Purpose: To ascertain the level of observer agreement for recently published diagnostic criteria for usual interstitial pneumonia (UIP) in a population of individuals with clinically diagnosed fibrotic lung disease, and the relationship between diagnostic concordance and extent of disease.Methods: The Pulmonary Fibrosis Foundation has established a patient registry and biorepository, with cases derived from 42 centers across the US.CT scans from these cases, obtained using local clinical protocol, have been sent to a central archive at National Jewish Health for curation and evaluation.Each case was read by two experienced thoracic radiologists for pattern according to the 2018 Fleischner and ATS/ERS/JRS/ALAT diagnostic criteria for IPF (4 categories -definite UIP, probable UIP, indeterminate, and suggestive of an alternative diagnosis).Discrepancies were adjudicated by a third radiologist.Extent of fibrotic abnormality was visually and quantitatively scored, the latter by data-driven textural analysis (DTA).Cohen's weighted κ coefficient (κ w ) was used to evaluate interobserver agreement for diagnostic category.Univariate association between visual and quantitative extent of fibrosis was assessed using Spearman correlation.Results: Of 181 cases read to date, 4 were omitted due to quality issues.In the remaining 177, the readings for radiologic pattern were concordant in 107 (60%) and discordant in 70 (40%) (see table ).The most common reason for discordance was disagreement between the 'indeterminate' and 'findings suggestive of an alternative diagnosis' categories.Interobserver agreement across the diagnostic category scores was moderate (κ w = 0.54, 95% confidence interval [CI] 0.44, 0.64).When these categories were grouped together, the concordance rate rose to 71% and κ w rose to 0.60 (95% CI 0.49, 0.60).Correlation between visual extent of fibrosis, averaged across readers, and DTA score was moderate (rho=0.62,p<0.0001).Conclusions: Interobserver agreement for the current Fleischner and ATS/ERS/JRS/ALAT CT criteria for UIP is moderate among thoracic radiologists, and correlation between visual and DTA extent of fibrosis was moderate, despite variation in CT technical parameters.Agreement increases if the indeterminate and alternative diagnoses are combined.
RATIONALE: Integrins α v β 6 and α v β 1 are upregulated in the lungs of patients with idiopathic pulmonary fibrosis (IPF), playing a key role in promoting transforming growth factor beta (TGF-β) activation and fibrosis.PLN-74809 is an oral, once-daily (QD), highly selective inhibitor of integrins α v β 6 and α v β 1 that was well tolerated in >180 healthy participants in Phase 1 studies at doses up to 320 mg.PLN-74809 showed antifibrotic activity (reduction in collagen deposition [Ashcroft Score]) in animal models of lung fibrosis and in live precision-cut lung tissue slices from patients with IPF, and reduced TGF-β activation in the lungs of healthy participants when dosed at 40 mg once daily.METHODS: INTEGRIS-IPF (PLN-74809-IPF-202; NCT04396756) is a Phase 2a, randomized, doseranging, double-blind, placebo-controlled study evaluating the safety, tolerability, and pharmacokinetics (PK) of PLN-74809 administered over 12 weeks in participants with IPF (ATS/ERS/JRS/ALAT, 2018).Approximately 84 participants with IPF will be enrolled in three planned ascending PLN-74809 dose groups (40 mg, 80 mg, or 160 mg QD), with a 3:1 randomization ratio (active:placebo) and stratification based on use of standard of care (SoC) therapy (pirfenidone or nintedanib [yes/no]).Key eligibility criteria include ≥40 years of age; forced vital capacity (FVC) ≥45% of predicted; diffusing capacity of the lung carbon monoxide ≥30%; forced expiratory volume in one second/FVC ratio ≥0.7; if receiving SoC, must be on stable regimen for ≥3 months; and no recent acute IPF exacerbation in the previous 6 months.RESULTS: The primary endpoint is the evaluation of PLN-74809 safety and tolerability, and the secondary endpoint is the assessment of PK across a dose range.Exploratory endpoints will measure change in FVC, Quantitative Lung Fibrosis score, cough symptoms via visual analog scale, and selected biomarkers over 12 weeks of treatment.Research sites will enroll across 10 participating countries from Australasia, Europe, and North America.CONCLUSIONS: This Phase 2a, randomized, dose-ranging study will evaluate the safety, tolerability, and PK of PLN-74809 for treatment of IPF.
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