Clinical trial NCT03449459: Prevention of Acute Exacerbation in Subjects With COPD by Bacterial Decolonization in Lower Respiratory Tract
Official title: A Randomized, Parallel, Controlled, Exploratory Study: the Efficacy and Safety of Taking Probiotics, Inhaled Antibiotics or Combined Vaccination to Prevent Acute Exacerbation in Subjects With Moderate to Severe COPD and Decolonize Bacteria in Lower Respiratory Tract.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: chronic obstructive pulmonary disease
aerosol inhaled amikacin
oral probiotics
combined influenza and pneumococcal vaccine inoculation
bacterial decolonization in lower respiratory tract
Lead sponsor: Shanghai Zhongshan Hospital
Sponsor class: OTHER
Collaborators: name: The First Affiliated Hospital of Guangzhou Medical University
name: Ruijin Hospital
First posted: 2018-02-28
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants are equally assigned to four groups in parallel to accept oral probiotics, aerosol inhaled amikacin, combined vaccination or blank control for the duration of the study.
Primary purpose: PREVENTION

Brief summary: The colonization of potential pathogenic bacteria in lower respiratory tract is thought to be accountable for acute exacerbation in subjects with moderate to severe COPD. However, there is no accepted therapy for patients with COPD to remove the colonized bacteria in lower respiratory tract. Therefore, we plan to perform a multi-center, randomized, controlled trial to study the efficacy and safety of oral probiotics, aerosol inhaled amikacin or combined vaccination to decolonize bacteria in lower respiratory tract and prevent acute exacerbation of COPD.

Detailed description: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by incomplete reversible airflow limitation, small airway obstruction and alveolar structural damage. About 3 million patients die from COPD every year around the world. The prevalence of COPD in Chinese people over the age of 40 is as high as 12 % and has risen by 50 % in the past nine years.

Acute exacerbation is the leading cause of death in patients with COPD , and accounts for a majority of expenditure of COPD management. The colonization of potential pathogenic bacteria in the lower respiratory tract is an important cause of the acute exacerbation especially in patients with moderate and severe COPD.

Some clinical studies show that aerosol inhaled antibiotics is promising in reducing acute exacerbation, but these exploratory studies have some defects so that they can't back up for the clinical application of aerosol inhaled antibiotics. Amikacin, a kind of aminoglycosides, is sensitive to the common pathogens of acute exacerbation of COPD in China. Therefore it is necessary to carry out a clinical trial to verify its efficacy and safety in pathogen decolonization and prevention of acute exacerbation.

In addition, owing to bacterial resistance and insufficient antibiotics concentration in lower respiratory tract, developing new antibacterial materials is necessary. Oral probiotics is an another way to regulate the bacterial load and inflammatory response in lower respiratory tract, which has been proven to effectively prevent acute exacerbation in cystic fibrosis and childhood asthma. Likewise, airway bacterial burden and inflammation are two main mechanisms of acute exacerbation in COPD. Hence, considering its convenience and safety of oral probiotics, we perform a trial to make clinical evaluation for it.

What's more, influenza and streptococcus pneumoniae vaccines are separately recommended for patients with COPD in the Global Initiative for Chronic Obstructive Pulmonary Disease(GOLD), but there have been no studies on the effects of combined vaccination on bacterial decolonization in lower respiratory tract or on the prevention of acute exacerbation.

Effects of these above methods on the decolonization of potential pathogenic bacteria in lower respiratory tract and the inflammatory reaction are not clear. Therefore, we plan to perform a multi-center, randomized, controlled trial to study the efficacy and safety of oral probiotics, aerosol inhaled amikacin or combined vaccination to decolonize bacteria in lower respiratory tract and prevent acute exacerbation of COPD.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent must be obtained before any assessment is performed
2. Male or female adults aged 18-65 years
3. Diagnosed with COPD according to GOLD 2016 (The ratio of post-bronchodilator forced expiratory volume in 1 second (FEV1) to force vital capacity (FVC)\<0.70 with the use of salbutamol 400ug)
4. Moderate to very severe airflow limitation (post-bronchodilator FEV1 \< 80% of the predicted normal value)
5. A documented history of at least 2 COPD exacerbation in the previous 12 months that required treatment with systemic glucocorticoids and/or antibiotics, or at least 1 exacerbation in the previous 12 months that requires hospitalization.
6. In the stable stage of COPD

Exclusion Criteria:

1. Patients who have clinically significant and chronic hepatic, renal, cardiovascular and gastrointestinal abnormalities or malignant tumor (except for lung cancer) which could interfere with the assessment of the efficacy and safety of the study treatment
2. Patients who are in critical conditions
3. Patients who have had a COPD exacerbation that required treatment with antibiotics and/or systemic corticosteroids or an acute exacerbation of any other diseases in the 4 weeks prior to screening
4. Patients with concomitant pulmonary disease (including but not limited to bronchiectasis, interstitial lung disease, asthma)
5. Patients who are highly likely to be lost during the 3-month treatment and the 1-year follow up
6. Pregnant or nursing (lactating) women
7. Patients who have been vaccinated against influenza in the current year, or against Streptococcus pneumoniae within five years, or have vaccination contraindications
8. Patients who are allergic to amikacin or other aminoglycosides
9. Patients who have participated in any interventional clinical trials in the three months prior to screening
10. Patients with mental diseases or cognitive disorders which could interfere with treatment and follow-up

Primary outcomes:
measure: Time to the first COPD exacerbation
timeFrame: 15 months
Secondary outcomes:
measure: Colonization of potential pathogenic bacteria in induced sputum
timeFrame: Baseline, 3 months
measure: Microbiome in induced sputum
timeFrame: Baseline, 3 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: serum C-reactive protein(CRP) levels
timeFrame: Baseline, 3 months
measure: interleukin(IL)-6 in induced sputum
timeFrame: Baseline, 3 months
measure: IL-8 in induced sputum
timeFrame: Baseline, 3 months
measure: IL-1β in induced sputum
timeFrame: Baseline, 3 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: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
state: Guangdong
city: Shanghai
country: China
facility: Ruijin Hospital, Shanghai Jiao Tong University
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Zhongshan Hospital
state: Shanghai
Study officials:
affiliation: Shanghai Zhongshan Hospital
name: Jing Zhang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: