Evaluation of Ciprofloxacin, Colistimethate Sodium, and Ceftazidime Pentahydrate Regimens for Early Pseudomonas aeruginosa Infection in Bronchiectasis Patients
- Trial ID
- 2023-504755-26-00
- Protocol
- ANTEIPA
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **non-inferiority** of a 14-day oral ciprofloxacin regimen combined with nebulized colistimethate sodium (colistin) for 3 months, compared to a 14-day systemic dual therapy that includes an intravenous anti-Pseudomonas aeruginosa (PA) beta-lactam, also combined with nebulized colistimethate sodium for 3 months. This comparison focuses on the 6-month PA eradication rate in patients with **bronchiectasis**. The clinical relevance of this objective lies in optimizing treatment strategies for early PA infections, potentially reducing the need for more invasive systemic therapies while maintaining effective eradication rates.
Secondary objectives include: - Comparing the two treatment arms in terms of clinical efficacy, measured by time to first exacerbation, exacerbation rate at 1 year, and quality of life assessed at 3 months and 1 year. - Evaluating microbiological efficacy by detecting PA at 3 months and 1 year, and time to first recurrence of PA. - Assessing treatment safety, including premature discontinuation due to adverse events, both serious and non-serious, and the emergence of fluoroquinolone-resistant strains of PA or other bacteria. - Analyzing treatment adherence, focusing on premature discontinuation and the proportion of unadministered doses of nebulized colistin. - Investigating the medico-economic impact, specifically the cost and incremental cost-effectiveness ratio at 1 year.
Participants
The clinical trial involves participants diagnosed with **bronchiectasis**, a condition characterized by abnormal widening of the bronchi or their branches, causing a risk of infection. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a confirmed diagnosis of bronchiectasis via thoracic CT-scan and a recent isolation of Pseudomonas aeruginosa in a respiratory sample. The trial does not include a vulnerable population. Participants must be either Pseudomonas naive or Pseudomonas free for at least one year, as evidenced by negative respiratory samples. All participants are affiliated with the French healthcare system and must be capable of understanding and signing a written informed consent form. The sponsor has not provided the total number of participants involved in the study. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the **non-inferiority** of a 14-day oral **ciprofloxacin** regimen combined with nebulized **colistimethate sodium** for 3 months, compared to a 14-day systemic dual therapy including an intravenous anti-PA beta-lactam combined with nebulized colistimethate sodium for 3 months. The primary objective is to assess the 6-month PA eradication rate in patients with **bronchiectasis**. This trial is a randomized, double-blind, controlled study, conducted over a period of approximately four years, with an estimated end date in March 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), diagnosis of bronchiectasis via thoracic CT-scan, and recent isolation of Pseudomonas aeruginosa (PA) in a respiratory sample. Following randomization, participants will receive their assigned treatment regimen. Follow-up visits will occur at regular intervals to monitor exacerbation rates, quality of life, treatment burden, and PA recurrence. The end-of-study visit will evaluate the primary and secondary endpoints, including PA eradication and recurrence, exacerbation assessment, and compliance to treatment.
The expected length of participant involvement is up to 12 months, with the treatment period lasting a maximum of 14 days for the systemic therapy and 3 months for the nebulized therapy. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or adverse events that compromise participant safety. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of three **antibacterial** agents, each with distinct pharmaceutical forms and administration routes. **Ciprofloxacin** is provided in tablet form for **oral use**. The maximum daily dose is 1.5 grams, with a total treatment period of 14 days. This medication is classified under antibacterials, specifically fluoroquinolones. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the trial.
**Colistimethate sodium** is administered as a nebuliser solution for **inhalation use**. The maximum daily dose is 6 million international units, with a treatment duration of 3 months. This medication falls under the category of other antibacterials, specifically polymyxins. The administration involves the use of a nebulizer system, specifically the PARI BOY device, which is CE marked. The target population for this medication includes patients with non-mucoviscidosis bronchopulmonary dysplasia, and it is indicated for the management of chronic pulmonary infections, focusing on eradication.
**Ceftazidime pentahydrate** is provided as a solution for **injection**. The maximum daily dose is 6 grams, with a treatment period of 14 days. This medication is classified under antibacterials for systemic use, specifically third-generation cephalosporins. The administration of this medication requires careful monitoring to ensure adherence to the dosing schedule and to assess participant compliance throughout the trial.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **PA-eradication rate** six months after the initiation of antibiotic therapy targeting Pseudomonas aeruginosa (PA) in patients with bronchiectasis. This primary endpoint will determine the effectiveness of the treatment regimens in eradicating PA from the respiratory system. Secondary endpoints will include the assessment of exacerbations at each follow-up visit, measuring the time in days from the start of antibiotic therapy to the first exacerbation. Additionally, the quality of life and treatment burden will be evaluated using validated questionnaires such as the Quality of Life-Bronchiectasis (QOL-B), Bronchiectasis Impact Measure (BIM), and Treatment Burden Questionnaire (TBQ), along with the EQ-5D-5L questionnaire for medico-economic analysis.
Further secondary endpoints will involve the detection of PA at three months and one year, the recurrence of PA in sputum or other lower respiratory tract samples, and the analysis of PA or other bacterial susceptibility to ciprofloxacin. Adverse events (AEs) and serious adverse events (SAEs) will be recorded during medical interviews and self-reported in the study booklet throughout the study. Compliance with treatment will also be monitored and documented during medical interviews and self-reports. The total cost and quality-adjusted life years (QALYs) in each group will be calculated to assess the economic impact of the treatment regimens. These efficacy parameters will be collected and analyzed at specified time points to ensure a comprehensive evaluation of the treatment's impact on patients with bronchiectasis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ≥18 years of age
- Diagnosis of bronchiectasis on thoracic CT-scan
- Isolation of PA in a respiratory sample (spontaneous or induced sputum or other lower respiratory tract sample obtained by bronchoscopy) taken no more than 3 months prior to randomisation, and if this sample was taken more than 4 weeks (28 days) prior to the planned randomisation date, a new respiratory sample must have been taken and confirmed the persistence of PA prior to randomisation.
- Patient either Pseudomonas naive (i.e., never previously isolated PA) or Pseudomonas free (i.e., infection-free for ≥1 year, proven by at least two PA negative respiratory sample during the last year)
- Patient affiliated with the French health care system
- Able to understand and sign a written informed consent form
Exclusion Criteria
- Confirmed diagnosis of cystic fibrosis
- Severe exacerbation requiring admission to an intensive care unit (e.g. for non-invasive ventilatory support, invasive mechanical ventilation, catecholamine or any other organ supportive therapy)
- Prior severe reaction, hypersensitivity reaction or other contraindication to any of the treatments in study (ciprofloxacin, beta-lactam, colistimethate sodium)
- Prior severe bronchospasm attributed to a nebulization
- Patients already receiving PA suppressive therapy with an inhaled antibiotic (long-term azithromycin therapy accepted)
- Prior PA-eradication antibiotic treatment (systemic antibiotic(s) active against PA for ≥ 14 days or nebulized anti-PA antibiotic) within the last year
- Antibiotic treatment active against PA (anti-PA beta-lactam antibiotic and/or FQ and/or aminoglycoside) for more than 3 days before randomisation
- Protected person (pregnant woman, nursing mother, person under guardianship, minor, person deprived of liberty, person unable to give consent)
- Patient who has already taken part in the ANTEIPA study
- Active cancer or haematological malignancy under active therapy
- Systemic corticosteroid therapy ≥ 20 mg/d. prednisone equivalent for a predictable duration > 4 weeks
- Non-tuberculous mycobacterial infection or positive non-tuberculous mycobacterial respiratory specimen within 1 year prior to inclusion
- Severe chronic renal failure defined by a creatinine clearance (Cockcroft or MDRD) ≤ 30 mL/min/1.73m2 or chronic haemodialysis
- Long-term oxygen therapy and/or noninvasive mechanical ventilation for chronic respiratory insufficiency (except continuous positive airway pressure for OSA) and/or forced expiratory volume at one second (FEV1) <25% of predicted value
- Patient participating to another interventional clinical trial
- Pregnancy or breastfeeding
- P. aeruginosa resistant to ciprofloxacin or ceftazidime
- Women of childbearing potential (following menarche and until becoming post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy)) who refuse to use effective contraception (hormonal or mechanical) for 3 months and/or to undergo pregnancy tests at baseline, 1 month and 3 months after baseline
- Isolation of P.Aeruginosa (PA) in a respiratory specimen (spontaneous or induced sputum or other lower respiratory tract specimen obtained by bronchoscopy) more than 3 months to 12 months prior to randomization
- Acute liver failure
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Mar 2024 | 196 |
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 |
|---|---|---|---|---|---|---|
COLISTIMETHATE SODIUM | Test | — | INHALATION USE | 6 | 3 | SUB06801MIG |
CIPROFLOXACIN | Test | — | ORAL USE | 1.5 | 14 | SUB07470MIG |
CEFTAZIDIME PENTAHYDRATE | Test | — | INJECTION | 6 | 14 | SUB01134MIG |