Amoxicillin Alone Versus Amoxicillin/Clavulanate for Community-acquired Pneumonia in Patients Aged 65 Years or Older, and Hospitalized in a Non-intensive Care Unit Ward

Official title

Amoxicillin Alone Versus Amoxicillin/Clavulanate for Community-acquired Pneumonia in Patients Aged 65 Years or Older, and Hospitalized in a Non-intensive Care Unit Ward: a Non-inferiority Randomized Controlled Trial

Overview

Reduce inappropriate antibiotic use is a priority of public health agencies. Community-acquired pneumonia (CAP) is one of the most important indications for antibiotic prescriptions. In the majority of the studies of CAP, there is a large proportion of cases with no pathogen identified. Thus, the choice of the empirical antibiotic depends on the most likely pathogen, individual risk factors, comorbidities, and allergies. Patients aged 65 years or older are often treated with amoxicillin/clavulanate or with another broad-spectrum antibiotic (third-generation cephalosporins, antipneumococcal fluoroquinolone). However, broad-spectrum antibiotic prescription in CAP is debated and concerns exist about side-effects and selective pressure for resistance. Due to lack of head-to-head antibiotic comparisons, a recent Cochrane review concluded that current evidence from Randomized Clinical Trials (RCTs) is insufficient to make evidence-based recommendations for the choice for antibiotic to be used, highlighting an important evidence gap.

Detailed description

Thus, the goal of the proposed trial is to compare clinical efficacy and safety of two CAP antimicrobial treatments, amoxicillin and amoxicillin/clavulanate, in patients aged 65 years or older and hospitalized in a non-intensive care unit (ICU) ward. The CAPTAIN study will be a multi-center, randomized, open, non-inferiority trial comparing clinical efficacy at Day 30 among patients ≥65 years of age, and hospitalized in a non-ICU ward, treated with narrow-spectrum (amoxicillin) versus broad-spectrum (amoxicillin/clavulanate) antimicrobial therapy for CAP. This will be a pivotal clinical trial that will provide evidence to inform CAP treatment guidelines.

Interventions

• Drug Amoxicillin
  Participants will be randomized to IV/oral amoxicillin or IV/oral amoxicillin/clavulanate for 5 days. Both agents are approved for treatment of respiratory infections. Amoxicillin PO: The dose is two capsule of 500 mg every 8 hours (that is 3 times daily). Amoxicillin IV: The dose is 1 g every 8 hours (that is 3 times daily)
• Drug Amoxicillin/clavulanate
  Participants will be randomized to IV/oral amoxicillin or IV/oral amoxicillin/clavulanate for 5 days. Both agents are approved for treatment of respiratory infections. Amoxicillin/clavulanate PO: The dose is two tablets of 500 mg/62.5 mg every 8 hours (that is 3 times daily, approved standard dose) Amoxicillin/clavulanate IV: The dose is 1 g/200 mg every 8 hours (that is 3 times daily, approved standard dose)

Primary outcome measures

• Non-inferiority [Time frame: Day 30 after inclusion (=Day 1)]

Secondary outcome measures (12)

• Rates of early clinical response [Time frame: Day 3 after inclusion (=Day 1)]
• Clinical cure after the end of treatment [Time frame: Within 30 days after inclusion (=Day 1) compared to baseline]
• To investigate total duration of antibiotic treatment, i.e., the total number of days with antibiotics during the Day 30 follow-up after hospital admission [Time frame: Day 30 after inclusion (=Day 1)]
• To investigate all-cause mortality at Day 30 after hospital admission [Time frame: Day 30 after inclusion (=Day 1)]
• To investigate the rate of polymerase chain reaction (PCR)-positive Clostridium difficile among patients with diarrhea [Time frame: Within 30 days after inclusion (=Day 1)]
• To investigate in-hospital mortality [Time frame: Within 30 days after inclusion (=Day 1)]
• To investigate ICU transfer during the Day 30 follow-up [Time frame: Day 30 after inclusion (=Day 1)]
• To investigate CAP recurrence and hospital readmissions up to day 30 from hospital admission [Time frame: Day 30 after inclusion (=Day 1)]
• To investigate adverse events attributable to antibiotics up to day 30 from hospital admission [Time frame: Day 30 after inclusion (=Day 1)]
• To investigate compliance with the antibiotic treatment [Time frame: Within 7 days after inclusion (=Day 1)]
• To investigate length of hospital stay [Time frame: Within 30 days after inclusion (=Day 1)]
• Analysis of sensitivity todiscordance [Time frame: Within 30 days after inclusion (=Day 1)]

Eligibility criteria

Inclusion criteria

• Patient aged 65 years or older with or without comorbidities defined by chronic diseases in immunocompetent patients,
• Patient admitted to the hospital for a CAP defined by at least two clinical signs of pneumonia (cough, sputum production, dyspnea, tachypnea, or pleuritic pain, abnormal lung auscultatory sounds, fever (temperature > 38°C) or hypothermia (<36°C)), and had radiological evidence of a new infiltrate confirming pneumonia
• Patient understanding oral and written French
• Written informed consent obtained from patient prior to participation in the study (if the patient is unable to express in writing: consent by a trusted person).
• Patients should be able to call and to answer to a phone call or to be with a relative who can help him to call or to answer questions notably raised by a medical staff belonging to the investigational site

Exclusion criteria

• Signs of severe CAP (abscess, massive pleural effusion, serious chronic respiratory insufficiency, ICU admission)
• Patient requiring ICU admission,
• Estimated Glomerular Filtration Rate < 30 ml/min,
• Known immunosuppression (asplenia, neutropenia, agammaglobulinemia, transplant, myeloma, lymphoma, known HIV and CD4<200/mm3),
• Exacerbation of chronic obstructive pulmonary disease,
• Life-threatening state expected to lead to possible imminent death,
• Suspected atypical bacteria requiring combined antibiotics therapy,
• Legionella suspected,
• Subjects with clinical or epidemiological environment leading to suspect a healthcare associated pneumonia with antibiotic resistant pathogen (including long-term care facility)
• Patient known to be colonized with Pseudomonas aeruginosa or Enterobacteriaceae in the respiratory tract,
• Suspicion of aspiration pneumonia,
• Administration of any antibiotic treatment for more than 24 hours before inclusion,
• History of jaundice/hepatic impairment associated with amoxicillin/clavulanate acid,
• History of bacterial pneumonia less than 1 month prior to study inclusion
• History of hypersensitivity or allergy to beta-lactam or to any excipients included in study antibiotics,
• Subject without health insurance,
• Subject without home address or difficulty in terms of follow-up (vacation, job transfer, geographical distance, lack of motivation),
• Patient under judicial protection,
• Diagnosis confirmed of SAR-Cov2 infection (PCR Test, covid antigen rapid test, chest computed tomography (CT) scan),
• Participation to another interventional study and having an exclusion period that is still in force during the screening phase or expected participation to another interventional study during participation to the CAPTAIN study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 19 centers

• CH Saint-Nazaire — Saint-Nazaire
• CH Saint-Nazaire — Saint-Nazaire
• Chu Angers — Angers
• CHU Angers — Angers
• CHU Avicenne AP-HP — Bobigny
• CHU Avicenne AP-HP — Bobigny
• CHRU Brest — Brest
• CHRU Brest — Brest
• … and 11 more centers

Identifiers

NCT: NCT06229288 · RC20_0015

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗