Title: Primary care use of a C-Reactive Protein (CRP) Point of Care Test (POCT) to help target antibiotic prescribing to patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) who are most likely to benefit (The PACE Study)
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Design: Individually Randomised Controlled Trial Setting: 60 General Practices in Wales, Thames Valley & South London Target Population: Adults with confirmed COPD (GOLD Grade 1 to 3, FEV/FVC<0.7 and FEV>30%) consulting with acute exacerbation (AECOPD) Health technology assessed: C-reactive protein point-of-care test (CRP-POCT) with training in test interpretation used in addition to current best practice to enhance antibiotic prescribing decisions. Comparator: Current best practice Measurement of cost and outcomes: Co-primary outcomes will evaluate whether addition of the CRP-POCT reduces antibiotic consumption (taking one or more doses of an antibiotic course) within 4 weeks of randomisation without negatively impacting on condition-specific Health-related Quality of Life (HRQoL) at 2 weeks using the Chronic Respiratory Disease Questionnaire Self-Administered Standardised (CRQ-SAS). Secondary outcomes: Prevalence of antimicrobial-resistant respiratory bacteria isolated at 4 weeks; condition specific and generic HRQoL, medication use, adverse effects, primary & secondary care consultations, pneumonia requiring hospitalisation, and costs within 4 weeks. A qualitative process evaluation will examine implementation and acceptability. Sample size: 650 patients. We need 434 participants (inflating to 544 to account for 20% loss to follow-up) to enable us to detect whether there is a reduction (superiority) in the intervention group from a current estimated antibiotic prescribing rate for AECOPD of 70% to 55% within 4 weeks from randomisation at the 5% significance level, with 90% power, and allowing for possible clustering effects. We need 490 participants (inflating to 600 to account for 20% loss to follow-up) to assess whether the intervention group is no worse (non-inferiority) in condition specific HRQoL at 2 weeks, assuming; expected difference between groups of 0, non-inferiority margin of 0.3 (lower than the lower limit of the 95% CI for the minimal clinically important difference), common standard deviation of 1.132, at the 5% significance level, with 90% power. Analysis: Co-primary outcomes; logistic (antibiotic consumption) and linear (CRQ-SAS) regression analysis, based on the intention-to-treat principle. Clustering effects (practice/GP) will be tested for, but not included in final models unless significant. Microbiology: Prevalence of antibiotic resistant bacteria in sputum at 4 weeks by trial arm and +/- antibiotics, adjusting for baseline prevalence. Cost-effectiveness: Analyses from a health service perspective, assessing the total health service costs against the primary co-outcomes and cost utility analysis (CUA) of total costs against generic HRQoL (EQ5D) to generate Quality Adjusted Life Years (QALY). Bootstraping will be used in estimating 95% confidence intervals. Incremental Cost Effectiveness Ratios (ICERs) will be reported. Qualitative data will be analysed thematically. Timetable: 33 months in total. Internal pilot (15 practices) in Year 1 (month 5 - Month 11), with clear stop-go criteria for progression to full trial (60 practices) in Year 2 (Month 15 - month 23). Expertise: Multi-disciplinary team with expertise in microbiology, clinical trials, general practice, respiratory medicine, social science, and health economics, with experience of conducting an RCT of CRP-POCT for respiratory infections in primary care.

Lay abstract: Diagnostic tests that can be used at the point-of-care to better target antibiotic prescribing for common conditions provide a major opportunity for improving antibiotic stewardship in primary care. About a million people in the UK are diagnosed with COPD, with a probable 2 million more as yet undiagnosed. People with COPD often experience a sudden worsening of symptoms, known as acute exacerbations (AECOPDs), which are typically treated in general practice. AECOPDs are usually treated with antibiotics, although environmental factors and viruses cause many AECOPDs, where antibiotics do not help recovery. People with COPD frequently express concern that they may be receiving too many antibiotics and that these may be causing them harm. This is particularly important because, in addition to the threats that antimicrobial resistance pose for society as a whole, frequent antibiotics in COPD can generate a population of bacteria in the lungs and elsewhere that become increasingly resistant to antibiotics. This may accelerate progression of the underlying disease and make subsequent AECOPDs harder to treat. However, neither doctors nor patients wish to avoid antibiotics where there is likelihood of patient benefit. C-reactive protein (CRP) is a protein in the blood that can quickly be measured from a finger prick blood sample using a ‘point of care test' (POCT). When CRP is low in AECOPD, patients are unlikely to benefit from antibiotics. The PACE study will determine whether GP use of a simple, rapid, one-step CRP POCT in addition to clinical assessment leads to improved antibiotic prescribing decisions for AECOPD in general practice, such that fewer antibiotics are prescribed overall without having adverse effects for patients. We will recruit 650 patients with AECOPD. Potentially eligible patients will be sent information about the study when general practices register for the study to allow patients to become informed and consider participating before they become unwell with an AECOPD. Those who get an AECOPD and provide consent will be randomly assigned to management using either; 1) current best practice with the addition of a CRP POCT, or 2) current best practice. Participating GPs will be trained in current best practice for AECOPD and interpretation of the CRP POCT results. Antibiotic prescribing decision will be based on clinical judgment, not just the CRP test result. Patients with very severe underlying COPD will not be eligible. PACE will determine whether adding the CRP POCT to current best practice reduces antibiotic consumption during the first four weeks after consulting, without negatively impacting on condition-specific Health-related Quality of Life measured at two weeks using the Chronic Respiratory Disease Questionnaire - Self-Administered Standardised. We will also assess whether the CRP-POCT has an impact on the numbers of bacteria resistant to commonly used antibiotics present in sputum at 4 weeks, and symptoms, health-related quality of life, medication, adverse effects, pneumonia requiring hospitalisation, and consultations in primary or secondary health care over the first 4 weeks. We will assess whether the cost of the test can be justified against any improvements in patient care and potential reduction in antibiotic resistance. Interviews with 20 patients and 20 clinicians will gather in-depth feedback on use of the test, which will help plan general uptake should the CRP POCT prove worthwhile.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: RESPIRATORY