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Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444

Importance: Intimate partner violence (IPV), elder abuse, and abuse of vulnerable adults are common and result in adverse health outcomes. Objective: To review the evidence on screening and interventions for IPV, elder abuse, and abuse of vulnerable adults to inform the US Preventive Services Task Force. Data Sources: MEDLINE, Cochrane Library, EMBASE, and trial registries through October 4, 2017; references; experts; literature surveillance through August 1, 2018. Study Selection: English-language randomized clinical trials (RCTs), studies evaluating test accuracy, and cohort studies with a concurrent control group assessing harms. Data Extraction and Synthesis: Dual review of titles and abstracts, full-text articles, and study quality; qualitative synthesis of findings. Data were not pooled, primarily because of heterogeneity of populations, interventions, and outcomes. Main Outcomes and Measures: Abuse or neglect, morbidity caused by abuse, test accuracy, and harms. Results: Thirty studies were included (N = 14959). Three RCTs (n = 3759) compared IPV screening with no screening; none found significant improvements in outcomes (eg, IPV or quality of life) over 3 to 18 months and 2 (n = 935) reported no harms of screening. Nine studies assessed tools to detect any past-year or current IPV in women; for past-year IPV (5 studies [n = 6331]), sensitivity of 5 tools ranged from 65% to 87% and specificity ranged from 80% to 95%. The accuracy of 5 tools (4 studies [n = 1795]) for detecting current abuse varied widely; sensitivity ranged from 46% to 94% and specificity ranged from 38% to 95%. Eleven RCTs (n = 6740) evaluated interventions for women with screen-detected IPV. Two enrolling pregnant women (n = 575) found significantly less IPV among women in the intervention group: 1 home visiting intervention (standardized mean difference [SMD], -0.34 [95% CI, -0.59 to -0.08]) and 1 behavioral counseling intervention for multiple risks (IPV, smoking, depression, tobacco exposure) (SMD, -0.40 [95% CI, -0.68 to -0.12]). No studies evaluated screening or interventions for elder abuse or abuse of vulnerable adults. One study assessing a screening tool for elder abuse had poor accuracy (sensitivity, 46% and specificity, 73% for detecting physical or verbal abuse). Conclusions and Relevance: Although available screening tools may reasonably identify women experiencing IPV, trials of IPV screening in adult women did not show a reduction in IPV or improvement in quality of life over 3 to 18 months. Limited evidence suggested that home visiting and behavioral counseling interventions that address multiple risk factors may lead to reduced IPV among pregnant or postpartum women. No studies assessed screening or treatment for elder abuse and abuse of vulnerable adults.

© Copyright 2017 by the American Thoracic Society. Background: Airway remodeling (AR) is a prominent feature of asthma and other obstructive lung diseases that is minimally affected by current treatments. The goals of this Official American Thoracic Society (ATS) Research Statement are to discuss the scientific, technological, economic, and regulatory issues that deter progress of AR research and development of therapeutics targeting AR and to propose approaches and solutions to these specific problems. This Statement is not intended to provide clinical practice recommendations on any disease in which AR is observed and/or plays a role. Methods: An international multidisciplinary group from within academia, industry, and the National Institutes of Health, with expertise in multimodal approaches to the study of airway structure and function, pulmonary research and clinical practice in obstructive lung disease, and drug discovery platforms was invited to participate in one internet-based and one face-to-face meeting to address the above-stated goals. Although the majority of the analysis related to AR was in asthma, AR in other diseases was also discussed and considered in the recommendations. A literature search of PubMed was performed to support conclusions. The search was not a systematic review of the evidence. Results: Multiple conceptual, logistical, economic, and regulatory deterrents were identified that limit the performance of AR research and impede accelerated, intensive development of AR-focused therapeutics. Complementary solutions that leverage expertise of academia and industry were proposed to address them. Conclusions: To date, numerous factors related to the intrinsic difficulty in performing AR research, and economic forces that are disincentives for the pursuit of AR treatments, have thwarted the ability to understandARpathology and mechanisms and to address it clinically. This ATS Research Statement identifies potential solutions for each of these factors and emphasizes the importance of educating the global research community as to the extent of the problem as a critical first step in developing effective strategies for: (1) increasing the extent and impact of AR research and (2) developing, testing, and ultimately improving drugs targeting AR.