Measurement of Breathing Parameters of Asthma and COPD Patients With Different Degrees of Disease Severity for the Computer Simulation of Lung Deposition of Aerosol Drugs
Conditions: Asthma, COPD
Sponsor: Medisol Development Kft.

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
Study protocol and statistical analysis plan  
Measurement of breathing parameters of asthma and COPD patients with 
different degrees of disease severity for the computer simulation of lung 
deposition of aerosol drugs  
Study short name: CHOICE  
Non-interventional, observational study 
 
Sponsor: Medisol Development Kft. 
 
 
Study protocol ID: TBEP-2110/01  
version: 2021 V2 
 
February 1, 2022 
 
 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
 
 
 
Initiator and scientific supercisor: Dr. Gabriella Gálffy PhD, director-general  
Workplace: County Institute of Pulmonology, Törökbálint 
2045 Törökbálint, Munkácsy Mihály utca 70  
Phone: +36-23-511570/121  
Mobile: 06 30 7005 688  
E-mail: kutatasititkarsag@torokbalintkorhaz.hu  
Supervisor of numerical simulations: Dr. Árpád Farkas PhD, head of department  
Workplace: Centre for Energy Research, Environmental Physics Department  
  1121 Budapest Konkoly-Thege Miklós út 29-33  
Phone: +3613922222/3404 
Mobile: +36 20 356 4255  
E-mail: farkas.arpad@ek-cer.hu  
  Sponsor: Medisol Development Kft  
1044 Budapest, Ezred utca 7. 2 ép. fszt 4  
Fiscal code: 28820835-2-19  
Mobile: +36 30 399 8022  
E-mail: czaun.peter@gmail.com  
Contact person: Dr. Árpád Farkas PhD  
Mobile: +36 20 356 4255  
E-mail: farkasar@gmail.com 
 
 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
I. 
Study Protocol 
I.1. The purpose of the study (research objective)  
Primary aim 
 Computer modelling of the lung deposition of aerosol drugs based on realistic 
individual breathing patterns to be measured within this study.*  
* given that there are currently several innovative and generic products that are available for the treatment of patients 
with asthma and COPD, however not all products have the necessary data for computer modelling provided by companies 
or retrievable in the open literature, hence we are only modelling for products that have input data on drug aerodynamic 
characteristics.  
  Secondary goals 
 Examination of the correlation between the lung deposition efficiency (the 
dose depositing in the lungs divided by the dose metered in the inhalation 
device) and the patients current health status.  
 Evaluation of patients’ inhalation device usage and suggestions for optimal 
usage according to the acquired breathing breathing data and calculated lung 
deposition values. 
 
I.2. Characteristics of patients to be included in the study (inclusion 
and exclusion criteria) 
Inclusion criteria  
□ diagnosed obstructive lung disease (asthma or COPD)  
□ proper usage of inhalation tool after being educated 
□ availability of whole body plethysmography measurement data from the last 6 
monts or the possibility to perform them before the start of the study (the most 
important parameter is reserve volume, RV) 
□ subject under outpatient/inpatient therapy  
□ over 18 years of age  
□ capable of acting and cooperating  
Exclusion criteria  
□ the patient doesn’t align with any of the criteria mentioned above  
□ the patient is incapable of filling out the questionnaire/questionnaires’ 
parts that are accorded to him/her  
□ the patient doesn’t agree to have data collected of him/her  
□ diagnosed heavy, not treated chronic illness  
□ not properly carried out /not evaluable lung function (spirometry) examination 
 
I.3. Sampling and recruiting principles  
Every involved medical professional should opt for randomness in sampling. This 
includes the selection process but also the device order. We are involving examiners 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
for our test from different levels of healthcare servicing (university centre, regional 
institute, county hospital, panel clinic) aiming to ensure that the sampling venues 
(centrum related) to minimize centre specific effects.  
Participation of patients is on a volunteer basis. Patient involvement in ambulant patient 
care occurs strictly in the time frame when the examination would take anyway place, no 
special visit (only for the study) will be needed. Only patients with proven records of 
COPD or asthma can be involved. In principle, in every centrum anyone who shows up 
for examination with asthma or COPD and is willing to cooperate can participate, given 
that it passes the inclusion criteria and no exclusion criterion applies to him/her. Children 
under 18 cannot be involved in the examination. There is no upper age constraint. There 
are no restrictions on gender or ethnicity. Minimum number of patients planned is 200.  
I.4. The examination  
Patient involvement will take place after the possibly emerging questions of the subject are 
answered and the patient is told about the whole goal of the examination and all of its details, 
has read and signed the leaflet and the patient-consent statement. After that the data of 
illnesses are obtainable according to the daily routine which are present suitably during the 
ambulant daily routine examination anyways.  
 
 
 
The study not involving intervention in the care and treatment of patients consists of only one 
visit. Within this, as indicated on the data sheet, answers to questions in accordance with 
standard medical practice and individual respiratory function profile are recorded. The latter 
takes place only if the doctor has planned lung function measurement independently of the 
study. 
 
I.5. Actions to be undertaken during the visit  
The table below summarizes the data collection during the visit. The patients can only be 
involved and data can be registered only if these data would have anyway been obtained 
through a regular visit. In addition to the patient data, the centrums’ data will be registered 
as well in the eCRF system, as complementary data helping the evaluation of the 
examination. 
 
 
 
visit 1 
anamnesis 

characteristics of the actual status of the patient 

lung function curve and parameters 

inhalation therapy 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
Patients’ data collection 
visit 1 (patient involvement) 
Time 
0th day 
Evaluation of the inclusion and exclusion 
criteria 
X 
Comprehensive informing of the patient 
X 
Signing of patient information leaflet and 
patient consent sheet 
X 
Recording of patient demographic data 
X 
Recording of the anamnesis 
X 
Recording of diagnostic 
X 
Recording of actual status 
X 
Smoking habit 
X 
Applied drug therapy, dose 
X 
Education on the use of inhalers 
X 
Whole 
body 
plethysmography 
measurement, only if it was not performed in 
the last 6 months (recording of RV and FVC) 
X 
Recording of inhalation time and breath-
holding time. 
X 
Registration of eventual side effects or 
unexpected events. 
X 
 
I.6. Beginning and duration of the examination  
The first patient can be involved if the Scientific Council for Health Scientific and 
Research Ethics Committee approves and afterwards the National Institute of 
Pharmacy and Food Health (OGYÉI) grants permission. In the first part of the 
study all the input data necessary for numerical modelling will be obtained. 
  
Beginning date: 2022.08.01  
End date: 2025.06.30  
 
 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
 
I.7. Legal background  
The legal frame is provided by: 
 The European Commission 520/2012/EU implementing regulation (Annex II, paragraph 
38), the 726/2004/EK Regulation of the European Parliament and of the Council and the 
2001/83/EK implementation of pharmacovigilance activities provided for in the 
Directive of the European Parliament and of the Council 
 XCV. law from 2005 on medicinal products for human use and amending other laws 
governing the pharmaceutical market  
 CLIV. Law on Health Care from 1997  
 235/2009. (X. 20.) Government regulation of medical research in humans, clinical 
examination of test artefacts for human use, and on the regulations of enabling the use 
of medical tools intended to be used for clinical examinations in humans.  
 23/2002. (V. 9.) EüM Regulation on medical research on humans. 
 15/2012. (VIII. 22.) EMMI Regulation on pharmacovigilance of 
medicinal products for human use.  
I.8. Data protection, publishing principles, IPD share plan  
The recorded personal information during the study is confidential. In all respects, the regulation 
of non-interventional examinations should be taken into account when collecting data (23/2002 
EüM regulation), according to the year 2011. CXII. Law on the right to information self-
determination, freedom of information, as well as the European Parliament and council (EU) 
679/2016 General Data Protection Regulation.  
The publication of the results of the study is likely to be useful information for pulmonologists, 
primary care workers, and also for specialists working in other fields, but its research value also 
manifests itself as research development potential. It can help to recognize the connections 
between the general condition of the patient, his drug use effectiveness, and the planning of later, 
prospective studies. It can also serve as a basis for more extensive studies. The head of the 
research shall decide on the preparation and publication of the communication on results as well 
as the naming of co-authors  
In the case of an appropriate sample number (at least 30 patients per medicine and device) it is 
also possible to conduct interim analysis and publish the results of the study. Individual lung 
function results allow individual (personalized) modelling of drug deposition to be performed. 
The test can also be considered successful if statistically representative groups are not able to be 
formed. In this case, we perform modelling for individual measurements without aggregate 
results. 
 
Individual Patient Data Share Plan 
The data sharing plan contains statements on the availability of individual participant data 
(including data dictionaries), information on what data in particlular will be shared, what other 
documents will be available, when will data be available, with whom, for what type of analyses. 
In addition, the plan specifies the mechanism the data are be made available. 
 According to the plan those IPD will be available that underlie the results published in research 
article(s) will be shared after deidentification. 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
The frame of IPD sharing is defined below: 
Supporting information: Study Protocol 
Time frame: Between months 9 and 36 after the publication of article(s). 
Access criteria: IPD will be shared with investigators whose proposed use of the data has been 
approved by an independent review committee identified for this purpose. IPD will be shared to 
achieve aims in the approved proposal. Proposal may be submitted to farkasar@gmail.com. 
URL: https://data.mendeley.com 
I.9. Exploitation of results  
The research team (all experts included in this research) is looking forward to making the results 
public in the form of presentations in national and international congresses and publicizing it 
even if the series of measurements does not end with a positive result that can be evaluated for 
the endpoints. Moreover, if the results show that the deposition results based on individual 
breathing patterns and the aerodynamic characteristics of different drug particles differ 
significantly among each other, then they will be used in research aiming at the optimisation and 
personalization of inhaler choice and aerosol drug therapy. 
 
I.10. Recording and reporting of side effects  
The head of research shall be responsible for reporting any undesirable drug effects detected by 
all researchers in connection with the study or in connection with the use of an inhaled medicine 
in connection with the study, and for complying with the relevant regulatory requirements in the 
field.  
Experienced side effects are reported individually by the researchers towards OGYÉI, and they 
shall immediately be noted to the head of research and the sponsor. The fact of side effects is 
also recorded on the test sheets on a mandatory basis, which can be checked by the sponsor and 
the head of research.  
The head of research takes responsibility to report the adverse reactions, side effects and other 
specific cases (hereinafter referred to collectively as "medicinal product safety information") 
experienced during the entire period of the non-interventional observational study and during the 
processing of the results as follows:.  
Side effect (adverse drug reaction): harmful and unwanted effects caused by medicines. 
According to the perceptive doctor, the side effect may be causal to the use of the medicine. In 
addition to the harmful and unwanted effects resulting from the use under the marketing 
authorisation during the normal administration of medicinal products, adverse unwanted effects 
resulting from the pharmaceutical error and use not covered by the marketing authorisation 
shall also be considered as a side effect, including improper use and abuse of the medicinal 
product. 
Unexpected side effect: a side effect which is not included in the prescription for use of the 
medicinal product or the frequency, nature, severity or outcome does not correspond to the side 
effect listed in the prescription for use.  
Serious side effect: a side effect that endangers life, requires or prolongs hospitalization, causes 
permanent or significant damage to health, disability, congenital abnormalities, birth defects or 
death. It is medically significant, i.e. it does not meet any of the severity criteria listed above, but 
without intervention it leads to the appearance of one of the criteria. 
 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
Special cases, which shall also be reported to the sponsor if there are no side 
effects associated with the case:  
- use of medicinal products during pregnancy  
- use of medicinal products during breastfeeding  
- overdose (either intentionally or accidental)  
- ineffectiveness  
- incorrect application  
- medication error  
- quality defect  
- drug interactions  
- paternal exposure  
- misuse of medicinal products  
- occupational harm to medicinal products  
- transmission of an infectious agent by medicinal product  
- off label (out-of-indication) drug application  
The above-described information on the safety of medicines, whether or not there have been 
any side effects in connection with the specific case, or whether the side effect is well 
known or unexpected, or serious or not serious, shall be forwarded to the head of research 
and sponsor within 24 hours of the date on which the person concerned became aware. 
Study participants can also report side effects to the National Institute of Pharmacy through 
the contact details provided on the Institute's official website.  
To avoid unnecessary administration and duplication, it is important that researchers report side 
effects only on one reporting route. The reports received by the head of research and sponsor will 
be forwarded/notified to the competent authorities in accordance with the legal requirements.  
I.11. Authorisation 
The document describing the study (with all its annexes, patient information, patient consent 
statement) is to be approved by the National Institute of Pharmacy and Nutrition (OGYÉI). The 
research plan is evaluated from an ethical point of view by the Scientific and Research Ethics 
Committee of the Medical Research Council (ETT TUKEB). 
 
 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
Bibliography  
1. Global Initiative for asthma (GINA) - https://ginasthma.org 
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD) - https://goldcopd.org 
3. Korányi Évkönyv - https://szakmai.koranyi.hu/bulletin/ -  
4. Borgström L, Derom E, Stahl E, Wahlin-Boll E, Pauwels R. The inhalation device 
influences lung deposition and bronchodilating effect of terbutaline. Am J Respir Crit 
Care Med 153:1636–1640, 1996.  
5. Borghardt JM, Kloft C, Sharma A. Inhaled Therapy in Respiratory Disease: The 
Complex Interplay of Pulmonary Kinetic Processes. Can Respir J. 2018;2018:2732017. 
Published 2018 Jun 19. doi:10.1155/2018/2732017 6. Busse WW, Brazinsky S, Jacobson 
K, Stricker W, Schmitt K, Vanden Burgt J, et al. Efficacy response of inhaled 
beclomethasone dipropionate in asthma is proportional to dose and is improved by 
formulation with a new propellant. J Allergy Clin Immunol 104: 1215–1222, 1999. 7. 
Buttini F, Brambilla G, Copelli D, Sisti V, Balducci AG, Bettini R, Pasquali I. Effect of 
Flow Rate on In Vitro Aerodynamic Performance of NEXThaler(®) in Comparison with 
Diskus(®) and Turbohaler(®) Dry Powder Inhalers. Journal of Aerosol Science and 
Pulmonary Drug Delivery 29: 167-178, 2015.  
8. Corradi M, Chrystyn H, Cosio BG, Pirozynski M, Loukides S, Louis R, Spinola M, Usmani 
OS. NEXThaler, an innovative dry powder inhaler delivering an extrafine dry powder 
combination of beclometasone and formoterol to treat large and small airways in asthma. 
Expert Opinion in Drug Delivery 11: 1497-1506, 2014.  
9. deBoer AH, Gjaltema D, Hagedoorn P, Frijlink HW. Can ’extrafine’ dry powder aerosols 
improve lung deposition? European Journal of Pharmaceutics and Biopharmaceutics 96: 
143-151, 2015.  
10. Grant AC, Walker R, Hamilton M, Garrill K. The ELLIPTA Dry Powder Inhaler: 
Design, Functionality, In Vitro Dosing Performance and Critical Task Compliance by  
Patients and Caregivers. J Aerosol Med Pulm Drug Deliv 28: 474-485, 2015. 11. Hamilton 
M, Leggett R, Pang C, Charles S, Gillett B, Prime D. In Vitro Dosing Performance of the 
ELLIPTA Dry Powder Inhaler Using Asthma and COPD Patient Inhalation Profiles 
Replicated with the Electronic Lung (eLungTM). J Aerosol Med Pulm Drug Deliv 28: 
498-506, 2015.  
12. Horváth, Alpár ; Balásházy, Imre ; Sárkány, Zoltán ; Tomisa, Gábor ; Bártfai, Zoltán ; 
Farkas, Árpád Optimized and individualised inhalation therapy targeted MEDICINA 
THORACALIS 69 : 2 pp. 76-86. , 11 p. (2016)  
13. Horváth A, Farkas Á, Szipőcs A, Tomisa G, Szalai Zs, Gálffy G. Numerical simulation of 
the effect of inhalation parameters, gender, age, and disease severity on the lung dose of drugs 
emitted by Turbuhaler®, Breezhaler® and Genuair® in COPD patients. European Journal of 
Pharmaceutical Sciences 154: 105508, 2020.  
14. Horváth A, Balásházy I, Tomisa G, Farkas Á. Significance of breath-hold time in dry 
powder drug therapy pf COPD patients. European Journal of Pharmaceutical Sciences 104: 
145-149, 2017. 
15. Jókay Á, Farkas Á, Füri P, Horváth A, Tomisa G, Balásházy I. Computer modelling of 
airway deposition of Foster® NEXThaler®and Seretide® Diskus®dry powder combination 
drugs. European Journal of Pharmaceutical Sciences 88: 210-218, 2016. 16. Lewis D. A 
priori design of metered dose inhalers. Respiratory  

 
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Drug Delivery Asia 187-197, 2016.  
17. Mariotti, F., Sergio, F., Acerbi, D., Meyer, T., Herpich, C. Lung deposition of 
extrafine dry powder fixed combination beclomethasone dipropionate plus 
formoterolfumarate via the NEXT DPI® in healthy subjects, asthmatic and 
COPD  
patients. Eur. Respir J. 38, 830, 2011.  
18. Saeed H, Salem HF, Rabea H, Abdelrahim MEA. Effect of Human Error, Inhalation Flow, 
and Inhalation Volume on Dose Delivery from Ellipta® Dry-Powder Inhaler. J Pharma Inno 
14: 239–244, 2019.  
19. Zanker D, Ehlich H, Sommerer K, Mariotti F, Riolo D, Cocconi D, Lutero E. Development 
of a robust technique of radiolabelling beclometasone dipropionate (BDP) with 
99mTechnetium in a BDP/Formoterol dry powder inhaler. Poster: Drug Delivery to the 
Lungs. In: DDL Conferences. Edinburgh, 2011. 
 
 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
II. Statistical analysis plan  
The data shall be processed and evaluated using statistical methods adopted in the 
case of tests not involving intervention. 
Single-variable statistical methods: frequency (distribution), relative frequency, average, standard 
deviation, median, lower and upper quartiles. Multivariate regression analysis is used to analyse 
primary and secondary endpoints, if necessary. 
 
The statistical analysis plan contains two parts, that is, the description of methods and tools for the 
processing of measured breathing parameters, and the description of methods and tools for the 
processing of the calculated deposited doses. 
 
II.1. Processing of the measured breathing data 
The analysis of the dependence of PIFdev for each selected device on patient demographic data 
(age, gender), anthropomorphic characteristics (height, weight), disease condition (expiratory 
volume at the end of the first second of forced exhalation: FEV1, forced vital capacity: FVC, 
Tiffeneau index: FEV1/FVC, GOLD grades) and baseline spirometric data characterizing the 
inhalation (peak inspiratory flow: PIF, inspiratory vital capacity: IVC, inhalation time: tin) is 
performed by an in-depth statistical evaluation of the interrelationships. 
 
Cross-correlation analysis of the above parameters (except gender, and GOLD grades) in 
connection with each device is performed. 
Correlations between different parameters are expressed by Pearson coefficients. 
Predictors of PIFdev are looked for by stepwise multiple regression analysis using a backward 
elimination technique. 
Mean PIFdev values of different patient subgroups upon gender, age, body mass index (BMI) and 
disease stages (GOLD grades) are analysed by conducting two-sample t-tests. Two age groups are 
formed. The cut-off age is 65 years. By the same token, two groups are formed upon BMI by 
using a cut-off value of 25 kg/m2. Two groups are analysed also based on disease severity. 
All statistical analyses are performed by the application of OriginPro 2018 (version b9.5.0.193, 
OriginLab Corporation, Northampton, Massachusetts, USA) and Minitab® (version 18.1, 
Minitab, Inc., State College, Pennsylvania, USA) software packages. A value of p < 0.05 is 
considered significant throughout the study. 
 
 
II.1. Processing of the computed lung deposition data 
 
An analysis of the correlation of the computed lung doses with the breathing parameters 
characterizing the inhalation through the selected devices (Q, tb-h, IV, tin, PIFdev) is performed. 
The strength of the correlation is expressed in terms of Pearson coefficients and any correlation is 
considered significant when p<0.05. 
 
In addition, the correlation of lung deposition with baseline spirometric breathing parameters 
expressing the breathing status of the patient (expiratory volume at the end of the first second of 
forced exhalation: FEV1, forced vital capacity: FVC, Tiffeneau index: FEV1/FVC, peak 
inhalation flow: PIF, peak expiratory flow PEF, inspiratory vital capacity: IVC) is studied. (PIF 
denotes the peak inhalation flow measured by standard spirometry, while PIFdev is the peak 
inhalation flow measured while inhaling through the device, PIFdev<PIF). 
 

 
County Institute of Pulmonology, Törökbálint 
TBEP-2110/01  
 
Mean values of lung doses characteristic of different age, gender and GOLD groups are analysed 
conducting two-sample t-tests. Two age groups are formed. The cutoff age is 65 years. Two 
groups are analysed also upon the classification of patients based on symptoms and exacerbation 
history. 
 
All statistical analyses are performed by the application of OriginPro 2018 (version b9.5.0.193, 
OriginLab Corporation, Northampton, Massachusetts, USA).