{
  "abstract": "Introduction and Objective Molecular detection and quantification of bacteria may enhance sensitivity and responsiveness of bacteriological endpoints in clinical trials compared to culture. Here we test a Pseudomonas aeruginosa (PA) ribosomal RNA targeting RT-qPCR assay (RNA-qPCR) as a potential outcome measure for the GREAT-2 clinical trial.Methods GRemubamab ErAdication Trial (GREAT-2) was a multi-centre, randomized, double-blind, placebo-controlled trial involving patients with CT-confirmed bronchiectasis and sputum cultures positive for PA. 37 patients were enrolled into GREAT-2 and randomised to receive either 1500 mg (n=12) or 500 mg (n=13) intravenous gremubamab—a monoclonal antibody targeting PcrV and Psl, PA virulence factors—or placebo (n=12). The primary outcome was the change in quantitative cultures of sputum samples from baseline to day 84 (end of treatment (EoT)). Quantitative culture was performed, and samples were stored in an RNA preservation buffer prior to RNA-qPCR assessment. Secondary outcomes included time to first exacerbation. Treatment arms were compared to the placebo arm through regression analysis; statistical significance was pre-specified at the one-sided p<0.1.Results Measured by quantitative culture, the 500 mg gremubamab treatment dose led to a significant reduction in bacterial load at EoT compared with placebo ([estimate]; -1.28 log-CFU; p=0.065), while a non-significant reduction was observed for the 1500 mg dose (-0.67; p=0.2). In comparison when measured by RNA-qPCR, the 1500 mg dose led to a significant reduction in bacterial load (-1.08 log-copies/reaction; p=0.030); and a non-significant reduction was observed for the 500 mg dose (-0.55; p=0.15). RNA-qPCR findings were corroborated by another molecular method (DNA based). RNA-qPCR quantification was positively correlated with quantitative culture ([Pearson]; r=0.42; p<0.001) and with PA DNA quantification (r=0.73; p<0.001). Time to first exacerbation was significantly delayed with gremubamab at both 1500 mg ([Hazard ratio-HR]; 0.203; p=0.023) and 500 mg (HR 0.379; p=0.058) compared with placebo.Conclusions Gremubamab reduced bacterial load and improved clinical outcomes in patients with bronchiectasis at both doses. RNA-qPCR identified a greater reduction in bacterial load at the 1500 mg dose which corresponded with clinical benefit suggesting the potential utility of molecular methods as an outcome measure in clinical trials.",
  "authors": [
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "D Alferes de Lima Headley"
    },
    {
      "affiliations": [
        "LifeArc, Nine Edinburgh BioQuarter, Edinburgh, UK"
      ],
      "name": "AJ Bell"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "R Hull"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "MB Long"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "J Stobo"
    },
    {
      "affiliations": [
        "LifeArc, Nine Edinburgh BioQuarter, Edinburgh, UK"
      ],
      "name": "P Emanuel"
    },
    {
      "affiliations": [
        "LifeArc, Nine Edinburgh BioQuarter, Edinburgh, UK"
      ],
      "name": "H Buchanan"
    },
    {
      "affiliations": [
        "LifeArc, Nine Edinburgh BioQuarter, Edinburgh, UK"
      ],
      "name": "E Mountjoy"
    },
    {
      "affiliations": [
        "LifeArc, Nine Edinburgh BioQuarter, Edinburgh, UK"
      ],
      "name": "D Gordon"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "C Hennayake"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "Q Du"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "R Galloway"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "E McIntosh"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "Z Eke"
    },
    {
      "affiliations": [
        "School of Pharmacy, Queen’s University Belfast, Belfast, UK"
      ],
      "name": "M Tunney"
    },
    {
      "affiliations": [
        "Respiratory and Immunology, AstraZeneca, Cambridge, UK"
      ],
      "name": "K Cartwright"
    },
    {
      "affiliations": [
        "Respiratory and Immunology, AstraZeneca, Cambridge, UK"
      ],
      "name": "R Hughes"
    },
    {
      "affiliations": [
        "Vaccine and Immune Therapies, AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "A DiGiandomenico"
    },
    {
      "affiliations": [
        "Respiratory and Immunology, AstraZeneca, Gothenburg, Sweden"
      ],
      "name": "MG Belvisi"
    },
    {
      "affiliations": [
        "Respiratory and Immunology, AstraZeneca, Gothenburg, Sweden"
      ],
      "name": "W Brailsford"
    },
    {
      "affiliations": [
        "LifeArc, Nine Edinburgh BioQuarter, Edinburgh, UK"
      ],
      "name": "R Dakin"
    },
    {
      "affiliations": [
        "LifeArc, Nine Edinburgh BioQuarter, Edinburgh, UK"
      ],
      "name": "R Holmes"
    },
    {
      "affiliations": [
        "LifeArc, Nine Edinburgh BioQuarter, Edinburgh, UK"
      ],
      "name": "C Clarke"
    },
    {
      "affiliations": [
        "Cambridge Centre for Lung Infection, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK"
      ],
      "name": "C Haworth"
    },
    {
      "affiliations": [
        "Division of Respiratory Medicine and Gastroenterology, University of Dundee, Dundee, UK"
      ],
      "name": "JD Chalmers"
    }
  ],
  "title": "S37 Molecular detection and quantification of pseudomonas aeruginosa in bronchiectasis: data from the GREAT-2 randomized controlled trial",
  "uid": "dfba321e-29a7-53d1-8c0a-eeeb78f48728"
}