DFV890: a new oral NLRP3 inhibitor-tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function.

BACKGROUND: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm. METHODS: This randomised, multinational study enrolled hospitalised patients (18-80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. FINDINGS: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals. INTERPRETATION: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04382053.

Comparative efficacy and safety of glycopyrronium/formoterol fixed-dose combination versus glycopyrronium monotherapy in patients with moderate-to-severe COPD.

Background: The safety and efficacy of fixed-dose combination (FDC) of glycopyrronium bromide 12.5 µg/formoterol fumarate 12 µg (GB/FF) twice daily as dry powder inhalers (DPIs) compared to glycopyrronium 50 µg monotherapy (GLY) once daily as DPI in subjects with moderate-to-severe chronic obstructive pulmonary disease (COPD) were evaluated. Methods: This was a phase-3, randomized, double-blind, active-controlled, parallel-group, superiority study conducted in India. COPD patients aged ≥40 to ≤65 years, current or ex-smokers with FEV1/FVC <0.70, using ICS, LAMA, or LABA for ≥1 month were included. Subjects were randomized (1:1) to GB/FF or GLY for 12 weeks. The primary efficacy endpoint was the change from baseline in peak FEV1 at the end of 12 weeks. The study is registered with the Clinical Trials Registry of India (CTRI/2017/02/007814). Results: Between March 2017 and July 2018, 331 patients were enrolled and randomized into GB/FF FDC (165 patients) and GLY monotherapy (166 patients) groups. At week 12, the difference in change from baseline in the peak FEV1 for GB/FF DPI versus GLY was 0.115 L (SE = 0.02; 95% CI = 0.061, 0.170; P < 0.0001). Trough FEV1 increased significantly in the GB/FF group compared to the GLY group with a treatment difference of 0.078 L (SE = 0.02; 95% CI = 0.015, 0.14; P = 0.01). There were no significant differences in adverse events between the groups. Conclusion: FDC of GB/FF (12.5/12 µg twice daily) as a DPI provides superior bronchodilation and lung function improvement over GLY (50 µg once daily) monotherapy. It is safe and well tolerated in symptomatic COPD patients.

Efficacy and safety of single-inhaler triple therapy of glycopyrronium, formoterol and fluticasone in patients with COPD: a double-blind, randomised controlled trial.

BACKGROUND: The aim of this work was to investigate the safety and efficacy of single-inhaler triple therapy with 12.5 µg glycopyrronium (GB)/12 µg formoterol fumarate (FF)/250 µg fluticasone propionate (FP), compared to 50 µg GB co-administered with a fixed dose of 12 µg FF/250 µg FP in subjects with COPD. METHODS: This was a phase 3, randomised, double-blind, active-control, parallel-group, noninferiority study conducted at 20 sites across India. COPD patients aged ≥40 to ≤75 years, with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70, using mono/dual therapy with inhaled corticosteroids (ICSs), long-acting muscarinic antagonists (LAMAs), or long-acting ß-agonists (LABAs) for ≥1 month, were included. Subjects were randomised 1:1 to GB/FF/FP or GB+FF/FP for 12 weeks. The primary efficacy end-point was the change from baseline in trough FEV1 at the end of 12 weeks. The study is registered with the Clinical Trials Registry of India (identifier number: CTRI/2019/01/017156). RESULTS: Between 23 March 2019 and 14 February 2020, 396 subjects were enrolled, with 198 patients each in the fixed-triple (GB/FF/FP) and open-triple (GB+FF/FP) groups. The difference in least-square mean (LSM) changes in pre-dose FEV1 from baseline at 12 weeks was noninferior between the groups (p<0.05). The LSM change from baseline in post-dose FEV1 was comparable (p=0.38). A superiority test showed comparable efficacy (p=0.12) for the difference in mean change from baseline in trough FEV1 between the groups. Adverse events (mild or moderate) were recorded in 25.3% and 24.9% of subjects in the GB/FF/FP and GB+FF/FP groups. CONCLUSIONS: Fixed triple therapy with GB/FF/FP provides comparable bronchodilation and lung function improvement as open-triple therapy. It is safe and well tolerated in symptomatic COPD patients with a history of exacerbations.

Efficacy and safety of the direct switch to indacaterol/glycopyrronium from salmeterol/fluticasone in non-frequently exacerbating COPD patients: The FLASH randomized controlled trial.

BACKGROUND AND OBJECTIVE: Combination long-acting ß2 -agonist/long-acting muscarinic antagonist (LABA/LAMA) has demonstrated superior clinical outcomes over LABA/inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) patients; however, data from blinded randomized controlled trials on direct switching from LABA/ICS to LABA/LAMA are lacking. FLASH (Assessment of switching salmeterol/Fluticasone to indacateroL/glycopyrronium in A Symptomatic COPD patient coHort) investigated if direct switch, without a washout period, from salmeterol/fluticasone (SFC) to indacaterol/glycopyrronium (IND/GLY) in COPD patients improves lung function and is well tolerated. METHODS: In this 12-week, multicentre, double-blind study, patients with moderate-to-severe COPD and up to one exacerbation in previous year, receiving SFC for ≥3 months, were randomized to continue SFC 50/500 µg twice daily (bd) or switch to IND/GLY 110/50 µg once daily (od). Primary endpoint was pre-dose trough forced expiratory volume in 1 s (FEV1 ) at Week 12. RESULTS: In total, 502 patients were randomized (1:1) to IND/GLY or SFC. Patients switched to IND/GLY demonstrated superior lung function (pre-dose trough FEV1 ) versus SFC at Week 12 (treatment difference (Δ) = 45 mL; P = 0.028). IND/GLY provided significant improvements in pre-dose trough forced vital capacity (FVC; Δ = 102 mL; P = 0.002) and numerical improvements in transition dyspnoea index (TDI; Δ = 0.46; P = 0.063). Rescue medication use and COPD assessment test (CAT) scores were comparable between groups. Both treatments had similar safety profiles. CONCLUSION: FLASH demonstrated that a direct switch to IND/GLY from SFC improved pre-dose FEV1 and FVC in COPD patients with up to one exacerbation in the previous year. No new safety signals were identified.

Is serum cholesterol a risk factor for asthma?

BACKGROUND: Proinflammatory role of serum cholesterol in asthma has been recently explored with contradicting results. Clarity on the link between serum cholesterol and asthma may lead to new evolutions in planning management strategies. The objective of our study was to examine the relationship between the serum cholesterol, asthma and its characteristics. MATERIALS AND METHODS: A total of 40 asthmatics and 40 normal subjects were examined cross-sectionally and their serum fasting cholesterol and serum high sensitivity C reactive protein (hsCRP) levels were measured along with other baseline investigations. All subjects were non-smokers. RESULTS: Serum total cholesterol (mean ± SD) among asthmatics was 176.45 ± 30.77 mgs/dL as compared to 163.33 ± 26.38 mgs/dL among normal subjects (P < 0.05). This higher serum cholesterol level was found to be associated with asthma independent of age, gender, body mass index (BMI), socio-economic status and serum hsCRP levels. However, the association was only modest (adjusted odds ratio 1.033; 95% confidence interval [CI] 1.008-1.059). There was no association between the serum cholesterol and asthma characteristics such as duration of illness, intake of inhaled steroids and frequency of emergency department visits. Other risk factors identified were poor ventilation (adjusted odds ratio 9.27; 95%CI 1.83-46.99) and overcrowding (adjusted odds ratio 41.9; 95% CI 3.15-557.46) at home. CONCLUSION: Our study found a modest but significant association between higher levels of serum cholesterol and asthma, which is independent of age, gender, BMI, socio-economic status and serum hsCRP. Future research is required in a larger population to substantiate above association and its clinical implications. Poor ventilation and overcrowding at home are risk factors for asthma possibly facilitating increased exposure to indoor allergens.

Parental atopy and exposure to pets on asthma: a hospital-based case-control study.

OBJECTIVES: Studies of parental atopy, exposure to pets, and the risk of asthma have provided conflicting results. We aimed to assess the relationship between asthma among adults with parental atopy, pet keeping inside, and pet keeping outside the home. This study involved a total of 159 adults. The clinically diagnosed cases were 53 adults with asthma as per Global Initiative for Asthma (GINA) guidelines and 106 controls without asthma. METHODS: The study design was a hospital based case-control study. Information on parental atopy and exposure to pets was collected by using a self-administrated questionnaire. We used the exposure odds ratio and 95% confidence interval (CI) to quantify the relation between determinants of interest and the risk of asthma. These were estimated using logistic regression analysis with SPSS version 11.5. RESULTS: The paternal and maternal history of asthma were found to have significant effect on asthma among adults with adjusted odds ratio (OR) of 6.70 (1.92-23.33 95%CI) and 3.33 (1.25-8.89 95% CI) respectively. Parental history and parental atopy significantly increased risk of asthma among adults with adjusted odds ratios of 5.78 (2.38-14.05 95% CI) and 3.65 (1.58-8.43 95% CI) respectively. There was no significant association between asthma and exposure to pets. The adjusted odds ratios for pet keeping inside and outside the house were 1.61 (0.55-4.7395%CI) and 1.32 (0.61-2.87 95%CI) respectively. CONCLUSIONS: Our results support the hypothesis that both parental history and parental atopy increase the risk of asthma among adults whereas pet keeping inside and outside the house during the previous 12-month period were not significantly associated with asthma among adults.