Daily Respiratory Research Analysis

BACKGROUND: Airway neutrophil inflammation with excessive neutrophil serine proteases is implicated in frequent exacerbations of bronchiectasis. HSK31858 is a novel reversible inhibitor of DPP-1. We aimed to assess the efficacy and safety of HSK31858 in decreasing the frequency of bronchiectasis exacerbations among adults with bronchiectasis. METHODS: SAVE-BE was a phase 2, double-blind, randomised, placebo-controlled trial in 25 tertiary centres in China. Participants were aged 18 years or older with a physician diagnosis of bronchiectasis, according to chest high-resolution CT showing bronchial dilatation and compatible respiratory symptoms, and at least two exacerbations within 12 months before screening. Participants were randomly assigned (1:1:1) via a central interactive web-response system to receive 20 mg HSK31858, 40 mg HSK31858, or placebo, orally, once daily for 24 weeks. Randomisation was stratified by exacerbation frequency in the previous year (less than three vs three or more annually) and study investigators and participants were masked to group assignment for analysis of study outcomes. The primary endpoint was the annualised exacerbation frequency over 24 weeks, assessed in the full analysis set. Safety was monitored throughout the study. This trial is registered with ClinicalTrials.gov, NCT05601778. FINDINGS: Between Dec 6, 2022, and March 31, 2024, 292 patients were screened, 226 of whom were enrolled and randomly assigned (75 to the 20 mg HSK31858 group, 76 to the 40 mg HSK31858 group, and 75 to the placebo group. 74 patients received 20 mg HSK31858, 75 received 40 mg HSK31858, and 75 received placebo and were included in the full analysis set. In the full analysis set, 136 (61%) participants were female and 88 (39%) were male. The mean annualised frequency of exacerbations was 1·00 per person-year (SD 1·44) in the 20 mg HSK31858 group, 0·75 per person-year (1·37) in the 40 mg HSK31858 group, and 1·88 per person-year (1·97) in the placebo group. The least-squares mean frequency of exacerbations was 1·05 per person-year (95% CI 0·73-1·51) in the 20 mg HSK31858 group, 0·83 per person-year (0·55-1·25) in the 40 mg HSK31858 group, and 2·01 per person-year (1·53-2·63) in the placebo group. The incidence rate ratio compared with placebo was 0·52 (95% CI 0·34-0·80; p=0·0031) for the 20 mg HSK31858 group and 0·41 (0·26-0·66; p=0·0002) for the 40 mg HSK31858 group. The incidence of adverse events was similar across the three groups. Neither HSK31858 dose was associated with an increased incidence of adverse events of special interest (eg, hyperkeratosis, gingivitis, or life-threatening infections). INTERPRETATION: Both HSK31858 doses improved clinical outcomes in adults with bronchiectasis, significantly reducing the exacerbation frequency compared with placebo. The development of new drugs targeted at amelioration of neutrophilic inflammation (eg, via suppression of DPP-1 activity) might lead to new options for hindering the progression of bronchiectasis. FUNDING: Haisco.

BACKGROUND: Low-dose CT screening reduces lung cancer mortality. In advance of planned national lung cancer screening programmes, research is needed to inform policies regarding implementation. We aimed to assess the implementation of low-dose CT for lung cancer screening in a high-risk population and to validate a multicancer early detection blood test. METHODS: In this prospective, longitudinal cohort study, individuals aged 55-77 years recorded as current smokers in their primary care records at any point within the past 20 years were identified from 329 primary care practices in London (UK) and invited for a lung health check via postal letter. Individuals meeting the 2013 United States Preventive Services Taskforce criteria (current or former smokers within the past 15 years with at least 30 pack-year smoking histories) or having a Prostate, Lung, Colorectal and Ovarian 2012 model 6-year risk of 1·3% or greater, and not currently receiving treatment for an active cancer (except adjuvant hormonal therapy), were eligible for the study. These individuals underwent lung cancer screening via non-contrast, thin collimation low-dose CT. In this analysis, we report the results of the baseline round of low-dose CT screening. Key primary endpoints were those associated with examining the performance of a lung cancer screening service. Outcome measures were analysed on a per-participant level using descriptive frequencies. The study was registered with ClinicalTrials.gov, NCT03934866. FINDINGS: Between April 8, 2019, and May 14, 2021, 12 773 participants were recruited and analysed. 7353 (57·6%) of 12 773 participants were male and 5420 (42·4%) were female, and 10 665 (83·5%) participants were White. 261 (2·0%) of 12 773 participants were diagnosed with lung cancer (including 163 [1·3%] participants with screen-detected lung cancer and 98 [0·8%] with delayed screen-detected lung cancer [ie, after a 3-month or 6-month nodule follow-up CT]) and 276 (2·2%) participants were diagnosed with any intrathoracic malignancy after a positive baseline screen. 207 (79·3%) of 261 individuals with prevalent screen-detected lung cancer were diagnosed at stage I or II and surgical resection was the primary treatment modality in 201 (77·0%) of 261 individuals. Including cases where multiple resections were done in the same participant (eg, for synchronous primaries), 28 (11·6%) of 241 surgical resections were benign, and there was one (0·4%) death within 90 days of surgery. At 12 months, the episode sensitivity of our low-dose CT screening protocol for detecting lung cancer was 97·0% (95% CI 95·0-99·1; 261 of 269 participants). The specificity was 95·2% (94·8-95·6; 11 905 of 12 504 participants), with a false-positive rate of 4·8% (4·4-5·2). INTERPRETATION: Large-scale lung cancer screening is effective and can be delivered efficiently to an ethnically and socioeconomically diverse population. FUNDING: GRAIL.

STUDY OBJECTIVES: Central sleep apnea (CSA) is common in heart failure (HF) patients, but its treatment's impact on cardiac function is unclear. Transvenous phrenic nerve stimulation (TPNS) is an emerging CSA therapy that may improve long-term left ventricular systolic function (LVEF) in HF. Given that the cardiovascular risk of sleep apnea appears contingent on respiratory event-related heart rate surges ("high ∆HR"), we hypothesized that TPNS treatment may preferentially improve LVEF in CSA patients with high ∆HR. METHODS: In the remedē System pivotal trial, ∆HR was calculated from baseline polysomnography in patients with HF. Primary analysis quantified whether treatment-related change in left ventricular ejection fraction (∆LVEF; echocardiography, biplane method) versus control was greater in "high ∆HR" (>14.6 beats/min, i.e. fourth quartile) versus "low ∆HR (≤4.2 beats/min, i.e. first quartile)" at 6 months (treatment × "high ∆HR" interaction). Longitudinal analysis quantified whether favorable LVEF changes from baseline were maintained longer term (6-12 months). RESULTS: In primary analysis (N = 79, M:F = 74:5, LVEF = 34 ± 12% [mean ± SD]), TPNS versus control was associated with a markedly greater improvement in LVEF in patients with high ∆HR versus low ∆HR (estimate [95% CI]: +7.8% [0.37, 15.2], pinteraction = 0.04). In longitudinal analysis, LVEF increased in patients with high ∆HR at 6, 9, and 12 months (+2.5% [-0.1, 5.1]; +3.9% [1.2, 6.5]; and  +3.7% [1.0, 6.4] from baseline, respectively) but not among low ∆HR (-0.1% [-2.8, 2.6]; -0.3% [-3.1, 2.4]; and -0.8% [-3.7, 2.1]). CONCLUSIONS: Compared to low ∆HR, patients with high ∆HR showed greater LVEF improvement with TPNS for CSA. High ∆HR, a potential reflection of CSA-related sympathetic overactivity, may identify those who benefit most from CSA treatment.