ImportanceThere is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).ObjectiveTo assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.Design, Setting, and ParticipantsThe 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.InterventionsPatients 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 MeasuresThe 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).ResultsAt 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 RelevanceZiritaxestat 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 RegistrationClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444

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Background. Asthma medication prescription trends, including those of short-acting β2-agonists (SABAs), are not well documented for South Africa (SA).Objectives. To describe demographics, disease characteristics and asthma prescription patterns in the SA cohort of the SABA use IN Asthma (SABINA) III study. Methods. An observational, cross-sectional study conducted at 12 sites across SA. Patients with asthma (aged ≥12 years) were classified by investigator-defined asthma severity, guided by the Global Initiative for Asthma (GINA) 2017 recommendations, and practice type (primary/ specialist care). Data were collected using electronic case report forms.Results. Overall, 501 patients were analysed − mean (standard deviation) age, 48.4 (16.6) years; 68.3% female − of whom 70.6% and 29.4% were enrolled by primary care physicians and specialists, respectively. Most patients were classified with moderate-to-severe asthma (55.7%; GINA treatment steps 3 - 5), were overweight or obese (70.7%) and reported full healthcare reimbursement (55.5%). Asthma was partly controlled/uncontrolled in 60.3% of patients, with 46.1% experiencing ≥1 severe exacerbations in the 12 months before the study visit. Overall, 74.9% of patients were prescribed ≥3 SABA canisters in the previous 12 months (over-prescription); 56.5% were prescribed ≥10 SABA canisters. Additionally, 27.1% of patients reported purchasing SABA over-the-counter (OTC); among patients with both SABA purchase and prescriptions, 75.4% and 51.5% already received prescriptions for ≥3 and ≥10 SABA canisters, respectively, in the preceding 12 months. Conclusion. SABA over-prescription and OTC purchase were common in SA, demonstrating an urgent need to align clinical practices with the latest evidence-based recommendations and regulate SABA OTC purchase to improve asthma outcomes.