Clinical trial NCT05213507: Inhaled Amikacin in Preventing AECOPD
Official title: Inhaled Amikacin in Preventing Acute Exacerbation of Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD): a Multicenter Clinical Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: COPD
COPD Exacerbation
Keywords: Amikacin
Respiratory Tract Diseases
Anti-Bacterial Agents
Anti-Infective Agents
Lead sponsor: Shanghai Zhongshan Hospital
Sponsor class: OTHER
First posted: 2022-01-28
Enrollment: 136
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The underlying bacterial colonization in lower respiratory tract (LRT) of COPD patients may be related to acute exacerbation of COPD (AECOPD) and disease progression. However, there is a lack of strong evidence on the effect of LRT bacterial decolonization on COPD. This study was designed to confirm the prophylactic effect of decolonization of LRT bacteria on AECOPD and establish a novel prophylactic therapy for sable COPD.

Detailed description: Chronic Obstructive Pulmonary Disease (COPD) has become the third leading cause of death all over the world. Frequent acute exacerbations can even increase the mortality of COPD. Therefore, preventing the acute exacerbation of COPD (AECOPD) might improve prognosis.

About 74% of stable COPD patients had underlying pathogen colonization, mainly Gram-negative bacteria, in lower respiratory tract (LRT). Bacterial colonization can damage the airways of COPD patients, leading to disease progression. Further disruption of airway defense mechanisms promotes the adhesion and growth of bacteria in reverse. Eventually, a vicious circle is formed between LRT bacterial colonization and the progression of COPD. Thus, moderate to severe COPD patients were more likely to have LRT colonization, and patients with higher load of LRT bacterial colonization tended to have more frequent acute exacerbations. Decolonization of LRT bacteria may be able to control the progression of COPD and prevent AECOPD through breaking the vicious circle.

Instead of proving that long-term use of antibiotics in stable stage of COPD can prevent AECOPD, previous clinical trials have found that it can lead to the development of severe adverse reactions and the growth of LRT drug-resistant bacteria. It is probably because the main colonized LTR bacteria were not sensitive to those investigational drugs. Additionally, drugs were delivered systematically in those previous studies. Theoretically, inhalation administration can deliver the drug directly to the lungs, leading to higher drug concentrations in the lungs and less occurrence of systemic adverse reactions. Therefore, inhalation administration can well make up for the deficiencies of systematic administration. Studies on cystic fibrosis and bronchiectasis have yielded promising results of the safety and effectiveness of inhaled antibiotics for LRT bacterial decolonization. As COPD has similar manifestations to the two diseases, the promising results indicated the feasibility of decolonization of LRT bacteria to prevent AECOPD.

Previously, a multicentral clinical trial conducted by our research team preliminarily investigated whether nebulized Amikacin combined with conventional therapy could prevent AECOPD and disease progression of COPD. However, whether decolonization of LRT bacteria plays a role in these process remains unknown. The main purpose of this research is to confirm the prophylactic effect of decolonization of LRT bacteria on AECOPD and establish a novel prophylactic therapy for sable COPD.

Eligibility criteria: Inclusion Criteria:

1. Diagnosed with COPD according to GOLD 2021 (The ratio of post-bronchodilator forced expiratory volume in 1 second (FEV1) to force vital capacity (FVC) \< 0.70 with the use of 400ug salbutamol)
2. Moderate to very severe airflow limitation (post-bronchodilator FEV1 \< 80% of the predicted value with the use of 400ug salbutamol)
3. A documented history of at least twice AECOPD in the previous 12 months that required treatment with systemic glucocorticoids and/or antibiotics.
4. In the stable stage of COPD.
5. At least once positive result of amikacin sensitive Gram-negative bacteria by semi-quantitative sputum culture, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumonia, etc.
6. Written informed consent must be obtained before any assessment is performed.
7. Male or female adults aged 18-80 years.

Exclusion Criteria:

1. Patients with concomitant pulmonary disease, including bronchiectasis, interstitial lung disease, asthma, etc.
2. Patients with alpha-1 antitrypsin deficiency.
3. Patients who have had AECOPD or acute exacerbation of any other diseases that required treatment with systemic glucocorticoids and/or antibiotics in the 4 weeks prior to screening.
4. Patients with long-term oral corticosteroid use.
5. Patients with Gram-negative bacterial infection requiring systemic treatment with antibiotics against Gram-negative bacteria.
6. Patients who have participated in any interventional clinical trials in the 3 months prior to screening.
7. Patients who are allergic to amikacin or other aminoglycosides.
8. Patients who have chronic hepatic, renal and gastrointestinal abnormality or malignant tumor, except for lung cancer, which could interfere with the assessment of the efficacy and safety of the intervention.
9. Patients with mental diseases or cognitive disorders which could interfere with treatment and follow-up.
10. Patients at high risk of being lost during the 3-month treatment and the 1-year follow up.
11. Pregnant or nursing (lactating) women.
12. Patients who are in critical conditions.

Primary outcomes:
measure: Time to the first COPD acute exacerbation
timeFrame: 15 months
Secondary outcomes:
measure: Number of the COPD acute exacerbations
timeFrame: 15 months
measure: Load of LRT colonized potential pathogenic bacteria in induced sputum
timeFrame: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months
measure: Minimum inhibitory concentration (MIC) of colonized potential pathogenic bacteria in induced sputum
timeFrame: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months
measure: Microbiome in induced sputum
timeFrame: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months
measure: Forced Expiratory Volume in 1 Second
timeFrame: Baseline, 3 months, 15 months
measure: COPD Assessment Test (CAT) Score
timeFrame: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months
measure: modified Medical Research Council (mMRC) scale
timeFrame: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months
measure: Number of Patients with Adverse Events, Serious Adverse Events, and Death
timeFrame: Baseline, 3 months, 6 months, 9 months, 12 months, 15 months
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai Zhongshan Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Jingan District Central Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Fifth People's Hospital, Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Qingpu Branch of Shanghai Zhongshan Hospital
state: Shanghai
city: Shanghai
country: China
facility: Wusong Branch of Shanghai Zhongshan hospital
state: Shanghai
Study officials:
affiliation: Zhongshan hospital, Shanghai Medical College, Fudan University
name: Jing Zhang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: