SATisfaction and Adherence to COPD Treatment
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
 
TITLE PAGE 
Non-interventional Study Protocol 
Document Number: 
Not applicable 
BI Study Number: 
1237.51  
BI Investigational 
Product(s): 
Not applicable 
Title: 
SATisfaction and adherence to COPD treatment 
Protocol version 
identifier: 
1.0 
Date of last version of 
protocol: 
31st July 2015 
PASS: 
No 
EU PAS register 
number: 
Not Applicable 
Active substance: 
Not Applicable 
Medicinal product: 
Not Applicable 
Product reference: 
Not Applicable 
Procedure number: 
Not applicable 
Marketing authorisation 
holder(s): 
Not Applicable 
Joint PASS: 
No 
Research question and 
objectives: 
Treatment satisfaction in COPD is associated with disease 
knowledge: subjects who claim to be more informed are more 
satisfied with their management. Literature data in Italian real 
world life setting about the relation between treatment 
satisfaction and clinical parameters  are lacking.  The present 
study will explore the patients’ satisfaction to COPD medical  
treatment (i.e. pharmacological and not pharmacological 
treatment) in a clinical real-world setting and how the satisfaction 
for medical treatment is related to clinical parameters, quality of 
life, illness  perception and treatment adherence evolution.  
Moreover health care resource consumption will be observed 
during the observation period. 
 
Primary Objective 
To describe the patients’ satisfaction to COPD medical  
treatments (by means of the TSQM9) during a 12-month 

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observation (namely, at enrolment, after 6 and 12 months) in 
real-world setting.  
  
Secondary Objectives 
To describe patient disease perception (by means of brief illness 
perception questionnaire B-IPQ), adherence to COPD  treatment 
(by means of MMAS4), health status (by means of CAT 
questionnaire) and dyspnea (by means of MMRC) during 12-
month observation period.  
2. To analyse the relation between  treatment satisfaction and 
demographic (such as age and gender) and clinical parameters 
(such as number of exacerbations and spirometric parameters) 
and PROs during a 12-month observation period.  
3. To describe the health care resources utilization and related 
cost according to the Italian National Health Service (INHS) 
during 12-month observation period.  
4. To assess the correlation between patients’ satisfaction and 
resource utilization. 
Country(-ies) of study: 
Italy  
Author: 
 
Marketing authorisation 
holder(s): 
Not applicable 
In case of PASS, add: 
MAH contact person: 
Not applicable 
In case of PASS, add: 
<EU-QPPV:> 
Not applicable 
In case of PASS, add: 
<Signature of EU-
QPPV:> 
Not applicable 
Date: 
Not applicable 
Proprietary confidential information 
© 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission 
 
 
 

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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ....................................................................................... 3 
2. 
LIST OF ABBREVIATIONS ................................................................................ 5 
3. 
RESPONSIBLE PARTIES .................................................................................... 6 
4. 
ABSTRACT ........................................................................................................... 7 
5. 
AMENDMENTS AND UPDATES ..................................................................... 17 
6. 
MILESTONES ..................................................................................................... 18 
7. 
RATIONALE AND BACKGROUND ................................................................ 19 
8. 
RESEARCH QUESTION AND OBJECTIVES ................................................. 21 
9. 
RESEARCH METHODS .................................................................................... 22 
9.1 
STUDY DESIGN ............................................................................................ 22 
9.2 
SETTING ........................................................................................................ 22 
9.3 
VARIABLES .................................................................................................. 23 
9.4 
DATA SOURCES ........................................................................................... 27 
9.5 
STUDY SIZE .................................................................................................. 28 
9.6 
DATA MANAGEMENT ................................................................................ 28 
9.7 
DATA ANALYSIS ......................................................................................... 29 
9.8 
QUALITY CONTROL ................................................................................... 32 
9.9 
STUDY MONITORING ................................................................................. 32 
9.10 
GUIDELINES FOR EPIDEMIOLOGICAL STUDIES ................................. 32 
9.11 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT RECORDS
 
32 
9.12 
INVESTIGATOR'S FILES / RETENTION OF DOCUMENTS ................... 33 
9.13 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 33 
9.14 
OTHER ASPECTS ......................................................................................... 34 
9.15 
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS ....... 34 
9.16 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 34 
9.16.1 
DATA QUALITY ASSURANCE .......................................................... 35 
9.16.2 
RECORDS .............................................................................................. 35 
9.16.3 
SOURCE DOCUMENTS ....................................................................... 35 
9.16.4 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS............ 35 
9.16.5 
STATEMENT OF CONFIDENTIALITY .............................................. 36 
9.16.6 
COMPLETION OF STUDY ................................................................... 36 

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9.16.7 
PROTOCOL VIOLATIONS ................................................................... 36 
9.16.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY .................................................................. 36 
10. 
PROTECTION OF HUMAN SUBJECTS .......................................................... 37 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ............................................... Errore. Il segnalibro non è definito. 
11.1 
Definitions of adverse events .................. Errore. Il segnalibro non è definito. 
11.2 
Adverse event and serious adverse event Collection and reporting .... Errore. Il 
segnalibro non è definito. 
11.3 
Reporting to heath Authorities ................ Errore. Il segnalibro non è definito. 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
 ............................................................................................................................. 42 
12.1 
Operative management of Medical Writing Aspects ...................................... 42 
12.2 
Ghostwriting and Guest/Ghost Authorship ..................................................... 43 
12.3 
Determining Order of Authorship ................................................................... 43 
13. 
REFERENCES .................................................................................................... 44 
13.1 
PUBLISHED REFERENCES ......................................................................... 44 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 48 
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 49 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 50 
 
 
 

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2. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
BMI 
Body Mass Index 
BIPQ 
Brief Illness Perception Questionnaire 
BITSPA 
Boehringer Ingelheim Italy S.p.A.  
CAT 
COPD Assessment Test 
CI 
Confidence Interval 
CML 
Local Clinical Monitor  
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMF 
Clinical Trial Master File 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
DLCO 
Diffusion Lung Capacity for carbon monoxide 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FVC 
Forced vital capacity 
FEV1 
Forced expiratory volume in the 1st second 
GCP 
Good Clinical Practice 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
LTOT 
Long-Term Oxygen Therapy  
MMAS-4 
Morisky medication Adherence Scale, 4 items 
MMRC 
Modified Medical Research Council Dyspnea Scale 
PRO 
Patient Related Outcome 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
TLC 
Total Lung Capacity 
TSQM-9 
      Treatment Satisfaction Questionnaire, 9 items 
VC 
Vital Capacity 
 

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3. 
RESPONSIBLE PARTIES 
List of all main responsible parties, including the principal investigators who signed this page, will be kept in a 
stand-alone document to be listed in Annex 1 and it will be available upon request. 
 
 

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4. 
ABSTRACT 
Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
Not applicable 
 
Name of active ingredient: 
Not applicable 
 
Protocol 
date: 
Study number: 
Version/Revision: 
Version/Revision date: 
31 July 2015 
1237.51 
1.0 
 
Title of 
study: 
SATisfaction and adherence to COPD treatment 
Rationale 
and 
background
: 
COPD is a debilitating disease characterized by poorly reversible airflow 
limitation, breathlessness on exertion (1-2), exercise intolerance (3) and 
limitations in the capacity to perform daily activities (4-5).  
In studies that have explored patient perspectives regarding the burden and 
impact of COPD, predominant complaints are shortness of breath and limitations 
in the ability to participate in activities (6), which negatively impact on social 
interactions and result in loss of independence (7-8).  
Patient satisfaction with their medication is shown to affect treatment-related 
behaviors, such as their likelihood of continuing to use their medication, to use 
their medication correctly and to adhere with medication regimen (9). Treatment 
satisfaction may give useful insights not only into the patients’ perspective on 
their current treatment but also about  differentiation among alternative 
treatments. Treatment satisfaction is defined as the individual’s rating of 
important attributes of the process and outcomes of his/her treatment experience 
(11). It focuses on one aspect of satisfaction with medical care and involves the 
interaction of expectations, preferences, and satisfaction with medical treatment. 
Treatment satisfaction assessment is potentially useful for understanding the 
patient’s perspective on their current treatment and can be helpful to differentiate 
among alternative treatments (14-15). Patient expectations, demographic 
characteristics, such as age and education, and personal preferences affect 
treatment satisfaction.  The pattern and characteristics (that is, side effects and 
effectiveness) of ongoing treatments for COPD, and the duration/severity of 
COPD influence perceptions of treatment satisfaction. More important are the 
factors most directly connected to the treatment, and the way the treatment is 
delivered and directly experienced by the patient. Outcomes of treatment, 
including impact on symptoms and adherence with the treatment regimen, 
represent an important determinant of treatment satisfaction. In 2012 only the 
14.3% of Italian patients affected by obstructive respiratory syndromes was 
adherent to treatment (48) 
The complexity, discomfort and convenience associated with treatment also affect 
patient perceptions and evaluations of satisfaction with the treatment. Finally, the 
individual’s intentions, as manifested by their willingness to continue therapy, or 
his/her preference for, or choice of the treatment over other alternative treatments 
are relevant.  

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Satisfaction to treatment is related to adherence and willingness to continue 
treatment (16). Almost half of patients with COPD do not adhere to their 
medications (32).  
Moreover, the course of COPD can be affected by acute events characterized by a 
worsening of the patient’s respiratory symptoms that is beyond normal day-to-day 
variations and leads to a change in medications, known as exacerbations (33). 
Despite treatment with maintenance medications, COPD patients continue to have 
exacerbations, so new medications and disease management interventions are 
warranted to reduce the severity and frequency of exacerbations and the related 
cost impact of the disease (34). The COPD assessment test (CAT) is a useful tool 
for the measurement of the health status during the exacerbation and for 
evaluation of recovery. 
Literature data in Italian real world setting about the relation between treatment 
satisfaction and clinical parameters  and PRO are lacking. In a general population 
survey conducted in ten countries of the Middle East and North Africa region, 
together with Pakistan on COPD subjects with respiratory symptoms the 
treatment satisfaction was relatively high, with 83.2% of respondents somewhat 
or very satisfied with their physician’s management. Treatment satisfaction was 
associated with not having exacerbations and with knowledge, subjects who 
claimed to be more informed being more satisfied with their management (37). 
Chronic obstructive pulmonary disease is a major cause of chronic morbidity and 
mortality worldwide, and its epidemiological, clinical, and socioeconomic impact 
is progressively increasing. A first estimate of the economic burden of COPD in 
Italy was conducted in 2008 (the SIRIO [Social Impact of Respiratory Integrated 
Outcomes] study) (40). Average direct costs and total societal costs in the year 
before enrollment were €2,932 and €3,291, respectively. Direct cost was €2,461 
(hospitalization: €1,570; outpatient: €344; and pharmaceutical: €547) in the first 
year of follow-up, while total societal cost was €2,707.  
Patients with COPD are at increased risk for lung infections and other pathologies 
(eg, pneumonia). A study on two cohorts of 84130 COPD patients each, showed 
that COPD patients with newly developed pneumonia have higher health care 
resource utilization and/or costs in all areas explored: hospitalizations, outpatient 
visits, ER visits, and prescription costs (38). In this study, the pneumonia cohort 
was approximately nine times more likely to have a hospitalization and four times 
more likely to have an ER visit during the 12 months of follow-up. A total cost 
savings of $22348 was estimated to be associated with the prevention of 
pneumonia based on the sum of the mean differences of $14353 in inpatient costs, 
$6891 in outpatient costs, and $1104 in pharmacy costs between the pneumonia 
and control cohorts. 
Poor adherence to treatment may contribute to the treatment gap in COPD. A 
large population-based study have shown that reduced adherence to treatment 
with 
tiotropium 
(TIO) 
alone 
or 
co-administered 
with 
fluticasone 
propionate/salmeterol (TIO + FSC) is associated with increased risk for 
exacerbations and higher health care utilization in COPD patients (39). 

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Research 
question and 
objectives: 
Long-term data on the patients’ satisfaction to COPD medical treatments (i.e. 
pharmacological and not pharmacological treatment) in Italy are scarce. Further, 
there is limited information on the relation between satisfaction and clinical and 
patients’ parameters. The present study will explore the patients’ satisfaction to 
COPD medical  treatment in a clinical real- world setting and how this is related 
to clinical parameters, quality of life, illness  perception and treatment adherence 
evolution during 12-month follow up.  
The patients will be also described as far as health status, presence of dyspnea, 
exacerbation occurrence, patient disease perception and awareness and adherence 
to COPD treatment during a 12-month follow up. Finally, health care resources 
utilization and related cost according to the Italian National Health Service during 
12-month observation will be estimated and the correlation between patients’ 
satisfaction and resource utilization will be assessed. 
 
Primary Objective 
To describe the patients’ satisfaction to COPD medical  treatments (by means of 
the TSQM9) during a 12-month observation period (namely, at enrolment, and 
after 6 and 12 months) in real- world setting.  
 
Secondary Objectives 
1. To describe patient disease perception (by means of illness perception 
questionnaire B-IPQ), adherence to COPD  treatment (by means of 
MMAS4), health status (by means of CAT questionnaire) and dyspnea (by 
means of MMRC) during a 12-month  observation period.  
2. To analyze the relation between treatment satisfaction and demographic 
(such as age, gender), clinical (such as number of exacerbations, spirometric 
parameters) parameters and PROs during a 12-month observation period.  
3. To describe the health care resources utilization and related cost according to 
the Italian National Health Service (INHS) during a 12-month observation 
period.  
4. To assess the correlation between patients’ satisfaction and resource 
utilization. 
Study 
design: 
This is a multi-center, non-interventional (observational) cohort study based 
mainly on newly collected data. 
In 20 Italian Pulmonary Centres about 400 consecutive COPD patients will be 
enrolled in approximately 8 months (from first patient enrolled). Patients will be 
followed up for 1 year, with an intermediate evaluation after 6 (+/-1) months from 
baseline (which is compatible with current clinical practice in Italy for COPD 
patients management). 
No treatment will be administered to the patients on the protocol basis, since this 
is an non-interventional study and the assessment and treatment of the enrolled 
patients will be applied according to standard clinical practice. The patients 
switching or stopping treatment during observation period will not be withdrawn 
from the study. Few patients are expected to stop treatment during study; if any, 
for primary objective evaluation they will be censored at the latest available visit. 
Population: 
All patients, both female and male gender, referring to pulmonary centers will be 

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consecutively enrolled according to the following criteria: 
 
Inclusion Criteria  
1. Patients aged ≥40 years 
2. Patients must have a documented diagnosis of chronic obstructive 
pulmonary disease (COPD) 
3. Patients with no exacerbations in the last 3 months 
4. Patients requiring regular treatment according to GOLD guidelines, i.e.: 
undergoing stable pharmacological treatment for COPD since at least 3 
months 
5. Written informed consent to both participation in the study and privacy 
form 
6.  Patients capable of discernment and able to read or write in Italian 
language. 
 
Exclusion Criteria  
1. Patients who are currently participating in  a clinical trial on experimental 
drugs. 
2. Patients naïve to pharmacological treatment for COPD 
3. Diagnosis of Asthma COPD Overlap Syndrome (ACOS) 
 
Study Exit criteria 
An individual patient may be withdrawn from the non-interventional study prior 
to completion if any of the following criteria apply: 
1. The patient withdraws consent, without the need to justify the decision. 
2. The patient is no longer able to participate (according to clinical judgment) 
3. Administrative reasons (inclusion in another clinical trial) 

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Variables: 
Table 1 below is the recommended assessment schedule that most likely mirrors 
the patterns of routine clinical care of most patients. 
Study Visits 
Visit 1 
Visit 2 
Visit 3 
Baseline 
Follow-
up  
Follow-
up 2 
Months 
0 
6 (+/-1)  
12 (+/- 1) 
Eligibility criteria 
Inclusion and exclusion criteria, 
Informed consent and privacy 
form 
X 
 
 
Baseline information 
(Socio-)demographic variables: 
age, gender, race,  geographic 
location, housing situation, 
marital status, educational and 
employment status 
X 
 
 
Weight, body mass index 
X 
X 
X 
Physical examination 
X 
X 
X 
Life Habits 
Smoking (yes/no, number of 
pack/years, smoke duration) 
X 
X 
X 
Medical History/Concomitant 
diseases. 
- Charlson Comorbidity Index. 
X 
X 
X 
COPD medical history:  
Date of COPD diagnosis (years 
from diagnosis); 
 n° of COPD exacerbations/year 
during the previous year to 
enrolment visit 
X 
 
 
Functional assessment  
Lung function test results 
(FEV1, FVC, FEV1 % of the 
predicted, RV, TLC,DLCO) 
according to clinical practice 
X 
X 
X 
CAT questionnaire 
X 
X 
X 
COPD Exacerbations** after 
enrollment 
Onset and resolution date 
Severity (mild, moderate, severe) 
X 
X 
X 
Disease severity (GOLD 
2015Guidelines) 
X 
X 
X 
Medications related to COPD, 
COPD exacerbations and 
adverse events (LABA, LAMA, 
X 
X 
X 

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SABA, SAMA, ICS/LABA, 
steroids, antibiotics, etc..): drug, 
dose, frequency, duration of 
therapy. 
- Long-Term Oxygen Therapy 
(liquid and/or concentrate). 
Change of therapy during 
observation period and reason 
for change. 
 
X 
X 
Non Pharmacological 
treatment  
- Pulmonary rehabilitation-  
X 
X 
X 
Health-care resource 
consumption  related to COPD, 
COPD exacerbations and 
adverse events: 
• 
Drugs 
• 
hospitalization (inward 
and day hospital) 
• 
emergency room access 
• 
outpatient visits 
• 
GP visits 
• 
laboratory tests 
• 
clinical examinations 
X 
X 
X 
Patient Reported Outcomes 
Questionnaires/scales 
 
 
 
TSQM-9 
X 
X 
X 
MMRC (modified MRC dyspnea 
scale)  
X 
X 
X 
CAT 
X 
X 
X 
MMAS-4 (Morisky Medication-
Taking Adherence Scale) 
X 
X 
X 
Brief Illness Perception 
Questionnaire 
X 
X 
X 
Awareness structured interview  
X 
X 
X 
S(AE) assessment 
 
X 
X 
Table 1.Recorded variables.  
** An exacerbation will be defined as  an increase or new onset of more than 1 
symptom (cough, sputum, wheezing, dyspnoea or chest tightness) with at least 1 
symptom lasting at least 3 days and leading to patient’s attending physician to 
initiate treatment with systemic steroids and/or antibiotics (moderate 
exacerbation) or hospital admission (severe exacerbation).  
 
Visit 2 (6+/-1 month), Visit 3 (12+/-1 month) are referred as being the current 
clinical practice in Italy for COPD patients management. 
 
Data will be collected at inclusion visit, 6 (±1) and 12 (±1) month follow up. 
 

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The 
following 
questionnaires/scales/patient 
reported 
outcomes 
will 
be 
administered to patients. They are briefly described below. 
• Treatment Satisfaction Questionnaire, 9 items (TSQM-9); 
• Brief Illness Perception Questionnaire (BIPQ); 
• Morisky medication Adherence Scale, 4 items (MMAS-4);  
• COPD Assessment Test (CAT); 
• Modified Medical Research Council Dyspnea Scale (MMRC). 

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Data 
sources: 
Source data will be medical records usually collected during routine clinical 
practice other than study-specific questionnaires.  
Collected variables are defined based on study objectives and according to the 
non-interventional nature of the study. They consist in data routinely collected in 
clinical practice, so they are expected to be available in medical charts. 
For Charlson Comorbidity Index.calculation ICD-9CM will be considered by 
clinical investigators. If ICD-9CM is not available according to routine clinical 
practice, main ongoing diseases at baseline will be anyway collected. 
The study data will be collected by means of remote data capture using an 
electronic case report form (eCRF). Investigators will be provided a user-friendly 
paper form which is intended as a supportive tool for data collection and will be 
filled in according to each site specific need (it will not be considered as a source 
data). 
Patient-reported outcomes, i.e. scales and questionnaires, will be collected on 
paper and they will constitute source data. 
Study size: 
The sample size was determined on the basis of feasibility criteria. In fact, 
according to the volume of patients managed by the centres involved in this 
study, inclusion of 400 subjects (20 patients/center) with the characteristics 
defined at Inclusion/Exclusion criteria paragraphs is deemed reasonable for the 
planned enrolment period (8 months). Assuming a drop-out rate ranging from of 
5% to 20% (including not evaluable, lost-to follow up and not on treatment 
patients), effective sample size is expected to range between 320 (drop out=20%) 
and 380 (drop out=5%). 
An evaluation of the possible achievable precision of the estimates was 
performed considering the primary objective of the study. No data on treatment 
satisfaction is available about COPD patients specifically, therefore available 
literature data was used as a reference to evaluate possible scenarios. In 
particular, literature data about TSQM was found on multiple sclerosis, psoriasis, 
etc, showing the global satisfaction mean score ranging from 54.4 to 79.7 [17,18]. 
Table 2 shows the 95% confidence interval half-width and standard error (SE) of 
the expected mean of global satisfaction score under different sample sizes. 
Expected Mean (SD) 
54.4 (21.4) 
79.7 (16.6) 
Sample Size 
380 
320 
380 
320 
95% confidence interval half width 
2.152 
2.345 
1.669 
1.819 
Standard error (SE) 
1.098 
1.196 
0.852 
0.928 
Table 2. 95% confidence interval (CI) half-width and standard error (SE)  of the 
expected mean assuming N=380/320 evaluable patients [19] 
In all considered scenarios the relative error of the estimate (CI half-
width/expected mean) is lower than 30%. The lower the sample size and the 
higher the standard deviation, the lower the estimate precision. 

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Data 
analysis: 
Descriptive analysis will be  means, medians, quantiles, proportions (with their 
respective 95% confidence intervals and SE when relevant) and contingency 
tables according to the nature of the variables. As a dispersion measurement the 
standard deviation and the interquartile range will be calculated. 
The statistical analysis will be done on all evaluable patients i.e. patients who 
enter the study without inclusion-exclusion criteria violations and with at least 
one TSQM-9 domain score (effectiveness, convenience and global satisfaction) 
calculated.  Patients with missing values will not be excluded from the analysis, 
their data will not be replaced; frequency of missing data will be given for all 
analyzed variables. Lost to follow up patients will be analyzed until their last 
available visit.   
The study objectives will be evaluated as described below. 
Primary objective  
The patients’ satisfaction for medical treatment will be assessed by the 9-item 
Treatment Satisfaction Questionnaire for Medication (TSMQ-9) at each study 
visit 46). It is composed by 3 domains covering efficacy, convenience and global 
treatment satisfaction. TSQM-9 scores will be calculated according to author’s 
instructions and summarized at each time point on all evaluable patients. Patients 
lost to follow up will be considered until their last available visit. 
The patients switching treatment during observation period will not be excluded 
from analysis and will be evaluated at each visit as above described. Few patients 
are expected to stop treatment during study; if any, for primary objective 
evaluation they will be censored at the latest available visit. Comparisons of 
satisfaction between different treatment/devices are not matter of this study, 
throughout all analysis treatments will be lumped together.  
Secondary objectives  
#1 To describe patient disease perception (B-IPQ), adherence to COPD  treatment 
(MMAS4), health status (CAT) and dyspnea (MMRC) during a 12-month 
observation period 
A description of B-IPQ, MMAS-4, CAT and MMRC scores will be provided at 
baseline and at follow-up visits. Scale scores will be summarized at each time 
point. Patients lost to follow up will be considered until their last available visit. 
Missing items of questionnaires/scales will be replaced where applicable 
according to scoring algorithms. 
#2 To analyse the relation between  treatment satisfaction for medical treatment 
and demographic/clinical parameters  and PROs during a 12-month observation 
period 
Three regression models (one for each TSQM-9 domain score) will be estimated; 
the dependent variable will be domain score and the independent ones will be: 
age and gender (at enrollment), number of exacerbations, relevant spirometry 
parameters, level of dyspnea (MMRC score),  impact of COPD on a patient’s life 
(CAT) and treatment adherence (MMAS-4 score) collected during observational 
period. Because dependent variable will be collected at each study visit, repeated 
measures models will be estimated taking into account all available values for 
dependent and independent variables.  
#3 To describe the health care resources utilization and related cost during a 12-
month observation period 
The health care resources consumption will take into consideration the following 

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events related to management of COPD and COPD exacerbations: inpatients and 
outpatients hospitalization (inward and day-hospital), accesses to emergency 
room, General Practitioner (GP)  and outpatient visits, laboratory tests and 
examinations, pharmacological and non-pharmacological therapies (pulmonary 
rehabilitation) occurred/administered during study period.  
Medications for adverse events will be considered too. 
The annual direct health care resource consumption and related cost will be 
provided by means of descriptive statistics of the variables mentioned above. In 
order to describe the health care cost from enrolment up to the end of 12-month 
follow-up according to the INHS point of view (26), a two steps approach will be 
followed: (i) first of all the resource consumed since enrolment will be calculated 
and then (ii) a monetary value will be assigned to the resource consumption. 
(i) 
Health care resources consumption exclusively related to COPD, COPD 
exacerbations and COPD-drug-related adverse events will be computed 
during observational period in terms of pharmacological and non-
pharmacological treatments, number of (inward and day-hospital) 
hospitalizations, number of emergency room accesses, number of GP 
visits, specialist visits, laboratory tests or examinations (spirometry, 
FEV1, FVC, FEV1 % of the predicted, RV, IC, TLC, DLCO).  
(ii) 
(ii) In order to estimate the economic impact on health care sector related 
cost (30)  of the above mentioned health services (hospital admissions, 
visits, treatments, examinations, spirometry) consumption, a monetary 
value to each event recorded will be assigned, as defined by the Italian 
Ministry of Health through the tariffs in force for outpatient setting (31). 
The cost of hospitalization will be valued according to the most recent 
available 
diagnosis-related 
group 
(DRG) 
tariffs 
(32); 
finally, 
pharmacological treatments will be costed at consumer price. All costs 
will be expressed in €2015. A monthly (or yearly) cost will be provided 
by taking into account patients according to duration of observation and 
parametrizing each patient to the 12-month observation period. 
Descriptive statistics (mean, standard deviation, median, minimum and 
maximum) of the annual direct health care resource consumption and related cost 
will be provided.  
Non-parametric bootstrap method will be applied to cost data for calculating 95% 
confidence intervals (22-23). 
#4 To assess the correlation between patients’ satisfaction and resource 
utilization. 
Correlation indexes will be calculated between treatment satisfaction domain 
scores of TSQM-9 and healthcare resource consumption (such as number of 
hospitalizations, emergency room accesses, GP visits, laboratory test. etc… 
during observation period) at 12-month follow-up visit. The patients switching 
treatment during observation period will not be excluded from analysis and will 
be evaluated at each visit. The patients stopping treatment during study will be 
censored at the latest available visit 
Milestones: 
- 
Start of data collection: November 2015 
- 
End of data collection: July 2017 
- 
Final report of study results: December 2017 
 

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5. 
AMENDMENTS AND UPDATES 
Any change or addition to the protocol requires a written protocol amendment that must be 
approved by BITSPA and all main responsible parties, the principal investigator and the 
relevant EC before implementation. Amendments only affecting administrative aspects of 
the study do not require formal protocol amendments or EC approval but the ECs have to be 
informed of such administrative changes. 
 

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6. 
MILESTONES 
 
The first patient enrolled in the study is expected in November 2015. The end of the data 
collection (including the follow-up period) is expected within July 2017, depending on the 
effective enrolment period necessary to collect data from about 400 consecutive COPD 
patients to be enrolled in approximately 8 months (from first patient enrolled). 
 
Milestone 
Planned Date 
Start of data collection 
November 2015 
End of data collection 
July 2017 
Final report of study results: 
December 2017 
 

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7. 
RATIONALE AND BACKGROUND 
COPD is a debilitating disease characterized by poorly reversible airflow limitation, 
breathlessness on exertion (1-2), exercise intolerance (3) and limitations in the capacity to 
perform daily activities (4-5).  
In studies that have explored patient perspectives regarding the burden and impact of 
COPD, predominant complaints are shortness of breath and limitations in the ability to 
participate in activities (6), which negatively impact on social interactions and result in loss 
of independence (7-8).  
Patient satisfaction with their medication is shown to affect treatment-related behaviors, 
such as their likelihood of continuing to use their medication, to use their medication 
correctly and to adhere with medication regimen (9). Treatment satisfaction may give useful 
insights not only into the patients’ perspective on their current treatment but also about  
differentiation among alternative treatments. Treatment satisfaction is defined as the 
individual’s rating of important attributes of the process and outcomes of his/her treatment 
experience (11). It focuses on one aspect of satisfaction with medical care and involves the 
interaction of expectations, preferences, and satisfaction with medical treatment. Treatment 
satisfaction assessment is potentially useful for understanding the patient’s perspective on 
their current treatment and can be helpful to differentiate among alternative treatments (14-
15). Patient expectations, demographic characteristics, such as age and education, and 
personal preferences affect treatment satisfaction.  The pattern and characteristics (that is, 
side effects and effectiveness) of ongoing treatments for COPD, and the duration/severity of 
COPD influence perceptions of treatment satisfaction. More important are the factors most 
directly connected to the treatment, and the way the treatment is delivered and directly 
experienced by the patient. Outcomes of treatment, including impact on symptoms and 
adherence with the treatment regimen, represent an important determinant of treatment 
satisfaction. In 2012 only the 14.3% of Italian patients affected by obstructive respiratory 
syndromes was adherent to treatment (48). 
The complexity, discomfort and convenience associated with treatment also affect patient 
perceptions and evaluations of satisfaction with the treatment. Finally, the individual’s 
intentions, as manifested by their willingness to continue therapy, or his/her preference for, 
or choice of the treatment over other alternative treatments are relevant.  
Satisfaction to treatment is related to adherence and willingness to continue treatment (16). 
Almost half of patients with COPD do not adhere to their medications (32). Illness and 
medication beliefs are important determinants of adherence in COPD.  A recent study 
showed that in an a cohort of adults with COPD from New York and Chicago, concerns 
about medications (evaluated by means of Brief Illness Perception Questionnaire and the 
Beliefs about Medications Questionnaire) were associated with non-adherence evaluated by 
means of Medication Adherence Report Scale (32). 
Although guidelines recommend monitoring symptoms in patients with COPD, there is 
limited information on the longitudinal changes in patient-reported dyspnea (PRD) related 
to activities of daily living. In a observational cohort study of symptomatic patients with 
stable COPD evaluated every 6 months for 2 years, PRD scores on the modified Medical 
Research Council (MMRC) scale demonstrate progression over two years despite stable 
lung function (36). Moreover, the course of COPD can be affected by acute events 
characterized by a worsening of the patient’s respiratory symptoms that is beyond normal 
day-to-day variations and leads to a change in medications, known as exacerbations (33). 

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COPD exacerbations have serious negative impact on patient quality of life, lung function, 
and socioeconomic costs so their prevention, early detection, and prompt treatment have a 
great importance in the management of the disease. Despite treatment with maintenance 
medications, COPD patients continue to have exacerbations, so new medications and 
disease management interventions are warranted to reduce the severity and frequency of 
exacerbations and the related cost impact of the disease (34). The COPD assessment test 
(CAT) is a useful tool for the measurement of the health status during the exacerbation and 
for evaluation of recovery; in an observational, prospective study aimed at assessment of the 
course of CAT scores during bacterial exacerbations of COPD treated in outpatient setting, a 
significant improvement in the patient’s health status during recovery from exacerbation as 
compared to their health status at the time of exacerbation was found (35). 
Literature data in Italian real world setting about the relation between treatment satisfaction 
and clinical parameters  and PRO are lacking. In a general population survey conducted in 
ten countries of the Middle East and North Africa region, together with Pakistan on COPD 
subjects with respiratory symptoms the treatment satisfaction was relatively high, with 
83.2% of respondents somewhat or very satisfied with their physician’s management. 
Treatment satisfaction was associated with not having exacerbations and with knowledge, 
subjects who claimed to be more informed being more satisfied with their management (37). 
Chronic obstructive pulmonary disease is a major cause of chronic morbidity and mortality 
worldwide, and its epidemiological, clinical, and socioeconomic impact is progressively 
increasing. A first estimate of the economic burden of COPD in Italy was conducted in 2008 
(the SIRIO [Social Impact of Respiratory Integrated Outcomes] study) (40). Average direct 
costs and total societal costs in the year before enrollment were €2,932 and €3,291, 
respectively. Direct cost was €2,461 (hospitalization: €1,570; outpatient: €344; and 
pharmaceutical: €547) in the first year of follow-up, while total societal cost was €2,707. 
The therapeutic approach followed in a specialist center, based on the application of clinical 
guidelines, has been shown to be a highly effective investment for the long-term 
management of COPD. A small increase of pharmaceutical costs per year allowed a 
substantial saving in terms of hospitalizations, costs related to outpatient services, and 
indirect costs. 
Patients with COPD are at increased risk for lung infections and other pathologies (eg, 
pneumonia). A study on two cohorts of 84130 COPD patients each, showed that COPD 
patients with newly developed pneumonia have higher health care resource utilization 
and/or costs in all areas explored: hospitalizations, outpatient visits, ER visits, and 
prescription costs (38). In this study, the pneumonia cohort was approximately nine times 
more likely to have a hospitalization and four times more likely to have an ER visit during 
the 12 months of follow-up. A total cost savings of $22348 was estimated to be associated 
with the prevention of pneumonia based on the sum of the mean differences of $14353 in 
inpatient costs, $6891 in outpatient costs, and $1104 in pharmacy costs between the 
pneumonia and control cohorts. 
Poor adherence to treatment may contribute to the treatment gap in COPD. A large 
population-based study have shown that reduced adherence to treatment with tiotropium 
(TIO) alone or co-administered with fluticasone propionate/salmeterol (TIO + FSC) is 
associated with increased risk for exacerbations and higher health care utilization in COPD 
patients (39).  
 

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8. 
RESEARCH QUESTION AND OBJECTIVES 
Treatment satisfaction in COPD is associated with disease knowledge: subjects who claim 
to be more informed are more satisfied with their management. Long-term data on the 
patients’ satisfaction to COPD medical treatments (i.e. pharmacological and not 
pharmacological treatment) in Italy are scarce. Further, there is limited information on the 
relation between satisfaction and clinical and patients’ parameters. The present study will 
explore the patients’ satisfaction to COPD medical  treatment in a clinical real- world setting 
and how this is related to clinical parameters, quality of life, illness  perception and 
treatment adherence evolution during 12-month follow up.  
The patients will be also described as far as health status, presence of dyspnea, exacerbation 
occurrence, patient disease perception and awareness and adherence to COPD treatment 
during a 12-month follow up. Finally, health care resources utilization and related cost 
according to the Italian National Health Service during 12-month observation will be 
estimated and the correlation between patients’ satisfaction and resource utilization will be 
assessed. 
 
Primary Objective 
To describe the patients’ satisfaction to COPD medical  treatments (by means of the 
TSQM9) during a 12-month observation period (namely, at enrolment, and after 6 and 12 
months) in real- world setting.  
 
Secondary Objectives 
5. To describe patient disease perception (by means of illness perception questionnaire 
B-IPQ), adherence to COPD  treatment (by means of MMAS4), health status (by 
means of CAT questionnaire) and dyspnea (by means of MMRC) during a 12-month  
observation period.  
6. To analyze the relation between treatment satisfaction and demographic (such as age, 
gender), clinical (such as number of exacerbations, spirometric parameters) 
parameters and PROs during a 12-month observation period.  
7. To describe the health care resources utilization and related cost according to the 
Italian National Health Service (INHS) during a 12-month observation period.  
8. To assess the correlation between patients’ satisfaction and resource utilization. 
 

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9. 
RESEARCH METHODS 
9.1 
STUDY DESIGN 
This is a multi-center, non-interventional (observational) cohort study based mainly on 
newly collected data. 
In 20 Italian Pulmonary Centres about 400 consecutive COPD patients will be enrolled in 
approximately 8 months (from first patient enrolled). Patients will be followed up for 1 year, 
with an intermediate evaluation after 6 (+/-1) months from baseline (which is compatible 
with current clinical practice in Italy for COPD patients management). 
No treatment will be administered to the patients on the protocol basis, since this is an non-
interventional study and the assessment and treatment of the enrolled patients will be 
applied according to standard clinical practice. The patients switching or stopping treatment 
during observation period will not be withdrawn from the study. Few patients are expected 
to stop treatment during study; if any, for primary objective evaluation they will be censored 
at the latest available visit. 
9.2 
SETTING 
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site. 
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons: 
 
1. Failure to meet expected enrolment goals overall or at a particular study site 
2. Any administrative reasons that could significantly affect continuation of the study 
according to signed site contract 
3. Violation of GCP, the CTP, or the contract by a study site or investigator, disturbing the 
appropriate conduction of the study 
 
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason). 
 
All patients, both female and male gender, referring to pulmonary centers will be 
consecutively enrolled according to the following criteria: 
 
Inclusion Criteria  
7. Patients aged ≥40 years 
8. Patients must have a documented diagnosis of chronic obstructive pulmonary disease 
(COPD) 
9. Patients with no exacerbations in the last 3 months 
10. Patients requiring regular treatment according to GOLD guidelines, i.e.: undergoing 
stable pharmacological treatment for COPD since at least 3 months 
11. Written informed consent to both participation in the study and privacy form 
12.  Patients capable of discernment and able to read or write in Italian language. 

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Exclusion Criteria  
4. Patients who are currently participating in  a clinical trial on experimental drugs. 
5. Patients naïve to pharmacological treatment for COPD 
6. Diagnosis of Asthma COPD Overlap Syndrome (ACOS) 
 
 
Study Exit criteria 
An individual patient may be withdrawn from the non-interventional study prior to 
completion if any of the following criteria apply: 
4. The patient withdraws consent, without the need to justify the decision. 
5. The patient is no longer able to participate (according to clinical judgment) 
6. Administrative reasons (inclusion in another clinical trial) 
 
9.3 
VARIABLES 
This is a non-interventional study and does not impose a therapy protocol, 
diagnostic/therapeutic procedure, or a visit schedule. Patients will be treated according to 
the local prescribing information, and routine medical practice in terms of visit frequency 
and types of assessments performed and only these data will be collected as part of the 
study.  
This is a descriptive study, where patients with COPD, who are on treatment, are enrolled 
and evaluated during 12-months follow-up.  
Exposure is defined as having diagnosis of COPD and being under treatment so in this study 
all enrolled patients are considered exposed.  
The treating physician is asked to complete if possible at every patient visit the appropriate 
CRF. 
Primary endpoint will be the patients’ satisfaction to COPD medical  treatments evaluated 
through the TSQM9 at baseline and at follow-up  visits. 
Secondary endpoints will be: patient disease perception (evaluated by means of illness 
perception questionnaire B-IPQ), adherence to COPD  treatment (evaluated by means of 
MMAS4), health status (evaluated by means of CAT questionnaire) and dyspnea (evaluated 
by means of MMRC) during a 12-month  observation period. Moreover, socio-demographic 
variables, smoking habits, medical history at baseline and lung function test results (by 
means of spirometry), COPD exacerbations, disease severity and medications for COPD, 
COPD exacerbations and adverse events during follow up will be collected. At each visit, 
each patient will fill in a structured interview aimed at assess his/her awareness of the 
disease.  
Measurements of parameters will be performed by validated questionnaires or widely 
accepted instruments (e.g. spirometry). 
Pulmonary function tests are a validated and well established measurement tool for lung 
function testing. Pulmonary function tests will be conducted at clinic visits using the site’s 

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own equipment. FEV1, FVC, and DLCO are standard measurements for the assessment of 
lung function. 
Finally,  health care resources related to COPD, COPD exacerbations and adverse events 
will be evaluated during the observation period. 
Table 1 below is the recommended assessment schedule that most likely mirrors the patterns 
of routine clinical care of most patients. 
 
Study Visits 
Visit 1 
Visit 2 
Visit 3 
Baseline 
Follow-up  
Follow-up 2 
Months 
0 
6 (+/-1)  
12 (+/- 1) 
Eligibility criteria 
Inclusion and exclusion criteria, Informed consent and privacy form 
X 
 
 
Baseline information 
(Socio-)demographic variables: age, gender, race,  geographic location, 
housing situation, marital status, educational and employment status 
X 
 
 
Weight, body mass index 
X 
X 
X 
Physical examination 
X 
X 
X 
Life Habits 
Smoking (yes/no, number of pack/years, smoke duration) 
X 
X 
X 
Medical History and concomitant diseases. 
- Charlson Comorbidity Index. 
X 
X 
X 
COPD medical history:  
Date of COPD diagnosis (years from diagnosis); 
 n° of COPD exacerbations/year during the previous year to enrolment 
visit 
X 
 
 
Functional assessment  
Lung function test results (FEV1, FVC, FEV1 % of the predicted, RV, 
TLC,DLCO) according to clinical practice 
X 
X 
X 
CAT questionnaire 
X 
X 
X 
COPD Exacerbations** after enrollment 
Onset and resolution date 
Severity (mild, moderate, severe) 
X 
X 
X 
Disease severity (GOLD 2015 Guidelines) 
X 
X 
X 
Medications related to COPD, COPD exacerbations and adverse 
events (LABA, LAMA, SABA, SAMA,  ICS/LABA, steroids, 
antibiotics, etc..): drug, dose, frequency, duration of therapy. 
- Long-Term Oxygen Therapy (liquid and/or concentrate). 
X 
X 
X 
Change of therapy during observation period and reason for change. 
 
X 
X 
Non Pharmacological treatment  
- Pulmonary rehabilitation-  
X 
X 
X 
Health-care resource consumption  related to COPD, COPD 
X 
X 
X 

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Study Visits 
Visit 1 
Visit 2 
Visit 3 
Baseline 
Follow-up  
Follow-up 2 
Months 
0 
6 (+/-1)  
12 (+/- 1) 
exacerbations and adverse events: 
• 
Drugs 
• 
hospitalization (inward and day hospital) 
• 
emergency room access 
• 
outpatient visits 
• 
GP visits 
• 
laboratory tests 
• 
clinical examinations 
Patient Reported Outcomes Questionnaires/scales 
 
 
 
TSQM-9 
X 
X 
X 
MMRC (modified MRC dyspnea scale)  
X 
X 
X 
CAT 
X 
X 
X 
MMAS-4 (Morisky Medication-Taking Adherence Scale) 
X 
X 
X 
Brief Illness Perception Questionnaire 
X 
X 
X 
Awareness structured interview  
X 
X 
X 
S(AE) assessment 
 
X 
X 
Table 1.Recorded variables.  
** An exacerbation will be defined as  an increase or new onset of more than 1 symptom (cough, sputum, 
wheezing, dyspnoea or chest tightness) with at least 1 symptom lasting at least 3 days and leading to patient’s 
attending physician to initiate treatment with systemic steroids and/or antibiotics (moderate exacerbation) or 
hospital admission (severe exacerbation).  
 
Visit 2 (6+/-1 month), Visit 3 (12+/-1 month) are referred as being the current clinical practice in Italy for 
COPD patients management. 
 
Data will be collected at inclusion visit, 6 (±1) and 12 (±1) month follow up. 
 
The following questionnaires/scales/patient reported outcomes will be administered to 
patients. They are briefly described below. 
• Treatment Satisfaction Questionnaire, 9 items (TSQM-9); 
• Brief Illness Perception Questionnaire (BIPQ); 
• Morisky medication Adherence Scale, 4 items (MMAS-4);  
• COPD Assessment Test (CAT); 
• Modified Medical Research Council Dyspnea Scale (MMRC). 
 
Treatment Satisfaction Questionnaire for Medication, 9 items (TSQM-9) 
Patient’s self-reported satisfaction or dissatisfaction with pharmacological treatments can be 
measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) Version 
1.4, a validated instrument (45). The TSQM-9 was derived from the original version, and it 
has a total of 9 items with responses to nearly all items rated on a five-point or seven-point 
rating scale that provide scores on three scales: effectiveness (3 items), convenience (3 

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items) and global satisfaction (3 items) (9) . The original version also recorded information 
about side effects in 5 items (45). However in naturalistic studies, administering the TSQM 
with the side effects domain could provoke the physician to assess the presence or absence 
of adverse events in a way that is clinically atypical, carrying the potential to interfere with 
routine medical care.  
The TSQM-9 domain scores (effectiveness, convenience and global satisfaction) will be 
calculated as recommended by the instrument authors (45,46). The TSQM-9 domain scores 
range from 0 to 100 with higher scores representing higher satisfaction on that domain. 
The questionnaire will be completed by patients at enrolment, 6- and 12-month follow up 
visits. 
 
Brief Illness Perception Questionnaire  
The patient disease perception will be evaluated by the Brief Illness Perception 
Questionnaire 
(Brief IPQ) that is a validated 9-item questionnaire designed to rapidly assess cognitive and 
emotional representations of illness (ref Broadbent 2006). All of the questionnaire items 
(except the causal question, item 9) are rated using a 0-to-10 response scale (17). Five of the 
items assess cognitive illness representations: consequences (Item 1), timeline (Item 2), 
personal control (Item 3), treatment control (Item 4), and identity (Item 5). Two of the items 
assess emotional representations: concern (Item 6) and emotions (Item 8). One item assesses 
illness comprehensibility (Item 7). Assessment of the causal representation is by an opened 
response item, which asks patients to list the three most important causal factors in their 
illness (Item 9).  
The questionnaire will be completed by patients at enrolment, 6- and 12-month follow up 
visits. 
 
Morisky medication Adherence Scale 4 items (MMAS-4) 
The MMAS-4 is a self-reported, medication-taking behavior scale and consists of four 
questions about the way patients might experience drug errors or omissions. Each item has a 
scoring scheme of “Yes” = 0 and “No” = 1.  Items are summed to give a non-adherence 
score ranging from 0 to 4 (42-44); higher score means better adherence to therapy.  
The scale will be completed by patients at enrolment, 6- and 12-month follow up visits. 
 
COPD Assessment Test (CAT) 
During the 12-month observation period the COPD symptoms will be evaluated by the COPD 
Assessment Test (CAT). The CAT is an 8-item unidimensional measure of health status 
impairment in COPD (41). It is designed to measure the impact of COPD on a person's life, and 
how this changes over time. It contains eight short, simple, patient-completed questions. Patients 
can choose a score from 0 to 5 for the extent to which the described impairment is true for them, 
thereby providing a measure of the impact of COPD on their individual health. 
The score ranges from 0 to 40; higher scores represent worse health. The CAT score is 
calculated as the sum of the responded items.  

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The questionnaire will be completed by patients at enrolment, 6- and 12-month follow up 
visits. 
 
Modified Medical Research Council (MMRC) dyspnea scale 
The modified Medical Research Council (MMRC) dyspnea scale [44]  has been in use for 
many years for grading the effect of breathlessness on daily activities [45, 46]. This scale 
measures perceived respiratory disability, the WHO definition of disability being “any 
restriction or lack of ability to perform an activity in the manner or within the range 
considered normal for a human being”. The MMRC dyspnea scale is simple to administer as 
it allows the physician to indicate the extent to which the breathlessness affects the mobility 
of the patient.  
The scale will be completed by patients at enrolment, 6- and 12-month follow up visits. 
The physician will ask the patient about his/her perceived breathlessness and will use the 
modified MRC dyspnea scale to classify it into MMRC dyspnea grades [44]: 
 
Grade 
0  
Breathless with strenuous exercise 
1  
Short of breath when hurrying on the level or walking up a slight hill 
2  
 Walks slower than people of the same age on the level because of breathlessness or 
stops for breath when walking at own pace on the level 
3  
Stops for breath after walking about 100 meters or after a few minutes on the level 
4  
Too breathless to leave the house or breathless when dressing or undressing 
 
9.4 
DATA SOURCES 
Source data will be medical records usually collected during routine clinical practice other 
than study-specific questionnaires.  
Collected variables are defined based on study objectives and according to the non-
interventional nature of the study. They consist in data routinely collected in clinical 
practice, so they are expected to be available in medical charts. 
For Charlson Comorbidity Index.calculation ICD-9CM will be considered by clinical 
investigators. If ICD-9CM is not available according to routine clinical practice, main 
diseases ongoing at baseline will be anyway collected. 
The study data will be collected by means of remote data capture using an electronic case 
report form (eCRF). Investigators will be provided a user-friendly paper form which is 
intended as a supportive tool for data collection and will be filled in according to each site 
specific need (it will not be considered as a source data). 
Patient-reported outcomes, i.e. scales and questionnaires, will be collected on paper and they 
will constitute source data. 
 

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9.5 
STUDY SIZE 
The sample size was determined on the basis of feasibility criteria. In fact, according to the 
volume of patients managed by the centres involved in this study, inclusion of 400 subjects 
(20 patients/center) with the characteristics defined at Inclusion/Exclusion criteria 
paragraphs is deemed reasonable for the planned enrolment period (8 months). Assuming a 
drop-out rate ranging from of 5% to 20% (including not evaluable,lost-to follow up and not 
on treatment patients), effective sample size is expected to range between 320 (drop 
out=20%) and 380 (drop out=5%). 
An evaluation of the possible achievable precision of the estimates was performed 
considering the primary objective of the study. No data on treatment satisfaction is available 
about COPD patients specifically, therefore available literature data was used as a reference 
to evaluate possible scenarios. In particular, literature data about TSQM was found on 
multiple sclerosis, psoriasis, etc, showing the global satisfaction mean score ranging from 
54.4 to 79.7 (17,18)]. 
 
Table 2 shows the 95% confidence interval half-width and standard error (SE) of the 
expected mean of global satisfaction score under different sample sizes. 
 
Expected Mean (SD) 
54.4 (21.4) 
79.7 (16.6) 
Sample Size 
380 
320 
380 
320 
95% confidence interval half width 
2.152 
2.345 
1.669 
1.819 
Standard error (SE) 
1.098 
1.196 
0.852 
0.928 
Table 2. 95% confidence interval (CI) half-width and standard error (SE)  of the expected mean 
assuming N=380/320 evaluable patients [19] 
 
In all considered scenarios the relative error of the estimate (CI half-width/expected mean) 
is lower than 30%. The lower the sample size and the higher the standard deviation, the 
lower the estimate precision. 
9.6 
DATA MANAGEMENT 
The CROs in charge of the study is 
.  
The data entered into the eCRFs by investigational staff will be reviewed for completeness 
and accuracy and the site personnel will be instructed to data entry data into the eCRFs and 
to make any required corrections or additions. In order to validate the e-CRF content a 
qualitative pre-test will be performed, by simulating data capture during study conduction. 
The Data Manager will perform the cleaning session by running post-entry checks by means 
of validation programs and data listings specific for the study. During this process, if 
clarifications are needed, the Data Manager will raise queries by means of data query forms 

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through the application. Designated investigator site staff is required to respond to the query 
and  make the correction to the database.  
Patients violating inclusion/exclusion criteria will not be considered for analyses. A 
description of reasons of violation will be provided anyway. After these actions have been 
completed and the database has been declared to be completed and accurate, it will be 
locked and made available for data analysis. Any changes to the database after that time can 
only be made by joint written agreement between the Medical Adviser, the Trial Statistician 
and the Data Manager. Only authorized and well-documented updates to the study data will 
be possible after database lock. 
Each participating site will maintain appropriate medical and research records for this study, 
in compliance with GPP and regulatory and institutional requirements for the protection of 
confidentiality of subjects.  
Patient initials or names will not be recorded in the database: patients will be associated to a 
unique identifier, assigned as a progressive number within each site.  Due to the 
observational nature of the study no independent review of the data will be performed.  
Data access rules, as well as data transfer to Sponsor, will be detailed in the Data 
Management Plan. 
 
9.7 
DATA ANALYSIS 
Descriptive analysis will be  means, medians, quantiles, proportions (with their respective 
95% confidence intervals and SE when relevant) and contingency tables according to the 
nature of the variables. As a dispersion measurement the standard deviation and the 
interquartile range will be calculated. 
Statistical analysis will be performed using the SAS software. 
The statistical analysis will be done on all evaluable patients i.e. patients who enter the 
study without inclusion-exclusion criteria violations and with at least one TSQM-9 domain 
score (effectiveness, convenience and global satisfaction) calculated. Enrolled patients not 
evaluable for analysis will be described in terms of frequency of violations and according 
main socio-demographic variables (such as age and gender), clinical (such as disease 
severity and number of exacerbations in the 12-month before enrollment) and treatment 
satisfaction scores (if available) at baseline.  
Patients with missing values will not be excluded from the analysis, their data will not be 
replaced; frequency of missing data will be given for all analyzed variables. Lost to follow 
up patients will be analyzed until their last available visit.   
  
Appropriate descriptive statistics for main socio-demographic (gender, age, race, education 
and employment status, smoking habits) and clinical variables (medical history for COPD 
and not, disease severity and awareness) at baseline visit will be presented to describe the 
study population at inclusion. Patients at inclusion in the study will be also described in 
terms of ongoing pharmacological and non pharmacological treatments for COPD.  
Moreover, the study population will be described in terms of number of exacerbations 
occurred during study period and changes in COPD medication since baseline. 
 

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The study objectives will be evaluated as below described. 
 
Primary objective  
The patients’ satisfaction for medical treatment will be assessed by the 9-item Treatment 
Satisfaction Questionnaire for Medication (TSMQ-9) at each study visit (45, 46). TSQM-9 
is a self-rated tool for evaluating patient satisfaction to medical therapy. It is composed by 3 
domains covering efficacy, convenience and global treatment satisfaction. TSQM-9 scores 
will be calculated according to author’s instructions and summarized at each time point on 
all evaluable patients. Patients lost to follow up will be considered until their last available 
visit. 
The patients switching treatment during observation period will not be excluded from 
analysis and will be evaluated at each visit as above described. Few patients are expected to 
stop treatment during study; if any, for primary objective evaluation they will be censored at 
the latest available visit. Comparisons of satisfaction between different treatment/devices 
are not matter of this study, throughout all analysis treatments will be lumped together. 
 
 
 
Secondary objectives  
#1 To describe patient disease perception (B-IPQ), adherence to COPD  treatment 
(MMAS4), health status (CAT) and dyspnea (MMRC) during a 12-month observation 
period  
A description of B-IPQ (consequences, timeline, personal control, treatment control, 
identity, concern, emotions and illness comprehensibility), MMAS-4, CAT and MMRC 
scores will be provided at baseline and at follow-up visits. Scale scores will be summarized 
at each time point. Patients lost to follow up will be considered until their last available 
visit. Missing items of questionnaires/scales will be replaced if applicable according to 
scoring algorithm [32-38]. 
#2 To analyse the relation between  treatment satisfaction for medical treatment and 
demographic/clinical parameters  and PROs during a 12-month observation period 
Three regression models (one for each TSQM-9 domain score) will be estimated; the 
dependent variable will be domain score and the independent ones will be: age and gender 
(at enrollment), number of exacerbations, relevant spirometry parameters (such as FEV1, 
FVC, FEV1 % of the predicted, RV, TLC, DLCO), level of dyspnea (MMRC score),  impact 
of COPD on a patient’s life (CAT) and treatment adherence (MMAS-4 score) collected 
during observational period. Because dependent variable will be collected at each study 
visit, repeated measures models will be estimated taking into account all available values for 
dependent and independent variables.  Patients could be classified in mild or 
moderate/severe according to lung function parameters. This will allow to evaluate 
treatment satisfaction in different groups of patients. 
The patients switching treatment during observation period will not be excluded from 
analysis and will be evaluated at each visit. The patients stopping treatment during study 
will be censored at last available visit. 
 
#3 To describe the health care resources utilization and related cost during a 12-month 
observation period 

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The health care resources consumption will take into consideration the following events 
related to management of COPD and COPD exacerbations: inpatients and outpatients 
hospitalization (inward and day-hospital), accesses to emergency room, General Practitioner 
(GP)  and outpatient visits, laboratory tests and examinations, pharmacological (LABA, 
LAMA, SABA, SAMA, ICS/LABA, steroids, antibiotics, long-Term Oxygen Therapy, etc.) 
and non-pharmacological therapies (pulmonary rehabilitation) occurred/administered during 
study period.  
Medications for adverse events will be considered too. 
The annual direct health care resource consumption and related cost will be provided by 
means of descriptive statistics of the variables mentioned above. In order to describe the 
health care cost from enrolment up to the end of 12-month follow-up according to the INHS 
point of view (26), a two steps approach will be followed: (i) first of all the resource 
consumed since enrolment will be calculated and then (ii) a monetary value will be assigned 
to the resource consumption. 
(i) Health care resources consumption exclusively related to COPD, COPD exacerbations 
and COPD-drug-related adverse events will be computed during observational period in 
terms of pharmacological and non-pharmacological treatments, number of (inward and day-
hospital) hospitalizations, number of emergency room accesses, number of GP visits, 
specialist visits, laboratory tests or examinations (spirometry, FEV1, FVC, FEV1 % of the 
predicted, RV, IC, TLC, DLCO). 
(ii) In order to estimate the economic impact on health care sector related cost (30)  of the 
above mentioned health services (hospital admissions, visits, treatments, examinations, 
spirometry) consumption, a monetary value to each event recorded will be assigned, as 
defined by the Italian Ministry of Health through the tariffs in force for outpatient setting 
(31). The cost of hospitalization will be valued according to the most recent available 
diagnosis-related group (DRG) tariffs (32); finally, pharmacological treatments will be 
costed at consumer price. All costs will be expressed in €2015. A monthly (or yearly) cost 
will be provided by taking into account patients according to duration of observation and 
parametrizing each patient to the 12-month observation period. 
Descriptive statistics (mean, standard deviation, median, minimum and maximum) of the 
annual direct health care resource consumption and related cost will be provided. 
Non-parametric bootstrap method will be applied to cost data for calculating 95% 
confidence intervals (22-23). 
A multiple linear regression model will be performed to investigate statistical significance 
of INHS cost predictors (24). 
 
#4 To assess the correlation between patients’ satisfaction and resource utilization. 
Correlation indexes will be calculated between treatment satisfaction domain scores of 
TSQM-9 and healthcare resource consumption (such as number of hospitalizations, 
emergency room accesses, GP visits, laboratory test. etc… during observation period) at 12-
month follow-up visit. The patients switching treatment during observation period will not 
be excluded from analysis and will be evaluated at each visit. The patients stopping 
treatment during study will be censored at their last available visit. 
 

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9.8 
QUALITY CONTROL 
The Quality control will be managed in accordance with 
 procedures as 
agreed with BITSPA. 
9.9 
STUDY MONITORING 
On site and remote monitoring will be performed by 
 who has been 
designated by BITSPA. 
It is understood that the monitor(s) will contact and/or visit the Investigator/centre before 
the study start up, regularly throughout the study and after the study data collection will 
have been completed, and that they will be permitted to inspect the various study records: 
eCRFs, filled questionnaire, Investigator study file and source data (source data is any data 
that is recorded elsewhere to the eCRFs), provided that subject confidentiality is respected. 
The purposes of these visits/phone contacts are: 
• 
to assess the progress of the study; 
• 
to review compliance with the study protocol; 
• 
to discuss any emerging issue; 
• 
to check the eCRFs for accuracy and completeness; 
• 
to validate the contents of the eCRFs against the source documents (only by on side 
visits). 
Prior to each on site monitoring visit, the Investigator or staff will record all data generated 
since the last visit on the eCRFs. The Investigator and/or study staff will be expected to be 
available for at least a portion of the monitoring visit to answer questions and to provide any 
missing information. 
During each remote monitoring contact, the Investigator or staff will will be expected to be 
available for the phone call to answer questions and to provide any missing information. 
 
9.10 
GUIDELINES FOR EPIDEMIOLOGICAL STUDIES 
The guidelines for Good Pharmacoepidemiology Practices (GPP) in non-interventional 
studies as well as recommendations for non-interventional study and principles of 
epidemiology studies will be respected [47]. This study is not in the scope of Good Clinical 
Practice (GCP) studies, but for several aspects it will be managed according to it. 
 
9.11 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT 
RECORDS 
All study documents are provided by the Sponsor to the Investigator and his/her appointed 
staff in confidence. None of this material may be disclosed to any party not directly 
involved in the study without written permission from BITSPA. 
The Investigator must assure that the subject’s anonymity will be maintained. The 
Investigator will keep a separate list with at least the initials, the subject’s study numbers, 
names and telephone numbers. The Investigator will maintain this for the longest period of 
time allowed by his/her own institution and, in any case, until further communication from 
BITSPA. 

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All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. Only the subject 
number will be recorded in the case report form. Study findings stored on a computer will 
be stored in accordance with local data protection laws.  
The investigators will maintain a list to enable subjects’ records to be identified. However, if 
the results of the study are published, the subject’s identity will remain confidential.  
Personal data - including sensitive data - collected during the execution of the activities will 
be processed in accordance with the local laws on data protection.  
 
9.12 
INVESTIGATOR'S FILES / RETENTION OF DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of this 
cohort study and the study data to be subsequently verified. These documents should be 
classified into two different separate categories (1) Investigator's Study File, and (2) subject 
clinical source documents. 
The Investigator's Study File will contain the observational protocol study/amendments, 
EC/IRB approval with correspondence, sample informed consent, staff curriculum vitae and 
authorization forms and other appropriate documents/correspondence etc. 
Subject clinical source documents would include subject hospital/clinic records, physician's 
and nurse's notes, appointment book, original laboratory reports, pathology and special 
assessment reports, signed informed consent and privacy forms, consultant letters and 
subject screening and enrollment logs. The Investigator must keep these two categories of 
documents on file according to local regulations after completion or discontinuation of the 
study. After that period of time the documents may be destroyed, subject to local 
regulations. 
Should the Investigator wish to assign the study records to another party or move them to 
another location, BITSPA must be notified in advance. 
 
9.13 
LIMITATIONS OF THE RESEARCH METHODS 
This is an non-interventional (observational) study which puts patients under observation 
for one year prospectively. However information, selection and/or recall bias have to be 
taken into account, as in all non-interventional studies.  
Investigators could select patients in order to enroll those ones who most probably will be 
followed up or most probably correctly understand the questionnaires (selection bias). In 
order to limit this bias, monitoring visits could be randomly performed in sites to verify 
whether enrolment was performed consecutively.  
The information to be captured is usually recorded in medical charts or on questionnaires 
filled in during visit: this also should  limit recall  bias of information.   
As regards confounding, the primary aim of the study is to evaluate the patients’ satisfaction 
for medical treatment irrespective of the ongoing treatment, no causality nor associations to 
treatments will be evaluated because of the lack of a control group. The regression models 
to analyze the relation between treatment satisfaction scores and demographic, clinical and 
PROs parameters during a 12-month observation (secondary objective #2) will provide 
adjusted estimates of the impact on satisfaction scores of each variable keeping constant the 
others included in the models. 

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Patients with missing values will not be excluded from the analysis, their data will not be 
replaced; frequency of missing data will be given for all analyzed variables. Patients with 
missing and not missing values in TSQM9 domain scores will be described according to 
main socio-demographic and clinical features. 
As far as generalizability of results, the study aims to provide information on COPD 
patients enrolled in the study; it does not mean to be generalized to the population of  Italian 
COPD patients, because sites are selected. However sampling is based on consecutive 
enrolment, in order to avoid patient selection during recruitment.  
Finally, target sample size is considered to be achievable during the enrolment period on the 
basis of preliminary feasibility considerations.  
 
9.14 
OTHER ASPECTS 
9.15 
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS 
The study will be carried out in compliance with the protocol, the principles laid down in 
the Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline 
for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.  
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results 
should be published prior to finalization of the Study Report. 
 
9.16 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
This study will be initiated only after all required legal documentation has been reviewed 
and approved by the respective Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and competent authority (CA) according to national and international 
regulations. The same applies for the implementation of changes introduced by 
amendments. 
Prior to patient participation in the study, written informed consent must be obtained from 
each patient according to ICH GCP and to the regulatory and legal requirements of Italy. 
Each signature must be personally dated by each signatory and the informed consent and 
any additional patient-information form retained by the investigator as part of the study 
records. A signed copy of the informed consent and any additional patient information must 
be given to each patient or the patient’s legally accepted representative. 
 
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient. 
 
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 

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9.16.1 
DATA QUALITY ASSURANCE 
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s study-related files and 
correspondence, and the informed consent documentation of this study at any time 
according to the Sponsor’s Standard Operating Procedures, in order to verify whether the 
study is being conducted in agreement with GPP.  
The Investigators and Institution must permit study-related monitoring, audits, IRBs/IECs 
review or regulatory inspection, providing direct access to source data/documents. 
 
9.16.2 
RECORDS 
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or via remote data capture.  
 
9.16.3 
SOURCE DOCUMENTS 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
 
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study; also 
current medical records must be available. 
 
For eCRFs all data must be derived from source documents 
 
9.16.4 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
The investigator / institution will permit study-related monitoring, audits, IRB /IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory 
and medical test results must be available at all times for review by the sponsor’s clinical 
study monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical 
Research Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and 
written informed consents. The accuracy of the data will be verified by reviewing the 
documents described in Section.  
 

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9.16.5 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
 
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB / IEC and the regulatory authorities. 
 
9.16.6 
COMPLETION OF STUDY 
The IRB/IEC/competent authority in Italy will be notified about the end of the study (date of 
termination of observational study, last patient patient out date, number of patients 
observed) or early termination of the observation.  
 
9.16.7 
PROTOCOL VIOLATIONS 
Not applicable 
 
 
9.16.8 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY 
Not applicable 
 

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10. 
PROTECTION OF HUMAN SUBJECTS 
This study was designed and shall be implemented and reported in accordance with the 
Guide on Methodological Standards in Pharmacoepidemiology (Revision 3, July 2014) of 
the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance 
(ENCePP), the STROBE (Strengthening the Reporting of Observational Studies in 
Epidemiology) guidelines, with the ethical principles laid down in the Declaration of 
Helsinki and with the laws and regulations of Italy in which the research is carried out, 
whichever affords the greater protection of the individual.  
The study will be notified to the Health Authority according to the legal requirements in 
Italy as unique participating country.   
Subjects selection will not start before the approval of the EC/IRB and notification of the 
study to the Health Authority. This study does not include treatments or diagnostic 
examinations other than those prescribed in the ordinary clinical practice, therefore no 
insurance agreements are applicable. 
 
 

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11. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
11.1 
DEFINITIONS OF ADVERSE EVENTS 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have a causal relationship with this treatment. An adverse event can therefore be 
any unfavourable and unintended sign (e.g. an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
 
Adverse reaction 
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorization or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors. 
 
Serious adverse event 
A serious adverse event is defined as any AE which 
- results in death,  
- is life-threatening,  
- requires in-patient hospitalization, or 
- prolongation of existing hospitalization,  
- results in persistent or significant disability or incapacity, or  
- is a congenital anomaly/birth defect  
 
Life-threatening in this context refers to a reaction in which the patient was at risk of death 
at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe. 
 
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization 
or development of dependency or abuse. Any suspected transmission via a medicinal 
product of an infectious agent is also considered a serious adverse reaction. 
 
Adverse Event of Special Interest (AESI) 
The term AESI relates to any specific AE that has been identified at the project level as 
being of particular concern for prospective safety monitoring and safety assessment within 

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this study, e.g. the potential for AEs based on knowledge from other compounds in the same 
class.  
 
No AESIs have been defined for this study. 
 
11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING 
The investigator shall maintain and keep detailed records of all AEs in their patient files.  
 
Collection of AEs 
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements 
have been defined. 
 
The following must be collected by the investigator in the (e)CRF from signing the 
informed consent onwards until the end of the study for the BI product administered for the 
disease in scope of the study:  
 
- all ADRs (serious and non-serious),  
- all AEs with fatal outcome ,   
- all pregnancies 
  
 
All ADRs , including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained. 
 
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.  
 
Causal relationship of adverse event 
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal 
relationship between a medicinal product and an occurrence is suspected.  
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.  
 
Arguments that may suggest a reasonable causal relationship could be: 
• 
The event is consistent with the known pharmacology of the drug  
• 
The event is known to be caused by or attributed to the drug class. 
• 
A plausible time to onset of the event relative to the time of drug exposure. 

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• 
Evidence that the event is reproducible when the drug is re-introduced 
• 
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications). 
• 
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome). 
• 
An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished). 
 
Arguments that may suggest that there is no reasonable possibility of a causal 
relationship could be: 
• 
No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within 
days/weeks of drug administration; an allergic reaction weeks after discontinuation 
of the drug concerned) 
• 
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). 
Of note, this criterion may not be applicable to events whose time course is 
prolonged despite removing the original trigger. 
• 
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
• 
Disappearance of the event even though the study drug treatment continues or 
remains unchanged. 
 
Intensity of adverse event 
The intensity of the AE should be judged based on the following: 
Mild: 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities 
 
 
Pregnancy: 
In rare cases, pregnancy might occur in a study. Once a subject, has been enrolled into the 
study after having taken the BI drug taken for the disease in scope of the study, the 
investigator must report any drug exposure during pregnancy which occurred in a female 
subject or in a partner to a male subject to the Sponsor by means of Part A of the Pregnancy 
Monitoring Form. The outcome of the pregnancy associated with the drug exposure during 
pregnancy must be followed up and reported by means of Part B of the Pregnancy 
Monitoring Form.  
 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
 
 
Expedited Reporting of AEs and Drug Exposure During Pregnancy 

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The following must be reported by the investigator on the NIS AE form (or pregnancy 
monitoring form if applicable) from signing the informed consent onwards until the end of 
the study for the BI product administered for the disease in scope of the study:  
 
Type of Report 
Timeline 
All SADRs  
immediately within 24 hours 
All AEs with fatal outcome  
immediately within 24 hours 
All non-serious ADRs  
7 calendar days 
All pregnancies 
7 calendar days 
 
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via 
telephone. This does not replace the requirement to complete and fax the NIS AE form. 
 
Information required 
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate (e)CRF pages and the NIS AE form. 
Reporting of related Adverse Events associated with any other BI drug 
The investigator is encouraged to report all adverse events related to any BI drug other than 
the BI drug taken for the disease in scope of the study according to the local regulatory 
requirements for spontaneous AE reporting at the investigator’s discretion by using the 
locally established routes and AE report forms. The term AE includes drug exposure during 
pregnancy, and, regardless of whether an AE occurred or not, any abuse, off-label use, 
misuse, medication error, occupational exposure, lack of effect, and unexpected benefit. 
 
11.3 
 REPORTING TO HEALTH AUTHORITIES 
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements. Also the investigator is encouraged to report all 
adverse event related to any drug to LHA according to local regulatory requirements 
 

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12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
The end of the data collection (including the follow-up period) for this observational study 
is expected within 2017. 
The final study report should be submitted as soon as possible within 12 months of the end 
of data collection. 
The final study report, including the statistical and clinical evaluations, shall be prepared 
and sent to the Advisory Board, for agreement and signature. 
At the end of the study a summary of the final study report will be provided to all ECs/IRBs, 
to the Italian Competent Authority, only if requested, and to Investigators. 
 
BITSPA is entitled to publish and/or present any results of this study at scientific meetings; 
BITSPA furthermore reserves the right to use such data for industrial purposes. 
Investigators will inform the Advisory Board and BITSPA before using the results of the 
study for publication or presentation, and agree to provide the Sponsor with a copy of the 
proposed presentation. Data from individual study sites shall not be published separately 
before main study paper based on global data collected will be published. 
 
12.1 
OPERATIVE MANAGEMENT OF MEDICAL WRITING ASPECTS 
The results of this study will be published or presented at scientific meetings. Participant 
Investigator agrees to submit all manuscripts or abstracts to BITSPA prior to submission. 
This allows the sponsor to protect proprietary information and to provide comments based 
on information from other studies that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, BITSPA will generally support 
publication of multicenter studies only in their entirety and not as individual center data. In 
this case, the Study Advisory Board will be designated. 
The investigator has to provide the sponsor all data derived by the investigator from the 
study. During the study, only the sponsor may make study information available to other 
study investigators or to regulatory agencies, except as required by law or regulation. Except 
as otherwise allowable in the clinical study site agreement, any public disclosure (including 
publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials, is the sole responsibility of the sponsor. 
Manuscript authorship for any peer-reviewed publication will appropriately reflect 
contributions to the production and review of the document. All publications and 
presentations must be prepared in accordance with this section and the Study Site 
Agreement, which has to be written consequently.  
BITSPA also adheres to any additional standards concerning authorship required by a 
specific journal or congress to which the publication is submitted. The responsible 

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individuals at BISPA apply, at a minimum, the following criteria to determine who is named 
as an author on a publication: 
• Substantial contributions to the concept and design, acquisition of data, or analysis 
and interpretation of data 
• Drafting of the publication or revising it critically for important intellectual content 
• Final approval of the version to be published 
• Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
Authorship criteria and obligations apply equally to BITSPA employees and non-
employees. Each listed author must have participated in the work enough to take public 
responsibility for appropriate portions of the content. 
Individuals contributing to the publication but not meeting authorship criteria may be 
appropriately acknowledged in the publication. 
 
12.2 
 GHOSTWRITING AND GUEST/GHOST AUTHORSHIP 
Ghostwriting, guest authorship, and ghost authorship are strictly prohibited. The 
contribution of a writer, which, when performed under the direction of the author(s), is 
considered a form of specialized, technical assistance, is acknowledged in the earliest draft 
in which the writer is involved. 
 
12.3 
DETERMINING ORDER OF AUTHORSHIP 
Author order is determined by mutual agreement at the earliest possible time, with due 
consideration to overall contributions to the study, to the publication, or to scientific 
knowledge of the subject matter. 
 
 
 
 
 
 
 

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13. 
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13.1 
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40. Dal Negro RW, Bonadiman L, Turco P, Tognella S. Costs of illness analysis in Italian 
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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
 
List of Advisory Board members 

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS 
A copy of the ENCePP Checklist for Study protocols available at website: 
encepp.eu/standards_and_guidances/index.html completed and signed by the main author of 
the study protocol should be included in Annex 2. 
 
The checklist will facilitate the review of the protocol and evaluation of whether 
investigators have considered important methodological aspects. 
 
In question 9.5 of the Checklist, Revision 1: 
 
“Study start” means “Start of data collection” 
“Study progress” means “Progress report(s)” 
“Study completion” means “End of data collection” 
“Reporting” means “Final report of the study results” 
 
See attached file 
 

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ANNEX 3. ADDITIONAL INFORMATION 
None.