REPLACE: Can Exercise Replace Inhaled Corticosteroid Treatment in Asthma? A Randomized Clinical Trial
Phase: NA
Conditions: Asthma
Sponsor: Bispebjerg Hospital

The REPLACE study 
Can exercise replace inhaled corticosteroid treatment in asthma?  
A randomized, clinical trial  
 
 
 
 
 
 
 
Study protocol for The REPLACE study 
Protocol version 3, 02 October 2017. 
Clinicaltrials.gov Trial registration identifier: NCT03290898 
 
 
 
 
 
 
 
 
 
Date: 23 December 2020 

Protocol 
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Project identification: H-17018372 
CLINICAL STUDY PROTOCOL 
 
The REPLACE study 
Can exercise replace inhaled corticosteroid treatment in asthma?  
A randomized, clinical trial  
 
Project responsible:  
Vibeke Backer1, Professor, Chief physician, MD, DMSci  
Project manager &  
 
 
Investigator: 
Anders Pitzner-Fabricius1, MD, PhD-student 
Investigator: 
Christian Dall2, PhD, PT, MSc 
Investigator: 
Morten Hostrup3, Associate Professor, PhD, Cand.Scient.  
Investigator: 
Marius Henriksen2, Professor, PhD, PT  
Investigator: 
Louise Tønnesen1, MD, PhD-student  
Sponsor: 
Respiratory Research Unit, Department of Respiratory Medicine, 
Bispebjerg University Hospital, Copenhagen, Bispebjerg Bakke 23, 
DK-2400 NV, Denmark. CVR: 29190623 
 
1: Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen 
2: Department of Physio- and Occupational Therapy, Bispebjerg-Frederiksberg Hospital, University 
of Copenhagen 
3: Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen 
 
 
 
 
 
 

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Index 
 
1: Summary 
2: Background 
3: Methods 
3.1 Design 
3.2 Recruiting asthma patients 
3.3 Patients flow and timeline of study 
3.4 Adjustment algorithm and clinical algorithm 
3.5 Randomization 
3.6 Outcomes 
3.7 Asthma patients 
 
3.8 Inclusion and exclusion criteria 
4: Intervention 
4.1 Exercise group 
4.2 Control group 
5: Data collection method 
6: Assessment of asthma control and inflammation 
6.1 Primary outcome 
6.2 Secondary outcomes 
7: Statistics and power calculation 
8: Ethics 
9: Feasibility and qualification of the research group 
10: Plans of dissemination 
11: Financial support 
12: Remuneration 
13: Availability of information for study subjects 
14: Insurance 
15: Organization and project partners 
16: Appendix  
A. Informed Consent Form  
B. Participant information sheet  

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C. Forsøgspersoners rettigheder i et sundhedsvidenskabeligt forskningsprojekt  
D. Recruitment material 
E. Protocol résumé 
F. Questionnaires: ACQ-5, mini AQLQ, Facts About You, Medical history questionnaires  
G. Project responsible: Identification, authorisation and qualification 
17:  References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 Summary 
The aim of this study is to investigate whether exercise as a supplementary treatment in asthma is of 
such a magnitude, that it is possible and safe to reduce asthma patients in inhaled corticosteroid.   
The study is a randomized, controlled parallel group, clinical trial. Outcome assessor is blinded 
throughout the first 6 months. 
2 Background 
Inflammation in asthma 
Asthma is an inflammatory disease characterized by local airway inflammation and airway 
hyperresponsiveness (AHR). However, recent research has shown, that asthma patients have 
increased systemic inflammation measured with high sensitivity C-Reactive Protein (hsCRP)1 and 
elevated pro-inflammatory cytokines such as IL-6, IL-8 and TNF-a in serum2 3 when compared to 
healthy subjects. 
Effects of exercise on asthma control and inflammation 
Physical exercise reduces low-grade inflammation in healthy individuals
4 and exercise has proven to 
attenuate inflammation in other inflammatory diseases such as diabetes, hypertension and 
cardiovascular disease.5 Exercise in asthma patients is safe and improves aerobic fitness. Studies 
shows that exercise in asthmatics reduce systemic and airway inflammation, decrease risk of exacerbation 
and improves quality of life.6 7 8 9 10 Additionally a meta-analysis evaluated the effects of exercise on 
airway inflammation in asthma and concluded that exercise might reduce the number of airway 
inflammatory cells11 but the included studies were too heterogeneous to draw any conclusions. 
The next step in the evaluation of the effects of exercise in asthma will be to investigate if the 
beneficial effects of exercise are in a magnitude that allows for down-titration of ICS without 
worsening asthma symptoms. Reduced ICS usage by means of regular exercise, will not only mean 
improved health and quality of life among the patients, but also represents an important risk 
reduction in the development of adverse effects of ICS and may reduce costs related to ICS.  
Such a study has, to our best of knowledge, not previously been conducted. 
 
 
 

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Rationale 
 Asthma patients have increased levels of systemic and local inflammation 
 Physical exercise decreases the level of systemic inflammation in healthy persons and in 
asthmatics 
 Physical exercise reduces airway inflammation and improves asthma symptom control 
 Decreased systemic inflammation is associated with reduced airway inflammation and 
better asthma control 
Hypothesis 
 Physical exercise intervention leads to an improved asthma control as measured by 
Asthma Control Questionnaire (ACQ-5) in such a magnitude that inhaled corticosteroid 
can be reduced in asthmatics. 
3 Methods 
3.1  
Design 
Randomized, parallel group, outcome assessor blinded, intervention study of 150 asthmatics 
running over 12 months. Following baseline examinations, participants will be randomized (2:1; 2 
to exercise – 1 to control) to either 6 months of supervised high intensity spinning exercise 3 times 
weekly or a control group (usual lifestyle). 
3.2 
Recruiting asthma patients 
Patients will be recruited from general practices and private pulmonary medical practices throughout 
the Copenhagen area. Asthma patients attending an Outpatient Department of Respiratory Medicine 
at any Hospitals within the Capital or Zealand region will be handed a letter of invitation to 
participate in the study.  
Moreover, advertising will be done (posters) at Universities and schools in Copenhagen, on the 
social media (e.g. Facebook), on the homepage www.forsoegsperson.dk, in newspapers and in 
magazines.  
 

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3.3  
Patients flow and timeline of study 
The recruiting and inclusion of study participants will be running. Inclusion is done during a period 
of maximum 35 days, which include a potential 28 day long run-in period, which is initiated if the 
participant’s medicine dose is changed in at enrollment. Baseline measurements are performed 1 to 
14 days prior to randomization, DEXA scan is performed within ±14 days with regards to 
randomization.  Eligible patients then undergo 6 months of intervention/control period according to 
figure 1 ("Study timeline").  
Patients will be enrolled from 1st of October 2017 until 31st of January 2019. Laboratory analyses, 
data analyses, pathology and publication will be performed throughout 2018, 2019 and 2020. 
 
Figure 1, Study timeline 
 
 
 
 
 
 
 
 

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The study consists of 8 visits; 3 pre-interventional, 3 during intervention and 2 follow-up visits.  
Table 1, clinical visit schedule 
Clinical visit schedule 
Screening 
Run-in 
Randomi-
zation 
Intervention 
Follow-up 
Visit 
100a
101a/101b*
102 
201
202
203
**
301 
302 
Time (days) 
-35 to -1  
-8 to -1  
61 
±7
122
±7
183
±7
274 
±7
365 
±7
 
 
 
 
 
 
 
 
 
Informed consent 
●
Review of inclusion and 
exclusion criteria 
● 
● 
 
 
 
 
 
 
Medical history
●
Medication review 
●
Conversion of deviceb
●
Adjustment of asthma 
medicinec 
 
● 
 
 
 
 
 
 
Questionnaires 
 
Baseline Questions 
 
ACQ 
 
miniAQLQ 
 
 
● 
● 
● 
 
 
 
● 
 
 
 
● 
 
 
● 
● 
 
 
● 
 
 
● 
● 
ICS titration 
●
●
●
●
●
Adherence 
 
Foster score 
 
Dosage counter 
 
Control inhalation 
technique 
 
 
● 
● 
● 
 
 
 
● 
● 
● 
 
 
● 
● 
● 
 
 
● 
● 
● 
 
 
● 
● 
● 
 
 
● 
● 
● 
 
Height and weight 
●
●
●
Spirometry 
●
●
●
●
●
●
Methacholined
(●)
(●)
Reversibilityd
(●)
(●)
FeNO 
●
●
●
●
●
●
Induced sputum 
●
●
Cardiopulmonary fitness 
test (VO2max) 
 
● 
 
 
 
● 
 
 
Blood test 
●
●
●
Allergy test (blood test) 
●
DEXA scane
●
●
Randomization 
●
a: may be on the same day;  
b: to dose counter;  
c: according to adjustment algorithm;  
d: Methacholine requires FEV1≥70% of predicted. If FEV1<70% of predicted, reversibility test is 
performed instead;  
e: Baseline DEXA scan is performed ±14 days after randomization. 
*Note: If inhaled medicine dose is changed in dose at visit 101a, a 28 days run-in period is required, 
and a visit 101b is performed. 
** If subject has a moderate or severe exacerbation at visit 203, an extra visit at 7 month is required. 
This visit will be identical to visit 203. 

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3.4 
Adjustment algorithm at enrollment 
Eligible subjects will at enrollment be adjusted in asthma medicine according to a pre-defined 
algorithm based on current treatment and asthma symptoms, figure 2. If dose is changed a 28 days 
run-in period is required. If using a device without dose counter, device will be converted to one 
with dose counter. If deemed necessary by judgement a medical doctor in the study team or by 
request of the participants, a device with no dose counter can be used.  
Long-acting muscarinic antagonists (LAMA) and leukotriene receptor antagonists (LTRA) will be 
discontinued. A washout period of 5 half-lives is required before subject can be randomized 
(LAMA: 10 days; LTRA: 2 days). 
 
Figure 2, adjustment algorithm at enrollment 
 
 
Clinical algorithm 
During the study period asthma treatment will be regulated according to pre-defined algorithm, 
modified from Gibson et al12. It’s based on asthma control, assessed by Juniper Asthma Control 
Questionnaires (ACQ-5)13. Cut-off points defined the patient as either well controlled (≤1.0), 
partially controlled (>1.0-1.5) or uncontrolled (>1.5), table 3. If well controlled, treatment is titrated 

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1 step down, if uncontrolled treatment is titrated 1 step up. If partially controlled, no change in 
treatment occurs, table 2. 
If ACQ score is >2.0 at 2 consecutive visits during intervention or follow up, or if ACQ score is> 
1.5 when the participant is at treatment step 5, the participant will be referred to a (blind) specialist 
assessment within 4 weeks. If the blind specialist considers that it is necessary for the participant to 
receive another treatment during the trial period, the participant will be treated as necessary and 
continue in the trial. If the participant is considered unable to complete any training intervention, 
the participant will be discontinued. Any exacerbation is treated accordingly to international 
guidelines. 
Table 2 – Clinical algorithm treatment steps 
 
Treatment
Step 1a 
SABA as required
Step 1b 
Budesonide 100µg twice per day
Step 2 
Budesonide 200µg twice per day
Step 3 
Budesonide 400µg twice per day
Step 4 
Budesonide 600µg and formoterol 12 µg twice per day
Step 5 
Budesonide 800µg and formoterol 24 µg twice per day
 
Table 3 – Algorithm for up- and down-titration of treatment during study 
 
ACQ score 
Treatment adjustment 
Uncontrolled 
>1.5 
↑1 step 
Partially controlled 
>1.0-1.5 
No change 
Well controlled 
≤1.0 
↓ 1 step 
 
3.5  
Randomization 
 
Patients will be unequal randomized 2:1 (2 to exercise: 1 to control) by a computer-based program 
in random block sizes, blinded to investigator. Stratification is done by sex, ACQ-score (≤1.75, 
assessed on a stable treatment regime) and blood eosinophilia (≥0.15), with a total number of strata 
2 x 2 x 2 = 8. Randomization is conducted by a non-investigational member of the study group. 
3.6  
Primary outcome measure: The proportion of participants at 6 months (visit 203) that have been 
down-titrated in ICS dose by at least 25%. 
 

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Secondary outcome measures:  
The proportion of participants at 12 months that have been down-titrated in ICS dose by at least 
25 % compared to baseline.  
 
Change from baseline in 
 Cumulated dose of ICS at 6 months 
 Cumulated dose of ICS at 12 months 
 Cumulated dose of LABA at 6 months 
 Cumulated dose of LABA at 12 months 
 Exacerbation rate 
 Asthma life quality evaluated by miniAQLQ 
 Airway inflammation measured by FeNO and cell count in sputum 
 Systemic inflammation (hsCRP, inflammatory cytokines, bloodEOS) 
 Airway hyperresponsiveness measured by methacholine test 
 Lung function: FEV1 and FVC 
 Cardiopulmonary fitness: Maximal oxygen consumption during an incremental bike 
ergometer test (VO2max) 
 Change in fat and muscle composition (DEXA scan)  
 
Explorative: The above-mentioned measurements, both primary and secondary, will also be carried 
out on subpopulations, stratified by blood eosinophilia at different cut-off values.  
3.7  
Asthma patients 
The diagnose of asthma is based on symptoms and at least one positive asthma test the last 5 years 
(AHR to either mannitol or methacholine, reversibility to beta2- agonist, peak flow variation or 
positive eucapnic voluntary hyperventilation test) and will be confirmed by a physician at the 
pulmonary research unit. If no exclusion criteria and all inclusion criteria but positive asthma test 
is met at visit 100, reversibility test and methacholine test is conducted as planned in V101. If 
both tests are negative, subject will be considered as screening failure. 

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All participants will fill out a questionnaire at baseline (V101) with questions concerning 
patient’s weekly activity level, smoking habits, adherence to asthma treatment and medical 
history. 
3.8  
Inclusion criteria 
 Asthma  
 18-75 years  
 ACQ ≥ 1 and ≤ 2.5  
 On a daily dose of ICS at a minimum of 400 µg budesonide or equivalent ICS for 3 months 
and with no changes in asthma medicine 4 weeks prior to enrollment 
 Untrained (no participation in vigorous exercise for more than 1 hour per week during the 
last 2 month)  
 Capable of exercising on bike 
 
Exclusion criteria 
 Unable to speak and understand Danish 
 Infection in the respiratory tract within 4 weeks prior to visit 100* 
 Asthma exacerbation within 4 weeks prior to visit 100* 
 Hospitalized for an asthma attack during the last 12 months. 
 Treatment with immunotherapy within 5 T½ of the treatment drug prior to visit 100 
 Initiation of allergen immunotherapy within 3 months prior to visit 100 or plan to begin 
therapy during study period. 
 Treatment with peroral prednisolone  
 Respiratory: other chronic pulmonary disease of clinically significance 
 Cardiovascular: Unstable ischemic heart disease, myocardial infarction within the last 
12 months, symptomatic heart failure (NYHA III-IV or EF <40%), symptomatic heart 
arrhythmia (documented with ECG), uncontrolled hypertension (>155/100) 
 Pregnancy or breastfeeding or planned pregnancy within the next 12 months.  
 Other inflammatory or metabolic diseases with the exception of rhinitis, atopy and 
well-controlled hypothyroidism treated with or without Eltroxin.  
 Vaccination less than 2 weeks prior to any visit requiring blood samples 

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 Current or former smokers with > 20 pack years 
 Subjects, who by investigators determination, will not be able to adhere to study protocol 
* If patients are excluded due to a recent infection or exacerbation, they can undergo re-screening 
after a total of 4 weeks after end of exacerbation treatment/clearing the infection. 
 
4 Intervention 
6 month of high intensity interval training. The exercise intervention will consist of spinning for 1 
hour (including a 10-minute warm up and cool down period. The 40 minutes will consist of short 
periods of high intensity intervals for 1-2 minutes above 80% of VO2max).   
4.1  
The exercise intervention 
The training consists of high-intensity interval training on spinning bikes indoor. Participants meet 
in teams of 10-12 subjects 3 times a week for a 1-hour training session at Frederiksberg hospital. At 
each training session, patients will be instructed by a bachelor of physiotherapy, sports science or a 
Bachelor of Medicine. Patients will wear heart rate monitors, which enable continuous monitoring 
of their heart rate during the spinning sessions, and the responsible spinning instructor will ensure 
patients adherence to the training protocol.  
4.2  
Control group 
The control group will not receive any intervention but should continue their previous level of 
physical activity. 
5 Data collection  
Data is collected during study visits and from the patient journal (see “Participant confidentiality”) 
During the study, if consent is given, electronic reminders (text message and email) may be sent to 
participants, and data can be collected electronically prior to study visit.  
Questionnaires are filled in on paper or on an electronic device directly into a secured electronic 
CRF, secureCRF (www.secureCRF.com; previously approved by Danish Data Protection Agency).  
All source documents in paper are entered in secureCRF. 
All source documents in paper are scanned/photographed and uploaded to secureCRF.  

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Test results (e.g. DEXA scan, spirometry, blood samples and bronchial provocation test) will be 
entered and uploaded to secureCRF.  
6 Outcome Assessment and risks 
 
 
6.1  
Primary Outcome 
Severity of symptoms is assessed with international standardized asthma control questionnaires 5-
item version (ACQ-5)1. Asthma treatment is adjusted according to pre-defined algorithm based on 
ACQ-5 score, see table 2 & 3. Baseline dose is registered as the dose after adjustment of treatment 
at enrollment. 6 months dose is registered as the dose after adjustment according to clinical 
algorithm at visit 203 (6 months).  
6.2  
Secondary Outcomes 
Respiratory questionnaires:  
International standardized questionnaires will be used regarding: 
 
Asthma Quality of Life Questionnaire (miniAQLQ)14 
Anthropometry and body composition: 
 Gender, age, height (without shoes) and bodyweight (lightly dressed). 
 DEXA scan at baseline and follow-up to assessment of changes in body composition. 
 Risk assessment: Radiation dose is low (5-10 µSv), less than 1/100 of the dose received 
from natural background radiation during one year.  
Fitness evaluation: At baseline and follow-up, all participants will undergo a standardized bicycle 
ergometer test to evaluated work capacity and maximal oxygen uptake15.  
Risk assessment: Negligible.  
Exacerbation:  
Severe exacerbation: Worsening of asthma symptoms (like shortness of breath, wheezing, cough or 
chest tightness) that requires systemic corticosteroid for at least 3 consecutive days and a need for 
hospitalization due to asthma or death do due to asthma.  

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Moderate exacerbation: occurrence of two or more of the following (1-3) and requirement for 
systemic corticosteroid for at least 3 consecutive days: 
1. Worsening of at least one asthma symptom (shortness of breath, wheezing, cough, or chest 
tightness) for at least 2 consecutive days 
2. Increased use of rescue inhaled bronchodilators defined by: 
a. >50% increase in SABA use and >8 puffs on 2 out of 3 consecutive days compared 
to baseline  
OR 
b. Night time awakenings requiring SABA use on at least 2 out of 3 consecutive nights 
3. >decrease 20% in FEV1 from baseline 
Mild exacerbation: The occurrence of at least one of the following without requirement of systemic 
corticosteroid or hospitalization: 
1. Worsening of at least one asthma symptom (shortness of breath, wheezing, cough or chest 
tightness)  
2. Increased use of rescue inhaled bronchodilators  
3. >decrease 20% in FEV1 from baseline 
 
Pulmonary function test:  
Spirometry including test for reversibility for short-acting beta-2-agonist is performed with 
EasyOneTM without nasal clamp in accordance with international guidelines of standardized 
spirometry16. The full in- and expiratory flow is recorded.  
Risk assessment: Negligible. Standard procedure in pulmonary diagnostics. 
Airway hyperresponsiveness  
 Methacholine challenge test:  
Performed as a dose-response test ad modum Yan17. Maximum cumulated dose is 
7,368µmol. A positive test is defined as a reduction of > 20% in FEV1 compared to baseline. 
Subjects with a pre-bronchodilated FEV1 < 70% will not have the test performed. 
Risk assessment: Low. Cough and shortness of breath mimicking a mild asthma attack. 
Standard procedure in pulmonary diagnostics. 
 Reversibility test for short-acting beta-2:  
A pulmonary function test in accordance with international standards as described above is 

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initially performed. Following the pulmonary function test, a standard dose of short-acting 
beta-2-agonist (400µg or 1mg terbutaline) is administered and another pulmonary test is 
performed.  
Risk assessment: Negligible. Salbutamol and terbutaline is known to cause mild side effects 
in the form of palpitations and unrest up to 30 minutes after administration. The test as a 
whole is without risk and a standard procedure in pulmonary diagnostics. 
Airway inflammation:  
 Sputum sample: Performed after provocation with nebulized saline. Collected with the aim 
of differential count and markers of inflammation. 
0.5-1ml will be collected at baseline and after 6 months (total of maximum 2 ml per 
participant) to analyse specific cytokines with relevance to asthma and inflammation, e.g. 
TNF alfa and IL-6. 
The sputum will be frozen at -80 degree and stored in a research biobank. The purpose of 
the research biobank is to store the biologic material under safe and controlled conditions 
until a full analysis of the collected material is possible. This procedure is chosen of 
economical and practical causes. The material will be pseudo anonymised in the laboratory 
at the Respiratory Research Unit, Bispebjerg Hospital, which complies with the regulations 
from the Danish Data Protection Agency.  
The material will be stored until analysis (projected at the end of year 2020 but maximally 5 
years) and destroyed after analysis.  
Risk assessment: Low. Cough, throat irritation and mild shortness of breath mimicking a 
mild asthma attack. 
 Fraction of exhaled nitrogen (FeNO): Measurement of fractional exhaled nitrogen oxide 
(FeNO). The subject inhales air without NO, followed by a 10-second exhalation. The 
concentration (parts per billion) of NO is measured. 
Risk assessment: Negligible. Standard procedure in pulmonary diagnostics. 
Markers of systemic inflammation: 
 Standard blood sample: 
Blood samples will be drawn from vv. cubiti with analysis of leukocytes incl. differential 
count, hemoglobin, thrombocytes, high-sensitivity CRP, creatinine, bilirubin, ASAT, 
albumin, blood sugar, Na+, K+, IgE and RAST test for standard allergens (birch (betula), 

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grass (phl. Praetense) mugwort, horse, dog, cat (fel d), house-dust mites (Der p1. and Der 
f2) and mold (alternaria, cladosporium and aspergillus fumigatus)). In total 75 mL blood is 
collected in total (3 visits of 25 ml). The analyses are done by central laboratory at 
Bispebjerg-Frederiksberg and are destroyed upon analyses; no samples are stored for later 
analyses. 
 Plasma and serum concentrations of inflammatory markers 
7 ml EDTA plasma and 7 ml serum will be collected at baseline, after 6 months and at 12 
months (3 visits x 7ml x 2 = 42 ml per participant) to analyse specific cytokines with 
relevance to asthma and inflammation, e.g. TNF alfa, IL-6 and IL-8.  
The EDTA plasma and serum will be frozen at -80 degree and stored in a research biobank. 
Please see “sputum sample” for further details regarding biobank ad storage procedures. The 
material will be stored until analysis (projected at the end of year 2020 but maximally 5 
years) and destroyed after analysis.  
Risk assessment: Negligible. Pain at puncture site, minor risk of superficial hematoma. Standard 
procedure in general diagnostics. 
Blinding assessment 
At the end of each study visit, assessor is asked whether they think that the participator is in the training 
or control group. 
7 Statistics and power calculation 
Data will be analysed using the statistical software program SPSS 23.0 (SPSS Inc., Illinois, USA). 
Sample size considerations: We assume that at 6 months 10% in the control group (usual lifestyle) 
will be down-titrated by spontaneous (or via self-management) changes in ACQ score and that 35% 
of patients in the exercise group will be down-titrated. For a comparison of two independent 
binomial proportions using Pearson's Chi-square statistic with a Chi-square approximation with a 
two-sided significance level of 0.05, a total sample size of 150 assuming an allocation ratio of 1 to 2 
has an approximate power of 0.941 when the proportions are 0.1 and 0.35. This corresponds to a 
number needed to treat (NNT) of 4 patients. 
 Even if NNT is 5, a sample of 150 patients (ITT) will still have sufficient power (0.82) to 
detect absolute difference in proportion of patients acquiring successful down-titration of 
20% (30% in exercise group vs. 10% in usual lifestyle). 

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 Should we not meet the a priori sample size, even a sample size of 102 will yield sufficient 
power to detect a difference corresponding to a NNT of 4 patients. 
 
 
8 Ethical considerations 
Participant withdrawal 
A participant may withdraw from the study at any time without this impacting on any future 
investigations and/or treatments at the site, by the investigators in this study or by other staff 
associated with the study. 
The investigator may discontinue any participant's participation for any reason, including an AE, 
safety concerns, or failure to comply with the protocol. 
Participants will be discontinued from the study immediately if any of the following occur: 
 Death. 
 Other significant illness. 
 Failure to adhere to the protocol. 
It is important to avoid any loss to follow-up participants for the efficacy assessment and 
meaningful analysis of the study. 
General considerations 
All potential trial participants are informed, both orally and in writing, about the purpose of this 
trial, its process and potential risks, as well as costs and benefits of participation. In addition, the 
Figure 3, power and sample size 
 

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leaflet 'Rettigheder som forsøgsperson i et sundhedsvidenskabeligt forskningsprojekt' will be 
handed out. All participants are informed of their rights to withdraw from the study at any time 
without this impacting on any future investigations and/or treatments at any site or by some of the 
members of the study group. After the information is delivered, read and understood, voluntary 
informed consent is given by the participant by signing a consent form before study participation 
can take place. 
It is the investigators opinion that the knowledge and potential individual benefit gained by 
participation in this study is commensurate with the efforts and difficulties associated with 
participation. Below are specific research ethics considerations related to information, consent, 
interventions, and outcome assessments. 
Oral information 
When a potential participant contacts the study, an appointment for an information interview is 
made. It will be stressed that the investigator is asking the participant to consider participation in the 
study, and that the potential trial participant has the right to bring a companion to the information 
interview.  
The oral information is based on the written information and will be given in a language easily 
understood without technical or value-laden terms. The information will be given in a considerate 
way that is tailored to each potential trial participants. The aim is that the conversation takes place 
without interference. It is the responsibility of the interviewer to ensure that the potential trial 
participant has understood the information. The information interview is performed by the 
investigator or in his absence by a designated delegate. Guidelines for the oral information are 
given in Appendix B. 
Informed consent 
Consent to participation in the trial is given on the basis of the written and oral information. 
An informed consent form (ICF; Appendix A) has been prepared. The form must be signed and 
dated by the participants prior to participation in the trial. A copy of the form is provided to the 
participants. The investigator or his designated delegates can receive the signed consent form. Prior 
to consent, it must be ensured that a potential participant has been given 24 hours to consider his or 
her participation. 

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The source documentation and CRFs will document for each participant that informed consent was 
obtained prior to participation in the study. The signed ICF must remain in each participant’s study 
file and must be available for verification by study monitors at any time. 
Research ethics approval 
This protocol, the informed consent form, written patient information and relevant supporting 
information must be submitted to the ethical committee, by the Sponsor, prior to study initiation. 
The study will be conducted in accordance with Danish law, the Helsinki declaration, and local 
research ethics committee requirements. 
The Sponsor is responsible for keeping the ethical committee informed of amendments or changes 
to the protocol, and the progress of the study, as appropriate. 
Notification to the Danish Data Protection Agency 
Because the study is carried out at hospital departments, it is regarded as "public" in accordance 
with the Data Protection Agency guidance. The study has been notified to the Data Protection 
Agency via the Capital Region of Copenhagen’s umbrella agreement with the Data Protection 
Agency. The study has been approved by the Data Protection Agency (ID: BFH-2017-067) 
Use of information from patient journal 
By signing informed consent participators grants investigators access to obtain necessary 
information from the patient journal regarding your health with relevance to the study or as a part of 
an investigation by relevant authorities regulatory control of the study. 
Participation will also include access to information regarding prescribed prescriptions and 
redeemed prescriptions as a part of your medication review and assessment of adherence to 
treatment.  
Participant confidentiality  
This study will be conducted under full adherence to the act on processing of personal data in 
current Danish legislation (lov om behandling af personoplysninger).  
Participant medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. 

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With the participant’s permission, medical information may be shared with his or her personal 
physician or with other medical personnel responsible for the participant’s welfare. 
If the data from this study are published, the presentation format will not include names, 
recognizable photos, personal information or other data which compromises the anonymity of 
participating participants. 
Retention of records 
Danish regulations require that the records and documents pertaining to this study must be retained 
by the Investigator for 5 years after completion of the study. 
Records to be retained include, but are not limited to, CRFs, consent forms, source documentation, 
test results, and regulatory documents. 
 
9 Feasibility and qualifications of the research group 
At Bispebjerg Respiratory Research Unit we have over the last two years conducted a large 
randomized controlled trial about the effects of diet and exercise in asthma including a total of 149 
asthma patients. The trial was conducted in a successful collaboration with researchers and staff 
from the Department of Nutrition, Exercise and Sports, Faculty of Science, University of 
Copenhagen. Therefore, training facilities and equipment have already been established and the 
planned exercise intervention has been proven to be feasible and safe. Moreover, at Bispebjerg 
Respiratory Research Unit we have a solid experience in conducting research within the field of 
asthma and exercise, and we have all necessary equipment available.   
Our recent study has shown that high-intensity interval training is both feasible and safe in 
sedentary non-obese asthmatics6. 
 
10 Plans of dissemination 
The study will be registered on www.clinicaltrials.gov. Results both negative, neutral and positive 
will be presented at congresses and in national and international peer-reviewed journals.  
 
11 Financial support 
This study is initiated and conceived by the Bispebjerg Respiratory Research Unit at Bispebjerg-
Frederiksberg Hospital. The project is supported financially by Bispebjerg Respiratory Research 
Unit. The salary of Vibeke Backer and Morten Hostrup is internally funded. Marius Henriksen’s 

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salary is partly guaranteed via a grant from the Oak Foundation to the Parker Institute at 
Bispebjerg-Frederiksberg Hospital. 
The project has received funding from Bispebjerg Hospital (DKK 250.000), Bispebjerg Hospital 
Scientific Scholarship Fund (DKK 80.000), Lungeforeningen (DKK 90.000), Per Henriksens Fond 
(DKK 300.000) and Aase og Ejnar Danielsens Fond (DKK 150.000). Funding is allocated to both 
VIP and TAP salary as well as diagnostic procedures and equipment.  
The project managers have no economical or commercial interests in the study results, be they 
positive or negative. 
The project is not fully funded yet. The project manager will continue to apply for financial support 
from private and public foundations during the study period and if grants are given the Ethical 
Committee as well as all participating patients will be informed. 
12 Remuneration 
Study participants will not receive any financial support.  
13 Availability of information for study subjects 
If requested, participators will be informed of their test results at any time during the study period. 
Contact information is found in the information letter. 
14 Insurance 
 
The participants are insured by the Danish Patient Insurance Association. Financing and insurance 
issues are addressed in the written information material. 
15 Organization and project partners 
 Prof. Vibeke Backer, Dept. of Resp. Med., BBH. is the project responsible and 
supervisor for PhD student Anders Pitzner-Fabricius. 
 MD, PhD student, Anders Pitzner-Fabricius, Dept. of Resp. Med., BBH is the project 
manager and investigator.  
 Assistant professor, PhD, Cand.scient. Morten Nielsen will assist in planning the 
exercise protocol and assist on a day-to-day basis in performing the bicycle ergometer 
work capacity tests. 
 PT, PhD, Christian Have Dall, Dept. of Physio- and Occupational Therapy, BFH, is 
responsible for supervising the physical exercise intervention and the development of 

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standard operation procedure for the bicycle ergometer work capacity test. 
Furthermore assisting on writing the protocol. 
 Prof. Marius Henriksen, Dept. of Physio- and Occupational Therapy, BFH, is 
supervisor for PhD student Anders Pitzner-Fabricius. 
 Medical students, Dept. of Resp. Med, BBH, will assist on carrying out visits: 
screening, run-in, intervention and follow-up (V100-V302). 
 Physiotherapeutic students, Department of Respiratory Medicine, BBH or Department 
of Physio- and Occupational therapy, BFH, will assist on carrying out exercise 
intervention. 
16 Appendix  
A. Informed Consent Form  
B. Participant information sheet  
C. Forsøgspersoners rettigheder i et sundhedsvidenskabeligt forskningsprojekt  
D. Recruitment material 
E. Protocol résumé 
F. Questionnaires: ACQ-5, mini AQLQ, Facts About You, Medical history questionnaires  
G. Project responsible: Identification, authorisation and qualification 
17 References 
 
1 Fujita M, Ueki S, Ito W, Chiba T, Takeda M, Saito N, Kayaba H, Chihara J. C-reactive protein 
levels in serum of asthmatic patients. Ann Allergy Asthma Immunol. 2007;99(1):48-53 
2 Yokoyama A, Kohno N, Fujino S, Hamada H, Inoue Y, Fujioka S, Ishida S, Hiwada K. 
Circulating interleukin-6 levels in patients with bronchial asthma. Am J Respir Crit Care Med. 
1995;151(5):1354-8. 
3 Silvestri M, Bontempelli M, Giacomelli M, et al. High serum levels of tumor necrosis factor-
α and interleukin-8 in severe asthma: markers of systemic inflammation. Clin Exp Allergy. 
2006;36(11):1373-81. 
4 Mather N, Pedersen BK. Exercise as a Mean to Control Low-Grade Systemic Inflammation. 
Mediators of Inflammation. 2008;109502 
5 Handschin C, Spiegelman BM. The role of exercise and PGC1 alpha in inflammation and chronic 
disease. Nature 2008;454:463-9. 

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6 Toennesen LL, Soerensen ED, Hostrup M Porsbjerg C, Bangsbo J and Backer V. Feasibility of 
high-intensity training in asthma – lessons from the EFFORT Asthma study. Not yet published. 
7 França-Pinto, A., Mendes, F. A. R., de Carvalho-Pinto, R. M., Agondi, R. C., Cukier, A., 
Stelmach, R., et al. (2015). Aerobic training decreases bronchial hyperresponsiveness and systemic 
inflammation in patients with moderate or severe asthma: a randomised controlled trial. Thorax, 
70(8), 732–739 
8 Mendes, F. A. R., Almeida, F. M., Cukier, A., Stelmach, R., Jacob-Filho, W., Martins, M. A., & 
Carvalho, C. R. F. (2011). Effects of aerobic training on airway inflammation in asthmatic patients. 
Medicine and Science in Sports and Exercise, 43(2), 197–203.  
9 Meyer, A., Günther, S., Volmer, T., Taube, K., & Baumann, H. J. (2015). A 12-month, moderate-
intensity exercise training program improves fitness and quality of life in adults with asthma: a 
controlled trial. BMC Pulmonary Medicine, 15(1).  
10 Chandratilleke MG, Carson KV, Picot J, Brinn MP, Esterman AJ, Smith BJ. Physical training for 
asthma. Cochrane Database of Systematic Reviews 2012, Issue 5. 
11 Pakhale S, Luks V, Burkett A, Turner L. Effect of physical training on airway inflammation in 
bronchial asthma: a systematic review. BMC Pulm Med. 2014;13:38. 
12 Heather Powell, Vanessa E Murphy, D Robin Taylor, Michael J Hensley, Kirsten McCaff ery, 
Warwick Giles, Vicki L Clifton, Peter G Gibson. Management of asthma in pregnancy guided by 
measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet 
2011; 378: 983–90 
13 Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying 'well-controlled' and 'not well- 
controlled' asthma using the Asthma Control Questionnaire. Respir.Med. 2006;100(4):616-21 
14 Pinnock H, Sheikh A, Juniper EF. Evaluation of an intervention to improve successful completion 
of the Mini-AQLQ: comparison of postal and supervised completion. Prim.Care Respir J 
2004;13(1):36-41. 
15 Guazzi M, Arena R, Halle M, Piepoli MF, Myers J, Lavie CJ. 2016 Focused Update: Clinical 
Recommendations for Cardiopulmonary Exercise Testing Data Assessment in Specific Patient 
Populations. Circulation. 2016;133(24):e694-711. 
16 M.R. Miller, J. Hankinson, V. Brusasco, F. Burgos et al. Standardisation of spirometry. European 
Respiratory Journal 2005 26: 319-338  
17 Yan K, Salome C, Woolcock AJ. Rapid method for measurement of bronchial responsiveness. 
Thorax. 1983;38(10):760-5.