Clinical trial NCT01968421
Conditions: Bronchiectasis With Acute Exacerbation
Keywords: OM-85, bronchiectasis, placebo, acute exacerbation
Sponsor: Chinese Academy of Medical Sciences
Start date: 2015-03-01; Completion date: 2018-11-23
Enrollment: 196 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Non-cystic fibrosis bronchiectasis is characterized by irreversible dilatation of the medium-sized bronchi as a result of airway injury due to recurrent or chronic inflammation and infection. Bronchiectasis airways are often colonized with bacterial species. Infections of the airways are thought to play an important role in bronchiectasis exacerbation. The non-specific prevention of recurrent airway infections by immunostimulating agents has gained growing scientific interest. OM-85, consisting extracts of eight kinds of bacteria important in respiratory infections, has shown the benefit for significantly reducing the incidence of exacerbations of chronic obstructive pulmonary disease (COPD). The purpose of this study is to investigate the PReventive effect of OM-85 on Bronchiectasis Exacerbation in Chinese patients (iPROBE).

This study is designed as a prospective randomised double-blind placebo-controlled multi-centred trial.

Detailed description:
Bronchiectasis is still a common chronic respiratory disease. Non-cystic fibrosis bronchiectasis is characterized by irreversible dilatation of the medium-sized bronchi as a result of airway injury due to recurrent or chronic inflammation and infection. Clinical features of bronchiectasis include chronic production of sputum often mucopurulent or purulent in nature, persistent bacterial colonization, recurrent lower respiratory tract infections. Bronchiectasis airways are often colonized with bacterial species. Infections of the airways are thought to play an important role in bronchiectasis exacerbation. Progressive lung damage in bronchiectasis results from a 'vicious cycle' of recurrent bacterial infection and a deregulated inflammatory response. The non-specific prevention of recurrent airway infections by immunostimulating agents has gained growing scientific interest. OM-85, consisting extracts of eight kinds of bacteria important in respiratory infections, has been known to support the respiratory tract resistance to the pathogens via activating pulmonary macrophages, increasing the ratio of CD4 to CD8 lymphocytes, and changing the level of a variety of cytokines in the lung. OM-85 has shown the benefit for significantly reducing the incidence of exacerbations of chronic obstructive pulmonary disease (COPD). Bronchiectasis exacerbations contribute substantially to rapid decline in lung function, reduced quality of life, and the medical costs. The purpose of this study is to investigate the PReventive effect of OM-85 on Bronchiectasis Exacerbation in Chinese patients (iPROBE).

This study is designed as a prospective randomised double-blind placebo-controlled multi-centred trial. A total of 244 patients with bronchiectasis, who have had at least one exacerbation of bronchiectasis in the previous year, will be included. The subjects will be randomly received two courses of 7mg of OM-85 or matching placebo to take one oral capsule per day for 10 days a month for 3 consecutive months at the beginning of the study, then 3 months later with the same schedule for 1 year.

We will investigate whether long-term therapy with an oral immunostimulant OM-85 can decrease exacerbations in patients with bronchiectasis over 1-year period. Besides, we will assess other outcomes including: the rate of event-based exacerbation, lung function parameters, the total scores on the St George's respiratory questionnaire and coughing, and inflammatory index. We hope that this study will provide novel information on the preventive effects of OM-85 treatment on bronchiectasis exacerbation and will address a knowledge gap for this poorly understood and under-studied disease.

Arms: arm 1: The subjects will be randomly received two courses of 7mg of OM-85 to take one oral capsule per day for 10 days a month for 3 consecutive months at the beginning of the study, then 3 months later with the same schedule for 1 year. arm 2: The subjects will be randomly received two courses of 7mg of matching placebo to take one oral capsule per day for 10 days a month for 3 consecutive months at the beginning of the study, then 3 months later with the same schedule for 1 year.
Interventions: intervention 1: OM-85 BV
Intervention descriptions: intervention 1: two courses of 7mg of OM-85 or matching placebo to take one oral capsule per day for 10 days a month for 3 consecutive months at the beginning of the study, then 3 months later with the same schedule for 1 year.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
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Title: To investigate the PRevention of OM-85 on 
Bronchiectasis Exacerbations (iPROBE) in Chinese 
patients  
PHASE IV 
 
 
 
iProbe Clinicaltrials.gov identifier NCT01968421 
 
 
 
 
February 2, 2020  
 
 
 
 


 
 
 
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PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED 
TRIAL OF BRONCHO-VAXOM FOR PREVETION OF 
BRONCHIECTASIS EXACERBATION 
 
PHASE IV 
 


 
 
 
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Confidential Material 
 
Name of Sponsor: 
 
Name of (Principal) 
Investigator: 
Jinming Gao 
Hospital/University/Institution: Peking Union Medical College Hospital 
Address: 
#1 shuaifuyuan, Dongcheng District, Beijing 
100730, China 
Phone: 
86-10-65295035 
Fax: 
86-10-65124875 
e-mail: 
gjinming@yahoo.com 
Study coordinator: 
Lun Li 
e-mail: 
meikeba@163.com 
Phone: 
86-10-69155031 
Fax: 
86-10-65124875 
CV attached: 
Yes: 
 Please see attached  
 


 
 
 
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TABLE OF CONTENTS 
1 
RATIONALE FOR THE STUDY ..................................................................................... 6 
2 
STUDY TYPE AND PHASE ............................................................................................ 8 
PHASE III .................................................................................................................................. 8 
3 
STUDY OBJECTIVES ...................................................................................................... 8 
4 
STUDY VARIABLES ....................................................................................................... 8 
4.1 
Efficacy variables............................................................................................... 8 
4.1.1 
Primary efficacy variable ................................................................... 8 
4.1.2 
Secondary efficacy variables ............................................................. 9 
4.1.3 
Other efficacy variables ..................................................................... 9 
4.2 
Exploratory variables ......................................................................................... 9 
4.3 
Safety variables .................................................................................................. 9 
4.3.1 
Primary safety variable ...................................................................... 9 
4.3.2 
Secondary safety variables ................................................................. 9 
4.3.3 
Other safety variable(s) ...................................................................... 9 
5 
STUDY DESIGN............................................................................................................. 10 
6 
STUDY DURATION PER SUBJECT ............................................................................ 10 
7 
PLANNED NUMBER OF SUBJECTS, SITES, AND STUDY MILESTONES ........... 10 
8 
ANTICIPATED REGIONS AND COUNTRIES ............................................................ 10 
9 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 10 
9.1 
Inclusion criteria .............................................................................................. 10 
9.2 
Exclusion criteria ............................................................................................. 11 
9.3 
Withdrawal criteria .......................................................................................... 11 
10 INVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................... 12 
11 STATISTICS ................................................................................................................... 12 
11.1 
Definition of analysis sets ................................................................................ 12 
11.2 
Planned efficacy analyses ................................................................................ 13 
11.2.1 
Analysis of the primary efficacy variable ........................................ 13 
11.2.2 
Other efficacy analyses .................................................................... 13 
11.3 
Planned safety and other analyses.................................................................... 14 
11.3.1 
Safety analyses ................................................................................. 14 
11.3.2 
Other analyses .................................................................................. 15 
11.4 
Planned interim analysis and data monitoring ................................................. 15 
11.5 
Determination of sample size ........................................................................... 15 
12 SCHEDULE OF STUDY ASSESSMENTS ................................................................... 16 
13 SCHEMATIC DIAGRAM .............................................................................................. 17 
CURRICULUM VITAE .............................................................. 错误！未定义书签。 


 
 
 
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LIST OF IN-TEXT TABLES 
Table 12:1. 
Schedule of study assessments ......................................................... 16 
 
 


 
 
 
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1 
RATIONALE FOR THE STUDY 
Bronchiectasis is a common, but underrecoginsed disease, in the Asia-Pacific 
and affected patients suffer from chronic sputum production and recurrent 
exacerbations. The prevalence of bronchiectasis in China is estimated as high as 
over 10% in adult patients although there lack of exact epidemiological data. 
Bronchiectasis is largely idiopathic although there is diverse aetiology. There are 
three distinct pathogenic elements, namely infection, inflammation and enzymatic 
actions. There appear to be two stages to the disease process: the initial insult that 
sets off the disease and then the ongoing, inflammatory process encompassing 
recurrent infection and progressive lung damage. Abnormalities in innate and 
adaptive immunity may predispose to bronchiectasis at both stages. Progressive 
lung damage results from a ‘vicious cycle’ of recurrent bacterial infection and a 
poorly regulated inflammatory response. Respiratory exacerbations in people with 
bronchiectasis are associated with reduced quality of life, accelerated decline in 
pulmonary function associated with physical disability, hospitalisation and even 
death. Nonenteric Gram-negative bacteria commonly infect areas of bronchiectasis, 
though Staphylococcus aureus and NTM are also commonly encountered as well 
(see below Table for a summary of the bacteriology of bronchiectasis).  
 
O’Donnel AE. CHEST 2008, 134: 815–23 


 
 
 
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Management of bronchiectasis is unsatisfactory with only very trials and there 
are no disease-modifying drugs or treatment guidelines. Immunomodulating agent 
such as low-dose macrolides have also been shown to have some efficacy although 
more data are needed to advocate their long-term usage. Antibiotic therapy is 
complex and limited in bronchiectasis, including short-term empirical treatment for 
acute exacerbation and long-term maintenance of oral, nebulized and i.v. therapy. 
Patients with bronchiectasis have some variants of IgG deficiency, often associated 
with a functional impairment of specific antibody response. Conjugate pneumococcal 
vaccine is part of the routine infant immunisation schedule in many countries. 
Current recommendations for additional pneumococcal vaccination include children 
and adults with chronic suppurative disease. However, current but limited evidence 
supports the use of 23-valent pneumococcal vaccine as routine management in 
adults with bronchiectasis. There is no data on the efficacy of pneumococcal vaccine 
on pulmonary decline. And there is neither evidence for, nor against, routine annual 
influenza vaccination for children and adults with bronchiectasis. This long-neglected 
illness should receive more research attention in order that we can have better 
understanding of its aetiology, pathogenesis and treatment. 
Immunostimulants represent a heterogeneous group of drugs which includes 
agents such as vaccines, interferons, chemical compounds and agents derived from 
bacteria. A detoxified example of this latter class is OM-85, an extract from 8 
bacteria frequently responsible for respiratory tract infections (Haemophilus 
influenzae, Klebsiella pneumoniae and ozaenae, Staphylococcus aureus, 
Streptococcus pneumoniae, pyogenes and viridans, Moraxella catarrhalis), which 
has been shown to significantly improve COPD exacerbation and other associated-
conditions in elderly patients.  
 
Our encouraging preliminary data from 25 patients with non-cystic 
fibrosis broniectasis showed that in 6 months’ administration, OM-85 
significantly decreased the numbers of acute exacerbation of bronchiectasis 
(from 4.2 2.5 to 2.8  1.3, p=0.05), prolonged the first time to exacerbation 


 
 
 
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(from 56.4  28.6 days to 93.7  43.8 days, p<0.05), and decreased suptum 
purulence and volume, improved the severity of cough and life quality. 
 
 
 
2 
STUDY TYPE AND PHASE 
STUDY TYPE:  This is a multicenter, randomized, double blind, placebo-controlled 
trial.  The study will be approved by the Institutional Review Board at each of the 
study sites.  Written informed consent will be obtained from each of the study 
participants. 
PHASE III 
3 
STUDY OBJECTIVES 
Primary 
 Broncho-vaxom could prevent against the acute exacerbations of 
bronchiectasis. 
Secondary: broncho-vaxom could:  
 prolong the first time to acute exacerbation; 
 improve  signs and symptoms and healthy life quality;  
 decrease the use of antibiotics;  
 improve lung ventilatory function (Forced expiartory volume in 1 s % predicted 
(FEV1%, FEV1/forced expiratory volume (FVC);   
 
4 
STUDY VARIABLES 
4.1 
Efficacy variables 
4.1.1 
Primary efficacy variable 
 The numbers of acute exacerbation. 


 
 
 
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4.1.2 
Secondary efficacy variables 
 The time to the first time of exacerbation (An exacerbation was defined as a 
clinical deterioration with all of the following: increasing cough, increasing 
sputum volume, worsening sputum purulence, and hempotysis). 
4.1.3 
Other efficacy variables 
 St George’s Respiratory Questionnaire (SGRQ);  
 Leicester Cough Questionnaire (LCQ) ; 
 kinds of antibiotics ; 
 FEV1, FVC, FEV1/FVC. 
 
4.2 
Laboratory variables 
 Levels of pro-inflammatory cytokines in blood and sputum (as feasible). 
 C-reactive protein in serum 
 Serum Ig level 
 Bacterial culture of sputum 
4.3 
Safety variables 
The safety and tolerability of OM-85 will be evaluated by recording adverse 
events during the study and safety laboratory parameters at trial inclusion and 
end. 
4.3.1 
Primary safety variable 
 Adverse events including severe adverse events 
4.3.2 
Secondary safety variables 
 laboratory test 
4.3.3 
Other safety variable(s) 
Not applicable 


 
 
 
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5 
STUDY DESIGN 
This is a multicenter, randomized, double blind, placebo-controlled trial in 
Chinese patients with non-cystic fibrosis bronchiectasis 
6 
STUDY DURATION PER SUBJECT 
 12 months of duration per patient and 12 visits totally. 
 Two courses of Broncho-vaxom®，(OM-85), one oral capsule of OM-85 (7mg) 
or placebo per day  for 10 days a month for 3 consecutive months at the 
beginning of the study, then 6 months later with the same schedule. 
7 
PLANNED NUMBER OF SUBJECTS, SITES, AND STUDY 
MILESTONES 
 
The target enrollment is 244 patients with non-cyctic fibrosis bronchiecatsis, and 
122 patients will be allocated to each arm. 
 Estimated start: March 2015 
 Estimated end: March 2017 
8 
ANTICIPATED REGIONS AND COUNTRIES 
 10 institutions from Beijing, Tianjin, Hangzhaou, Shenyang. All sites are with 
mainland China. 
9 
SELECTION AND WITHDRAWAL OF SUBJECTS 
9.1 
Inclusion criteria 
To be eligible to participate in this study, all of the following criteria must be met: 
1. An Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)approved written Informed Consent form is signed and dated by the subject 
or by the parent(s) or legal representative. The Informed Consent form or a 
specific Assent form, where required, will be signed and dated by minors. 
2. Subject/legal representative is considered reliable and capable of adhering to the 
protocol (eg, able to understand and complete diaries), visit schedule or 
medication intake according to the judgment of the investigator. 


 
 
 
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3. Subject with both genders is adult patients (>18 years) diagnosed with 
brochiectasis by high-resolution computer tomography (HRCT) having acute 
exacerbation, defined by increased sputum, color sputum, fever, and hemoptysis, 
when recuiting.  
9.2 
Exclusion criteria 
Subjects are not permitted to enroll in the study if any of the following criteria is met: 
1. Subject has previously participated in this study or subject has previously been 
assigned to treatment in a study of the medication under investigation in this 
study. 
2. Subject has participated in another study of an investigational medicinal product 
(IMP) or a medical device within the last 30 days or is currently participating in 
another study of an IMP or a medical device.  
3. Subject has a history of chronic alcohol or drug abuse within the last 6 months).  
4. Subject has any medical or psychiatric condition that, in the opinion of the 
investigator, could jeopardize or would compromise the subject’s ability to 
participate in this study. 
5. Subject has a known hypersensitivity to any components of the IMP or 
comparative drugs as stated in this protocol. 
6. Recent immunostimulant in last 3 months, cancer, stroke, severe cardiovascular 
disease, hepatic/kidney impairment, immuno-related diseases. 
9.3 
Withdrawal criteria 
Subjects are free to withdraw from the study at any time, without prejudice to their 
continued care. 
Subjects should be withdrawn from the study if any of the following events occurs: 
1. Subject develops an illness that would interfere with his/her continued 
participation. 
2. Subject is noncompliant with the study procedures or medications in the opinion 
of the investigator. 


 
 
 
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3. Subject takes prohibited concomitant medications as defined in this protocol. 
4. Subject withdraws his/her consent. 
5. There is confirmation of a pregnancy during the study, as evidenced by a positive 
pregnancy test. 
6. The sponsor or a regulatory agency requests withdrawal of the subject. 
Investigators should attempt to obtain information on subjects, in the case of 
withdrawal or discontinuation. For subjects considered as lost to follow-up the 
investigator should make an effort (at least 1 phone call and 1 written message to 
the subject), and document his/her effort (date and summary of the phone call and 
copy of the written message in the source documents) to complete the final 
evaluation. All results of these evaluations and observations, together with a 
narrative description of the reason(s) for removing the subject, must be recorded in 
the source documents. The case report form must document the primary reason for 
withdrawal or discontinuation. 
Investigators should contact the Medical Monitor whenever possible to discuss the 
withdrawal of a subject in advance. 
10 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
 Two courses of Broncho-vaxom®，(OM-85), one oral capsule of OM-85 (7mg) 
or placebo per day  for 10 days a month for 3 consecutive months at the 
beginning of the study, then 6 months later with the same schedule. 
11 
STATISTICS 
11.1 
Definition of analysis sets 
There are three analysis populations in the study: Full Analysis Set, Per 
Protocol Set and Safety Set. The primary endpoint will be analyzed on Full Analysis 
Set, which is the primary population and will be supported by Per Protocol Set. The 
secondary endpoint and baseline information will be analyzed on Full Analysis Set. 
Safety analyses will be performed on Safety Set.  


 
 
 
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Full Analysis Set (FAS): FAS is defined as all randomized subjects who took 
at least one dose of either trial medications and had at least one efficacy evaluation 
after treatment. 
Per Protocol Set (PPS): PPS is a subset of FAS which complied with the 
protocol sufficiently. It’s all subjects in the FAS who:  
 are in compliance with treatment, with study drug exposure more than 80%, and  
 provide the primary endpoint evaluation , and  
 have no major protocol violation 
Safety Set: All the subjects who have been randomized and taken at least one 
dose of either trial medications. 
 
11.2 
Planned efficacy analyses 
11.2.1 
Analysis of the primary efficacy variable 
The primary efficacy variable is the numbers of acute exacerbation during the 
treatment. It will be analyzed on FAS population and supported by PPS population.  
Statistical description and Statistical inference will be conducted. Mean, standard 
deviation, median, maximum and minimum will be presented as a statistical 
description by study group.  
Statistical inference consists of parameter estimation and hypothesis test. 
Comparison between two groups will be performed using student-t test or Wilcoxon 
test depending on data distribution. 2-tailed 95% confidence interval of the difference 
between groups will also be presented. 
 
11.2.2 
Other efficacy analyses 
The secondary objective will be analyzed based on full analysis set.  
The data analysis includes statistical description and statistical inference. Mean, 
standard deviation, median, maximum and minimum will be presented in each visit 
by group for continuous variables as a statistical description. For categorical 
variables, frequency and proportion will be summarized by group.  


 
 
 
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Comparison between groups will be performed. For continuous variables, 
student-t test will be performed according to the distribution of data analyzed. The 
categorical data will be analyzed by Pearson chi-square test or Fisher exact test. 
The change after and before treatment within each group will be described and 
tested by paired t test or signed- ranks test. 
The time to the first time of acute exacerbation will be analyzed as survival 
data. Kaplan-Meier curve of two groups will be presented and Log-rank test will be 
used to test the difference between two groups.  
 
11.3 
Planned safety and other analyses 
Analysis on safety will be done using safety set. 
11.3.1 
Safety analyses 
Analysis on safety will be done using safety set. All adverse events will be coded 
using the last version of MedDRA. 
 Adverse Events(AEs) and Serious Adverse Events (SAEs) 
Total frequency and incidence of AE and SAE will be described. The frequency 
of AE in each group will be tabulated by system organ class and the preferred term. 
The severity and relationship with the study will be summarized by each group. 
Adverse events related (definitely related, probably related and possibly related) 
will be described and listed separately by the two groups. Adverse events (AE) led to 
withdrawal from the study will be described and summarized separately by the two 
groups.  
 
 Laboratory tests 
Clinical significant changes of Laboratory tests will be described and 
summarized separately by the two groups.  
Clinical significant change is defined as a change from normal or no -clinical 
significant abnormal at baseline to clinical significant abnormal after dosing. 


 
 
 
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11.3.2 
Other analyses 
The baseline and demographic data will be described by group using the Full 
Analysis Set. 
11.4 
Planned interim analysis and data monitoring 
No interim analysis is planned. 
11.5 
Determination of sample size 
The sample size is determined by the numbers of acute exacerbation. 
According ton the pilot data of 25 patients, assuming the average numbers of acute 
exacerbation is 2.8 for OM-85 group and 3.5 for control group after 12 months. The 
standard deviation is supposed to 1.5 conservatively.   
Group sample sizes of 97 and 97 can achieve 90% power to detect a difference of 
0.7 between the null hypothesis that both group means are 3.5 and the alternative 
hypothesis that the mean of test group is 2.8 with known group standard deviations 
of 1.5 and 1.5 and with a significance level (alpha) of 0.05 using a two-sided two-
sample t-test. Considering the possibility of dropout, 244 subjects are needed (122 
subjects per group).  
 


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12 
SCHEDULE OF STUDY ASSESSMENTS 
Table 12:1. Schedule of study assessments 
 
Assessments  
(add day, month etc. if appropriate) 
Screening and 
Randomization 
visit 
Treatment Period 
Follow-Up/ 
Discharge 
V1-2 
V3-V11 
V12 
Day-3 and Day 
1 
V3-V11 
(days 30, 60, 90, 120, 150, 180, 210, 240, 270, 
300, 330) 
Day 360 
Written informed consent 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
Verification of inclusion/exclusion 
criteria 
X 
 
 
 
 
Withdrawal criteria 
 
X 
X 
 
 
General medical/procedures history 
X 
 
 
 
 
Habits and lifestyle 
X 
 
 
 
 
Physical examination 
X 
 
 
 
X 
Vital signs  
X 
X 
X 
X 
X 
Recording of medication and 
procedures 
 
X 
X 
X 
X 
Recording of adverse events 
X 
X 
X 
X 
X 
Study drug dispensing and return 
 
X 
X 
X 
X 


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13 
SCHEMATIC DIAGRAM 
Flow of patients through the study. 
 
 
 
 
 
Screen for recuitment 
(Bronchiectasis) 
Ineligible: 
 
Failed inclusion criterial 
 
Met exclusion criterial 
 
Refused consent 
Consent, baseline evaluation, 
Stratified randomization 
Allocated to BV group 
Allocated to control group 
Follow up at days 30, 120, 210, 300, 
180, 210, 240, 270, 300, 330, 360 
analyzed 
Lost to followup 
(reasons) 
Lost to followup 
(reasons) 


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 We will document the baseline data including the number of acute exacerbation 
in the previous year, lung function measures, sputum volume and color. On 
every visit, we will record the change in the baseline data. We will compare the 
difference between the baseline data and the data from the last visit in the two 
groups. (see the flow chart) 


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 Scientific communication plan: 
Type of scientific communication:  
Clinical Trial  
Journal: 
Respiratory Medicine                                                   not applicable 
 
Meeting/conference: 
European Respiratory Society Conference                 not applicable 
 
Anticipated dates: 
2014 
 
 Relevant literature: 
(1)  Sprenkle MD, et al. Clinical efficacy of OM-85 BV in COPD and chronic bronchitis: a systematic 
review. COPD. 2005, 2:167-75. 
(2) Solèr M, et al. Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic 
obstructive pulmonary disease. Respiration. 2007, 74: 26-32. 
(3) Collet JP, et al. Economic impact of using an immunostimulating agent to prevent severe acute 
exacerbations in patients with chronic obstructive pulmonary disease. Can Respir J. 2001, 8: 27-33.  
(4) Pasteur MC, et al. British Thoracic Society guideline for non-CF bronchiectasis. Thorax. 2010, 65: 
577.  
 
 Requested support: 
Clinical supply:  
 
No: 
            Yes: 
 
 
Estimated Quantity: 
 
Financial support: 
No: 
            Yes: 
 
 
Estimated costs for the whole 
project, itemized budget + 
requested budget support  
[ in US $ or €] 
                             € 100,000 
 
Other sources of funding 
No: 
            Yes: 
 if Yes, please specify: