The Efficacy of Mepolizumab in Patients With Severe Eosinophilic Asthma Treated in Poland. The Real-life Observational Study
Conditions: Asthma; Eosinophilic
Sponsor: Medical University of Lodz

BIOETHICS COMMITTEE AT THE MEDICAL UNIVERSITY OF LODZ 
Pl. Hallera lB, 90-647 Łódź, tel. 785 911 596, 42 272-52-43, bioetyka@umed.lodz.pl 
 
RESOLUTION 
BIOETHICS COMMITTEE ON THE MEDICAL EXPERIMENT PROJECT 
Number RNN/188/20/EC of 14 July 2020 
(when corresponding regarding this decision, please refer to the above number and date  of the 
Resolution each time) 
Principal investigator and executive: 
Prof.dr hab.n.Marek L. Kowalski, MD, Department of Immunology and Allergy, Chair of 
Clinical Immunology and Rheumatology, Medical University of Lodz, 
 Pomorska 251, 92-213 Łódź 
Co-investigators: Aleksandra Wardzyńska, PhD; Monika Antczak-Marczak, PhD  
Study title: 
The efficacy of mepolizumab in patients with severe eosinophilic asthma treated in Poland. 
The real-life observational study 
Pursuant to the Act of 5 December 1996 on the professions of doctor and dentist (i.e. Dz. U. of 2017, item 
125, as amended.), the Act of  6 September 2001 on Pharmaceutical Law (i.e. Dz. U. of 2016, item 2142, as 
amended.), the Regulation of the Minister of Health of 2 May 2012 on  templates of documents to be submitted in 
connection with a clinical trial of a medicinal product and on the amount and manner of payment  of fees for 
submitting an application for the initiation of a clinical trial (Journal of Laws of 2012 U. of 2012, item 491), the 
Act   of 20 May 20  IO on Medical Devices (Journal of Laws of 20 I7.item 211 as amended.), Regulation of the 
Minister of Health of 17 February 2016. on  templates of applications submitted in connection   with a clinical trial, 
the amount of fees for submitting applications and the final report on the performance  of a clinical trial (Journal 
of Laws, item 208), Regulation of the Minister of Health and Social Welfare  of 11 May 1999.  on the detailed rules 
for the appointment and financing and operation of bioethics  committees (Journal  of Laws No. 47, item 1). 480), 
Ordinance No. 8/2015 of 16 February 2015 of the Rector of the Medical University of Lodz on the introduction of 
the Rules  of Procedure of the Bioethics Committee at  the Medical University of Lodz and Ordinance No. 57/2017 
of 5 February 2015September 2017 of the Rector of the Medical University of Lodz on the appointment  of the 
Bioethics Committee at  the Medical University of Lodz after analysing the application,  getting acquainted with 
the draft opinion on the submitted study,  in a secret ballot,  
 The Bioethics Committee at the Medical University  of Lodz (fulfilling the obligations of the 
ICH GCP) resolves as follows: 
§1 
1. Opinions the request positively, without reservations , based on Complex Documents, the 
list of which is set out in Annex No. 1. The resolution enters into life with the day of taking. 
§2 
The opinion concerns only the application  under consideration, taking into account the submitted draft. 
Each change and modification requires a separate opinion. The applicant  is obliged to inform about any 
corrections, adverse events and unforeseen circumstances. 
An appeal against this resolution shall be lodged through the Bioethics Committee at the   
Medical University of Lodz to  the Bioethics Appeal Committee, within 14 days from  the date  of receipt 
of the resolution expressing the opinion. 
Chairman of  the Bioethics Committee  
                                              at the Medical University of Łódź 

ATTACHMENT NO. 1 TO THE RESOLUTION 
BIOETHICS COMMITTEE ON THE MEDICAL EXPERIMENT PROJECT 
Number RNN/188/20/EC of 14 July 2020 
(when corresponding regarding this decision, please refer  to the  above 
number and date of the Resolution each time) 
 
 
Principal investigator and executive: 
Prof.dr hab.n.med. Marek L. Kowalski, Department of Immunology and 
Allergy, Department of Clinical Immunology and Rheumatology, Medical 
University of Lodz,  251 Pomorska Street, 92-213 Lodz 
Co-investigators: Aleksandra Wardzyńska, PhD;  Monika Antczak-Marczak, PhD   
Study title: 
The efficacy of mepolizumab in patients with severe eosinophilic asthma 
treated in Poland. The real-life observational study 
 
The Commission received the following documents: 
1. Request to the Bioethics Committee 
2. Study protocol 
3. List of sites participating in the study 
4. CV of Prof.Marek L. Kowalski, MD 
5. Consent of the director of the SP ZOZ Central Clinical Hospital  of the Medical 
University of Łódź 
 
 
 
 
 
Chairman of the Bioethics Committee at the 
Medical University of Lodz
 
 

NON-INTERVENTIONAL STUDY PROTOCOL 
 
 
 
THE EFFICACY OF MEPOLIZUMAB IN PATIENTS WITH SEVERE 
EOSINOPHILIC ASTHMA TREATED IN POLAND.  
THE REAL-LIFE OBSERVATIONAL STUDY 
     
 
 
 
 
 
 
 
  
 

 
 
TABLE OF CONTENTS 
NON-INTERVENTIONAL STUDY PROTOCOL ............................................................................................. 1 
1. 
BACKGROUND AND RATIONALE ...................................................................................................... 3 
2. 
OBJECTIVES ...................................................................................................................................... 3 
3. 
RESEARCH METHODOLOGY ............................................................................................................. 3 
3.1. 
Study Design ............................................................................................................................ 3 
3.2. 
Data Source / Data Collection ................................................................................................. 4 
3.3. 
Study Population ..................................................................................................................... 4 
3.3.1. 
Inclusion Criteria .............................................................................................................. 4 
3.3.2. 
Exclusion Criteria ............................................................................................................. 5 
3.4. 
Variables .................................................................................................................................. 5 
3.4.1. 
Outcome Definitions ....................................................................................................... 5 
3.4.2. 
Exposure Definitions ........................................................................................................ 5 
3.5. 
Sample Size .............................................................................................................................. 5 
4. 
DATA ANALYSIS CONSIDERATIONS .................................................................................................. 6 
5. 
LIMITATIONS .................................................................................................................................... 6 
6. 
STUDY CONDUCT, MANAGEMENT & ETHICS .................................................................................. 6 
6.1. 
Ethical Approval and Subject Consent..................................................................................... 6 
6.2. 
Adverse Event (AE), Pregnancy Exposure, and Incident Reporting ......................................... 6 
7. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .......................................... 6 
8. 
REFERENCES .................................................................................................................................... 7 
 
 

1. 
BACKGROUND AND RATIONALE 
 
Mepolizumab is a humanized monoclonal antibody (IgG1, kappa) against IL-5, which mediates the role 
of the eosinophils  in the inflammatory process of the airways. The drug has a high affinity to IL-5 and 
blocks the binding of IL 5 to the alpha chain of the IL-5 receptor complex expressed on the eosinophil 
cell surface. At present, mepolizumab is registered in the European Union as an adjunctive therapy in 
adults and paediatric patients aged 6-17 years  with inadequately controlled severe eosinophilic 
asthma. In Poland mepolizumab has been a reimbursable drug since 1st November, 2017 and is 
available under the national drug program for adults with severe eosinophilic asthma. 
The published results of the clinical trials show that the use of mepolizumab in the treatment of 
patients with severe eosinophilic asthma reduces the exacerbation rates, as well as decreases the 
doses of glucocorticosteroids (with the maintenance of asthma control). Moreover, mepolizumab 
demonstrates: long-term reduction of eosinophilic inflammation, consistent and sustained 
exacerbation reductions and improvements in asthma control for the duration up to 4.5 years. 
The proposed real-life observation study can deliver valuable information about mepolizumab efficacy 
complementing the results of clinical trials. Multicentre design of the study will allow to collect data 
from relatively large group of patients treated   at least one year within the Polish Drug programme.  
The added value of this retrospective study relies in the specifics  of the Polish drug programme which 
has unique inclusion criteria with respect to the number of eosinophil cells in blood. (the unique 
inclusion criteria in the Polish drug programme is ≥350 eos/ul) Therefore we can test the efficacy of 
mepolizumab in the specific treatment group. To this time no study has been published about the 
efficacy of mepolizumab in Poland. 
 
2. 
OBJECTIVES 
To evaluate the efficacy of mepolizumab 100 mg SC every 4 weeks in patients with severe eosinophilic 
asthma who have been  treated for at least 12 months   in several Polish allergy/asthma centres under 
the same protocol .  
3. 
RESEARCH METHODOLOGY 
3.1. 
Study Design 
Retrospective multicentre observational study will involve 130 patients with severe eosinophilic 
asthma ( SEA ) who have been treated in six  Severe Asthma Treatment Centres  ( SATCs) in Poland.  
In each SATC all  data available  in the program questionnaires  will be transferred to the Study Data 
Sheet (questionnaire), and  will be send to the study coordinator within 5 months from the study 
beginning    
The start-up meeting  including partners from  all centres involved will be organized to discuss the 
study protocol and to unify data collection  
 
 

The evaluation parameters (exacerbations rate, OCS dose) will be analysed at least at three time 
points: pre-MEPO, after 24 weeks of MEPO and after 1 year of MEPO administration (some of the 
outcomes will be observed every 4 weeks, for the details see ‘study endpoints’ section). 
In addition the following  parameters  which are available in patients’ records will be analysed:  
• 
ACQ-5 score (measured at qualification for the treatment and every 4 weeks thereafter)  
• 
AQLQ score (measured at qualification for the treatment and every 4 weeks thereafter) 
• 
Pre-bronchodilator FEV1 (measured at qualification for the treatment and every 4 weeks 
thereafter) 
 
Research activities will include: 
 
• 
collecting raw data from the clinical centres (paper version) and constructing a raw dataset 
(digital version), 
• 
data cleaning, computation of variables, 
• 
statistical analysis typical for pre-post study design (the statistical analysis will be outsourced to 
the specialized private institute). 
 
Clinical improvements observed at 24 weeks and at  52 weeks of treatment with Mepolizumab  will 
be referred to  the following characteristics of patients at baseline:  
• 
demographics,  
• 
presence of comorbidities including the atopic status,  
• 
concomitant pharmacotherapy,  
• 
clinical status,  
• 
eosinophilia.  
 
We will control for mepolizumab use regarding dose, treatment duration and dosing frequency as 
well as for the safety profile based on the AEs reporting in the medical documentation.    
3.2. 
Data Source / Data Collection 
Patients recruited to the study had been treated with mepolizumab between December 2017 and 
December 2019.  
All the data planned to be used in the proposed study  were systematically collected in the form of 
the clinical documentation (paper version) and will be transferred in the study centres into the study 
Data Sheets. 
Collaborating Researchers (Severe Asthma Centres’ Leaders) will provide the data input into the 
dedicated online questionnaire. 
 
3.3. 
Study Population 
 130 Patients who were treated with mepolizumab in six severe-asthma clinics in Poland between   
December 2017  and December 2019 . In the drug program in Poland it was mandatory to conduct the 
control examinations at  the 24th  and 52nd week of the treatment . In the proposed study we will use 
this information to evaluate study endpoints. Only patients who have been treated  for at least 52 
weeks are included into the study 
3.3.1. 
Inclusion Criteria 
• 
The availability of the complete data  

• 
Duration of treatment with mepolizumab: ≥ 52 weeks 
• 
Satisfying the Polish drug programme inclusion criteria:  
• 
Age >18 
• 
Before treatment with mepolizumab (BSAT inclusion criteria): 
 High doses of ICS + one other controlling medication (i.e. LABA)  
 ≥2 exacerbations in the previous year 
 ≥350 eosinophil cells/μl in the blood at the time of qualifying, or in the previous year 
 Pre-bronchodilator FEV1 < 80% 
3.3.2. 
Exclusion Criteria 
• 
Duration of treatment with mepolizumab < 52 weeks 
• 
Lack of  complete data  
3.4. 
Variables 
The main outcome variables are listed as the primary or secondary endpoints. Asthma exacerbation 
is defined as in the Polish drug programme (see 3.4.1.1.).  
Variables concerning the primary endpoints 
• 
Asthma exacerbations measured at qualification for the treatment (in the period of previous 52 
weeks) and at the 24th and 52nd week of the treatment. 
• 
Oral Corticosteroids  use  dose (documented at qualification for the treatment and at the 24th 
and 52nd week of the treatment) 
 
Variables concerning the secondary endpoints 
• 
ACQ-5 score (measured at qualification for the treatment and every 4 weeks thereafter)  
• 
AQLQ score (measured at qualification for the treatment and every 4 weeks thereafter) 
• 
Pre-bronchodilator FEV1 (measured at qualification for the treatment and every 4 weeks 
thereafter) 
• 
Blood eosinophil counts (measured at qualification for the treatment and at the 24th and 52nd 
week of the treatment) 
 
3.4.1. 
Outcome Definitions 
3.4.1.1. 
Asthma Exacerbation 
Asthma exacerbations, defined according to the Polish drug programme, is the worsening in asthma 
requiring (1) use of systemic corticosteroids or (2) increase in dose  of OCS for more than 3 days in 
case of patients who are chronically treated with OCS. 
3.4.2. 
Exposure Definitions 
There are no exposure variables to be defined in this study. 
3.5. 
Sample Size 
Retrospective multicentre observational study will involve 130 patients with SEA who have been 
treated in  six severe asthma treatment centres in Poland. The sample includes all individuals who 
participated in the drug programme in Poland at least for 52 weeks between December 2017 and 
December 2019  

The motivation to focus on this sample was the  following:  
• 
a relatively large sample of patients (N=130), 
• 
the unique and complete dataset containing patients’ characteristics and treatment results (all 
severe asthma centres participating in the drug programme are obliged to collect all the data we 
use in this study), 
• 
the opportunity to study the treatment results under the unique inclusion criteria of the Polish 
drug programme (≥350 eos/ul) (see 3.3.1). 
4. 
DATA ANALYSIS CONSIDERATIONS  
• 
Exacerbations rates in 24th and 52nd week with comparison to rate of exacerbations during the 
pre-treatment year.  Also the frequency of exacerbations in 6- and 12-month follow-up period 
will be described as patient count and percentage as categorical variable (0,1,2,3,4+ 
exacerbations).  
• 
OCS median doses in 24th and 52nd week with comparison to the median dose at baseline 
• 
ACQ-5, AQLQ, FEV1 measured on the monthly basis, the mean score at baseline will be compared 
with every post-treatment monthly score.  
• 
Blood eosinophil geometric mean in 24th and 52nd week with comparison to the geometric mean 
at baseline  
5. 
LIMITATIONS 
• 
The real-life observational studies are only complimentary to the clinical trials 
 
6. 
STUDY CONDUCT, MANAGEMENT & ETHICS 
6.1. 
Ethical Approval and Subject Consent  
This study will comply with all applicable laws regarding subject privacy.  No direct subject contact or 
primary collection of individual human subject data will occur.  Study results will be in tabular form 
and aggregate analyses that omits subject identification. The Polish ethics committee approval is 
required.  Any publications and reports will not include subject identifiers. 
6.2. 
Adverse Event (AE), Pregnancy Exposure, and Incident 
Reporting 
The planned study is a retrospective analysis. All the adverse events (AEs) and serious adverse events 
(SAEs) resulting in therapy termination will be scrutinized and qualitatively analysed.  
 
7. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
The study results are planned for external distribution (presentation at conferences and publication). 
The study will be closed upon sign-off of the final report document. Manuscript development 
activities will follow the final report sign-off. Planned Publication date (manuscript): October 2020. 
 

8. 
REFERENCES 
1. GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, 
prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive 
pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease 
Study 2015. Lancet Respir Med 2017; 5: 691-706. 
2. Chung KF, Wenzel SE, Brozek JL et al. International ERS/ATS guidelines on definition, evaluation 
and treatment of severe asthma. Eur Respir J 2014; 43:343-73. 
3. Clutterbuck EJ, Hirst EM, Sanderson CJ. Human interleukin-5 regulates the production of 
eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6 and GM-
CSF. Blood 1989; 73:1504–1512 
4. Varricchi G, Bagnasco D, Borriello F. et al.: Interleukin-5 pathway inhibition in the treatment of 
eosinophilic respiratory disorders: evidence and unmet needs. Curr Opin Allergy Clin Immunol 2016; 
16: 186-200 
5. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 
2012; 18:716–725 
6. Charakterystyka Produktu Leczniczego Nucala, 2018 
7. www.ginasthma.org.2019  
8. http://www.ema.europa.eu.&#13; 9. Obwieszczenie Ministra Zdrowia w sprawie wykazu 
refundowanych leków, środków spożywczych specjalnego przeznaczenia żywieniowego oraz 
wyrobów medycznych na dzień 1 listopada 2017 (www.mz.gov.pl). 
10. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of 
mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 
2007;176:1062-71 
11. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory 
eosinophilic asthma. N Engl J Med 2009; 360: 973–84 
12. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with 
sputum eosinophilia. N Engl J Med 2009; 360: 985–93. 
13. Pavord ID, Korn S, Howarth P et al. Mepolizumab for severe eosinophilic asthma (DREAM): a 
multicentre, doubleblind, placebo-controlled trial. Lancet 2012; 380: 651-9. 
14. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic 
asthma. N Engl J Med 2014; 371: 1198-207. 
15. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in 
eosinophilic asthma. N Engl J Med 2014; 371: 1189-97. 
16. Lugogo N, Domingo CH, Chanez P, et al. Long-term efficacy and safety of mepolizumab in patients 
with severe eosinophilic asthma: a multi-center, open-label, Phase IIIb study.  
Clin Ther 2016; 38: 2058-70 
17. Chupp GL, Bradford ES, Albers FC, et al. Efficacy of mepolizumab add-on therapy on health-
related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a 
randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet 
Respir Med 2017;5:390-400 
18. Ortega HG, Yancey SW, Mayer B, et al. Severe eosinophilic asthma treated with mepolizumab 
stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. 
Lancet Respir Med 2016; 4: 549–56. 
19. Yancey SW, Keene ON, Albers FC, Ortega H, Bates S, Bleecker ER, Pavord I. Biomarkers for severe 
eosinophilic asthma. J Allergy Clin Immunol. 2017;140:1509–18. 
20. Pouliquen IJ, Kornmann O, Barton SV, Price JA, Ortega HG. Characterization of the relationship 
between dose and blood eosinophil response following subcutaneous administration of 

mepolizumab. Int J Clin Pharmacol Ther 2015; 53:1015-27 
21. Khatri S. i wsp. Assessment of the long-term safety of mepolizumab and durability of clinical 
response in patients with severe eosinophilic asthmaJ Allergy Clin Immunol. 2018