PCT-guided Treatment Regarding Antibiotic Use for Acute COPD Exacerbations

Study Overview
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Brief Summary
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This study the investigators will examine whether procalcitonin-guided treatment regarding antibiotic therapy is non-inferior to usual care in patients who are admitted because of an acute COPD exacerbation when it comes to treatment failure on day 30.

Detailed Description
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Chronic obstructive pulmonary disease (COPD) is a prevalent disease, worldwide, and in the Netherlands with approximately 600.000 patients. COPD is currently the 3rd leading cause of death worldwide and is also a leading cause of disability-adjusted life years. Given the contribution of exacerbations both to loss in quality of life and to health-care costs, it is of paramount importance to improve the current treatment of exacerbations. Pulmonary physicians are well aware of overuse of antibiotics, but lack the tools to decide which medication to give in the clinical setting. Biomarkers may aid towards a more personalized treatment of acute COPD exacerbations (AECOPD). Procalcitonin (PCT), the precursor of calcitonin, is released in response to a bacterial infection by many tissues within 6-12 hours after the onset of infection, while the concentration is only minimally raised in viral infections, making it a relative specific diagnostic tool for bacterial infection. Several trials have shown a reduction in antibiotic consumption in AECOPD when using a PCT-guided treatment algorithm. Recent systematic reviews concluded that appropriately powered trials are lacking to confirm that clinical outcomes are comparable with usual care. In this study the investigators will examine whether a PCT-guided treatment regarding antibiotic therapy is non-inferior to usual care in patients who are admitted because of an acute COPD exacerbation when it comes to treatment failure on day 30.

Official Title
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Procalcitonin-guided Treatment Regarding Antibiotic Use for Acute COPD Exacerbations: a Prospective Randomised Controlled Trial

Conditions
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COPD Exacerbation, COPD, Acute Copd Exacerbation

Intervention / Treatment
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* Diagnostic Test: Procalcitonin
* Other: Physician's decision


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: COPD, according to GOLD 2018 definition Indication for hospitalization because of acute severe exacerbation of COPD, as defined by GOLD 2018 and modified Anthonisen criteria Presence of at least 2 major symptoms of the modified Anthonisen criteria (acute deterioration in sputum volume, sputum purulence and dyspnea) or the presence of 1 major symptom and 1 minor symptom (coughing, wheeze, nasal discharge, sore throat, fever) Post-bronchodilator FEV1/FVC < 0,70 and FEV1% < 80%pred. within last 5 years At least 40 years Smokers or ex-smokers with > 10 packyears Written informed consent Start of symptoms no more than 7 days before admission Exclusion Criteria: Indication for ICU and or non-invasive ventilation < 72h of admission Pneumonia, radiologically confirmed Infection at another site and/or sepsis according to the SIRS criteria (with tachycardia and tachypnea not being caused by the exacerbation) COPD before age 40 Asthma, without presence of COPD. Patients with COPD , with or without a history of asthma (in childhood or as an adolescent) will NOT be excluded/are allowed to participate. Patients with Asthma/COPD overlap syndrome (with current asthma AND COPD) will NOT be excluded/are allowed to participate. Clinically relevant heart failure or myocardial ischemia Chronic use of immunosuppressants, including prednisolone (a prednisone equivalent of 10mg or less is allowed/is NOT an exclusion criterion) Known bronchiectasis as a primary diagnosis Colonisation with Pseudomonas spp. or other micro-organisms in recent cultures (last 60 days) not susceptible to amoxicillin-clavulanic acid Pregnancy Recent exacerbation (last 28 days)

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a prospective randomized clinical multi-center study to evaluate procalcitonin-guided treatment regarding antibiotic use in patients who are admitted because of an acute COPD exacerbation. Patients who are admitted are randomly assigned to either procalcitonin-guided treatment (in which antibiotics are started when the procalcitonin concentration is above 0.25 ng/mL) or usual care in which the treating physician decides whether or not to start with antibiotic treatment. Patients will be stratified for study center.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PCT-guided treatment<br>Patients randomized to this arm will only receive antibiotic treatment when the procalcitonin concentration is > 0.25ug/L. | Diagnostic Test: Procalcitonin<br>* blood test, measuring the concentration of PCT in ug/L<br>* Other names: PCT;|
| Active Comparator: Usual care<br>Patients randomized to this arm will receive antibiotic treatment based on the physician's decision. | Other: Physician's decision<br>* The physician's decided whether the patient will receive antibiotic treatment or not<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure | Treatment failure is defined as disease-related mortality, need for endotracheal intubation or vasopressors, renal failure (defined as Kidney Disease: Improving Global Outcomes (KDIGO) stage 3 - new renal replacement therapy, tripling of baseline creatinine, or serum creatinine > or = 350 umol/L), lung abcess/empyema, development of pneumonia or rehospitalization within 30 days after inclusion. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incomplete resolution of the clinical signs and symptoms | Incomplete resolution of the clinical signs and symptoms associated with the AECOPD at day 30 after inclusion of the study (i.e. not reaching the baseline condition prior to the AECOPD) scored using the modified Anthonisen criteria | change between baseline and after 30 days | 
| Incomplete resolution of the clinical signs and symptoms | Incomplete resolution of the clinical signs and symptoms associated with the AECOPD at day 30 after inclusion of the study (i.e. not reaching the baseline condition prior to the AECOPD) scored using the modified Anthonisen criteria | day 30 | 
| Modified Anthonisen criteria | Patients fill in the modified Anthonisen criteria card on day 1 as a baseline measure | baseline | 
| Modified Anthonisen criteria | Patients fill in the modified Anthonisen criteria card on day 3 | day 3 | 
| Modified Anthonisen criteria | Patients fill in the modified Anthonisen criteria card on day 1 as a baseline measure | day 5 | 
| Modified Anthonisen criteria | Patients fill in the modified Anthonisen criteria card on day 1 as a baseline measure | day 10 | 
| Decision to start antibiotic therapy after an initial opposite decision (after 48 hours) | Decision to start antibiotic therapy after an initial opposite decision (after 48 hours) | 30 days | 
| Side effects of antibiotic treatment | Side effects of antibiotic treatment, such as gastro-intestinal complaints, allergic reactions | 30 days | 
| Cumulative antibiotic consumption | The cumulative amount of antibiotic treatment consumed by the patient during follow-up | 30 days | 
| Cumulative prednisolone consumption | The cumulative amount of prednisolone consumed by the patient during follow-up | 30 days | 
| Length of hospitalization | Duration of time (in days) of the admission in hospital for the index exacerbation during follow-up | up to 30 days | 
| Re-exacerbation | The presence of a new exacerbation, requiring treatment (prednisolone and/or antibiotic treatment) during follow-up | 30 days | 
| EXACT respiratory questionnaire | PROM symptom score: EXACT - Respiratory symptoms scale | change between baseline and after 30 days | 
| EXACT respiratory questionnaire | PROM symptom score: EXACT - Respiratory symptoms scale | baseline | 
| EXACT respiratory questionnaire | PROM symptom score: EXACT - Respiratory symptoms scale | day 10 | 
| EXACT respiratory questionnaire | PROM symptom score: EXACT - Respiratory symptoms scale | day 30 | 
| CAT | COPD assessment test, quality of life questionnaire | baseline | 
| CAT | COPD assessment test, quality of life questionnaire | day 10 | 
| CAT | COPD assessment test, quality of life questionnaire | day 30 | 
| CAT | COPD assessment test, quality of life questionnaire | change between baseline and day 30 | 
| EQ-5D-5L | quality of life questionnaire | baseline | 
| EQ-5D-5L | quality of life questionnaire | day 10 | 
| EQ-5D-5L | quality of life questionnaire | day 30 | 
| EQ-5D-5L | quality of life questionnaire | change between baseline and day 30 | 
| iMCQ | Medical consumption questionnaire, measuring the total amount of medical consumption (admission, ER visits, outpatient visits) during follow-up | 30 days | 
| Non-invasive ventilation after 72 hours of admission | Need for non-invasive ventilation after 72 hours of admission | 30 days | 
| Time to complete resoluation of symptoms | · Time to complete resolution of symptoms according to daily symptom diaries evaluating the modified Anthonisen criteria | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Procalcitonin