Effect of Vaxoral® (OM-85) on Frequency of Respiratory Tract Infections and Size of Adenoid Tissue in Preschool Children With Adenoid Hypertrophy
Phase: PHASE4
Conditions: Adenoid Hypertrophy, Adenoid Hyperplasia, Respiratory Tract Infections, Preschool Children
Sponsor: Dr. Sami Ulus Children's Hospital

 
STUDY PROTOCOL 
Effect of Vaxoral® (OM-85) on frequency of upper respiratory tract infections and size 
of adenoid tissue in preschool children with adenoid hypertrophy 
Study Product(s) 
Vaxoral® (OM-85) 
Indication 
Recurrent RTIs, adenoid hypertrophy 
Sponsor 
Dr Sami Ulus Maternity and Children Research and Training 
Hospital, Department of Pediatric Allergy and Immunology, 
Ankara, TURKEY 
 
Anticipated 
Countries 
Turkey 
Introduction 
OM-85 significantly reduces RTIs in children. This effect was 
proved by many clinical studies and meta-analyses1. A Cochrane 
meta-analysis first published in 2006 and updated recently (Del-
Rio-Navarro 2012) showed that immunostimulants (IS) could 
reduce acute RTIs (ARTIs) by almost 39% when compared to 
placebo. Among the different IS, OM-85 showed the most robust 
evidence with 4 trials of “A quality” according to the Cochrane 
grading criteria. Pooling six OM-85 studies, the Cochrane review 
reported a mean number of ARTIs reduction by -1.20 [95% CI: -
1.75, -0.66] and a percentage difference in ARTIs by -35.9% [95% 
CI: -49.46, -22.35] compared to placebo1. 
Adenoid hypertrophy (AH) is one of the most important respiratory 
disease in preschool children2. In normal conditions adenoid tissue 
enlarges up to 5 years and become smaller afterwards. But in some 
children who have recurrent URTIs, it keeps growing and this can 
be associated with complications2. AH may cause recurrent 
respiratory infections and each infection contributes to enlargement 
of adenoid tissue thus promoting a vicious cycle. Additionally 
enlarged adenoids are known to be reservoir for microbes and cause 
of recurrent or long lasting RTIs3. 
AH is associated with chronic cough, recurrent and chronic 

sinusitis, recurrent tonsillitis, recurrent otitis media with effusion, 
recurrent other respiratory problems such as, nasal obstruction and 
sleep disturbances, sleep apneas2-3. Eventually, AH causes loss of 
appetite and growth delay; it is often associated with misuse or over 
use of antibiotics and often eventually requires surgery. It decreases 
quality of life both in children and parents and it represents a burden 
not only for families but also for HCS and society due to  increased 
health cost4. 
In one study which investigated the structural and immunological 
aspects of tonsils and adenoids of 105 children (54 males and 51 
females, aged between 4 and 18 years) who were affected by 
chronic inflammatory hypertrophy of palatine tonsils and adenoids 
which had not responded to previous medical treatments and who 
underwent adenotonsillectomy because of recurrent inflammatory 
episodes with fever, it was demonstrated that deficit in the 
activation of the immune system could be represented by the small 
quantity of mRNAs for interleukin-2 (IL-2) and interleukin-4 (IL-4) 
detected in our population, suggesting a defective activation of Th1 
and Th2 lymphocytes5. 
Clinical research question: Can OM-85 reduce the recurrence of 
infections in children with AH by stimulating the immunological 
response of the host and therefore, as a consequence reduce the size 
of adenoid tissue in children with adenoid hypertrophy?  
Can this prevent further complications as surgery need?  
References: 
1. Del-Rio-Navarro BE et al. Immunostimulants for preventing 
respiratory tract infection in children (Review) Evid.-Based 
Child Health (A Cochrane Review Journal).2012;7(2): 629–717. 
2. Zautner AE. Adenotonsillar disease. Recent Pat Inflamm Alergy 
Drug Discov. 2012 May;6 (2):121-9. 
3. Battistini A, Siepe F, Marvasi R. The tonsils and adenoids as a 
site of infection and the cause of obstruction. Pediatr Med 
Chir. 1998 Jul-Aug; 20(4):237-47. 

4. Ericsson E, Lundeborg I, Hultcrantz E. Child behavior and 
quality of life before and after tonsillotomy versus tonsillectomy. 
Int J Pediatr Otorhinolaryngol. 2009 Sep;73 (9):1254-62. 
5. Passali D, et al. Structural and ımmunological characteristics of 
chronically ınflamed adenotonsillar tissue in childhood. Clinical 
and Diagnostic Laboratory Immunology 2004; 11 (6): 1154–
1157 
Rationale 
OM-85 is an oral bacterial lysate of 21 different strains of 8 species 
and sub-species of the most common respiratory tract pathogens 
that has been administered in millions of children above 1 year of 
age. OM-85 stimulates the innate immune system by improving 
alveolar macrophage activity in the BAL fluid of patients with 
airway disease, increasing dendritic cells activation and increasing  
antibodies in the lung of patients with airway diseases. OM-85 
stimulates Th1 immunity and inhibits Th2 immunity1. 
Its clinical efficacy in reducing the rate of RRTIs in children is 
supported by several well-designed and conducted clinical studies 
and it has showed a good benefit risk profile, unchanged in nature 
and frequency over more than 30 years of clinical paediatric use.  
A recent meta-analysis by Schaad et al. 20102 of 8 double-blind 
placebo-controlled trials conducted in children aged 1-12 years 
affected by recurrent infective episodes (≥ 3 RTIs in 6 months) has 
shown that the administration of OM-85 significantly reduced the 
mean number of RTIs by 35% vs placebo and that a lower 
proportion of treated patients (26.2%) experienced RRTIs. This 
effect was more evident in patients with the highest number of 
infectious in the year prior to study entry2. 
The majority of studies used a children posology of 1 daily dose 
(3.5mg) for 10 days repeated for 3 consecutive months followed by 
3 months or 9 months follow-up. In one study 2 cycles (10 days/3 
months) at a 6-months intervals were used. 
An effective and well tolerated prevention of RRTIs with OM-85 
could result not only in a positive effect on children’s quality of life 

but also in economic benefit for patients’ families and societies as 
recently reported in a pharmacoeconomic study by Zaniolo et al. 
20133 and Ravasio et al. 20154. 
Because OM-85 significantly reduces RTIs in children, it is 
expected to be able to reduce the adenoid tissue size as a 
consequence of fewer inflammatory RTIs. 
References: 
1. De Benedetto F, at al. Prevention of respiratory tract infections 
with bacterial lysate OM-85 Broncho-munal in children and 
adults: a state of the art. Multidiscip Respir Med. 2013 May 
22;8(1):33 
2. Schaad UB. OM-85 BV, an immunostimulant in pediatric 
recurrent respiratory tract infections: a systematic review. 
World J Pediatr 2010; 6(1): 5-12.  
3. Zaniolo O et al. Costo/efficacia della prevenzione di infezioni 
alle prime vie aeree mediante un estratto batterico 
immunostimolante aspecifico (OM-85). Farmaeconomia e 
percorsi terapeutici 2013; 3(6):169-184 
4. Ravasio R.  Economic analysis of the immunostimulant OM-85 
for the prevention of paediatric recurrent upper respiratory tract 
infections. Global & Regional Health Technology Assessment 
2015; 0(0): 00-00. DOI: 10.5301/GRHTA.5000200. 
Objectives 
Primary Objective: 
• 
Reduction of number of RTIs within 12 months 
Secondary Objective(s): 
• 
Reduction in duration of RTIs 
• 
Reduction of antibiotic use 
• 
Reduction of absenteeism (missed school days or missed days of 
work for parents) 
• 
Adenoid and tonsil health survey  

(described in appendix 1) 
• 
Reduction of the size of adenoid tissue (described in appendix 3)  
• 
Reduction of surgery need 
Design, incl. 
Treatment 
This is a randomised, double-blind, placebo-controlled, parallel 
group, phase IV study. 
First group will receive OM-85 (10-10-10 standard treatment 
regimen) 
Second group will receive matching placebo at the same posology 
(10-10-10). 
A second cure of treatment will be given 6 months after inclusion. 
Patients will be recruited from 01 September 2017 to 01 March 
2018. The trial will begin in September 2017 and will be completed 
in March 2019. 
By this way every patient will be studied over all seasons (1 year 
study). 
 
  
Inclusion Criteria 
• 
Children (age: 2-6 years) 
• 
Who experienced recurrent RTIs (at least 3 episodes in 6 
months before the inclusion)  
• 
Who have symptoms of AH (snoring; mouth breathing 
awake; mouth breathing asleep; nasal congestion; hyponasal 
voice; chronic nasal discharge; daytime drowsiness, or 
hyperactivity; restless sleep; sleep apnoea <15 sec; night 
cough; and poor oral intake/weight loss) based on the 
symptoms score questionnaire (described in appendix 1). 
Exclusion Criteria 
• 
Atopy 
• 
Gastroesophageal reflux 
• 
Immune deficiency 
• 
Asthma or allergic rhinitis 
• 
Premature delivery 
• 
Anatomic alterations of the respiratory tract; chronic 
respiratory 

diseases (tuberculosis and cystic fibrosis); autoimmune 
disease; liver 
• 
Kidney failure; malnutrition; cancer 
• 
Treatment with inhaled or systemic corticosteroids  within 
the previous month 
• 
Treatment with immunosuppressants, immunostimulants, 
gamma globulins, or anticonvulsive drugs within the 
previous 6 months. 
Endpoints 
Primary Endpoint: Cumulative number of RTIs over the 12 
months. 
Secondary Endpoints:  
• 
Duration in days of RTIs 
• 
Antibiotic use (n. of cycles and days) 
• 
Missed school/work days 
• 
Adenoid and tonsil survey (described in appendix 1 of the 
original protocol) 
• 
Size of adenoid tissue over the 12 months according to 
radiographic and flexible nasopharyngoscopic evaluation (described 
in appendix 3 of original protocol). 
• 
Surgery need 
• 
AEs 
Procedures 
Patients will be recruited from 01 September 2017 to 01 March 
2018. The trial will begin in 01 September 2017 and will be 
completed 01 March 2019. 
Children with the ages of 2-6 years who have recurrent RTIs and 
AH will be evaluated for the eligibility for the study. When eligible 
for the study, children's all demographic characteristics will be 
recorded (Table 1). Eligible children will be evaluated by ear-nose-
throat (ENT) specialist and flexible laryngoscopy and radiographic 
evaluation of adenoid size will be performed in order to measure the 
adenoid size. All children will be evaluated by an allergy specialist. 
Complete blood count, serum IgG, IgA, IgE, IgM will be measured. 

Skin prick test will be performed with common allergens. 
All children will be randomized into two study arms (active 
treatment and placebo). OM-85 3.5 mg capsule or placebo will be 
given according to the standard treatment schedule (10-10-10) for 
the three consecutive months. All patients will receive 2 cures of 
treatment at the beginning and 6 Months after inclusion in the study. 
Every patients will be followed-up for 12 months.   
Patients (and care giver/parents) will be given a symptom score 
form (Table 2) in order to record all nasal symptoms, signs and 
duration of RTIs, antibiotic use, days of absenteeism from school 
and from work for family members, monthly.  
All patients will be asked to come to the clinic when they have 
symptoms of RTI in order to diagnose the type of RTIs. Then they 
will be asked to complete the infection form during the acute RTIs 
(Table 3).  
Every 3 months they will fill in the Tonsil and Adenoid Health 
Status Survey (Table 4).  
Every 3 months patients will be asked to come to the clinic and all 
their records will be collected and they will be evaluated by the 
ENT specialist for the adenoid tissue size. All these parameters will 
be recorded in specific forms by the investigator (Table 5). 
Patients will be allowed to use nasal corticosteroids, antihistaminic 
drugs and flu vaccine during the study period and all these study 
medications will be recorded. 
At the end of the study (12 months), immunoglobulin levels will be 
measured to compare them with basal level.  
 

Sample Size 
A total of 68 patients will be randomized in the study in a 1:1 ratio 
to Active or  Placebo groups. 
Active group: 34 patients  
Placebo group: 34 patients 
No Sites  
Number of study centers: 1 
Study center: Dr Sami Ulus Maternity and Children Research and 
Training 
Hospital, 
Department 
of 
Pediatric 
Allergy 
and 
Immunology, Ankara, TURKEY. 
Study Coordinator and Principal Investigator:  
Serap Ozmen M.D. Associate Prof. of Pediatrics and Pediatric 
Allergy,  Training staff on Pediatric Allergy  
Other Investigators: 
Ilknur Bostanci M.D. Professor of Pediatrics & Subspecialist on 
Pediatric Allergy and Pediatric Pulmonology  
Chief of Pediatric Allergy and Immunology Department  
Vedat Tas M.D. Otolaryngologist  
Emin Cakmakci  M.D. Radiologist  
Statistical Methods 
Statistical method: 
All analyses will performed with a commercially available software 
program (SPSS Statistical Software, version 11.5; SPSS, Inc, 
Chicago,Ill). 
The Shapiro-Wilks test will use to evaluate normality of the 
distributions collected. When variables were normally distributed, 
they were expressed as means (SDs); otherwise, they will express as 
medians and interquartile ranges (25th-75th percentiles). The ᵡ2 test 
will use for categorical variables and expressed as observation 
counts (in percentages). An ANOVA (or Mann-Whitney U 
depending on the normality of data) statistics will be used to 
compare means between both treatment groups for continuous 
variables. Bonferroni multiple comparison test will use to compared 
paired intervals (0-3, 0-6 months). All P values are 2-tailed; a P 

value of less than .05 are considered statistically significant.  
Sample Size: 
In one study OM-85 group showed 3 less RTIs compared with 
placebo over 12 months period. A sample size of 54 randomized 
patients (27 per group) will provide at least 80% power to detect a 
mean difference of at least 2.0 RTIs between the two groups 
assuming a SD of 2.55 and assuming a drop-rate of 20% after 6 
months, total of  68 patients (34 per group) will recruit to the study.1 
Reference: 
1. María Dolores Gutiérrez-Tarango and Arturo Berber. Safety 
and Efficacy of Two Courses of OM-85 BV in the Prevention 
of Respiratory Tract Infections in Children During 12 Months. 
CHEST 2001; 119:1742–1748 
Planned Timelines  
Planned date first patient consented/enrolled/observed: 01 
September 2017 
Planned date last patient consented/ enrolled/ observed: 01 March 
2018 
Planned date last patient last observation/ treatment: 01 March 2019 
Planned date CSR (Clinical study report) available: June 2019 
 
 
1. 
Visit 
Randomitaz
ion of the 
patients 
2. 
Visit  
After randomization treatment 
plan  
 (OM-85 capsules or placebo 
given in the first 10 days of each 
month for 3 months) 
3. 
Visit  
Control at the end of 
3rd month of 
treatment (20 days 
after the last 
medicine/drug or 
placebo) 
 
4. 
Visit  
Control after 3 months of 
last drug or placebo intake  
and   
Given the product by the 
previous randomization 
again for 3 months 
 
5. 
Visit 
At the end of the 
second 3-month 
treatment (20 days 
after the last drug) 
6. 
Visit 
Control after 3 months 
of the last drug or 
placebo intake 
(20 days after the last 
medicine/drug or 
placebo) 
 
 
Patients will be assessed for type of respiratory infection and additional treatment by researchers (pediatric allergy specialists and/or ENT specialists) in the 
Pediatric Allergy and Immunology outpatient clinic when symptoms of respiratory tract infection is present. 

 
Parents will be asked to fill in the relevant form [Symptom Score Form] during this acute respiratory tract infection. 
 
Every 3 months, parents will be filled.QoLQ "Tonsil and Adenoid Health Status Survey".  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Appendix 1. Study Forms 
 
Table 1. Demographic charecteristics 
PATİENT FOLLOW-UP FORM 
Date 
 
Patient Number 
 
Treatment group (Randomisation code) 
 
Name Surname 
 
Birth date 
 
Gender 
 
Smoking at home 
 
Family history of asthma 
 
Family history of atopy 
 
DPT 
 
IgG 
 
IgA 
 
IgE 
 
IgM 
 
FİRST VİSİT 
RTIs in previous 12 months 
 
RTIs in previous 6 months 
 
Number of hospitalisation in previous 12 months  
 
Total days of hospitalisation in previous 12 months 
 
Total days of absenteisim from school 
 
Total days of absenteisim from work for mother 
 
Total days of absenteisim from work for father 
 
Antibiotic use in previous 12 months  
 
 
Number of box 
 
 
Total number of days 
 
Symptome score 
 

QoLQ (Score) 
 
Adenoid size 
 
 
Radiological (AC/SP ratio) 
 
 
Nasopharingoscope (perceived percent 
obstruction of the choana) 
 
 
 
 
 
Table 2. Symptomes score (will be completed for each month) 
Scores from eleven symptoms were added together to provide a total symptom score of 33. 
1- Sclafani AP, Ginsburg J, Shah MK, Dolitsky JN. Treatment of symptomatic chronic adenotonsillar hypertrophy with 
amoxicillin/ clavulanate potassium: short and long-term results. Pediatrics 1998; 101: 675-81. 
2-  Demain JG, Goetz DW. Pediatric adenoidal hypertrophy and nasal airway obstruction: reduction with aqueous nasal 
beclamethasone. Pediatrics 1995; 95:355-64. 
 
 
 
Table 3. Infection form (will be completed for each infection) 
Type of RTI 
 
Duration of RTI 
 
Antibiotic consumption (days) 
 
Days of absenteism from school  
 
Days of absenteism from work for family members 
 
 
 
 
 
 
 
Table 4. Tonsil and Adenoid Health Status Survey (It will be completed by the parents in every  
3 months) 
Symptomes 
none  
(0 point) 
rarely  
(1 point) 
frequently  
(2 points), 
constantly  
(3 points) 
Snoring 
 
 
 
 
mouth breathing awake 
 
 
 
 
mouth breathing asleep 
 
 
 
 
nasal congestion 
 
 
 
 
hyponasal voice 
 
 
 
 
chronic nasal discharge 
 
 
 
 
daytime drowsiness, or 
hyperactivitiy 
 
 
 
 
restless sleep 
 
 
 
 
sleep apnea <15 sec 
 
 
 
 
night cough 
 
 
 
 
poor oral intake/weight loss 
 
 
 
 

 
 
 
 
Table 5. Follow-up form 
Visit (3-6-9-12 months) 
Date: 
Number of RTIs in previous 3 months: 
 
 Type 
AOM 
AS 
AT 
AN 
AC 
P 

 Number 
 
 
 
 
 
 
 Duration (days) 
 
 
 
 
 
 
Antibiotic use in previous 3 months 
 
 Type 
 
 Number (box) 
 
 Duration (days) 
 
Hospitalisation: 
 
 Number 
 
 Duration (days) 
 
Symptome score 
 
QoLQ (Score) 
 
Adenoid size 
 
 Radiological (AC/SP ratio) 
 
 Nasopharingoscope (perceived percent 
obstruction of the choana) 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 2. Definition of infections: 
Acute nasopharengitis (Common cold); was defined when nasal stuffiness or drainage, sore or 
scratchy throat, sneezing, hoarseness, cough, with or without fever and headache were present which 
resolved in 7-10 days. 
Simasek M, Blandino DA. Treatment of the common cold. Am Fam Physician 2007;75: 515-20, 522. 
Sinusitis; was defined when persistent symptoms of URTI (rhinoviral illness) were present without 
improvement after 10 days or a worsening of symptoms after 5 to 7 days with purulent nasal 
discharge, nasal congestion, postnasal drip, cough, and continued unwell state with or without fever, 
irritability, lethargy and facial pain 
American Academy of Pediatrics Subcommittee on Management of Sinusitis and Committee on 
Quality Improvement. Clinical practice guideline: Management of sinusitis. Pediatrics 2001;108:798. 
 
Acute otitis; was defined when acute onset of earache with erythema and limited mobility of the 
tympanic membrane determined by pneumatic otoscopy was present. 

Tonsillitis; was defined when inflammation of one or both tonsils associated with a catarrhal exudate 
over the tonsil or the discharge of caseous or suppurative material from the tonsillar crypts was 
present 
Viral croup; was defined when hoarseness, stridor and the characteristic “croupy” or barking cough 
developed after a viral prodrom by 12 to 72 hours of low-grade fever and coryza and resolved within 
one week. 
Knutson D, Aring A. Viral Croup. Am Fam Physician 2004;69:535-40,541-2. 
Pneumonia; was defined when fever, cyanosis, and more than one of the following signs of 
respiratory distress: tachypnea, cough, nasal flaring, retractions, rales, and decreased breath sounds 
were present with abnormal chest X-ray. (5,12,13). Pneumonia was diagnosed when tachypnea 
occured in a patient younger than two years with a temperature higher than 38°C temperature. 
Children without fever or symptoms of respiratory distress didn’t have the diagnosis of pneumonia. 
Ostapchuk M, Roberts Dm, Haddy R. Community-Acquired Pneumonia in Infants and Children. Am 
Fam Physician 2004;70: 899-908. 
Respiratory infections were also considered as mild or severe according to validated published criteria. 
Mild ARTIs involved the acute nasopharyngitis (common cold), tonsillitis or viral croup. Severe ARTIs 
involved the sinusitis, acute otitis or pneumoniae. Antibiotics were prescribed in the case of tonsillitis, 
otitis, sinusitis or lower ARTI.  
Bardin PG, Fraenkel DJ, Sanderson G, Dorward M, Lau LCK, Johnston SL et al. Amplified rhinovirus 
colds in atopic subjects. Clin Exp Allergy 1994;24: 457-464. 
Appendix 3. Radiographic evaluation of adenoid size: 
 
Radiographic evaluation of adenoid size by the method of Cohen and Konak (1). Thickness (mm) of 
“Airway column” (A) and “Soft palate” (B) is measured and A/B ratio is calculated in order to evaluate 
nasopharyngial airway patency. 
Lateral neck radiographs will taken and interpreted by the method of Cohen and Konak by a blinded 
radiologis (1). According to this method, the thickness of the soft palate (SP) in its superior anterior 
part and the airway column (AC) immediately posterior to it will measured and AC/SP ratio 
was calculated. The measurement will done about 1 cm below the upper end of the soft palate in 
children > 3 years of age and half a centimetre in younger children. A radiographic example of this 
method is demonstrated in Figure 1. 
 
Degree of obstruction was graded as follows:  
AC/SP ≥1 (grade 0 or no obstruction),   

AC/SP= 0.50-0.99 (grade 1 or mild obstruction),   
AC/SP= 0.01-0.49 (grade 2 or severe obstruction),  
AC/SP= 0 (grade 3 or total obstruction). 
 
Cohen D, Konak S. The evaluation of radiographs of the nasopharynx. Clin Otolarngol 1985; 10: 73-8. 
 
Flexible nasopharyngoscope: 
Topical anesthesia will use in the form of a mixture of lidocaine/ neosynephrine spray that will applied 
by pressurized nozzle prior to endoscopic examination. The patient will be seated upright in the 
examination chair without restraint during the exam. A standard 4.0 mm flexible nasopharyngoscope 
with attached fiberoptic light will be used to perform the nasopharyngoscopy. The data will be recorded 
as a perceived percent obstruction of the choana by the adenoid pad, as seen through the endoscope. 
 
Lertsburapa K, SchroederJW, Sullivan c. Assessment of adenoid size: A comparison of lateral 
radiographic measurements, radiologist assessment, and nasal endoscopyInternational Journal of 
Pediatric Otorhinolaryngology 74 (2010) 1281–1285