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 (CAPTAIN)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Community-acquired Pneumonia
• Intervention / Treatment: Drug: Amoxicillin; Drug: Amoxicillin/clavulanate

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.

• Study Type: Interventional
• Enrollment (Estimated): 326
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Emmanuel MONTASSIER, Professor; Phone Number: +33 02 53 48 20 38; Email: emmanuel.montassier@chu-nantes.fr

Study Locations

• France
  • Angers, France
    • Recruiting
    • Chu Angers
    • Contact: Rafaël MAHIEU, MD; Phone Number: +33 0241353930; Email: rafael.mahieu@chu-angers.fr
  • Bobigny, France
    • Recruiting
    • CHU Avicenne AP-HP
    • Contact: Frederic MECHAI, MD; Phone Number: +33 0148955428; Email: frederic.mechai@aphp.fr
  • Brest, France
    • Recruiting
    • CHRU BREST
    • Contact: Rozenn LE BERRE, MD; Phone Number: +33 029822333; Email: rozenn.leberre@chu-brest.fr
  • La Roche-sur-Yon, France
    • Recruiting
    • CHD Vendee
    • Contact: Dominique MERRIEN, MD; Phone Number: +33 0251446385; Email: dominique.merrien@ght85.fr
  • La Tronche, France
    • Recruiting
    • CHU Grenoble-Alpes
    • Contact: Perrine DUMANOIR, MD; Phone Number: +33 0476767088; Email: PDumanoir@chu-grenoble.fr
  • Marseille, France
    • Recruiting
    • Assistance Publique Hopitaux de Marseille
    • Contact: Aurélie DAUMAS, MD; Phone Number: +33 0491388719; Email: aurelie.daumas@ap-hm.fr
  • Nantes, France
    • Recruiting
    • CHU de NANTES
    • Principal Investigator: Emmanuel Montassier, MD
    • Contact: Emmanuel MONTASSIER, MD; Phone Number: +33 0253482038; Email: emmanuel.montassier@chu-nantes.fr
  • Périgueux, France
    • Recruiting
    • CH Périgueux
    • Contact: Alexandrine VIDAL, MD; Phone Number: +33 0553452525; Email: alexandrine.vidal@ch-perigueux.fr
  • Toulouse, France
    • Recruiting
    • CHRU - TOULOUSE Hôpital Purpan
    • Contact: Guillaume MARTIN-BLONDEL, MD; Phone Number: +33 0561779699; Email: martin-blondel.g@chu-toulouse.fr
  • Toulouse, France
    • Recruiting
    • CHRU TOULOUSE - Hôpital Rangueuil
    • Contact: Xavier DUBUCS, MD; Phone Number: +33 0561775919; Email: dubucs.x@chu-toulouse.fr
  • Vannes, France
    • Recruiting
    • Centre hospitalier Bretagne Atlantique
    • Contact: Pierre BARSI, MD; Phone Number: +33 0297014893; Email: pierre.barsi@ch-bretagne-atlantique.fr
  • France
    • Saint-Nazaire, France, France, 44600
      • Recruiting
      • CH Saint-Nazaire
      • Contact: Dorothée BOISSEAU, Doctor; Phone Number: +33 0272278434; Email: d.boisseau@ch-saintnazaire.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient aged 65 years or older with or without comorbidities defined by chronic diseases in immunocompetent patients,
2. 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
3. Patient understanding oral and written French
4. 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).
5. 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:

1. Signs of severe CAP (abscess, massive pleural effusion, serious chronic respiratory insufficiency, ICU admission)
2. Patient requiring ICU admission,
3. Estimated Glomerular Filtration Rate < 30 ml/min,
4. Known immunosuppression (asplenia, neutropenia, agammaglobulinemia, transplant, myeloma, lymphoma, known HIV and CD4<200/mm3),
5. Exacerbation of chronic obstructive pulmonary disease,
6. Life-threatening state expected to lead to possible imminent death,
7. Suspected atypical bacteria requiring combined antibiotics therapy,
8. Legionella suspected,
9. Subjects with clinical or epidemiological environment leading to suspect a healthcare associated pneumonia with antibiotic resistant pathogen (including long-term care facility)
10. Patient known to be colonized with Pseudomonas aeruginosa or Enterobacteriaceae in the respiratory tract,
11. Suspicion of aspiration pneumonia,
12. Administration of any antibiotic treatment for more than 24 hours before inclusion,
13. History of jaundice/hepatic impairment associated with amoxicillin/clavulanate acid,
14. History of bacterial pneumonia less than 1 month prior to study inclusion
15. History of hypersensitivity or allergy to beta-lactam or to any excipients included in study antibiotics,
16. Subject without health insurance,
17. Subject without home address or difficulty in terms of follow-up (vacation, job transfer, geographical distance, lack of motivation),
18. Patient under judicial protection,
19. Diagnosis confirmed of SAR-Cov2 infection (PCR Test, covid antigen rapid test, chest computed tomography (CT) scan),
20. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Amoxicillin; Amoxicillin is an antibiotic treatment approved in France and in many countries. The investigational medicinal products (IMPs) are: - Amoxicillin capsules : Formulated as a 500 mg capsules for PO administration (commercially available). Description in IMP file. Amoxicillin capsules contain compendial excipients listed in the Summary Product Characteristics (SmPC), current version, and are kept in a cool dry place where the temperature stays at 15- 25°C. - Amoxicillin IV vials : Formulated as a 1000 mg vial for IV administration (commercially available). Description in IMP file. Amoxicillin IV vials contain compendial excipient listed in the Summary Product Characteristics (SmPC), current version, and are kept in a cool dry place where the temperature stays at 15-25°C.	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); Other Names: Experimental drug
Active Comparator: Amoxicillin/clavulanate; Amoxicillin/clavulanate is recommended by French and European guidelines for the treatment of patients aged 65 years or older, and hospitalized in a non-ICU ward, as reported above. The active comparators (IMPs) are: - Amoxicillin/clavulanate tablets: Formulated as a tablet for PO administration (commercially available). Description in IMP file. Tablets contain 500 mg of amoxicillin trihydrate and 62.5 mg of clavulanate. Amoxicillin/clavulanate tablets contain compendial excipients listed in the Summary Product Characteristics (SmPC), current version, and are kept in a cool dry place where the temperature stays at 15-25°C. - Amoxicillin/clavulanate vials Vials contain 1000 mg of amoxicillin and 200 mg of clavulanate. Description in IMP file. Amoxicillin/clavulanate vials contain compendial excipients listed in the Summary Product Characteristics (SmPC), current version, and are kept in a cool dry place where the temperature stays at 15-25°C	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); Other Names: active comparator drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-inferiority	To investigate non-inferiority in terms of clinical efficacy among patients aged 65 years or older, hospitalized in a non-ICU ward for a CAP, and treated with narrow-spectrum (amoxicillin) versus broad-spectrum (amoxicillin/clavulanate) antimicrobial therapy, at Day 30 since hospital admission. To answer this question, clinical success rate at Day 30 since admission, defined as survival after completion of antibiotic treatment course, resolution of signs and symptoms of the infection (cough, purulent sputum production, dyspnea, or pleuritic chest pain) present at baseline with no new symptoms or complications attributable to CAP and no need for further antibacterial therapy will be determined	Day 30 after inclusion (=Day 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rates of early clinical response	Early clinical response will be defined as survival with improvement of one or more levels relative to baseline in two or more symptoms of CAP and no worsening of one or more levels in other symptoms of community-acquired bacterial pneumonia, without receipt of rescue antibacterial therapy	Day 3 after inclusion (=Day 1)
Clinical cure after the end of treatment	The proposed endpoint of clinical cure after the end of treatment is defined as resolution in relevant signs and symptoms reported at baseline, no worsening of symptoms, and no change in antimicrobial regimen	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	Days taking antibiotics from the first dose until the interruption of any antibiotic treatment during hospitalization and at late follow-up at Day 30 after hospital admission (to identify the use of any other antibiotic after hospital discharge defined as no IV, regain of autonomy identical to baseline, good clinical response and favorable evolution following initiation of antibiotics, other criteria left at the discretion of the investigators according to centers' practices)	Day 30 after inclusion (=Day 1)
To investigate all-cause mortality at Day 30 after hospital admission	All-cause mortality at Day 30 after hospital admission	Day 30 after inclusion (=Day 1)
To investigate the rate of polymerase chain reaction (PCR)-positive Clostridium difficile among patients with diarrhea	Number of positive polymerase chain reaction (PCR)-positive Clostridium difficile among patients with diarrhea	Within 30 days after inclusion (=Day 1)
To investigate in-hospital mortality	Number of deaths during hospitalization	Within 30 days after inclusion (=Day 1)
To investigate ICU transfer during the Day 30 follow-up	Number of patients transferred to the ICU during the Day 30 follow-up	Day 30 after inclusion (=Day 1)
To investigate CAP recurrence and hospital readmissions up to day 30 from hospital admission	Number of hospital readmissions and CAP recurrence up to day 30 from hospital admission	Day 30 after inclusion (=Day 1)
To investigate adverse events attributable to antibiotics up to day 30 from hospital admission	Number of adverse events attributable to antibiotics and number of days with adverse events up to day 30 from hospital admission	Day 30 after inclusion (=Day 1)
To investigate compliance with the antibiotic treatment	Number of days of antibiotic treatment taken	Within 7 days after inclusion (=Day 1)
To investigate length of hospital stay		Within 30 days after inclusion (=Day 1)
Analysis of sensitivity todiscordance	To investigate the agreement between the early clinical response endpoint and the investigator's clinical judgment: the agreement between early clinical response (main endpoint) and the investigator's clinical judgement (clinical success or clinical failure) will be assessed	Within 30 days after inclusion (=Day 1)

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Investigators: Principal Investigator: Frederic BALEN, Doctor, Toulouse UH; Principal Investigator: Guillaume MARTIN-BLONDEL, Doctor, Toulouse UH; Principal Investigator: Perrine DUMANOIR, Doctor, Grenoble Hospital; Principal Investigator: VIGLINO Damien, Doctor, Grenoble Hospital; Principal Investigator: Alexandrine VIDAL, Doctor, Perigueux Hospital; Principal Investigator: Delphine PLARD, Doctor, Angers UH; Principal Investigator: Rafaël MAHIEU, Doctor, Angers UH; Principal Investigator: Anne-Laure FERAL-PIERSSENS, Doctor, Avicenne AP-HP; Principal Investigator: Frederic MECHAI, Doctor, Avicenne AP-HP; Principal Investigator: Aurelie DAUMAS, Professor, Marseille Timone Hospital; Principal Investigator: Dominique MERRIEN, Doctor, CHD La Roche sur Yon; Principal Investigator: Sylvain LE GENTIL, Doctor, CHD La Roche sur Yon; Principal Investigator: Pierre BARSI, Doctor, Vannes Hospital Bretagne Atlantic; Principal Investigator: Rozenn LE BERRE, Doctor, Brest Hospital; Principal Investigator: Sylvain JAFFUEL, Doctor, Brest Hospital; Principal Investigator: Xavier DUBUCS, Doctor, Toulouse UH; Principal Investigator: Matthieu THIBAULT, Doctor, Saint-Nazaire Hospital; Principal Investigator: BOISSEAU Dorothée, Doctor, Saint-Nazaire Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 25, 2024
• Primary Completion (Estimated): May 25, 2027
• Study Completion (Estimated): May 25, 2027

Study Registration Dates

• First Submitted: January 10, 2024
• First Submitted That Met QC Criteria: January 19, 2024
• First Posted (Actual): January 29, 2024

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Amoxicillin; Community-acquired pneumonia; Amoxicillin/clavulanate
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Pneumonia; Community-Acquired Infections; Community-Acquired Pneumonia; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Amides; Drug Combinations; Penicillin G; beta-Lactams; Lactams; Clavulanic Acid; Clavulanic Acids; Ampicillin; Penicillins; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Drugs, Investigational
• Other Study ID Numbers: RC20_0015

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No