Conditions: Wheezy Bronchitis Asthmatic Bronchitis Wheezing Obstruction Airway
Keywords: wheeze shortness of breath
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
This study evaluates the effect of intermittent tiotropium bromide and salbutamol as needed versus intermittent fluticasone propionate and salbutamol as needed, or solely, salbutamol as needed on episode-free days in infants and toddlers with recurrent episodes of wheeze and/or shortness of breath.

Detailed description:
Up to 30% of all children suffer from episodic wheeze or shortness of breath, i.e. asthmatic bronchitis, during the first three years of life. The condition is usually induced by viral respiratory infections, and short-acting beta-agonists are recommended as a monotherapy for symptoms unless there are at least four physician-confirmed episodes of wheeze or shortness of breath, or three episodes plus asthma risk factors. There is a current need for new therapeutic agents to treat asthmatic bronchitis in young children.

In viral-induced wheeze, increased parasympathetic nerve activity results in increased acetylcholine release from nerve endings. Tiotropium bromide, an inhaled anticholinergic agent, prevents the acetylcholine function and achieves mild bronchodilatation and decrease in mucus secretion from the submucosal glands.

The aim of the study is to find out the effect of intermittent tiotropium bromide and salbutamol as needed versus intermittent fluticasone propionate and salbutamol as needed, or solely, salbutamol as needed on episode-free days in infants and toddlers with recurrent episodes of wheeze and/or shortness of breath. Episode-free days are defined as those days during which there are no symptoms of wheeze and/or shortness of breath, no unscheduled medical visits for wheeze and/or shortness of breath, and no use of rescue or supplementary controller medications.

Arms:
arm 1: Inhaled Tiotropium Bromide 5 µg once a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled Salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath arm 2: Inhaled Fluticasone Propionate 125 µg twice a day, beginning at the onset of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and inhaled Salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath arm 3: Inhaled Salbutamol 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath

Interventions: intervention 1: Tiotropium Bromide intervention 2: Fluticasone Propionate intervention 3: Salbutamol
Intervention descriptions: intervention 1: Tiotropium Bromide 2.5 µg/dose inhaled aerosol intervention 2: Fluticasone Propionate 125 µg/dose inhaled aerosol intervention 3: Salbutamol 0.1 mg/dose inhaled aerosol

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
 
 
 
Study Title: Efficacy of Intermittent Tiotropium in Early Childhood Wheezing 
Trial number: NCT03199976 
Version: 4.2 / 1.11.2018 
Online Publication: https://doi.org/10.1542/peds.2021-055860 
 
 


 
 
2
Sponsor - Principal Investigator: 
Professor Mika J. Mäkelä 
Skin and Allergy Hospital, University of Helsinki and Helsinki University Hospital (HUH) 
P.O. Box 160, FI-00029 HUS, Helsinki, FINLAND 
Tel: +358 9 4711 
 
Trial sites and investigators: 
HUH Skin and Allergy Hospital, Meilahdentie 2, Helsinki, FINLAND 
• Mika J. Mäkelä, MD, Paediatrician and Paediatric Allergologist, Professor in Clinical 
Allergology 
HUH Jorvi Hospital, Turuntie 150, Espoo, FINLAND 
• Timo 
Klemola, 
MD, 
Paediatrician, 
Paediatric 
Allergologist 
and 
Paediatric 
Gastroenterologist 
Porvoo Hospital, Sairaalantie 1, Porvoo, FINLAND 
• Henrikka Aito, MD, Paediatrician 
Hyvinkää Hospital, Sairaalankatu 1, Hyvinkää, FINLAND 
• Outi Jauhola, MD, Paediatrician 
 
Subinvestigators: 
HUH Skin and Allergy Hospital, Meilahdentie 2, Helsinki, FINLAND 
• Anne Kotaniemi-Syrjänen, MD, Paediatrician 
• Anna S. Pelkonen, MD, Paediatrician and Paediatric Allergologist 
• Kristiina Malmström, MD, Paediatrician and Paediatric Allergologist 
• Petri Koponen, MD, Paediatrician 
• L. Pekka Malmberg, MD, Clinical Physiologist 
• Seppo Sarna, PhD, Professor in Biometrics 
HUH Children's Hospital, Stenbäckinkatu 11, Helsinki, FINLAND 
• Eero Rahiala, MD, Paediatrician 
 
Clinical laboratories: 
HUSLAB, P.O. Box 340, FI-00029 HUS, Helsinki, FINLAND 
 
Monitoring: 
Monitoring Services of Clinical Research Institute HUCH Ltd. 
Biomedicum Helsinki 1, P.O. Box 700, FI-00029 HUS, Helsinki, FINLAND 
 
 
 


 
 
3
BACKGROUND  
 
Wheezing in early childhood 
 
During the first three years of life, up to 30% of all children suffer from episodic wheeze or 
shortness of breath [Martinez et al. 1995, Skytt et al. 2012], i.e. asthmatic bronchitis, usually 
induced by viral respiratory infections. The condition causes significant burden to the affected 
children and their families, including need for acute health care visits, hospitalizations, and 
costs related to parents’ days off from work. However, early childhood wheezing is rarely 
associated with eosinophilic inflammation of the airways seen in asthma [Saglani et al. 2005], 
and only one third of these infants and toddlers with wheezing will actually develop asthma 
[Martinez et al. 1995, Skytt et al. 2012].  Because the condition is very heterogeneous, short-
acting beta-agonists are recommended as a monotherapy for symptoms unless there are at 
least four physician-confirmed episodes of wheeze or shortness of breath, or three episodes 
plus risk factors according to the modified asthma predictive index [Guilbert et al. 2004] 
criteria [Finnish Current Care Guidelines for Lower respiratory tract infections in children and 
for Asthma; http://www.kaypahoito.fi/web/english/home]. Thereon, inhaled corticosteroids 
or leukotriene modifiers are usually administered as intermittent or regular medication to 
prevent symptoms. However, these medications used to control asthma have, at its best, only 
modest effect on early childhood wheezing [Castro-Rodriguez et al. 2009]. In addition, daily 
use of inhaled corticosteroids may affect growth [Kelly et al. 2012]. Accordingly, there is a 
current need for new therapeutic agents to treat young children with recurrent troublesome 
lung symptoms. 
 
 
Effects of tiotropium in the airways 
 
In viral-induced wheeze, increased parasympathetic nerve activity results in increased 
acethylcholine release from nerve endings [Quizon et al. 2012]. Acethylcholine interacts with 
muscarinic receptors of the airways causing smooth muscle contraction, mucus secretion and 
vasodilation [Quizon et al. 2012]. Tiotropium bromide (Spiriva®) is an inhaled anticholinergic 
agent which selectively binds to muscarinic receptors of the airways [Quizon et al. 2012, 
Heredia et al. 2009] and by preventing the acetylcholine function, achieves mild 
bronchodilatation and decrease in mucus secretion from the submucosal glands [Quizon et al. 
2012, Heredia et al. 2009]. When added to an inhaled glucocorticoid, tiotropium provided 
significantly superior results in comparison with doubling the dose of inhaled glucocorticoid, 
both with regard to improvement in symptoms and lung function [Peters et al. 2010]. In 
addition, inhaled tiotropium has been shown a protective effect against methacholine-
induced bronchoconstriction in asthmatic patients with mild to moderate airways 
hyperresponsiveness in a short-term follow-up [Terzano et al. 2004]. 
 
Tiotropium may also have anti-inflammatory effect by binding to the muscarinic receptors of 
the airway epithelial and inflammatory cells [Quizon et al. 2012]. In line, adding salmeterol 
and tiotropium to fluticasone reduced exhaled nitric oxide levels significantly, although the 
dose of fluticasone was reduced to half from baseline [Fardon et al. 2007].  
 
 


 
 
4
Pharmacokinetics of tiotropium 
 
Tiotropium has a long duration of action, making once-a-day dosing possible [see Summary of 
Product 
Characteristics 
(SPC) 
for 
Spiriva 
Respimat 
2.5 
µg; 
https://www.medicines.org.uk/emc]. Approximately 40% of the inhaled dose is deposited in 
the lungs, the target organ, and the remaining amount is deposited in the gastrointestinal 
tract. However, due to electrical charge, tiotropium is poorly absorbed by the gastrointestinal 
tract, bioavailability of oral solutions being 2-3%. Of the inhaled tiotropium, 33% of the dose 
reaches the systemic circulation, and maximum tiotropium plasma concentrations are 
observed 5-7 minutes after inhalation. The drug has a plasma protein binding of 72%, and 
studies in rats have shown that tiotropium does not pass the blood-brain barrier. Following 
inhalation, the effective half-life of the drug is 27-45 hours. Majority (74% of the drug in 
healthy volunteers) of the tiotropium that reaches systemic circulation is excreted unchanged 
in urine. Consequently, tiotropium has low systemic bioavailability and few systemic side-
effects [Heredia et al. 2009, Befekadu et al. 2014, Rodrigo and Castro-Rodriguez 2015]. 
 
 
Interaction with other drugs and overdosage of tiotropium 
 
Although no formal drug interaction studies have been performed, tiotropium bromide has 
been used concomitantly with other drugs, including sympathomimetic bronchodilators, 
methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leukotriene modifiers, 
cromones, and anti-IgE treatment without clinical evidence of drug interactions [see SPC for 
Spiriva Respimat 2.5 µg; https://www.medicines.org.uk/emc]. Use of long-acting beta 
agonists or inhaled corticosteroids has not been found to alter the exposure to tiotropium. 
The co-administration of tiotropium bromide with other anticholinergic containing drugs has 
not been studied and therefore is not recommended. Overdose of tiotropium may lead to 
undesired anticholinergic effects. However, single inhaled dose of up to 340 µg tiotropium 
bromide in healthy volunteers caused no systemic anticholinergic adverse effects [see SPC for 
Spiriva Respimat 2.5 µg; https://www.medicines.org.uk/emc]. Additionally, no relevant 
adverse effects, beyond dry mouth/throat and dry nasal mucosa, were observed following 14-
day dosing of up to 40 µg tiotropium inhalation solution in healthy volunteers with the 
exception of pronounced reduction in salivary flow from day 7 onwards [see SPC for Spiriva 
Respimat 2.5 µg; https://www.medicines.org.uk/emc]. 
 
Tiotropium in preclinical studies 
According to SPC for Spiriva Respimat 2.5 ug [see https://www.medicines.org.uk/emc], in 
preclinical safety studies, many effects observed in animals - including reduced food 
consumption, inhibited body weight gain, dry mouth and nose, reduced lacrimation and 
salivation, mydriasis and increased heart rate - can be explained by the anticholinergic 
properties of tiotropium bromide. In repeated dose toxicity studies following effects were also 
observed: mild irritancy of the respiratory tract in rats and mice evinced by rhinitis and 
epithelial changes of the nasal cavity and larynx, and prostatitis along with proteinaceous 
deposits and lithiasis in the bladder in rats. In juvenile rats exposed from postnatal day 7 to 
sexual maturity, the same direct and indirect pharmacological changes were observed as in 


 
 
5
the repeat-dose toxicity studies as well as rhinitis. No systemic toxicity was noted and no 
toxicologically relevant effects on key organ development were seen. 
Harmful effects with respect to pregnancy, embryonal/foetal development, parturition or 
postnatal development could only be demonstrated at maternally toxic dose levels. 
Tiotropium bromide has not been teratogenic in rats or rabbits. In a general reproduction and 
fertility study in rats, there was no indication of any adverse effect on fertility or mating 
performance of either treated parents or their offspring at any dosage. 
The respiratory (irritation) and urogenital (prostatitis) changes and reproductive toxicity was 
observed at local or systemic exposures more than five-fold the therapeutic exposure. Studies 
on genotoxicity and carcinogenic potential revealed no special hazard for humans. 
 
 
Tiotropium in clinical studies in adults 
 
According to the records of PubMed (see www.ncbi.nlm.nih.gov/pubmed), since 1993 until 
the end of June 2015, there were 257 reports published on clinical trials with tiotropium in 
chronic obstructive pulmonary disease (COPD) and 26 reports on clinical trials with tiotropium 
in asthma. In a recent review with a meta-analysis of 13 randomized double-blind placebo-
controlled trials on tiotropium in asthma, tiotropium was considered noninferior to salmeterol 
and superior to placebo in patients with asthma inadequately controlled with inhaled 
corticosteroids with or without salmeterol [Rodrigo and Castro-Rodriguez 2015]. The 
improvement of lung function and the reduction of asthma exacerbations were considered as 
major benefits of tiotropium in patients with uncontrolled asthma [Rodrigo and Castro-
Rodriguez 2015]. There were no significant differences in incidences of serious adverse events 
between those receiving tiotropium (1.9%) and those receiving conventional therapy (2.1-
2.5%) [Rodrigo and Castro-Rodriguez 2015]. 
 
 
Tiotropium studies in children 
 
In Clinical Trial Registries (see www.clinicaltrials.gov and www.clinicaltrialsregister.eu), there 
are altogether 7 clinical trials on tiotropium as add-on therapy in asthma in children: one study 
including children aged 1 to 5 years (trial number: NCT01634113), three studies including 
children aged 6 to 11 years (trials: NCT01634139, NCT01634152, NCT01383499), and three 
studies including adolescents (trials: NCT01257230, NCT01122680, NCT01277523). Results on 
efficacy and safety issues have recently been published for asthmatic adolescents (trials 
number: NCT01122680, NCT01257230) [Vogelberg et al. 2014, Hamelmann et al. 2016], and 
children aged 6 to 11 years (trial number: NCT01383499) [Vogelberg et al. 2015], and children 
aged 1 to 5 years (trial number: NCT01634113) [Vrijlandt et al. 2018]. In addition, tiotropium 
has been investigated in children suffering from cystic fibrosis [Konstan et al. 2015, Ratjen et 
al. 2015], and in children with postinfectious bronchiolitis obliterans [Teixeira et al. 2013].  
 
 
Safety of tiotropium in clinical studies in adults 
 
The main side effect of tiotropium reported in clinical studies is dryness of the mouth in <2% 
of patients [Befekadu et al. 2014, Kerstjens et al. 2012, Kerstjens et al. 2015]. In a 48-week 


 
 
6
intervention with tiotropium in severe asthma poorly controlled with standard combination 
therapy in 912 adults, drug-related adverse events were similar in the tiotropium group (5.7%) 
and in the placebo group (4.6%). Serious adverse events were reported for 8.1% of the 
patients in the tiotropium group and 8.8% in the placebo group; drug-related cardiac events 
being rare (0.4%), including no deaths [Kerstjens et al. 2012]. In a recent report combining 
data on two 24-week trials on tiotropium in moderate asthma, serious adverse events 
occurred in 2% of the 2100 patients included [Kerstjens et al. 2015]. Incidence of serious 
adverse events was similar between the intervention groups, and none of the life-threatening 
serious adverse events occurring in four patients was regarded as drug-related, and there 
were no deaths [Kerstjens et al. 2015]. 
 
 
Efficacy and safety of tiotropium in children 
 
This far, the evidence of efficacy and safety of tiotropium in asthmatic children has been 
mainly limited on ongoing clinical trials. In a recently published report including 105 
adolescent patients with symptomatic asthma despite inhaled corticosteroids [Vogelberg et 
al. 2014], tiotropium 5 µg was regarded superior to placebo with regard to improvement of 
lung function, whereas treatment differences between tiotropium 2.5 µg and placebo, and 
tiotropium 1.25 µg and placebo did not reach statistical significance. Overall incidence of 
adverse events was balanced across treatment groups with no dose-dependence [Vogelberg 
et al. 2014]. Four serious adverse events -- none of which were life-threatening or fatal -- were 
experienced by two patients (1.3%) during the study: pre-syncope in a patient receiving 
tiotropium 5 µg, and asthma exacerbations, H1N1 influenza and mycoplasmal pneumonia 
occurred in a patient receiving tiotropium 1.25 µg. None of these serious adverse events were 
considered as to be related to the study medication. Another study on tiotropium in asthmatic 
adolescents [Hamelmann et al. 2016] reports similar rates (1.4-2.2%) of serious adverse 
events, none of which was considered drug-related. Serious undesirable effects consistent 
with anticholinergic effects including urinary retention, constipation, intestinal obstruction, or 
acute glaucoma, were reported in none of these studies. 
 
The results of the trial including children aged 6 to 11 years old with moderate asthma (trial 
number: NCT01383499) were recently published [Vogelberg et al. 2015]. It was reported that 
tiotropium as add-on therapy to medium-dose inhaled corticosteroids, with or without a 
leukotriene modifier, was efficacious in children with symptomatic asthma, and the safety and 
tolerability of tiotropium were comparable with those of placebo, with no serious adverse 
events and no events leading to discontinuation [Vogelberg et al. 2015]. 
 
The preliminary results of the tiotropium trial including asthmatic children from age of 1 year 
on (trial number: NCT01634113) [Vrijlandt et al. 2018], showed no differences in safety 
profiles between those receiving tiotropium 5 µg, those receiving tiotropium 2.5 ug, and those 
receiving placebo. No serious adverse events occurred in either of the tiotropium groups 
during the 12-week intervention period, whereas 3 of the 34 children receiving placebo 
experienced a serious adverse event (i.e. appendicitis, bronchopneumonia and exacerbation 
of asthma, viral upper respiratory infection), requiring hospital admission. Among other 
adverse events, there were no undesirable anticholinergic effects, or no differences in 
occurrence of adverse events between the intervention groups [Vrijlandt et al. 2018].  


 
 
7
 
In addition, an earlier clinical trial on a short-acting non-selective anticholinergic agent, 
ipratropium bromide, in 25 children aged 5 to 15 years with severe acute asthma, found no 
significant differences in side effects between the study groups [Reisman et al. 1988]. 
Moreover, there is a recent report on tiotropium in cystic fibrosis, including 24 children aged 
5 to 11 years, and 24 patients aged 12 years or older [Konstan et al. 2014]. Only two of these 
patients with cystic fibrosis experienced a serious adverse event, neither of which was 
considered drug-related [Konstan et al. 2014]. 
 
 
OBJECTIVE 
 
The primary AIM of the study is 
 
1) to find out the effect of intermittent tiotropium bromide and salbutamol as needed 
(TBS) versus intermittent fluticasone propionate and salbutamol as needed (FPS), or 
solely, salbutamol as needed (SA) on episode-free days in infants and toddlers with 
recurrent episodes of wheeze and/or shortness of breath. 
 
Episode-free days are defined as those days during which there are no symptoms of 
wheeze and/or shortness of breath, no unscheduled medical visits for wheeze and/or 
shortness of breath, and no use of rescue or supplementary controller medications 
[Guilbert et al. 2006]. 
 
 
The secondary AIMS of the study are 
 
to find out the effect of TBS versus FPS or SA treatment on 
1) number of unscheduled physician visits for episodes of wheeze and/or shortness of 
breath, 
2) need for bronchodilative medication, 
and to evaluate 
3) the safety of TBS versus FPS or SA treatment by paying attention to possible adverse 
events during treatment 
in infants and toddlers with recurrent episodes of wheeze and/or shortness of breath. 
 
 
STATISTICAL POWER OF THE STUDY 
 
The primary endpoint of the study is the proportion (%) of episode-free days in the TBS group, 
compared with the SA, after a 48-week intervention period. To ensure a 80% power to detect 
a 15% difference (corresponding to 1 day per week) in episode-free days between the 
treatment groups, at least 64 children per group were required, assuming a standard deviation 
of 27% for symptom-free days seen in a previous study [Bisgaard et al. 2006], and a possible 
drop-out percent of 20%. The calculation is based to reject the primary hypothesis with 5% 
significancy level. 
 


 
 
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STATISTICAL ANALYSIS PLAN 
 
Normality of the distribution of continuous variables are to be evaluated by Shapiro-Wilk 
test. The overall difference between the treatment groups is to be evaluated by using either 
analysis of variance, Kruskal-Wallis, log-rank, chi-squared, or Fisher’s exact tests. Pairwise 
analyses are to be performed by using Mann-Whitney U, chi-squared, or Fisher’s exact tests.  
Bonferroni correction is to be applied in pairwise analyses by multiplying each P-value by 3. 
Influence of confounding factors on the primary outcome is to be assessed by conducting 
the two-way factorial analysis of variance. P<0.05 is to be considered statistically significant. 
All study participants are to be included in safety analyses, and those with diary data 
available are to be included in primary analysis. All analyses are to be performed as 
intention-to-treat. IBM SPSS Statistics (version 22.0; Armonk, NY, US) is to be used for all 
analyses. 
 
 
RESEARCH METHODS AND MATERIAL, ETHICAL ISSUES 
 
Inclusion criteria: 
 
1. Children at the age of 6 to 35 months. 
2. Two to four physician-confirmed episodes of wheeze and/or shortness of breath. 
3. Parents/legal representatives with sufficient written and spoken skills in Finnish 
language 
 
 
Exclusion criteria: 
 
1. Birth before 36th week of gestation. 
2. Suspected/diagnosed chronic parenchymal lung disease or a structural airway defect, 
or a history of thoracotomy with pulmonary resection. 
3. A history of congenital or acquired heart disease, including any unstable or life-
threatening cardiac arrhythmia. 
4. Constipation with a need of regular medication, or a diagnosed/suspected structural 
defect in the gastrointestinal tract. 
5. A history of malignancy, or other significant chronic disorder, disease, or defect. 
 
 
Study population and study design 
 
195 consecutive patients will be recruited in the study. Before enrolment, respiratory 
infections should be treated, and significant thoracic anomalies should be excluded by taking 
a chest X-ray scan. Background information is questioned as follows: gestational stature, birth 
weight and length, ethnic background, allergy to food and inhaled allergens diagnosed or 
strongly suspected by a physician, respiratory symptoms, wheezing episodes confirmed by a 
physician, other significant illnesses or diagnoses, operations, medication, atopic diseases in 
family members, smoking and pets at home, moist or mould problems at home. 
 


 
 
9
The study children will be randomized into three groups. One third of the patients (SA group, 
n=65) will receive inhaled salbutamol (Ventoline Evohaler® 0.1 mg/dose), i.e. rescue 
medication, to be used 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath 
via a plastic spacer, Babyhaler®, during the whole study (i.e. SA group). One third of the 
patients (FPS group, n=65) will be randomized to receive fluticasone propionate (Flixotide 
Evohaler® 125 µg/dose), to be given 125 µg twice a day via Babyhaler®, beginning at the onset 
of an upper respiratory tract infection and continuing for 7 to 14 days as needed, and in 
addition, inhaled salbutamol (Ventoline Evohaler® 0.1 mg/dose), i.e. rescue medication, to be 
used 0.2 mg 4 to 6 times a day as needed for wheeze and shortness of breath via Babyhaler®, 
during the whole study. One third of the patients (TBS group, n=65) will be randomized to 
receive tiotropium bromide (Spiriva Respimat® 2.5 µg/dose), to be given 5 µg once a day via 
AeroChamber Plus®, beginning at the onset of an upper respiratory tract infection and 
continuing for 7 to 14 days as needed, and in addition, inhaled salbutamol (Ventoline 
Evohaler® 0.1 mg/dose), i.e. rescue medication, to be used 0.2 mg 4 to 6 times a day as needed 
for wheeze and shortness of breath via AeroChamber Plus®, during the whole study. The 
intervention will last for 48 weeks. The drugs and the plastic spacers will be supplied by the 
pharmacy of Helsinki University Hospital. 
 
The parents are taught to keep diary on wheeze and shortness of breath, and on the use of 
rescue and intervention medication. The use of medications is controlled by measuring 
weights of the inhalators at the end of the 48-week intervention. After the 48-week 
intervention period, medication for episodes of wheeze and shortness of breath will be 
planned individually and the patients are remitted back. 
 
Control phone calls by a research nurse will take place at 4, and 8 weeks from the beginning 
of the intervention. The control visits will take place at 12, 24, 36, and 48 weeks from the 
beginning of the intervention. In all cases, the first (week 0) and last (week 48) visits are to be 
organized at HUH Skin and Allergy Hospital. For those subjects living in Helsinki, the control 
visits at 12, 24, and 36 weeks will take place at HUH Skin and Allergy Hospital, and for those 
living in surrounding municipalities of Helsinki, the control visits (at 12, 24, and 36 weeks) will 
take place at a local hospital (Jorvi, Porvoo, or Hyvinkää), i.e. nearest hospital of the living 
place of the study subject. 
 
Adverse events requiring unscheduled medical attendances, as well as serious adverse events 
requiring hospital admission are to be charted. In case the study patient is diagnosed a chronic 
illness needing regular controls and physician care, the investigator will evaluate the situation 
and considers, case by case, a withdrawal of the patient from the study. However, 
hospitalization for wheezing or shortness of breath, or administration of drugs other than the 
interventional ones are not considered as indications for the discontinuation of the study, as 
these occasions are regarded as normal occurrences in early childhood wheezing illnesses. Per 
oral or inhalant corticosteroids may be used in any of the study groups as additional 
medications if they meet the criteria stated in the Finnish Current Care Guidelines for asthma 
in children [see http://www.kaypahoito.fi/web/english/home]. 
In case of the discontinuation, wheezing episodes of the study children will be treated 
according to the Finnish Current Care Guidelines for asthma in children [see 
http://www.kaypahoito.fi/web/english/home].  
 


 
 
10
Blood and urine samples  
A venous blood sample is a part of the routine diagnostic evaluation and is drawn from all 
children (5-15 ml of blood, <1% of the circulating blood volume) during the first visit, and at 
the 48-week visit. In addition, a urine sample is collected during the first visit, and at the 48-
week visit. Following parameters are to be analysed: total blood cell count, serum allergen-
specific immunoglobulin E concentrations for a mixture of inhalant and food allergens 
(Phadiatop combi®). In addition, serum 1-2 ml and urine 10 ml are taken for storage for 
analysis of immunological markers in future. 
 
 
Handling of data 
Detailed personal information on the study patients is collected by interviewing the caregivers 
during the study visits and by phone calls by study investigators and registered study nurses, 
and by collecting data from patient files in medical records. No data enabling identification of 
the patient is included in the case report forms or electronic files including the study data. IBM 
SPSS version 22.0 is used for electronic handling of the study data, including saving and 
analysing study material in an electronic form. The case report forms are saved in lockers in 
locked storage rooms. Only certain named investigators, a study monitor, and study nurses 
have access to the case report forms and the electronic study data. Whenever any changes 
are performed in the case report forms, the changes are to be verified by a signature. In case 
the changes are made in electronic data, a new file is to be created to document changes in 
the data. 
 
Discontinuation of the study leads to the intention-to-treat analysis of the collected case-
specific data.  
 
The study files and data are preserved until the study children reach school age, in order to 
give an opportunity for a final evaluation of the study patients’ respiratory state. However, 
such long-term evaluations reaching school age are out of the scope of the present research 
protocol.   
 
 
Insurances 
 
Injuries related to the actions of investigating physicians or nurses, or injuries related to the 
study investigations or measurements are to be covered with a patient insurance. 
Pharmaceutical injuries insurance covers possible unexpected study drug-related adverse 
events. 
 
 
Ethical considerations 
 
To date, repeated episodes of wheezing or other persistent troublesome lung symptoms are 
treated only with short-acting beta-2-agonists unless there are multiple physician-confirmed 
episodes and risk factors present [Finnish Current Care Guidelines for Lower respiratory tract 


 
 
11
infections in children and for Asthma; http://www.kaypahoito.fi/web/english/home]. In the 
study protocol, an earlier start of an intermittent controller therapy for those randomized to 
TBS or FPS groups, as well as intensive follow-up of symptoms for all intervention groups can 
be seen as advantages of the study. 
 
Possible unexpected drug-related adverse events can be seen as possible disadvantages of the 
study; however, occurrence of drug-related adverse events is attempted to be minimized by 
including conditions that may increase the risk for drug-related adverse events in the exclusion 
criteria. 
 
Approval of the study protocol is to be asked from the National Committee on Medical 
Research Ethics (TUKIJA), and written informed consent is to be obtained from each patient’s 
legal representative prior to randomization. The trial is to be conducted in accordance with 
the guiding principles of the Declaration of Helsinki, and in accordance with the International 
Conference on Harmonisation Good Clinical Practice guidelines and local regulations. 
 
Any substantial amendments in the study protocol are to be announced in a written form 
(Substantial Amendment Notification Form) both to the Finnish Medicines Agency (Fimea) and 
to TUKIJA. In addition, any changes among study personnel (i.e. investigators) and/or study 
sites are to be announced to Fimea and TUKIJA. 
 
 
IMPLEMENTATION: TIMETABLE, BUDGET, DISTRIBUTION OF WORK 
 
Timetable 
 
Recruitment of patients was started in April 2016. Based on the number of referrals of patients 
with wheezing episodes or other persistent troublesome lung symptoms to the hospital 
district of Helsinki and Uusimaa, it is estimated that the last patient will be recruited in the 
study at the end of year 2019. The last follow-up visit will be timed at the end of year 2020. 
Thereafter, all the study data will be saved in an electronic form, analysed, and published in 
international forums. 
 
 
Budget 
 
The budget (approximately 300 000 euros) includes the salary for a post-doctoral researcher, 
Anne Kotaniemi-Syrjänen, working in the Paediatric Unit of HUH Skin and Allergy Hospital. In 
addition, the budget includes costs of medicines for the intervention, costs of materials for 
office work, costs for laboratory measurements, costs for services like proofreading of the 
manuscripts, and consulting of a professional statistician and a computer scientist. Study visits 
at weeks 12 and 36 are regarded as additional visits not included in the follow-up schema 
presented in Finnish Current Care Guidelines for Lower respiratory tract infections in children 
and for Asthma (see http://www.kaypahoito.fi/web/english/home). In addition, for those 
children living in surrounding municipalities of Helsinki, the first and last study visits are 


 
 
12
regarded as nonconventional visits causing extra mobility for them. The costs of these two 
additional visits and the nonconventional visits are included in the study budget. The salary 
for the post-doctoral researcher and other costs are to be covered with personal grants and 
project grants from research funds and foundations until the end of year 2019. Thereafter 
costs are to be planned to be covered with grants from research foundations. 
 
 
Tasks for the study members and collaborators 
Principal Investigator, MD Mika Mäkelä, Paediatrician and Paediatric Allergologist, Professor 
in Clinical Allergology, is in charge for designing the study, follow-up of the patients, and 
reporting. 
MD Anne Kotaniemi-Syrjänen, Paediatrician, is in charge for designing the study, recruiting 
the patients, follow-up, and reporting. 
MD Anna Pelkonen, Paediatrician and Paediatric Allergologist, is in charge for designing the 
study, follow-up of the patients, and reporting. 
MD Kristiina Malmström, Paediatrician and Paediatric Allergologist, is in charge for designing 
the study, recruiting the patients, follow-up, and reporting. 
MD Pekka Malmberg, Clinical Physiologist, is in charge for designing the study, and reporting. 
MD Timo Klemola, Paediatrician, Paediatric Allergologist and Paediatric Gastroenterologist, is 
in charge for recruiting the patients, follow-up, and reporting. 
MD Henrikka Aito, Paediatrician, is in charge for recruiting the patients, follow-up, and 
reporting. 
MD Petri Koponen, Paediatrician, is in charge for recruiting the patients, follow-up, and 
reporting. 
MD Outi Jauhola, Paediatrician, is in charge for recruiting the patients, follow-up, and 
reporting. 
MD Eero Rahiala, Paediatrician, is in charge for screening the emergency department patients, 
and reporting. 
PhD Seppo Sarna, Professor in Biometrics, is in charge for the statistical evaluation of the study 
data. 
RN Anssi Koivuselkä is in charge for recruiting the patients, control phone calls, and follow-up. 
 
 
Monitoring of the study 
 
Monitoring of the study will be organized before the start of the recruitment of the study 
patients, and thereafter once a year during the recruitment and follow-up, and at the end of 
the study. Monitoring will be accomplished by Monitoring Services of Clinical Research 
Institute HUCH Ltd. 
 
 


 
 
13
LITERATURE 
 
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Castro-Rodriguez JA, Rodrigo GJ. Efficacy of inhaled corticosteroids in infants and preschoolers 
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Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term 
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2006;354:1985-97. 
 
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wheezing in the first six years of life. N Engl J Med 1995;332:133-8. 
 
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