RCT Abstract - Effectiveness of hypertonic saline (HTS 6%) and carbocisteine in reducing bronchiectasis exacerbations (Results of the CLEAR randomised trial)

2025-09-27

<bold>Background:</bold> Bronchiectasis guidelines show inconsistent evidence of the benefits of mucoactives. EMBARC data reveals geographical variability in their use. No large trials have tested their safety and efficacy. <bold>Aims:</bold> To determine if hypertonic saline (6%, 2x daily) and/or carbocisteine (750mg, 3x daily for 8 weeks, then 2x daily) reduce exacerbations over 52 weeks. <bold>Methods:</bold> CLEAR (<ext-link>ISRCTN89040295</ext-link>) was a 2x2 factorial, randomised, open-label trial in bronchiectasis patients (confirmed on CT) experiencing frequent exacerbations and daily sputum production, at 20 UK sites. Exclusions: current smokers, long-term mucoactive treatment. Patients were randomised into four groups: standard care + HTS, standard care + carbocisteine, both treatments, or standard care alone. Planned sample size was 288 patients. The primary outcome was mean exacerbations over 52 weeks. Secondary outcomes/safety were assessed. Analysis was on a modified intention to treat (mITT) basis (post-baseline efficacy assessment at week 8 or later), followed by per-protocol analysis (week 52), adjusted for macrolide use, site, and antibiotic use. <bold>Results:</bold> 288 patients were recruited. No treatment interactions were found. The adjusted mean difference (95% CI) in exacerbations over 52 weeks for HTS (n=126) vs. no HTS (n=141) was -0.27 (-0.56, 0.03), and for carbocisteine (n=129) vs. no carbocisteine (n=138) was -0.02 (-0.31, 0.27). No significant differences in key secondary outcomes. AEs/SAEs related to study drugs were not significant. <bold>Conclusion:</bold> For bronchiectasis patients, carbocisteine or hypertonic saline showed no significant benefit in reducing mean exacerbations over 52 weeks.

Drug response assessment trials for inhaled hypertonic saline in patients with bronchiectasis: Analysis of data from the CLEAR trial

2025-09-27

<bold>Background:</bold> Patients are recommended to undergo a drug response assessment (DRA) before starting hypertonic saline (HTS) due to the risk of bronchoconstriction. As part of a randomized, open-label trial of HTS and/or carbocisteine vs usual care in bronchiectasis (CLEAR, <ext-link>ISRCTN89040295</ext-link>), we investigated the usefulness of DRAs. <bold>Aims:</bold> To remotely train/ assess staff competency in performing DRAs and assess patient HTS safety/tolerability. <bold>Methods:</bold> Staff were remotely trained/assessed as DRA competent using a study guideline (Daniels, T <italic>et al.</italic> ACPCF 2017: 3rd ed). DRAs were conducted in HTS assigned patients; failure was classified as ≥15% FEV₁ drop or 10-15% drop with symptoms. <bold>Results:</bold> 54 staff at 20 sites were remotely trained/deemed competent and 52 conducted at least one DRA. 145 patients completed DRAs: 144/145 were correctly classified, 1/145 was misclassified as a pass (found during quality checks). 142/145 were classified as pass and entered the trial. 12/145 were classified as fail in the first DRA: 7 had ≥ 15% FEV₁ drop, 2 had 10-15% FEV₁ drop with symptoms, 1 had severe coughing (clinical team did not recruit), and for 2 the reason was not clearly documented. 11 repeated the DRA; 9 passed and entered the trial and 2 failed and were not recruited. Of 142 patients who entered the trial, 46 later discontinued HTS. 7/46 discontinued relating to issues with HTS tolerance despite passing the first DRA. <bold>Conclusion:</bold> Remote staff training for DRAs is feasible. Only 3/145 patients failed the DRA and were not recruited to the trial. The DRA was insufficient in predicting failure to remain on HTS, challenging the value of routine DRAs in bronchiectasis.

Hypertonic Saline or Carbocisteine in Bronchiectasis

New England Journal of Medicine · 2025-09-28 · 20 citations

BACKGROUND: Bronchiectasis guidelines are inconsistent with regard to the effectiveness of mucoactive agents, and their use varies geographically. Large trials are needed to assess safety and effectiveness. METHODS: For this open-label, randomized, two-by-two factorial trial at 20 sites in the United Kingdom, we enrolled participants with non-cystic fibrosis bronchiectasis who had frequent pulmonary exacerbations and daily sputum production. Current smokers and persons who had recently received mucoactive treatments were excluded. All participants received standard care and were also assigned either to one of three mucoactive-drug groups - hypertonic saline (the hypertonic-saline group), hypertonic saline and carbocisteine (the combination group), or carbocisteine (the carbocisteine group) - or to standard care alone. The comparisons were between hypertonic saline and no hypertonic saline and between carbocisteine and no carbocisteine, with each category consisting of two groups. The primary outcome was the number of pulmonary exacerbations over a 52-week period. Key secondary outcomes were scores on disease-specific health-related quality-of-life assessments, time to next pulmonary exacerbation, and safety. RESULTS: A total of 288 participants underwent randomization. No treatment interactions were found. The mean number of adjudicated fully qualifying pulmonary exacerbations over the 52-week period was 0.76 (95% confidence interval [CI], 0.58 to 0.95) with hypertonic saline as compared with 0.98 (95% CI, 0.78 to 1.19) with no hypertonic saline (adjusted between-group difference in the means, -0.25 [95% CI, -0.57 to 0.07; P = 0.12]) and 0.86 (95% CI, 0.66 to 1.06) with carbocisteine as compared with 0.90 (95% CI, 0.70 to 1.09) with no carbocisteine (adjusted between-group difference in the means, -0.04 [95% CI, -0.36 to 0.28; P = 0.81]). Secondary outcomes and the incidence of adverse events, including serious adverse events, were similar across the groups. CONCLUSIONS: In participants with bronchiectasis, neither hypertonic saline nor carbocisteine significantly reduced the mean incidence of pulmonary exacerbations over a period of 52 weeks. (Funded by the National Institute for Health and Care Research Health Technology Assessment Programme and others; ISRCTN Registry number, ISRCTN89040295.).

Structural insights into the role and targeting of EGFRvIII

Structure · 2024-06-21 · 5 citations

Airway total bacterial density, microbiota community composition and relationship with clinical parameters in bronchiectasis

Respiratory Medicine · 2024-12-04 · 1 citations

BACKGROUND AND OBJECTIVE: This study explored the relationship between total bacterial density, airway microbiota composition and clinical parameters in bronchiectasis. We determined changes with time during clinical stability and following antibiotic treatment of a pulmonary exacerbation. METHODS: % predicted, lung clearance index, C-reactive protein, white cell count and Quality of Life] were collected when participants were clinically stable and pre/post-antibiotic treatment of an exacerbation. Total bacterial density and microbiota community composition was measured by quantitative polymerase chain reaction and sequencing of the V4 region of bacterial 16S rRNA, respectively. RESULTS: at 69 % predicted. In participants who remained clinically stable (n = 15), no significant changes were observed in bacterial density, microbiota diversity, richness, evenness, and dominance (p = 0.30, 0.45, 0.54, 0.23 and 0.43; respectively) across four time points over a 1-year period. Similarly, for participants with paired pre/post-antibiotic treatment samples (n = 19), no significant changes were observed (p = 0.30, 0.46, 0.44, 0.71 and 0.58; respectively). However, considerable fluctuation in community composition between samples was apparent for most patients. Total bacterial density and microbiota composition did not correlate with clinical parameters at baseline (n = 75). CONCLUSIONS: Stability in bacterial density and microbiota diversity, richness, evenness and dominance was observed over time at a population level but considerable fluctuation was apparent in samples from individual patients.

Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial

The Lancet Child & Adolescent Health · 2024 · 34 citations

• Medicine
• Internal medicine
• Virology

BACKGROUND: Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged in April, 2020. The paediatric comparisons within the RECOVERY trial aimed to assess the effect of intravenous immunoglobulin or corticosteroids compared with usual care on duration of hospital stay for children with PIMS-TS and to compare tocilizumab (anti-IL-6 receptor monoclonal antibody) or anakinra (anti-IL-1 receptor antagonist) with usual care for those with inflammation refractory to initial treatment. METHODS: We did this randomised, controlled, open-label, platform trial in 51 hospitals in the UK. Eligible patients were younger than 18 years and had been admitted to hospital for PIMS-TS. In the first randomisation, patients were randomly assigned (1:1:1) to usual care (no additional treatments), usual care plus methylprednisolone (10mg/kg per day for 3 consecutive days), or usual care plus intravenous immunoglobulin (a single dose of 2 g/kg). If further anti-inflammatory treatment was considered necessary, children aged at least 1 year could be considered for a second randomisation, in which patients were randomly assigned (1:2:2) to usual care, intravenous tocilizumab (12 mg/kg in patients <30 kg; 8mg/kg in patients ≥30 kg, up to a maximum dose of 800 mg), or subcutaneous anakinra (2 mg/kg once per day in patients ≥10 kg). Randomisation was by use of a web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was duration of hospital stay. Analysis was by intention to treat. For treatments assessed in each randomisation, a single Bayesian framework assuming uninformative priors for treatment was used to jointly assess the efficacy of each intervention compared with usual care. The trial was registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between May 18, 2020, and Jan 20, 2022, 237 children with PIMS-TS were enrolled and included in the intention-to-treat analysis. Of the 214 patients who entered the first randomisation, 73 were assigned to receive intravenous immunoglobulin, 61 methylprednisolone, and 80 usual care. Of the 70 children who entered the second randomisation (including 23 who did not enter the first randomisation), 28 were assigned to receive tocilizumab, 14 anakinra, and 28 usual care. Mean age was 9·5 years (SD 3·8) in the randomisation and 9·6 years (3·6) in the second randomisation. 118 (55%) of 214 patients in the first randomisation and 39 (56%) of 70 patients in the second randomisation were male. 130 (55%) of 237 patients were Black, Asian, or minority ethnic, and 105 (44%) were White. Mean duration of hospital stay was 7·4 days (SD 0·4) in children assigned to intravenous immunoglobulin and 7·6 days (0·4) in children assigned to usual care (difference -0·1 days, 95% credible interval [CrI] -1·3 to 1·0; posterior probability 59%). Mean duration of hospital stay was 6·9 days (SD 0·5) in children assigned to methylprednisolone (difference from usual care -0·7 days, 95% CrI -1·9 to 0·6; posterior probability 87%). Mean duration of hospital stay was 6·6 days (SD 0·7) in children assigned to second-line tocilizumab and 9·9 days (0·9) in children assigned to usual care (difference -3·3 days, 95% CrI -5·6 to -1·0; posterior probability >99%). Mean duration of hospital stay was 8·5 days (SD 1·2) in children assigned to anakinra (difference from usual care -1·4 days, 95% CrI -4·3 to 1·8; posterior probability 84%). Two persistent coronary artery aneurysms were reported among patients assigned to usual care in the first randomisation. There were few cardiac arrythmias, bleeding, or thrombotic events in any group. Two children died; neither was considered related to study treatment. INTERPRETATION: Moderate evidence suggests that, compared with usual care, first-line intravenous methylprednisolone reduces duration of hospital stay for children with PIMS-TS. Good evidence suggests that second-line tocilizumab reduces duration of hospital stay for children with inflammation refractory to initial treatment. Neither intravenous immunoglobulin nor anakinra had any effect on duration of hospital stay compared with usual care. FUNDING: Medical Research Council and National Institute of Health Research.

Airway Total Bacterial Density, Microbiota Community Composition and Relationship with Clinical Parameters in Bronchiectasis

SSRN Electronic Journal · 2024-01-01

Data from Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance

2023-04-03

&lt;div&gt;Abstract&lt;p&gt;Acquired resistance to cetuximab, an antibody that targets the EGFR, impacts clinical benefit in head and neck, and colorectal cancers. One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA-approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab-resistant substitution, S468R (or S492R, depending on the amino acid numbering system). We determined an X-ray crystal structure to 2.8 Å resolution of the necitumumab Fab bound to an S468R variant of EGFR domain III. The arginine is accommodated in a large, preexisting cavity in the necitumumab paratope. We predict that this paratope shape will be permissive to other epitope substitutions, and show that necitumumab binds to most cetuximab- and panitumumab-resistant EGFR variants. We find that a simple computational approach can predict with high success which EGFR epitope substitutions abrogate antibody binding. This computational method will be valuable to determine whether necitumumab will bind to EGFR as new epitope resistance variants are identified. This method could also be useful for rapid evaluation of the effect on binding of alterations in other antibody/antigen interfaces. Together, these data suggest that necitumumab may be active in patients who are resistant to cetuximab or panitumumab through EGFR epitope mutation. Furthermore, our analysis leads us to speculate that antibodies with large paratope cavities may be less susceptible to resistance due to mutations mapping to the antigen epitope. &lt;i&gt;Mol Cancer Ther; 17(2); 521–31. ©2017 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Supplementary Tables S1-S4 and Supplementary Figures S1-S6 from Molecular Basis for Necitumumab Inhibition of EGFR Variants Associated with Acquired Cetuximab Resistance

2023-04-03

&lt;p&gt;Supplementary Table S1 - Therapeutic antibody induced EGFR ECR mutations; Supplementary Table S2 - Mean SPR KD values for binding of wild type (WT) and cetuximab resistance variants of sEGFR to immobilized Fab fragments from cetuximab (FabC225) and necitumumab (Fab11F8) and to EGF; Supplementary Table S3 - Crystallographic data collection and refinement statistics; Supplementary Table S4 - Changes in experimental binding and DSC4.1 computed energy terms for interaction of cetuximab (C225) and necitumumab (11F8) with wild type and epitope mutated EGFR variants; Supplementary Figure S1 - Binding of necitumumab and cetuximab to LK2 and HELA cells; Supplementary Figure S2 - Electron density near R468 in sEGFRd3-S468R/Fab11F8 structure; Supplementary Figure S3 - Comparison of the paratopes of necitumumab and panitumumab; Supplementary Figure S4 - Necitumumab exhibits structural plasticity in binding to sEGFRd3-S468R; Supplementary Figure S5 - Location of the epitope substitutions in the experimental test set and evaluation of the side chain conformations modeled with DSC4.1; Supplementary Figure S6 - CDR dynamics for necitumumab and cetuximab when bound to three cetuximab resistance variants, evaluated by MD simulations&lt;/p&gt;

Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

The Lancet Diabetes & Endocrinology · 2023 · 38 citations

• Medicine
• Emergency medicine
• Internal medicine

BACKGROUND: Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic, and haemodynamic effects. The RECOVERY trial aimed to assess its safety and efficacy in patients admitted to hospital with COVID-19. METHODS: In the randomised, controlled, open-label RECOVERY trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. In this analysis, we assess eligible and consenting adults who were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus oral empagliflozin 10 mg once daily for 28 days or until discharge (whichever came first) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality; secondary outcomes were duration of hospitalisation and (among participants not on invasive mechanical ventilation at baseline) the composite of invasive mechanical ventilation or death. On March 3, 2023 the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on March 7, 2023. The ongoing RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between July 28, 2021 and March 6, 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Primary and secondary outcome data were known for greater than 99% of randomly assigned patients. Overall, 289 (14%) of 2113 patients allocated to empagliflozin and 307 (14%) of 2158 patients allocated to usual care died within 28 days (rate ratio 0·96 [95% CI 0·82-1·13]; p=0·64). There was no evidence of significant differences in duration of hospitalisation (median 8 days for both groups) or the proportion of patients discharged from hospital alive within 28 days (1678 [79%] in the empagliflozin group vs 1677 [78%] in the usual care group; rate ratio 1·03 [95% CI 0·96-1·10]; p=0·44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (338 [16%] of 2084 vs 371 [17%] of 2143; risk ratio 0·95 [95% CI 0·84-1·08]; p=0·44). Two serious adverse events believed to be related to empagliflozin were reported: both were ketosis without acidosis. INTERPRETATION: In adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death so is not indicated for the treatment of such patients unless there is an established indication due to a different condition such as diabetes. FUNDING: UK Research and Innovation (Medical Research Council) and National Institute of Health Research (MC_PC_19056), and Wellcome Trust (222406/Z/20/Z). TRANSLATIONS: For the Nepali, Hindi, Indonesian (Bahasa) and Vietnamese translations of the abstract see Supplementary Materials section.