Study to Demonstrate That Antibiotics Are Not Needed in Moderate Acute Exacerbations of COPD

Study Overview
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Brief Summary
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The ultimate goal is to reduce unnecessary antibiotic prescriptions which drive the development of antibiotic resistance in the community. The primary objective of ABACOPD is to demonstrate in a sufficiently sized clinical study that there is no relevant increase in the failure-rate for patients with acute moderate exacerbations of COPD (AE-COPD) treated with placebo instead of antibiotic treatment both on top of standard of care. A patient is classified as treatment failure if additional antibiotic therapy is required during treatment period or until the test of cure visit (TOC at day 30, primary endpoint).

Official Title
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Randomized Double Blind Placebo-controlled Study to Demonstrate That Antibiotics Are Not Needed in Moderate Acute Exacerbations of COPD - The ABACOPD Study

Conditions
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Chronic Obstructive Pulmonary Disease (COPD)

Intervention / Treatment
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* Drug: Sultamicillin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults, either sex, older or equal than 40 years of age For female patients, the following conditions are to be met: has been postmenopausal for at least 1 year, or is surgically incapable of bearing children, or is of childbearing potential, and the following conditions are met: has a negative pregnancy test (urine- or serum-based) immediately before study entry (i.e., before the start of treatment or any other study procedure that could potentially harm the fetus), and one or more of following criteria must agree to abstinence or use an accepted method of contraception. The subject must agree to continue with the same method throughout the study. having only female sexual partners sexual relationship with sterile male partners only Patients diagnosed with COPD stages I-IV as defined by the Global initiative for chronic Obstructive Lung disease (GOLD). and Doctor's diagnosis of acute (onset < 7 days) moderate exacerbation of COPD defined by a sustained worsening of the patient's condition (including at least 2 of the following symptoms: increased dyspnea, increased sputum production, sputum purulence and increased cough), from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in patient with underlying COPD, needing additional medical assistance. Absence of community acquired pneumonia or lower respiratory tract infection with a clear indication for antibiotic treatment as determined by Procalcitonin level < 0.25 ng/mL and/or absence of pulmonary infiltrates on routine chest x-ray. Smoking history of at least 10 Pack Years or more. Patients must be able to complete diaries and quality of life questionnaires. Patients must sign and date an informed consent prior to any study procedures. Exclusion Criteria: Severe exacerbation: defined by need for ventilatory support (indicated by severe dyspnea with failure to respond to emergency treatment and/or persistent hypoxemia (PaO2 <50 mm Hg despite O2 administration and / or respiratory acidosis (pH <7.35 and PaCO2> 45mmHg)) or mental confusion or circulatory insufficiency (need of vasopressors) Fever (>38.5°C) Known impaired hepatic or renal function Active or suspected tuberculosis infection of the respiratory tract Acute exacerbation of asthma Suspected or known hypersensitivity to, or suspected serious adverse reaction to sultamicillin; suspected or known hypersensitivity to penicillins or cephalosporins Immunosuppression or Immunosuppressive therapy (cytostatic chemotherapy within last 28 days or neutropenia (neutrophils < 1000/µ)l; systemic corticosteroids (≥20 mg prednisolon equivalent/day > 14 days; HIV-infection; immunosuppression after organ- or bone marrow transplant)- Patients with metastatic or hematological malignancy, splenectomized patients or patients with known hyposplenia or asplenia Oral/parenteral antibiotic use within 30 days prior to randomization (a singular administration of antibiotics prior to randomization is allowed) In-patient treatment within the last 30 days An antibiotic is clearly indicated for treatment of a known infection Known MRSA (methicillin-resistant Staphylococcus aureus) colonization or infection Patients with known bronchiectasis Patients with known bacterial airway colonization (>3 positive sputum cultures in the previous year) Progressively fatal disease, or life expectancy ≤6 months Mononucleosis Lymphatic leukemia Severe gastro-intestinal disorders with vomiting and diarrhea Women who are breast feeding Patients who have received treatment with any other investigational drug within 1 month prior to study entry, or have such treatment planned for the study period during treatment and follow up phase. Patients with mental conditions rendering them unable to understand the nature, scope, and possible consequences of the study. Patients unlikely to comply with the protocol, e.g., uncooperative attitude, inability to return for follow up visits, and unlikelihood of completing the study.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: lactose pill<br>Placebo for 5 days as supplement to standard of care for patients with AE-COPD | Drug: Placebo<br>* Standard of care: Each patient will receive inhaled fast-acting bronchodilators (up to a maximum of 4 - 6 times daily 2 puffs (100µg) of salbutamol or other equivalent inhaled fast-acting bronchodilators), systemic corticosteroids (prednisolone 40mg/d p.o. for 7 - 10 days) and oxygen in case of hypoxemia in a standardized fashion. The pre-existing COPD medication will be continued as indicated. Control intervention: Placebo for 5 days as supplement to standard of care for patients with AE-COPD<br>* Other names: Placebo: Lactose pill;|
| Experimental: Sultamicillin<br>Antibiotic therapy with aminopenicillin + betalactamase inhibitor (oral Sultamicillin (2 x 750mg)) for 5 days as supplement to standard of care for patients with AE-COPD | Drug: Sultamicillin<br>* Standard of care: Each patient will receive inhaled fast-acting bronchodilators (up to a maximum of 4 - 6 times daily 2 puffs (100µg) of salbutamol or other equivalent inhaled fast-acting bronchodilators), systemic corticosteroids (prednisolone 40mg/d p.o. for 7 - 10 days) and oxygen in case of hypoxemia in a standardized fashion. The pre-existing COPD medication will be continued as indicated. Experimental intervention: Antibiotic therapy with aminopenicillin + betalactamase inhibitor (oral Sultamicillin (2 x 750mg)) for 5 days as supplement to standard of care for patients with AE-COPD.<br>* Other names: aminopenicillin + betalactamase inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Additional antibiotic therapy to study medication during treatment period or until the test of cure visit (at day 30) | Assessment of additional antibiotic therapy: Patients will be asked at every visit about use of additional antibiotic therapy. In the case of use of additional antibiotic therapy the exact starting date, the active compound, the dose administered, the route of administration,the length of treatment and the indication will be registered. Only additional antibiotic therapy for AE-COPD will be counted as treatment failure. | up to day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate long-term consequences of Placebo treatment | Relapse rate Time to relapse | up to 1 year | 
| To assess patient's clinical improvement relative to treatment | Clinical cure rate at the end of therapy visit (at day 6) Clinical cure rate at the test Of cure visit (at day 30) (both determined by patient-centered outcomes (diary cards)) | up to 30 days | 
| To assess additional efficacy endpoints and health outcome evaluations | Changes in COPD Assessment Test(CAT) Changes in Exacerbations of Chronic Pulmonary Disease Tool-Patient reported outcome (EXACT-PRO) Additional antibiotic therapy Time to next exacerbation Number of exacerbations during follow up Per-subject relapse rate at the LFU (Late Follow Up) visits in the subset of subjects in the CE population who were clinically cured at the TOC visit Changes in length of stay in hospital for hospitalized patients All cause mortality | up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute exacerbations of Chronic obstructive pulmonary disease, COPD, AE-COPD, Chronic obstructive pulmonary disease