Choice of Inhalation Device in Asthma and COPD Patients
Phase: NA
Conditions: Asthma, COPD
Sponsor: Universitair Ziekenhuis Brussel

 
 
 
 
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Study Protocol  
 
Study Title: Choice of Inhalation Device in Asthma and COPD  
Study Acronym: CIDAC 
Phase of Development: NA 
Protocol Number: 
Protocol Version and Date: Version number 1, 05/03/2021 
 
EudraCT Registry Number: (ter info: zal gebeuren via studieloket UZ Brussel zodra ik 
goedkeuring ethisch committee heb)  
ClinicTrials.gov Registry Number: (idem zie boven) 
Indication: obstructive lung disease  
 
 
 
 
 
Investigational product or Medical Device: NA 
 
 
 
 
 
 
 
Sponsor: NA 
  
Coordinating/Principal Investigator: Laure Vandermeersch 
 
 
 
The information contained in this document is the property of the Sponsor/Coordinating 
Investigator and may not be reproduced, published or disclosed to others without written 
authorization of the Sponsor/Coordinating Investigator. 
PROTOCOL SIGNATURE PAGE 
Protocol Version and date: Version number 1, 5 March 2021   
 
Protocol Title: Choice of inhalation device in asthma and COPD patients 
 
 
Sponsor: This study is an academic study and has no sponsor. 
 
 
 
 
 
Principal Investigator:  Laure Vandermeersch  
 
I agree: 
- 
to assume responsibility for the proper conduct of this study 
- 
to conduct the study in compliance with this protocol and any future amendments  
- 
not to implement any deviations from or changes to the protocol without prior review 
and written approval from the Ethics Committee, except where necessary to eliminate 
an immediate hazard to the subjects, or for administrative aspects of the study (where 
permitted by all applicable regulatory requirements) 
- 
that I am thoroughly familiar with the appropriate use of the investigational drug, as 
described in this protocol  
- 
to ensure that all persons assisting me with the study are adequately informed about 
the investigational drug and their study-related duties and functions as described in the 
protocol  
- 
that I am aware of and will comply with the current good clinical practice (GCP) 
guidelines and ethical principles outlined in the Declaration of Helsinki 
- 
to conduct the study in accordance with all applicable laws and regulations 
 
 
 
 
Printed name                                                      Signature                                         Date 

 
 
 
 
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Table of Contents 
1 
Trial Registration/Protocol Summary ................................................................................... 6 
2 
Protocol Version History ...................................................................................................... 8 
3 
Sponsor/Coordinating Investigator Information.................................................................... 8 
4 
List of Abbreviations ........................................................................................................... 8 
5 
Introduction ....................................................................................................................... 8 
5.1 
Overview of Disease Pathogenesis .................................................................................................. 8 
5.2 
Epidemiology ..................................................................................................................................... 9 
5.3 
Current Treatments ........................................................................................................................... 9 
5.4 
Study Rationale and Purpose ......................................................................................................... 10 
5.5 
Rationale for Study Design ............................................................................................................. 11 
5.6 
Rationale for Dose and Regimen/Schedule Selection.................................................................... 11 
6 
Study Schematic and Schedule of Activities ........................................................................ 12 
6.1 
Study Schematic ............................................................................................................................. 12 
6.2 
Study Activities ................................................................................................................................ 12 
7 
Study Objectives and Endpoints ......................................................................................... 13 
7.1 
Primary Objective ............................................................................................................................ 13 
7.2 
Secondary Objectives ..................................................................................................................... 13 
7.3 
Endpoints ........................................................................................................................................ 14 
8 
Investigational Plan ........................................................................................................... 14 
8.1 
Overall Study Design ...................................................................................................................... 14 
8.2 
Study Duration for Subjects ............................................................................................................ 14 
8.2.1 
Screening .................................................................................................................................... 14 
8.2.2 
Treatment Period ........................................................................................................................ 14 
8.2.3 
Unscheduled Visit(s) ................................................................................................................... 14 
8.2.4 
Early Study Termination ............................................................................................................. 14 
8.2.5 
End of Study ............................................................................................................................... 14 
9 
Selection of Subjects ......................................................................................................... 14 
9.1 
Selection of Study Population ......................................................................................................... 14 
9.2 
Inclusion Criteria ............................................................................................................................. 14 
9.3 
Exclusion Criteria ............................................................................................................................ 14 

 
 
 
 
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9.4 
Contraception/Pregnancy Avoidance ............................................................................................. 15 
10 
Screening and Randomization ........................................................................................... 15 
10.1 
Screening and Enrollment ............................................................................................................... 15 
10.2 
Randomization ................................................................................................................................ 15 
10.3 
Blinding Procedures ........................................................................................................................ 15 
11 
Interventions/Treatment ................................................................................................... 16 
11.1 
Treatments Administered ................................................................................................................ 16 
11.2 
Product Characteristics ................................................................................................................... 16 
11.3 
Randomization and Stratification .................................................................................................... 16 
11.4 
Direction of Administration .............................................................................................................. 16 
11.5 
Dosing Regimen.............................................................................................................................. 16 
11.5.1 
Dose Modifications and Dose Delay ...................................................................................... 16 
11.5.2 
Treatment Interruption and Treatment Discontinuation ......................................................... 16 
11.6 
Treatment Compliance .................................................................................................................... 16 
11.7 
Study Drug or Medical Device Accountability ................................................................................. 16 
11.8 
Storage, Packaging and Labeling ................................................................................................... 16 
11.9 
Blinding............................................................................................................................................ 16 
11.10 Prior and Concomitant Medication .................................................................................................. 16 
11.11 Non-Drug Therapies........................................................................................................................ 16 
11.12 Prohibited Medication ..................................................................................................................... 16 
11.13 Prohibited Procedures .................................................................................................................... 16 
11.14 Other Interactions............................................................................................................................ 16 
11.15 Study Disposal and Destruction ...................................................................................................... 16 
11.16 Known Undesirable Effects of Study Drug...................................................................................... 16 
12 
Study Assessments and Procedures ................................................................................... 16 
12.1 
Study Assessments......................................................................................................................... 17 
12.1.1 
Screening ............................................................................................................................... 17 
12.1.2 
Baseline .................................................................................................................................. 17 
12.1.3 
Run-In ..................................................................................................................................... 17 
12.1.4 
Treatment Period .................................................................................................................... 17 
12.1.5 
Follow-Up ............................................................................................................................... 17 
12.1.6 
End of Study ........................................................................................................................... 17 
12.1.7 
Re-screening .......................................................................................................................... 17 
12.1.8 
Early Termination ................................................................................................................... 17 
12.1.9 
Unscheduled Visits ................................................................................................................. 17 

 
 
 
 
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12.2 
Assessment Types .......................................................................................................................... 17 
12.2.1 
Efficacy Assessment .............................................................................................................. 18 
12.2.2 
Safety and Tolerability Assessments ..................................................................................... 18 
12.2.3 
Physical Examination ............................................................................................................. 18 
12.2.4 
Vital Signs, Height, Weight… ................................................................................................. 18 
12.2.5 
ECG…. ................................................................................................................................... 18 
12.2.6 
Laboratory Evaluation ............................................................................................................ 18 
13 
Safety Monitoring and Reporting ....................................................................................... 18 
13.1 
Adverse Events ............................................................................................................................... 18 
13.1.1 
Definitions and Reporting ....................................................................................................... 18 
13.1.2 
Reporting Period .................................................................................................................... 18 
13.1.3 
Laboratories Test Abnormalities ............................................................................................ 18 
13.2 
Serious Adverse Events .................................................................................................................. 18 
13.2.1 
Definitions ............................................................................................................................... 18 
13.2.2 
Immediate Reporting .............................................................................................................. 18 
13.3 
Suspected Unexpected Serious Adverse Events (SUSAR) ........................................................... 19 
13.3.1 
Definitions ............................................................................................................................... 19 
13.3.2 
Reporting ................................................................................................................................ 19 
13.4 
Other safety data requiring an immediate declaration .................................................................... 19 
13.5 
Procedures for Handling Special Situations ................................................................................... 19 
13.5.1 
Pregnancy .............................................................................................................................. 19 
13.5.2 
Overdose Management .......................................................................................................... 19 
13.6 
Annual Safety Report ...................................................................................................................... 19 
14 
Data Collection and Management ...................................................................................... 19 
14.1 
Monitoring ....................................................................................................................................... 19 
14.1.1 
Composition of data monitoring committee ............................................................................ 19 
14.1.2 
Interim analysis ...................................................................................................................... 19 
14.2 
Data Collection ................................................................................................................................ 19 
14.3 
Database Management and Quality Control................................................................................... 19 
14.4 
Statistical Considerations and Data Analysis ................................................................................. 19 
15 
Ethical Considerations....................................................................................................... 20 
15.1 
Ethical conduct of the study ............................................................................................................ 20 
15.1.1 
Declaration of Helsinki............................................................................................................ 20 
15.1.2 
Ethics Committee ................................................................................................................... 20 
15.2 
Informed Consent............................................................................................................................ 20 
15.3 
Patient and Study Data Protection .................................................................................................. 20 
15.4 
Subject Identification ....................................................................................................................... 20 
16 
Finance and Insurance ...................................................................................................... 20 
17 
Reporting and Dissemination ............................................................................................ 21 

 
 
 
 
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18 
Conflict of Interest Statement ............................................................................................ 21 
19 
Tables and Figures............................................................................................................ 22 
20 
References ....................................................................................................................... 23 
 
 
 

 
 
 
 
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1 Trial Registration/Protocol Summary 
 
Information 
EudraCT number: 
Date of registration: 
Application for registration in a clinical trial registry will be done after obtaining 
approval from the ethics committee 
ClinicalTrials.gov: 
Please see previous line  
Official Title: 
Choice of inhalation device in asthma and COPD  
Study Phase/Type: 
Single center, single visit cross-sectional interventional study without device or 
investigational product. 
 
Condition: 
Asthma and COPD (Chronic Obstructive Pulmonary Disease) 
Objectives: 
To 
identify 
patient/inhalation 
device 
mismatch 
by 
using 
objective 
measurements. 
Investigational 
Product or Medical 
Device: 
NA 
Interventions: 
The intervention will be a three-step evaluation.  
Patients will perform a deep voluntary inspiration. This inspiration will be 
assessed by the investigator. Secondly, the peak inspiratory flow will be 
measured over 5 different resistances with an In-check Dial device.  
Subsequently, patients will receive education about good coordination 
technique, which is necessary for the optimal use of pressured metered dose 
inhalers (pMDIs). By using a placebo pMDI, the investigator will assess the 
coordination of the patient. The evaluation of voluntary deep inspiration, PIF’s 
and coordination will be by pass or fail evaluation.  
Endpoints: 
To assess if the choice of inhaler device category differs when based on 
objective assessments, as compared to the choice made by the treating 
physician (during routine clinical practice), which is primarily based on 
subjective evaluation.  
Study population: 
Asthma and COPD patients treated with inhaled medications. Subjects will be 
recruited in the respiratory outpatient clinic in UZ Brussel after a scheduled 
consultation with their pulmonologist. 
Number of patients: 
40 COPD patients (GOLD II-IV); 20 patients with severe asthma, 40 patients 
with asthma aged ≥ 70y, 40 patients with mild-to moderate asthma aged < 70y  
Overview of  
study design: 
Single center, single visit cross-sectional interventional study without device or 
investigational product 
Statistical  
Considerations: 
Descriptive analysis will be used to describe the prevalence patient/device 
mismatch. 
Multiple regression analysis will be performed to identify patient characteristics 
associated with inability to use the 3 main classes of inhalation devices 
respectively. Due to the exploratory nature of this study, no formal power 
calculation can be performed.  
Sponsor: 
This study is an academic study and has no sponsor. 
Inclusion Criteria: 
- 
COPD patients (GOLD II-IV) 
- 
Patients with severe asthma  
- 
Patients with asthma aged ≥ 70y 
- 
Patients with mild-to moderate asthma aged < 70y 
Exclusion Criteria: 
- 
Patients with asthma or COPD not on inhaled therapy for maintenance 
treatment 
- 
Patients younger than 18y  
- 
Patients unable to give their informed consent due to mental or 
physical disability 
- 
Patients who don’t speak Dutch or French 
Target Date of first  
enrolment: 
To be determined. Probably Q4 2021. 

 
 
 
 
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Target sample size: 
No target sample size calculation could be performed due to exploratory nature 
of the study (please see above) 
 
 
 

 
 
 
 
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2 Protocol Version History 
 
Version No. 
Release Date 
Summary of Changes 
 
 
 
 
 
 
 
 
 
 
3 Sponsor/Coordinating Investigator Information 
 
Coordinating Investigator (promotor): Prof. Dr. Eef Vanderhelst 
Sponsor: NA 
Principal Investigator Laure Vandermeersch 
Co-investigators: Prof. Dr. Eef Vanderhelst, Dr. Shane Hanon (co-promotor), Mr Daniël 
Schuermans, Mss Cindy Zienebergh 
 
 
Additional co-researchers: NA 
 
 
 
Statistician  
 
 
 
 
Laboratory (ies): NA 
Pharmacy: NA 
 
 
 
  
Study Coordinator; Daniël Schuermans 
Study sites and co-investigators; respiratory outpatient clinic UZ Brussel 
4 List of Abbreviations 
COPD = Chronic Obstructive Pulmonary Disease 
FEV1 = Forced Expiratory Volume in one second  
FVC = Forced Vital Capacity  
ICS = Inhaled corticosteroids 
LABA = long acting beta-agonists 
LAMA = long acting muscarinic antagonists  
GOLD = Global Initiative for Chronic Obstructive Lung Disease 
GINA = Global Initiative for Asthma  
5 Introduction 
5.1 
Overview of Disease Pathogenesis 
Pathogenesis of asthma 
Asthma is a heterogeneous disease, which is normally characterized by the presence of chronic 
airway inflammation. Asthma is defined by the history of respiratory symptoms such as shortness of 
breath, wheeze, cough, chest tightness. These symptoms can fluctuate over time and in intensity in 
combination with a variable expiratory airflow limitation. (1)  
 
 
Pathogenesis of COPD  
Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease 
that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway 
and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases 

 
 
 
 
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an influenced by host factors including abnormal lung development. Significant comorbidities may 
have an impact on morbidity and mortality.  
The most common respiratory symptoms of COPD are cough and/or sputum production, dyspnea. 
Underreporting of these symptoms by patients can occur.  
The most important risk factor for COPD is tobacco smoking. Other environmental exposures such 
as air pollution and biomass fuel exposure may contribute. (2)  
 
5.2 
Epidemiology  
Epidemiology of asthma 
Currently, 4.3% of the population worldwide has asthma. The prevalence of asthma in the United 
States is 8.4%. The prevalence of asthma is on the rise. Asthma is more prevalent in black than in 
white persons. It is remarkable that the prevalence of asthma decreases with each successive higher 
poverty level group. Asthma has a significant impact on morbidity and mortality. (3) 
 
Epidemiology of COPD 
The global prevalence of physiologically defined chronic obstructive pulmonary disease (COPD) in 
adults aged >40 years is approximately 9-10 per cent. (4)  
The worldwide prevalence of chronic obstructive pulmonary disease (COPD) in adults older than 
40 years old is approximately 9-10%.  COPD is the fifth leading cause of years lost through early 
mortality or handicap (disability-adjusted life years). Country, sex and age are factors that influence 
the prevalence of COPD. (2) 
 
 
5.3 
Current Treatments 
Treatment of asthma 
The current pharmacological treatment of asthma consists of the stepwise approach by GINA. The 
goal is to optimize the personalized asthma management by assessing, adjusting and reviewing the 
response to treatment.  
The treatment depends on the number of step of GINA. The 5 different GINA steps are 
characterized by different treatments. Inhaled corticosteroids (ICS), short acting β2- agonists 
(SABA) and long acting β2 agonists (LABA) 
There are 3 different types of inhalers: dry powder inhalers (DPI), pressurized metered dose inhaler 
(pMDI) and soft mist inhalers (SMI).  
SMI’s and pMDI’s can be used in combination with an inhalation chamber. (5) 
 
 

 
 
 
 
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Figure 1: treatment of asthma  
 
Treatment of COPD  
The treatment of COPD depends on the group guided by GOLD: group A, B, C or D.  
The corner stone of the pharmacological treatment consists of bronchodilatation: LABA (long 
acting beta-agonists), LAMA (long acting muscarinic antagonists).  A triple therapy: ICS, LABA 
and LAMA, is recommended in COPD GOLD D patients. (6) 
 
5.4 
Study Rationale and Purpose 
Inhalation therapy is the cornerstone therapy in asthma and COPD patients. Unfortunately, many 
errors are associated with the use of inhalers, which leads to poor outcome for patients. Problems 
with the use of pressurized metered dose inhalers were described shortly after the launch of pMDI 
and still persist today. The use of dry powder inhalers (DPI’s) is also frequently associated with 
errors. 
The most common errors in the use of pMDI’s are incorrect coordination, insufficient depth and/or 
speed of inspiration and no postinhalation breath-hold in.  
The post frequent DPI errors are no complete expiration before inhalation, incorrect preparation and 
lack of postinhalation breath-hold in.  
The overall prevalence of poor technique was 31%, of acceptable technique 41% and of correct 
technique only 31%. It can be concluded that incorrect inhaler technique in asthma and COPD 
patients is unacceptably frequent. Over the past 40 years, the prevalence of correct inhaler 
technique has not improved. The lack of correct inhalation technique may be a major obstacle, 
which withholds patients from achieving optimal asthma or COPD control. (7)  
Incorrect use of inhalers is associated with reduced disease control. The strongest associations have 
been found between incorrect inhaler technique and older age, lower schooling and lack of 

 
 
 
 
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instruction about the correct inhaler technique by healthcare workers. These associations are 
independently of the inhaler type. Poor inhaler use is most common in older ages, but can occur at 
all ages. The misuse of inhalers is associated with an elevated risk of hospitalization, visits to the 
emergency department, treatments with oral corticosteroids and antimicrobials, and poor disease 
control. Instruction by healthcare workers about the correct use of inhalers is the only modifiable 
factor that can be useful to reduce the prevalence of inhaler misuse. (8)  
The choice of inhalation device is an important decision and is often as important as the medication 
put in the device to achieve optimal outcomes for patients with asthma or COPD. The optimization 
of treatment could be established by switching between devices instead of increasing or changing 
the pharmacological therapy. There are multiple differences between the various devices such as 
particle size, release mechanism, drug deposition and required inspiratory flow. Switching devices 
should never be done without the patient consent. A patient should feel comfortable with their 
device in order to use it properly, which makes that switching of device is a careful process in 
which the patient has to be involved. (9) 
 
In conclusion, the purpose of the study is to identify patient/inhalation mismatch by using objective 
measurements.  
 
5.5 
Rationale for Study Design 
All assessments can be made on the spot following the consultation, which allows a cross sectional 
design.  
 
5.6 
Rationale for Dose and Regimen/Schedule Selection NA  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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6 Study Schematic and Schedule of Activities 
6.1 
Study Schematic 
Characteristics of the study  
 
Informed consent procedure: 
▪ Available in Dutch and French 
▪ Signature and date written by 
participant 
Inclusion criteria:  
 
▪ COPD patients (GOLD II-IV) 
▪ Patients with severe asthma 
▪ Patients with asthma aged ≥ 70y 
▪ Patients with mild-to moderate asthma 
aged < 70y  
Exclusion criteria: 
▪ Patients with asthma or COPD not on 
inhaled 
therapy 
for 
maintenance 
treatment 
▪ Patients younger than 18y  
▪ Patients unable to give their informed 
consent due to mental or physical 
disability 
▪ Patients who don’t speak French or 
Dutch 
Collection of data form patient file: 
▪ Choice of inhaler by physician (current 
inhaled maintenance treatment) 
▪ GOLD grade and group (COPD 
patients) 
▪ GINA treatment step (asthma patients) 
▪ Smoking status 
▪ Height 
▪ Weight 
▪ Age 
▪ FEV1, FVC, PIF if available 
▪ Oral corticosteroid maintenance dose 
Study assessments: 
▪ Voluntary deep inhalation 
▪ Peak inspiratory flows (PIF’s) 
▪ Coordination (through a placebo pMDI) 
Reporting to treating physician in case of  
patient/device mismatch 
▪ To avoid prescription of inappropriate 
inhaler 
 
 
6.2 
Study Activities 
The study will take place in the respiratory outpatient clinic. Patients will be invited to participate in 
the study after the consultation with the pulmonologist. All pulmonologists have a flowchart 
regarding the optimal choice of inhaler at their disposition. 
 
Patients will be provided sufficient time to read the informed consent file and to ask questions about 
the study. After giving their informed consent they will be screened for eligibility by an 

 
 
 
 
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investigator. Demographic data and characteristics will be retrieved from the medical record (EMD) 
of study participants. 
 
 
The intervention will consist of three different steps. 
 
First, the patient will perform a deep voluntary inspiration. The patient’s ability to perform this 
inspiration will be assessed and scored by the investigator.  
 
Secondly, the peak inspiratory flows (PIF) will be measured with an In-check Dial device over 5 
different resistances.  
The minimal and optimal peak inspiratory flow rates (PIFRs) differ by device. A minimum flow of 
30 L/min is required for most DPI’s. The optimal flow varies from 30 L/min to 35, 45, 50, 60 or 65 
L/min. (10) 
Due to the fact that there is still discussion about the effectiveness of PIF’s going from 30 to 60 
L/min, an arbitrary cut-off value will be set at 45 L/min. This cut-off value for sufficient PIF will be 
measured over a moderate resistance to distinguish subtherapeutic from therapeutic levels. (11) If 
the patient reaches a PIF lower than 45 L/min, the patient will be asked to make a second attempt.  
 
Subsequently, the patient will receive education about the correct coordination, which is necessary 
in the use of dose inhalers. The patient will be evaluated for sufficient actuation-inhalation 
coordination, through a placebo pMDI.   
 
The evaluation of the voluntary deep inspiration, PIF and coordination will be by pass or fail 
evaluation. Subsequently, the fitness of a patient to use any of the three inhaler classes will be 
determined by using a diagram designed by a Belgian expert group (unpublished to date; courtesy 
of Didier Cataldo, ULiège). 
 
If a mismatch between prescribed inhaler and suitable inhaler types is found, the treating physician 
of the patient will be informed. By doing so, we wish to avoid patients receiving prescriptions for 
inhalers that they cannot use properly.  
 
7 Study Objectives and Endpoints 
7.1 
Primary Objective 
To study the prevalence of patient/device mismatch based on objective assessments.   
7.2 
Secondary Objectives 
To assess the proportion of patient/device mismatch per patient subgroup.  
 
To assess the fail rates for each objective measurement separately for the entire study population 
and per patient group. 
 
To correlate the fail rates for each objective measurement separately with patient’s characteristics 
per patient subgroup and overall (age, sex, height, weight, FEV1, FVC, PIF, GOLD grade and 
group, smoking status, GINA treatment step, oral corticosteroid dose). 

 
 
 
 
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To correlate fail rates for each objective measurement with patient’s characteristics.  
7.3 
Endpoints 
Cfr 7.1 and 7.2 
 
8 Investigational Plan 
8.1 
Overall Study Design 
Cross sectional study design 
 
8.2 
Study Duration for Subjects  
8.2.1 
Screening 
Patients will be recruited following their consultation with their pulmonologist. The recruitment of 
the patients will take place in the respiratory outpatient clinic of UZ Brussel.  
8.2.2 
Treatment Period NA  
8.2.3 
Unscheduled Visit(s) NA 
8.2.4 
Early Study Termination NA 
8.2.5 
End of Study  
The duration of the study for each individual patient will be around 5 to 10 minutes. Participation 
ends when the patient leaves the pulmonology division at the outpatient clinic. 
9 Selection of Subjects 
9.1 
Selection of Study Population 
The selection of study population will take place in the respiratory outpatient clinic in UZ Brussel. 
The patients will be recruited following their consultation with the pulmonologist. 
 
9.2 
Inclusion Criteria  
- COPD patients (GOLD II-IV) 
- Patients with severe asthma included in the Belgian Severe Asthma registry aged <70 
- Patients with asthma of any severity aged ≥ 70y 
- Patients with mild-to moderate asthma aged < 70y  
9.3 
Exclusion Criteria 
- Patients with asthma or COPD not on inhaled therapy for maintenance treatment 
- Patients younger than 18y  

 
 
 
 
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- Patients unable to give their informed consent due to mental or physical disability 
- Patients who don’t speak French or Dutch 
 
9.4 
Contraception/Pregnancy Avoidance NA 
 
10 Screening and Randomization 
10.1 
Screening and Enrollment  
Patients who gave their informed consent will be screened for eligibility by an investigator.  
10.2 
Randomization NA 
10.3 
Blinding Procedures NA  
 
 

 
 
 
 
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11 Interventions/Treatment 
11.1 
Treatments Administered   
 
The intervention consists of physiological measurements. No treatment, drug or 
product will be administered. No device will be tested. The In-check-dial-device and 
placebo pMDI are merely tools to perform the physiological measurements. 
11.2 
Product Characteristics NA 
11.3 
Randomization and Stratification NA 
11.4 
Direction of Administration NA 
11.5 
Dosing Regimen NA 
11.5.1 
Dose Modifications and Dose Delay 
11.5.2 
Treatment Interruption and Treatment Discontinuation 
11.6 
Treatment Compliance NA 
11.7 
Study Drug or Medical Device Accountability NA 
11.8 
Storage, Packaging and Labeling NA 
11.9 
Blinding NA  
11.10 Prior and Concomitant Medication NA 
11.11 Non-Drug Therapies NA 
11.12 Prohibited Medication NA  
11.13 Prohibited Procedures NA 
11.14 Other Interactions NA  
11.15 Study Disposal and Destruction NA 
11.16 Known Undesirable Effects of Study Drug NA 
12 Study Assessments and Procedures 
Please see section 6.2: study activities 

 
 
 
 
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12.1 
Study Assessments:   
12.1.1 
Screening 
cfr supra (6.2 and 10.1) 
12.1.2 
Baseline:  NA 
12.1.3 
Run-In: NA 
 
12.1.4 
Treatment Period: NA  
12.1.5 
Follow-Up 
12.1.6 
End of Study 
The study will end when the anticipated number of participants will be reached.  
12.1.7 
Re-screening NA  
12.1.8 
Early Termination NA 
12.1.9 
Unscheduled Visits NA 
NA= not applicable for this cross-sectional study 
12.2 
Assessment Types  
This study will assess physiological data (ability to perform a voluntary inhalation, PIF, and 
actuation-inhalation coordination with a pMDI). Cfr supra. 

 
 
 
 
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12.2.1 
Efficacy Assessment NA 
12.2.2 
Safety and Tolerability Assessments NA 
12.2.3 
Physical Examination NA  
12.2.4 
Vital Signs, Height, Weight… 
 
The height and weight of patients will be collected from the patient file.  
12.2.5 
ECG…. NA  
12.2.6 
Laboratory Evaluation NA   
12.2.6.1 Clinical Chemistry  
12.2.6.2 Hematology 
12.2.6.3 Urine Analysis  
12.2.6.4 Pharmacokinetics…. 
13 Safety Monitoring and Reporting  
Patient safety during the assessments is monitored by the investigators. In the highly unlikely event 
of an adverse event (AE) or severe adverse event (SAE), this will be reported in the CRF and the 
treating physician will immediately be notified by the investigator.  
The assessments of a deep inhalation, PIF maneuvers over a resistance and the use of a placebo 
pMDI do not differ from the maneuvers performed in daily life, when inhaler therapy is used by 
patients.  
13.1 
Adverse Events NA 
13.1.1 
Definitions and Reporting 
Reporting in the CRF 
13.1.2 
Reporting Period 
Duration of the study for the individual patient 
13.1.3 
Laboratories Test Abnormalities: NA 
13.2 
Serious Adverse Events  
13.2.1 
Definitions  
13.2.2 
Immediate Reporting  
Immediate reporting in the CRF and to the treating physician by the investigator 
 
 

 
 
 
 
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13.3 
Suspected Unexpected Serious Adverse Events (SUSAR) NA 
13.3.1 
Definitions 
13.3.2 
Reporting 
13.4 
Other safety data requiring an immediate declaration NA 
13.5 
Procedures for Handling Special Situations NA 
13.5.1 
Pregnancy 
13.5.2 
Overdose Management 
13.6 
Annual Safety Report NA 
14 Data Collection and Management 
14.1 
Monitoring  
14.1.1 
Composition of data monitoring committee: NA 
14.1.2 
Interim analysis: NA 
14.2 
Data Collection 
By the investigator (from medical records and study assessments).  
14.3 
Database Management and Quality Control  
The promotors and investigators from UZ Brussel’s respiratory division assume database 
management and quality control. 
 
14.4 
Statistical Considerations and Data Analysis 
The promotors and investigators from UZ Brussel’s respiratory division will perform the 
statistical analysis, with the help of VUB statistician Professor Kurt Barbé.  
The statistical plan was discussed during a meeting with professor Barbé (see below). 
 
Sample size calculation 
 
This is a purely explorative study, since there is no a piori hypothesis to be confirmed. Hence, 
no formal sample size calculation is possible. 
The findings of this study could later on be confirmed and assessed more extensively in larger 
dedicated studies. 
For this study however, it is important that the patient groups be stratified according to their 
occurrence in society. We believe this will be the case when the in-and exclusion criteria for 
this study will be applied.  
 
 
 

 
 
 
 
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Statistical analysis 
 
Descriptive statistics will be used to describe the prevalence of patient/device mismatch for the 
entire study population. 
The comparison of the prevalence of patient/device mismatch between patient subgroups and 
the comparison of the fail rates for each objective measurement separately between patient 
subgroups will be done by means of the Chi-square test and will be visualized in cross-tables. 
 
To study correlations between patient characteristics (independent variables) and pass or fail 
rates for each of the three test criteria (dependent variables), box-plots will be used for         
continuous variables (for example weight and length), whereas the Chi-square test will be used 
for categorical variables (for example diagnosis, age expressed in years, GOLD stage and 
GOLD group). 
15 Ethical Considerations 
15.1 
Ethical conduct of the study 
15.1.1 
Declaration of Helsinki  
The study will be conducted in accordance with the principles and guidelines of the 
declaration of Helsinki. 
15.1.2 
Ethics Committee 
Application for approval of this protocol by UZ Brussel’s ethics committee is being 
prepared. 
15.2 
Informed Consent 
Patients will sign an informed consent before participating in the study. The informed consent 
will be available in Dutch and French.  
15.3 
Patient and Study Data Protection  
This study will be performed in accordance with the standards applied by the UZ Brussel’s Data 
Protection Officer. 
Paper CRF’s (source data) will be stored only in UZ Brussel’s respiratory division. Anonymized 
data (excel file) will be stored on UZ Brussel’s S-drive. 
15.4 
Subject Identification  
Data will be anonymized before storage. 
16 Finance and Insurance 
The conduct of this academic study will be financed by UZ Brussel’s respiratory division. An 
insurance will be taken out for this study. 

 
 
 
 
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17 Reporting and Dissemination 
The principal investigator will report the results of the study in her master thesis. The results may 
also be presented at a scientific conference or be published. The investigators hold all publication 
rights.  
18 Conflict of Interest Statement 
The investigators have no conflicts of interest related to this study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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19 Tables and Figures 
 
 
Figure 1: Diagram designed by a Belgian expert group: unpublished to date; used under permission 
of Prof. Dr. Didier Cataldo and courtesy of Prof. Dr. Didier Cataldo, University of Liège.  
 
Legend of the used colours in this diagram:  
Green = optimal indication 
Yellow = not indicated  
Red = not indicated  
 
 
 
 

 
 
 
 
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20 References 
 
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