defined by an increase in the sum of diameters). Patients with progression of non-target disease and those with new lesions had shorter PFS than patients with progression defined by the target lesions (median PFS, 2.8 months [95% confidence interval {CI}: 1.9 months, 3.7 months] and 3.6 months [95% CI: 3.3 months, 3.7 months] vs 5.4 months [95% CI: 5.0 months, 5.5 months], respectively [P < .01]). Conclusion The most common causes for radiologic progression of renal cell carcinoma were based on non-target disease and new lesions rather than change in target lesions, despite this being considered uncommon in the Response Evaluation Criteria in Solid Tumors version 1.1 literature. © RSNA, 2019 See also the editorial by Kuhl in this issue.

Reliability and minimal clinically important differences of forced vital capacity: Results from the Scleroderma Lung Studies (SLS-I and SLS-II).

OBJECTIVES: To assess the reliability and the minimal clinically important differences (MCID) for FVC% predicted in the Scleroderma Lung Study I and II. METHODS: Using data from SLS I and II (N=300), we evaluated the test-retest reliability for FVC% predicted (FVC%; screening vs. baseline) using intra-class correlation (ICC). MCID estimates at 12 months were calculated in the pooled cohort (SLS-I and II) using 2 anchors: Transition Dyspnea Index (≥change of 1.5 units for improvement and worsening, respectively) and the SF-36 Health Transition question: "Compared to one year ago, how would you rate your health in general now?", where "somewhat better" or "somewhat worse" were defined as the MCID estimates. We next assessed the association of MCID estimates for improvement and worsening of FVC% with patient reported outcomes (PROs) and computer-assisted quantitation of extent of fibrosis (QLF) and of total ILD (QILD) on HRCT. RESULTS: Reliability of FVC%, assessed at a mean of 34 days, was 0.93 for the pooled cohort. The MCID estimates for the pooled cohort at 12 months for FVC% improvement ranged from 3.0 % to 5.3% and for worsening from -3.0% to -3.3%. FVC% improvement by ≥MCID was associated with either statistically significant or numerical improvements in some PROs, QILD, and QLF, while FVC% worsening ≥MCID was associated with statistically significant or numerical worsening of PROs, QILD, and QLF. CONCLUSION: FVC% has acceptable test-retest reliability, and we have provided the MCID estimates for FVC% in SSc-ILD based changes at 12 months from baseline in two clinical trials. Clinical trial registration available at www.clinicaltrials.gov, IDs NCT00004563 and NCT00883129.

Interpretation of HRCT Scans in the Diagnosis of IPF: Improving Communication Between Pulmonologists and Radiologists.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD). In this review, we describe the central role of high-resolution computed tomography (HRCT) in the diagnosis of IPF and discuss how communication between pulmonologists and radiologists might be improved to make the interpretation of HRCT scans more effective. Clinical information is important in the interpretation of HRCT scans, as the likelihood that specific radiologic features reflect IPF is not absolute, but dependent on the clinical context. In cases where the clinical context or HRCT pattern are inconclusive, multidisciplinary discussion (MDD) between a pulmonologist and radiologist (and, where relevant, a pathologist and rheumatologist) experienced in the differential diagnosis of ILD is necessary to establish a diagnosis. While it can be challenging to convene a face-to-face meeting, MDD can be conducted virtually or by telephone to enable each specialty group to contribute. To make the MDD most effective, it is important that relevant clinical information (for example, on the patient's clinical history, exposures and the results of serological tests) is shared with all parties in advance. A common lexicon to describe HRCT features observed in ILD can also help improve the effectiveness of MDD. A working diagnosis may be made in patients who do not fulfill all the diagnostic criteria for any specific type of ILD, but this diagnosis should be reviewed at regular intervals, with repeat of clinical, radiological, and laboratory assessments as appropriate, as new information pertinent to the patient's diagnosis may become available.

Safety and Immunogenicity of Adenovirus 35 Tuberculosis Vaccine Candidate in Adults with Active or Previous Tuberculosis. A Randomized Trial.

RATIONALE: Administration of tuberculosis (TB) vaccines in participants with previous or current pulmonary TB may have the potential for causing harmful postvaccination immunologic (Koch-type) reactions. OBJECTIVES: To assess the safety and immunogenicity of three dose levels of the AERAS-402 live, replication-deficient adenovirus 35-vectored TB candidate vaccine, containing three mycobacterial antigens, in individuals with current or previous pulmonary TB. METHODS: We performed a phase II randomized, placebo-controlled, double-blinded dose-escalation study in an HIV-negative adult South African cohort (n = 72) with active pulmonary TB (on treatment for 1-4 mo) or pulmonary TB treated at least 12 months before study entry and considered cured. Safety endpoints included clinical assessment, flow volume curves, diffusing capacity of the lung for carbon monoxide, pulse oximetry, chest radiograph, and high-resolution thoracic computerized tomography scans. Cytokine expression by CD4 and CD8 T cells, after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools, was examined by intracellular cytokine staining. MEASUREMENTS AND MAIN RESULTS: No apparent temporal or dose-related changes in clinical status (specifically acute, Koch phenomenon-like reactions), lung function, or radiology attributable to vaccine were observed. Injection site reactions were mild or moderate. Hematuria (by dipstick only) occurred in 25 (41%) of 61 AERAS-402 recipients and 3 (27%) of 11 placebo recipients, although no gross hematuria was reported. AERAS-402 induced robust CD8+ and moderate CD4+ T-cell responses, mainly to Ag85B in both vaccine groups. CONCLUSIONS: Administration of the AERAS-402 candidate TB vaccine to participants with current or previous pulmonary TB induced a robust immune response and is not associated with clinically significant pulmonary complications. Clinical trial registered with www.clinicaltrials.gov (NCT 02414828) and in the South African National Clinical Trials Register ( www.sanctr.gov.za DOH 27-0808-2060).

Interstitial lung disease points to consider for clinical trials in systemic sclerosis.

Interstitial lung disease causes major morbidity and mortality in patients with systemic sclerosis (SSc-ILD). Large randomized clinical trials in SSc-ILD have provided important information regarding the feasibility, reliability and validity of outcome measures. Forced vital capacity percentage predicted should be considered as a primary outcome measure, with inclusion of appropriate radiological and patient-reported measures. We provide practical recommendations for trial design in SSc-ILD.

SPIROMICS Protocol for Multicenter Quantitative Computed Tomography to Phenotype the Lungs.

Multidetector row computed tomography (MDCT) is increasingly taking a central role in identifying subphenotypes within chronic obstructive pulmonary disease (COPD), asthma, and other lung-related disease populations, allowing for the quantification of the amount and distribution of altered parenchyma along with the characterization of airway and vascular anatomy. The embedding of quantitative CT (QCT) into a multicenter trial with a variety of scanner makes and models along with the variety of pressures within a clinical radiology setting has proven challenging, especially in the context of a longitudinal study. SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), sponsored by the National Institutes of Health, has established a QCT lung assessment system (QCT-LAS), which includes scanner-specific imaging protocols for lung assessment at total lung capacity and residual volume. Also included are monthly scanning of a standardized test object and web-based tools for subject registration, protocol assignment, and data transmission coupled with automated image interrogation to assure protocol adherence. The SPIROMICS QCT-LAS has been adopted and contributed to by a growing number of other multicenter studies in which imaging is embedded. The key components of the SPIROMICS QCT-LAS along with evidence of implementation success are described herein. While imaging technologies continue to evolve, the required components of a QCT-LAS provide the framework for future studies, and the QCT results emanating from SPIROMICS and the growing number of other studies using the SPIROMICS QCT-LAS will provide a shared resource of image-derived pulmonary metrics.

FG-3019 anti-connective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary fibrosis.

FG-3019 is a fully human monoclonal antibody that interferes with the action of connective tissue growth factor, a central mediator in the pathogenesis of fibrosis.This open-label phase 2 trial evaluated the safety and efficacy of two doses of FG-3019 administered by intravenous infusion every 3 weeks for 45 weeks in patients with idiopathic pulmonary fibrosis (IPF). Subjects had a diagnosis of IPF within the prior 5 years defined by either usual interstitial pneumonia (UIP) pattern on a recent high-resolution computed tomography (HRCT) scan, or a possible UIP pattern on HRCT scan and a recent surgical lung biopsy showing UIP pattern. Pulmonary function tests were performed every 12 weeks, and changes in the extent of pulmonary fibrosis were measured by quantitative HRCT scans performed at baseline and every 24 weeks.FG-3019 was safe and well-tolerated in IPF patients participating in the study. Changes in fibrosis were correlated with changes in pulmonary function.Further investigation of FG-3019 in IPF with a placebo-controlled clinical trial is warranted and is underway.

Relationship between quantitative radiographic assessments of interstitial lung disease and physiological and clinical features of systemic sclerosis.

OBJECTIVES: Extent of systemic sclerosis (SSc)-related interstitial lung disease (ILD) assessed from thoracic high-resolution CT (HRCT) predicts disease course, mortality and treatment response. While quantitative HRCT analyses of extent of lung fibrosis (QLFib) or total interstitial lung disease (QILD) are more sensitive and reproducible than visual HRCT assessments of SSc-ILD, these analyses are not widely available. This study evaluates the relationship between clinical disease parameters and QLFib and QILD scores to identify potential surrogate measures of radiographic extent of ILD. METHODS: Using baseline data from the Scleroderma Lung Study I (SLS I; N=158), multivariate regression analyses were performed using the best subset selection method to identify one to five variable models that best correlated with QLFib and QILD scores in both whole lung (WL) and the zone of maximal involvement (ZM). These models were subsequently validated using baseline data from SLS II (N=142). Bivariate analyses of the radiographic and clinical variables were also performed using pooled data. SLS I and II did not include patients with clinically significant pulmonary hypertension (PH). RESULTS: Diffusing capacity for carbon monoxide (DLCO) was the single best predictor of both QLF and QILD in the WL and ZM in all of the best subset models. Adding other disease parameters to the models did not substantially improve model performance. Forced vital capacity (FVC) did not predict QLF or QILD scores in any of the models. CONCLUSIONS: In the absence of PH, DLCO provides the best overall estimate of HRCT-measured lung disease in patients from two large SSc cohorts. FVC, although commonly used, may not be the best surrogate measure of extent of SSc-ILD at any point in time. TRIAL REGISTRATION NUMBERS: SLS I: www.clinicaltrials.gov NCT 00000-4563; SLS II: www.clinicaltrials.gov NCT 00883129.