Evaluation of Customized Antibiotic Treatment Duration in Hospitalized Patients with Moderately Severe Community-Acquired Pneumonia Using Pristinamycin and Drug Combination
- Trial ID
- 2023-504208-27-00
- Protocol
- APHP220814
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate if the efficacy of an experimental strategy on **antibiotic** treatment duration, based on stopping treatment when stability criteria are reached after at least 48 hours of treatment, is non-inferior to the efficacy of standard antibiotic duration in patients with community-acquired pneumonia (CAP) treated in the hospital setting. This is clinically relevant as it may allow for a reduction in antibiotic exposure, potentially minimizing adverse effects and the development of antibiotic resistance.
Secondary objectives include:
- Assessing if the efficacy of the experimental strategy on antibiotic treatment duration compared to standard care in CAP patients is non-inferior in terms of persistence of cure at Day 30, all-cause mortality rate on Day 30, and evolution of pneumonia symptoms and quality of life via CAP score and CAP Sym at various time points.
- Comparing between the two study arms at Day 30 of antibiotic treatment regarding the total duration of antibiotic treatment, the length of initial hospital stay, and the frequency and severity of adverse events during the 30 days after the start of treatment.
- Exploring the impact of reduced antibiotic treatment duration for CAP on the oropharyngeal resistome.
Participants
The clinical trial focuses on evaluating the efficacy of an experimental strategy for antibiotic treatment duration in patients with **community-acquired pneumonia**. The study population includes adult patients aged 18 years and older, encompassing both male and female participants. The trial does not involve a vulnerable population. Participants are selected based on specific inclusion criteria, such as being admitted to the hospital with suspected community-acquired pneumonia, confirmed by clinical and radiological evidence, and having received antibiotic treatment for a minimum of 48 hours. The trial population is required to have a clinical response within the last 24 hours, characterized by stable vital signs and no other site of infection besides the respiratory system. Participants must be affiliated with health insurance or government medical aid and have provided informed consent. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of an experimental strategy for antibiotic treatment duration in patients with **community-acquired pneumonia**. This is a Phase III, pragmatic, non-inferiority, randomized, double-blind, controlled trial with two parallel arms. Participants will be randomly assigned in a 1:1 ratio to either a standard treatment duration group or an experimental group where treatment is stopped based on stability criteria after a minimum of 48 hours of treatment. The trial is expected to run from December 2023 to May 2027, with participant involvement lasting up to 30 days from the start of treatment.
Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, clinical presentation, and radiological evidence of pneumonia. Participants will then be randomized and begin treatment. Follow-up visits will occur at key intervals: Day 0 (retrospective assessment), Day S (stability), Day 7, Day 15, and Day 30. These visits will assess the primary endpoint of cure rate at Day 15 and secondary endpoints including cure rate at Day 30, all-cause mortality, symptom evolution, and quality of life. The end-of-study visit will coincide with the Day 30 assessment.
Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include failure to meet stability criteria, adverse events, or withdrawal of consent. The trial will utilize a range of antibiotics, including **pristinamycin**, **amoxicillin**, **ceftriaxone**, **levofloxacin**, and **cefotaxime**, administered either orally or via intravenous/intramuscular routes, depending on the specific medication and patient needs. The maximum treatment period for any antibiotic is 10 days, with dosages adjusted according to clinical guidelines.
Treatment
The clinical trial involves the administration of several **antibiotics** to evaluate their efficacy in treating moderately severe community-acquired pneumonia. **Pristinamycin** is one of the experimental medications used in this study. It is administered orally in a pharmaceutical form identified as PHF00082MIG. The maximum daily dose is 3 grams, with a total maximum dose of 30 grams over a treatment period of up to 10 days. The administration is monitored to ensure compliance with the dosing schedule.
**Amoxicillin** is another experimental medication included in the trial. It is also administered orally, with a pharmaceutical form designated as PHF00170MIG. The dosing regimen allows for a maximum daily dose of 3 grams and a total maximum dose of 30 grams over a 10-day period. Participant compliance is monitored to ensure adherence to the prescribed dosing schedule.
**Ceftriaxone** is administered either through intravenous infusion or intramuscular injection. The pharmaceutical form is identified as PHF00201MIG. The maximum daily dose is 2 grams, with a total maximum dose of 20 grams over a 10-day treatment period. The administration method and dosing schedule are closely monitored to ensure participant compliance.
**Levofloxacin** is administered orally in the form PHF00082MIG. The maximum daily dose is 1 gram, with a total maximum dose of 10 grams over a 10-day period. Compliance with the dosing schedule is monitored throughout the trial.
The combination of **Amoxicillin and Clavulanic Acid** is also used in the study. This medication is administered orally, with a pharmaceutical form identified as PHF00082MIG. The maximum daily dose is 3 grams, and the total maximum dose is 30 grams over a 10-day period. Participant adherence to the dosing schedule is monitored.
**Cefotaxime**, marketed as Cefotaxime Panpharma, is administered as a solution for injection, either intramuscularly or intravenously. The maximum daily dose is 12 grams, with a total maximum dose of 120 grams over a 10-day treatment period. The administration method and dosing schedule are monitored to ensure compliance.
The trial also includes a non-experimental treatment group receiving **Macrolides**. This group serves as a comparator to evaluate the efficacy of the experimental treatments. The Macrolides are administered orally, with a maximum daily dose of 9 million international units and a total maximum dose of 90 million international units over a 10-day period. Compliance with the dosing schedule is monitored to ensure accurate comparison with the experimental treatments.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the **rate of cure** at Day 15 after treatment initiation. Cure at Day 15 is defined by the persistence of stability criteria, which include body temperature ≤ 37.8°C, heart rate ≤ 100/min, systolic blood pressure > 90mmHg, oxygen saturation ≥ 92%, respiratory rate < 24/min, and normal mental status. Additionally, no further antibiotic treatment targeting community-acquired pneumonia (CAP) should be required after the initial treatment. Patients who do not meet these criteria or who have died will be classified as failures at Day 15.
Secondary endpoints include the rate of cure at Day 30, defined similarly to the primary endpoint, and all-cause mortality on Day 30. Other secondary measures involve the evolution of pneumonia symptoms and quality of life assessed at various timepoints, including Day 0, Day S (stability), Day 7, Day 15, and Day 30. The duration of antibiotic treatment targeting CAP and for all indications during the 30 days post-treatment initiation will also be evaluated. Additional assessments include the length of the initial hospital stay, the frequency and severity of adverse events, and the analysis of microbiome and resistance genes at Day S and Day 30.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult patient (≥18 years old)
- Admitted to hospital for suspected CAP defined by the presence of at least 2 of the following diagnostic clinical criteria: o Fever (temperature > 38°C) or hypothermia (< 36°C) o Dyspnea o Cough o Production of purulent sputum o Crackles
- Radiological evidence of a new infiltrate (chest X-ray or CT scan)
- Treated for a minimum of 48 hours and a maximum of 7 days with antibiotics chosen according to the French recommendations for suspected CAP (excluding azithromycin due to its prolonged half-life) and currently under antibiotic treatment for his suspected CAP (i.e. the last dose of ATB has been administered to the patient less than 24 hours ago)Patient presenting a clinical response within the last 24 hours defined by the presence of all the following criteria: o apyrexia (T°C ≤ 37.8) o heart rate < 100/min o respiratory rate < 24/min, according to the patient's usual mode of oxygenation, o arterial oxygen saturation ≥ 92%, according to the patient's usual mode of oxygenation, o systolic blood pressure ≥ 90mmHg, The last occurring of these criteria must have appeared within the last 24 hours.
- No other site of infection besides respiratory
- Affiliated to Health insurance or patients with government medical aid called AME
- Has given informed consent
- Patient understanding oral and written French, or presence of a relative who can explain and help him complete the study documents (Patient 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 medical staff belonging to the investigational site)
- Patient presenting a clinical response within the last 24 hours (up to 7 days after the start of antibiotic treatment, if planned treatment duration > 7 days) defined by the presence of all the following criteria: apyrexia (T°C ≤ 37.8), heart rate ≤ 100/min, respiratory rate < 24/min, arterial oxygen saturation ≥ 90% on room air, systolic blood pressure ≥ 90mmHg
- Negative viral respiratory testing (positive viral testing will be allowed only if bacterial documentation is confirmed by PCR or culture)
- Antibiotic treatment anticipated to be prescribed for a minimum of one additional day if the patient is not randomized into the experimental group
Exclusion Criteria
- Signs of severe CAP (abscess, massive pleural effusion, serious chronic respiratory insufficiency insufficiency with long-term oxygen therapy, ICU admission)
- Treatment of suspected CAP with azithromycin (due to its prolonged half-life)
- Concomitant steroid treatment (only for patients treated with fluoroquinolones antibiotics)
- Pregnant or breastfeeding woman
- More than 24 hours of efficacious antibiotics prior to hospital admission (except for oral fosfomycin, furadantin and pivmecillinam used in accordance with the marketing authorisations)
- Positive family history of aneurysm disease or congenital heart valve disease, patients diagnosed with pre-existing aortic aneurysm and/or dissection or heart valve disease, patients with presence of other risk factors or conditions predisposing: for both aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behcet´s disease, hypertension, rheumatoid arthritis) or additionally .for aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren’s syndrome) or additionally .for heart valve regurgitation/incompetence (only for patients treated with fluoroquinolones antibiotics)
- Life expectancy < 1 month
- Patient under legal guardianship (French “tutelle” or “curatelle”)
- Patient without fixed address
- Patient enrolled in another interventional clinical trial on antibiotic treatments
- Known immunosuppression (asplenia, neutropenia, agammaglobulinemia, bone marrow transplant, myeloma, lymphoma, known HIV and CD4<200/mm3)
- Suspected or confirmed legionellosis
- Any other infection necessitating concomitant antibiotic treatment (except if treated by oral fosfomycin, furadantin and pivmecillinam used in accordance with the marketing authorisations)
- Confirmed aspiration pneumonia or healthcare-associated pneumonia
- Contra-indications to study antibiotics
- Patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products (for patients treated with fluoroquinolones)
- History of bacterial pneumonia less than 1 month prior to study inclusion
- Bronchopulmonary diseases : cystic fibrosis; severe bronchiectasis; lung cancer under active anti-cancer treatment (patients considered in remission and having received no treatment (chemotherapy, radiotherapy, targeted therapy or immunotherapy) for at least 6 months may be included); ongoing tuberculosis or major sequelae of tuberculosis
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 15 Dec 2023 | 424 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PRISTINAMYCIN | Test | PHF00082MIG | ORAL USE | 3 | 10 | SCP188790 |
AMOXICILLIN | Test | PHF00170MIG | ORAL USE | 3 | 10 | SCP25949199 |
CEFTRIAXONE | Test | PHF00201MIG | INTRAVENOUS INFUSION OR INTRAMUSCULAR INJECTION | 2 | 10 | SCP6107511 |
LEVOFLOXACIN | Test | PHF00082MIG | ORAL USE | 1 | 10 | SCP5577983 |
AMOXICILLIN AND BETA-LACTAMASE INHIBITOR | Test | PHF00082MIG | ORAL USE | 3 | 10 | SCP2149338 |
CEFOTAXIME PANPHARMA 1 g, poudre pour solution injectableIM-IV | Test | POUDRE POUR SOLUTION INJECTABLE (IM-IV) | INTRAMUSCULAR AND INTRAVENOUS | 12 | 10 | PRD343413 |
- | Test | PHF00082MIG | ORAL USE | 9 | 10 | J01FA |