Real-world Data of Moderate to Severe Inflammatory Bowel Disease in Argentina: A Non-interventional, Multicenter Study to Evaluate Disease Control, Treatment Patterns, Burden of Disease and Quality of Life
Conditions: Crohn Disease, Colitis, Ulcerative, Inflammatory Bowel Disease
Sponsor: Takeda




Title: BD-5004 - Real-world data of Moderate to Severe Inflammatory Bowel Disease in 
Argentina: a non-interventional, multicenter study to evaluate disease control, treatment 
patterns, burden of disease and quality of life (RISE AR)
NCT Number: NCT03488030
Protocol Approve Date: 24Jan2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

IBD-5004 
Observational/Non-Interventional 
Study Protocol 
 Version 1.0 – 24Jan2018 
Page 1 of 43 
Non-Interventional Study Protocol 
Short title: 
Non-interventional Study of Moderate to Severe Inflammatory Bowel Disease in 
Argentina 
Title: 
Real-world data of Moderate to Severe Inflammatory Bowel Disease in Argentina: a 
non-interventional, multicenter study to evaluate disease control, treatment patterns, 
burden of disease and quality of life (RISE AR) 
Study ID: 
IBD-5004 
Sponsor: 
Takeda Pharma S.A. 
Tronador 4890 C1430DNN - Buenos Aires - Argentina 
Phone:  +54 (011) 4546-4700  
Fax:  
+54 (011) 4546-4711  
Study phase:  Medical Affairs, Non-registration Company Sponsored (Observational) 
Date of version of protocol: Version 1.0 – 24Jan2018 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 4 of 43 
 
 
1.4 Summary 
Short Title of Study 
Non-interventional Study of Moderate to Severe Inflammatory Bowel Disease in Argentina. 
 
Study sites 
The study will be conducted in approximately 7 sites in Argentina. 
 
Objectives 
Knowledge regarding the control of disease activity in Inflammatory Bowel Disease (IBD) is limited 
in Argentina. Therefore, it is pertinent to describe the journey of moderate to severe IBD patients in 
Argentina, their characteristics and how they are managed, and to understand treatment patterns, 
particularly on the use of available biologic therapies. 
Primary Objective: 
 
To evaluate the proportion of moderate to severe IBD patients with active disease at Day 1 (active 
Crohn’s Disease (CD) defined as Harvey Bradshaw Index (HBI) score ≥ 8 or Crohn’s Disease 
Activity Index (CDAI) ≥ 220 points; active Ulcerative Colitis (UC) defined as 9-point partial 
Mayo ≥5). 
Secondary Objectives: 
 
To characterize socio-demographic and clinical aspects of moderate to severe IBD. 
 
To characterize treatment patterns for IBD during the 3 years previous to Day 1, including the use 
of biologic therapies and failure to these therapies (if any). 
 
For each IBD type, to compare patients with moderate to severe disease activity with patients with 
no or mild activity regarding socio-demographic and clinical variables of interest and treatment 
patterns. 
 
To evaluate the quality of life (SF-36, EQ-5D and IBDQ) in moderate to severe IBD patients. 
 
To evaluate the work productivity impairment (WPAI) experienced by moderate to severe IBD 
patients. 
 
To describe the use of healthcare resources related with the management of IBD during the 3 
years previous to Day 1. 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 5 of 43 
 
 
 
To estimate UC or CD-related healthcare costs during the 3 years previous to Day 1. 
 
Methodology 
This is a multicenter, non-interventional, cross-sectional study aiming primarily to determine the rate 
of control of IBD activity (Crohn’s Disease [CD] or Ulcerative Colitis [UC]). At each center, eligible 
subjects will be identified consecutively as they attend a scheduled clinical appointment with their 
physician (Day 1). Upon written consent, data regarding disease activity, treatment patterns, burden of 
disease and quality of life will be collected from the patients’ medical records and administered 
Patient Report Outcome (PRO) questionnaires, including quality of life (SF-36, EQ-5D and IBDQ) 
and work productivity (WPAI) questionnaires. Besides the cross-sectional data collection, the study 
will have an additional retrospective data collection referring to the three years previous to Day 1, 
regarding the previous IBD treatments (drug, dose, treatment duration and drug changes), and use of 
other healthcare resources related with the management of IBD. 
 
Number of subjects 
It is expected to include 246 patients regardless of IBD type.  
This sample size will allow estimates with 95% confidence interval and a margin of error less than 
5%, and assuming a rate of inadequate control of disease of 20% (conservative approach), regardless 
of IBD type. The following formula was used:  
𝑛= 1.962 × 𝑝× (1 −𝑝)
𝑀𝐸2
 
Rate of uncontrolled disease (p) = 20%  
Margin of error (ME) = 0.05 
Expected recruitment period: 6 months 
 
Diagnosis/Disease/Condition and main criteria for inclusion 
Subjects must meet all of the following inclusion criteria: 1) male or female subjects, 2) subjects aged 
18 years or older, 3) with diagnosis of moderate to severe CD or UC for at least 6 months prior to Day 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 6 of 43 
 
 
1 appointment based on clinical, endoscopic, or imaging criteria, 4) who provided the written 
informed consent. 
Patients will be excluded if 1) presenting indeterminate or not classified colitis, 2) having current or 
previous participation in interventional clinical trials (within the last 3 years), 3) presenting mental 
incapacity, unwillingness or language barriers precluding adequate understanding or cooperation. 
 
Duration of data collection per subject 
Cross-sectional at Day 1, with retrospective data collection over the previous 3 years. 
 
Criteria for evaluation 
Population descriptors 
Date of birth, gender, smoking habits, professional status (employed, unemployed, retired, student, 
other), date of diagnosis of CD or UC, date of diagnosis of moderate to severe CD or UC (if not the 
same as previous), family history of IBD, disease presentation (location, behavior, extraintestinal 
manifestations), steroid behavior, comorbidities. 
 
Main outcome variables 
Primary Endpoints: 
 
For Crohn’s Disease: Proportion of patients with active disease (HBI ≥ 8 or CDAI ≥ 220 points - 
based on criteria used by the site) at Day 1. 
 
For Ulcerative Colitis: Proportion of patients with active disease (9-point partial Mayo ≥5) at 
Day 1. 
Secondary Endpoints: 
 
Distribution of age, gender, smoking habits, professional status, family history, educational level, 
subject income by IBD type. 
 
Distribution of clinical variables (steroid behaviour, anthropometric information, medical history 
and comorbidities, clinical characterization of disease) by IBD type. 
 
 Therapies for IBD (aminosalicylates, steroids, immunomodulators, immunosupressors biologics, 
antibiotics, probiotics and surgeries) and the length of these therapies during the previous 3 years. 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 7 of 43 
 
 
 
Proportion of biologic-experienced patients. 
 
Proportion of patients who have not responded previously to biologic therapies and reason. 
 
IBD treatment introduced at Day 1 (if applicable). 
 
Socio-demographic, clinical and treatment-related variables in patients with moderate to severe 
activity of CD (HBI ≥ 8 or CDAI ≥ 220 points) versus patients with mild or no activity (HBI < 8 
or CDAI < 220 points). 
 
Socio-demographic, clinical and treatment-related variables in patients with moderate to severe 
activity of UC (partial Mayo score ≥5) versus patients with mild or no activity (partial Mayo <5). 
 
Mean score of EQ-5D by IBD type. 
 
Mean score of different components of SF-36 by IBD type. 
 
 Mean total score of IBDQ and by domain (bowel symptoms, systemic symptoms, emotional 
function and social function). Patients with ostomy will not be evaluated since this questionnaire 
is not validated to be used in this population. 
 
Mean total percentage of work impairment (WPAI). 
 
Mean work time missed (WPAI). 
 
Mean impairment while working (WPAI). 
 
Mean total activity impairment (WPAI). 
 
Proportion of patients who quit their job due to IBD and have not been able to return to work. 
 
Healthcare resources (previous 3 years): drug therapies, imaging and laboratory testing, surgeries, 
hospitalizations and consultations. 
 
Statistical methods 
Data will be summarized for total IBD patients and by IBD type (Crohn’s Disease and Ulcerative 
Colitis). Descriptive statistics will be used for all variables including mean, median, standard 
deviation and range for numerical variables and absolute and relative frequencies for categorical 
variables. 95% confidence intervals will be computed whenever relevant. 
For each IBD type, patients with disease activity will be compared with patients with mild or no 
activity regarding socio-demographic and clinical variables of interest. Chi-square/Fisher tests will be 
used to compare activity vs non activity regarding qualitative variables and t-test/Mann-Whitney will 
be used for comparison of quantitative variables. All tests will be two-sided with a significance level 
of 5%. 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 8 of 43 
 
 
 
Table of Contents 
1 
Administrative information............................................................................................................... 2 
1.1 
Contacts .................................................................................................................................. 2 
1.2 
Amendments and updates ....................................................................................................... 2 
1.3 
Approval ................................................................................................................................. 3 
1.4 
Summary ................................................................................................................................ 4 
Table of Contents ..................................................................................................................................... 8 
List of Abbreviations and Definition of Terms ...................................................................................... 11 
2 
Introduction ..................................................................................................................................... 13 
2.1 
Study Rationale .................................................................................................................... 14 
3 
Study Objectives ............................................................................................................................. 15 
4 
Study Administrative Structure ...................................................................................................... 15 
4.1 
Study Sites ............................................................................................................................ 15 
4.2 
Sponsor Personnel ................................................................................................................ 16 
4.3 
Contract Research Organisation (CRO) ............................................................................... 16 
4.4 
Essential Documents ............................................................................................................ 16 
5 
Ethics .............................................................................................................................................. 17 
5.1 
Ethical conduct of the Study ................................................................................................. 17 
5.2 
Independent Ethics Committee ............................................................................................. 17 
5.3 
Subject Information and Written Informed Consent ............................................................ 18 
6 
Study Design and Plan .................................................................................................................... 19 
6.1 
Study Schedule ..................................................................................................................... 20 
6.2 
Discussion of Study Design .................................................................................................. 20 
6.3 
Selection of Study Population .............................................................................................. 22 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 9 of 43 
 
 
6.3.1 
Inclusion Criteria ................................................................................................... 22 
6.3.2 
Exclusion Criteria ................................................................................................. 22 
6.3.3 
Enrolment .............................................................................................................. 22 
6.4 
Treatments ............................................................................................................................ 23 
7 
Conduct ........................................................................................................................................... 23 
7.1 
Data collection overview ...................................................................................................... 23 
7.2 
Study Variables .................................................................................................................... 24 
8 
Management and Reporting of Adverse Events ............................................................................. 27 
8.1 
Definitions ............................................................................................................................ 27 
8.2 
Classifications ...................................................................................................................... 29 
8.3 
Collection of Adverse Events, Special Situation Reports and Product Quality Issues ......... 30 
9 
Data Quality Control and Assurance .............................................................................................. 31 
9.1 
Quality Control ..................................................................................................................... 31 
9.2 
Audit from Quality Assurance Unit...................................................................................... 31 
9.3 
Inspection by IEC or Competent Authority .......................................................................... 32 
9.4 
Data Management ................................................................................................................. 32 
9.4.1 
Data Collection Tools and Flow ........................................................................... 32 
10 Statistical Methods and Determination of Sample Size .................................................................. 33 
10.1 Statistical Analysis Plan ....................................................................................................... 34 
10.1.1 
Study Endpoints .................................................................................................... 34 
10.1.2 
Statistical analyses overview................................................................................. 35 
10.2 Primary Analyses.................................................................................................................. 36 
10.3 Secondary Analyses.............................................................................................................. 36 
10.4 Interim Analyses ................................................................................................................... 39 
10.5 Handling of missing data ...................................................................................................... 39 
10.6 Determination of Sample Size .............................................................................................. 40 
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Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 10 of 43 
 
 
11 Reports ............................................................................................................................................ 40 
12 Publications ..................................................................................................................................... 40 
13 Archiving of Study Documentation ................................................................................................ 40 
14 References ....................................................................................................................................... 41 
 
 
 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 11 of 43 
 
 
List of Abbreviations and Definition of Terms 
AE 
 
Adverse Event 
ADR 
 
Adverse Drug Reaction 
CA 
 
Competent Authority 
CCSI  
Company Core Safety Information 
CD 
 
Crohn’s Disease 
CDAI  
Crohn’s Disease Activity Index 
CI 
 
Confidence interval 
CPI 
 
Consumer price index 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
CV 
 
Curriculum Vitae 
eCRF  
electronic Case Report Form  
EDC 
 
Electronic Data Capture 
EIM 
 
Extraintestinal Manifestations 
EQ-5D  
5-dimensional EuroQoL measure 
GPP 
 
Good Pharmacoepidemiology Practices 
HBI 
 
Harvey Bradshaw Index 
IBD 
 
Inflammatory Bowel Disease 
IBDQ  
Inflammatory Bowel Disease Questionnaire 
ICH 
 
International Conference on Harmonisation 
IEC 
 
Independent Ethics Committee 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCS 
 
Mental Component Summary 
PCS 
 
Physical Component Summary 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 12 of 43 
 
 
pMayo  
partial Mayo score 
PRO 
 
Patient Reported Outcomes 
QoL 
 
Quality of Life 
SAE 
 
Serious Adverse Event 
SADR  
Serious Adverse Drug Reaction 
SAP 
 
Statistical Analysis Plan 
SF-36  
36-item Short Form health Survey 
SSR 
 
Special Situation Report 
UC 
 
Ulcerative Colitis 
VAS 
 
Visual Analog Scale 
WPAI  
Work Productivity and Activity Impairment questionnaire 
 
 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
        Version 1.0 – 24Jan2018 
 
 
Page 13 of 43 
 
 
2 Introduction 
Inflammatory bowel diseases (IBD) comprise mainly Crohn’s disease (CD) and ulcerative colitis 
(UC) (1). Signs and symptoms of active IBD may include abdominal pain, rectal bleeding, and 
fatigue. Treatment is not curative although it is generally effective in relieving symptoms (2). In some 
cases, surgery may be a solution but postoperative complications may occur, alongside with 
continued abnormal bowel function, and poor improvement in patient quality of life (QoL) (3). 
IBD are multifactorial diseases associated with genetic, immunological and environmental factors, 
and with episodes of relapse and remission (4). IBD impact on patient QoL is particularly relevant as 
it affects mainly young individuals, with unpredictable disease flares and, sometimes, severe 
symptoms (5). Alongside with loss of patient QoL, symptoms may also impact work productivity 
thus increasing the economic burden of these diseases (4,6,7). 
Globally, the incidence of UC varies between 0.5-24.5/105 inhabitants, while CD incidence varies 
between 0.1-16/105 inhabitants worldwide; overall, IBD prevalence is estimated to reach up to 396 
per 105 people (8). Furthermore, the incidence of IBD has been increasing in several world regions, 
namely in developing countries (9,10). In South American countries, incidence of IBD seems to be 
lower than in Europe and North American countries but some studies have reported an increase in 
recent years (4,11). There are no available data to estimate the incidence and prevalence in Argentina, 
nationwide. Linares et al have estimated incidences of UC and CD were 2.2 and 0 per 105 people, 
respectively, during 1987-1993 in the district of Partido General Pueyrredón (12). More recently, a 
local study in Córdoba city have described a prevalence ratio of UC (86.8%) and CD (12.3%) of 
7.04:1, during 2014-2016 (13). Besides the scarce information about IBD epidemiology, there is no 
published study about the disease pattern and treatment in Argentina.  
There are several strategies available for the treatment of IBD, which remains challenging (1,14). 
Corticosteroids are indicated to induce clinical remission in active UC of moderate to severe intensity 
and active CD of mild to severe intensity (4). However, resistance and dependence may occur, 
ranging from 8%-20% and from 15%-36%, respectively, among CD cases. In UC, corticosteroid-
resistance and dependence were 29% and <10%, respectively (15). Furthermore, prolonged exposure 
with steroids is not recommended, given the lack of efficacy in the maintenance of remission and risk 
of adverse events (4). 
Sulfasalazine and 5-ASA are indicated to induce and maintain clinical remission of mild to moderate 
UC but are not recommended in CD treatment neither moderate to severe UC cases (4,16,17). 
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Observational/Non-Interventional 
Study Protocol 
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Immunosuppressors are effective in maintaining remission in CD and UC and while promoting 
corticosteroid withdrawal in corticosteroid-dependent patients. However, methotrexate is nowadays a 
second-line immunosuppressor for CD patients resistant or intolerant to azathioprine or 6-
mercaptourine, and is not recommended in the maintenance treatment of UC (4). Cyclosporine seems 
to have no therapeutic value in treatment of CD (4). 
The use of biological therapy has been increasing, namely for moderate to severe IBD or when there 
is no response to conventional treatments (4). In fact, infliximab, adalimumab and vedolizumab have 
shown to be effective in induction and maintenance of clinical remission of UC and CD (4,16,17). 
Side effects usually occur in less than 10% of cases, and it has been described that biological therapy 
can promote endoscopic and histologic improvement. Biologics have also the potential to improve 
QoL in IBD patients (18).  
The therapy with vedolizumab is an alternative for patients with refractory CD or those who cannot 
tolerate treatment with corticosteroids, thiopurines (azathioprine or mercaptopurine) and who have 
failed with anti-TNF therapy. Treatment with vedolizumab is effective for the induction and 
maintenance of remission in patients with CD who have never received biological therapy with anti-
TNF (4). 
In face of IBD complexity and heterogeneity, treatment decision should consider the activity and 
severity level, the extension of inflammatory process and corticoid dependency (4). Furthermore, if 
the first-line immunosuppressive maintenance therapy fails, several other factors should be taken into 
account when deciding the following treatment, including patient’s wishes, fecundity and patient age 
(14). 
 
2.1 Study Rationale 
No studies have been conducted in Argentina with large territorial coverage, to evaluate demographic 
and clinical aspects of IBD, namely the level of disease activity and the burden of disease. Therefore, 
it is pertinent to gather information regarding the population with a moderate to severe IBD and the 
burden of the disease, and to understand their treatment patterns, particularly on the use of available 
biologic therapies. 
 
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Observational/Non-Interventional 
Study Protocol 
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Page 15 of 43 
 
 
3 Study Objectives 
Primary Objective: 
 
To evaluate the proportion of moderate to severe IBD patients with active disease at Day 1 (active 
CD defined as Harvey Bradshaw Index [HBI] ≥ 8 or Crohn’s Disease Activity Index [CDAI] ≥ 
220 points; active UC defined as 9-point partial Mayo score ≥5). 
 
Secondary Objectives: 
 
To characterize socio-demographic and clinical aspects of moderate to severe IBD. 
 
To characterize treatment patterns for IBD during the 3 years previous to Day 1, including the use 
of biologic therapies and failure to these therapies (if any). 
 
For each IBD type, to compare patients with moderate to severe disease activity with patients with 
no or mild activity, regarding socio-demographic and clinical variables of interest and treatment 
patterns. 
 
To evaluate the quality of life (SF-36, EQ-5D and IBDQ) in moderate to severe IBD patients. 
 
To evaluate the work productivity impairment (WPAI) experienced by moderate to severe IBD 
patients. 
 
To describe the use of healthcare resources related with the management of IBD during the 3 
years previous to Day 1. 
 
To estimate UC or CD-related healthcare costs during the 3 years previous to Day 1. 
 
 
4 Study Administrative Structure 
4.1 Study Sites 
The study is planned to be conducted in approximately 7 sites in Argentina. The selected sites are 
public and private institutions in Argentina recognized by their large experience in the IBD 
management, and that follow IBD patients in ambulatory care.  
 
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IBD-5004 
Observational/Non-Interventional 
Study Protocol 
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 
Subject Information Sheet and Informed Consent Form in local language, approved by 
Independent Ethics Committees (IEC) as locally required. 
 
Written IEC approval according to local regulations. 
 
Authority approval according to local regulations (i.e., Notification of Clinical Trial). 
 
 
5 Ethics 
This study is an observational study where the existence of the study has no impact on the subject 
except for collection of informed consent to use of the subject’s data and use of Patient Report 
Outcome (PRO) tools, to collect information about health related quality of life and work productivity 
impairment due to IBD (19). These procedures will not impact the usual care provided to the subjects. 
PRO tools will be submitted to IEC for ethical approval. 
 
5.1 Ethical conduct of the Study 
This study will be conducted in accordance with the protocol, the current version of the Declaration of 
Helsinki (20), Good Pharmacoepidemiology Practices (GPP) (21), and Argentine regulations. Special 
attention will be paid to subject’s data protection and confidentiality. 
Takeda/the appointed CRO will ensure that the protocol, any amendments and the Subject 
Information Sheet/Informed Consent Form are submitted to the relevant Independent Ethics 
Committees (IECs) according to local requirements. 
Takeda, as the sponsor, is responsible for meeting the ICH requirement for yearly updates to the IECs, 
if applicable. 
 
5.2 Independent Ethics Committee  
IEC 
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According to applicable regulations, the appointed CRO or the Study Site Responsible will notify or 
obtain approval from the relevant IEC of the protocol, any amendments and the Subject Information 
Sheet / Informed Consent Form and other study-related documents, e.g., PRO tools. 
The appointed CRO or the Study Site Responsible will submit required documents to the IEC, such 
as: 
 
periodic updates on the progress of the study; 
 
notification of the end-of-study; 
 
a summary of the study results. 
Sponsor will keep an updated list of all submission and approval dates of all documents submitted to 
the IEC and will provide the Study Site Responsible with a copy of this list. Copies of the documents 
will be distributed upon request. 
 
Authorities 
Sponsor or the appointed CRO will send required documents to the competent authority (CA) and/or 
other national or regional authorities. Sponsor will keep an updated list of submission and approval 
dates and a copy of all documents submitted.   
 
5.3 Subject Information and Written Informed Consent 
The Study Site Responsible must give the subject (and if applicable, parent or legal guardian) oral and 
written information about the study in a form that the subject can understand, and obtain the subject’s 
written consent before collection of identifiable subject information (hereinafter referred to as 
personal data). Before consenting, the subject must be left with ample time to consider and to pose 
questions. Since the study is observational, the consent only concerns the data collection per see and 
is not consent to any interventional procedure or treatment.  
The subject must agree that sponsor personnel, their representatives or IEC or CA personnel (national 
or other) may require direct access to the subject’s data / personal records which were collected, 
processed and stored in an anonymous form.   
The subject must agree that his / her data will be processed and stored in an anonymous form for 
evaluation of this study and any later overviews. Data may also be transferred in anonymous form to 
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third parties, e.g., other companies or authorities, that may be located in other countries with 
potentially different regulations for data.  
The subject has the right to withdraw his/her consent at any time without prejudice. In the Informed 
Consent Form (ICF) it is stated that if consent is withdrawn, any data collected before withdrawal of 
consent will be kept. The original, signed ICF must be kept on the Site. 
For details, see the Subject Information Sheet and ICF. 
 
 
6 Study Design and Plan 
This study is a ‘non-interventional study’ as defined in: G-STND-PV-006, G-SOP-MA-005, 
Directive 2001/20/EC and will follow the guidelines for GPP.  
This means that: 
 
The assignment of a subject to a particular therapeutic strategy is not decided in advance by the 
study protocol but falls within current practice. 
 
No additional diagnostic or monitoring procedures shall be applied to the subjects. 
 
Epidemiological methods shall be used for the analysis of collected data. 
This is a multicenter, non-interventional study to evaluate the control of disease activity (Figure 1), 
with a cross-sectional evaluation at Day 1 complemented with retrospective chart review. 
 
 
Figure 1. Study design scheme 
Day 1 
(enrollment) 
Cross-sectional evaluation 
(Day 1)  
 
 
 
 
 
Retrospective evaluation (3 years) 
• Previous IBD treatment 
• Medical history & comorbidities 
• Treatment patterns for IBD 
• Use of health resources (surgeries, hospitalizations, 
appointments, laboratory and imaging tests)  
• Disease activity 
• Treatment patterns  
• Burden of disease 
• Quality of life   
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At each site, eligible subjects will be identified consecutively as they attend scheduled clinical 
appointment with their physician (Day 1). Upon written consent, data regarding disease activity, 
treatment patterns, burden of disease and quality of life will be collected from medical records and 
PRO tools, including quality of life (SF-36, EQ-5D and IBDQ) and work productivity (WPAI) 
questionnaires. Retrospective data will refer to the previous three years and will include the previous 
IBD treatments (drug, dose, treatment duration, drug changes, surgeries), and use of other healthcare 
resources related with the management of IBD. 
 
6.1 Study Schedule 
Planned Start of Study:  
 
  
1st quarter 2018 
Planned collection of first data point: 
 
1st quarter 2018 
Planned End of Study:   
 
 
1st quarter 2019 
Planned completion of the Study Report: 
3rd quarter 2019 
 
The Start of Study is defined as date of last protocol signature and planned to occur on the 1st quarter 
2018. The collection of first data point (first patient in) will start during 1st quarter 2018. The 
recruitment period is expected to last up to 6 months. The End-of-Study is defined as the date of 
collection of the last data point for the last patient recruited. 
CRO (on behalf of the Sponsor) will ensure that End-of-Study notification is submitted to the 
concerned authorities and IEC for each site, for the country and for the complete study, as locally 
required. 
Based on upcoming knowledge, Takeda might choose to terminate the study prematurely. In such 
case, the Committee(s), study sites, IECs and authorities will be informed promptly. 
 
6.2 Discussion of Study Design 
This is a non-interventional study, with a cross-sectional evaluation and retrospective chart review, 
designed to evaluate disease control, treatment patterns, burden of disease and health related quality 
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of life among patients with IBD. The cross-sectional design with no control group is suitable and 
feasible to address the study objectives, which are mainly descriptive.  
In terms of external validity, two major points should be considered. First, the 7 study sites will be 
selected among reference public and private institutions for IBD management in different districts in 
Argentina. It is expected that their patients will be representative of patients with moderate to severe 
IBD in Argentina. In addition, the inclusion and exclusion criteria are not restrictive and will enable 
the assessment of real-world data about IBD control in Argentina. Internal validity will be reinforced 
by training of Investigators and the use of same study procedures and forms. Hence, observation bias 
is not expected to occur during the cross-sectional evaluation. Although retrospective data collection 
is challenged by the quality of medical records, treatment patterns and hospitalizations are frequently 
recorded and no significant missing data is expected, which could lead to underestimation of health 
care utilization data. In addition, it is expected that completeness of medical records will be high in 
the last 3 years (retrospective period), namely regarding the use of biological treatments (if 
prescribed). 
Because this is an observational study, some limitations should be minimized. All eligible patients 
will be consecutively invited to the study and the enrolment period will be of at least 6 months. 
Disease control may be underestimated due to selection bias, since patients with active IBD are 
expected to have more medical appointments and thus, may be have more frequent visits to the center. 
Nevertheless, the 6-month period will also enable the inclusion of patients with mild or no active 
disease (although, for the same reason, these patients may be underestimated). 
Potential confounders will be addressed at: 
 
Enrolment – with the exclusion of patients with indeterminate or not classified colitis and that 
have participated in interventional clinical trials during the last 3 years. In fact, during a trial 
the subject has access to special and specific treatment and diagnosis procedures. The 
participation in an interventional trial during the previous 3 years may cause 
misunderstanding about treatment patterns and resources utilization, because in this project 
the retrospective data will be collected exactly about this period. 
 
Statistical analysis – with the inclusion in the logistic regression models of variables 
associated with both disease control and other variables of interest.  
 
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6.3  Selection of Study Population 
Subjects should be included in the study only once.  
Data erroneously collected from subjects for which written consent is not available, will not be 
included in or will be deleted from the database. 
 
6.3.1 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria: 
1) Male or female subjects. 
2) Subjects aged 18 years or older. 
3) Diagnosis of moderate to severe CD or UC for at least 6 months prior to Day 1 appointment 
based on clinical or endoscopic or image criteria (16,17). 
4) Subjects who provided the written informed consent. 
 
6.3.2 Exclusion Criteria 
Subjects will be excluded if presenting at least one of the following: 
1) Indeterminate or not classified colitis. 
2) Current or previous participation in interventional clinical trials (within the last 3 years). 
3) Presenting mental incapacity, unwillingness or language barriers precluding adequate 
understanding or cooperation. 
 
6.3.3 Enrolment 
Each Study Site Responsible (Investigator) should include consecutive subjects who meet eligibility 
criteria, from patients attending pre-scheduled routine medical appointments.  
The expected recruitment of study subjects will occur during a 6-month period. A patient tracking log 
form will be used by each site. 
Subjects should be included in the study only once. Data erroneously collected from subjects for 
which written consent is not available, will not be included in or will be deleted from the database. 
 
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6.4 Treatments 
Non-interventional study – no treatments/pharmacotherapy are predefined in the protocol.  
All clinical decisions will be full responsibility of the investigator. 
7 Conduct 
7.1 Data collection overview 
Table 1. Study Flow Chart 
Study variables 
Day 1 
Retrospective data 
Collection data points approximately 3 years 
Timing of data collection 
Day 1 visit 
During visit 
Informed consent 
X 
 
Inclusion criteria 
X 
 
Exclusion criteria 
X 
 
Socio-demographic variables 
X 
 
Smoking habits 
X 
 
Anthropometric Information (Weight, Height, BMI) 
X 
X 
IBD type (CD or UC) 
X 
 
Date of diagnosis of CD or UC (based on medical 
records) 
X 
 
Date and criteria of diagnosis of moderate to severe 
CD or UC (based on medical records) 
X 
 
Steroid behavior 
X 
 
Family history of IBD 
X 
 
Medical history / Comorbidities 
X 
X 
Disease activity: CD (HBI score or CDAI); UC 
(partial/total Mayo Score) 
X 
X 
Clinical Characterization of Disease: location, 
behavior, EIM 
X 
 
SF-36 
X 
 
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Study variables 
Day 1 
Retrospective data 
Collection data points approximately 3 years 
EQ-5D 
X 
 
IBDQ** 
X 
 
WPAI 
X 
 
Previous treatments or regimens 1 
X 
X 
Treatment started at Day 1 (if applicable) 
X 
 
Previous surgeries for IBD 
 
X 
IBD-related hospitalizations 
 
X 
Previous medical appointments related with IBD 
management 
 
X 
Previous CDAI, HBI, Mayo score (when available) 
 
X 
Previous calprotectin levels and colonoscopy (when 
available) 
 
X 
Other previous imaging, laboratory (including PCR) 
and histology testing (when available) 
 
X 
¹ Excludes new treatments prescribed at Day 1 visit.  
** Not applicable for patients who have a colostomy or ileostomy. 
 
7.2 Study Variables 
Data will be collected from medical charts and during the routine clinical appointment, for the 
following variables: 
Socio-Demographic variables 
 
Date of birth; 
 
Gender; 
 
Professional status (employed, unemployed, retired, student, other). 
 
Clinical variables 
 
IBD type: CD or UC; 
 
Date of diagnosis of CD or UC (and disease duration at Day 1); 
 
Date of diagnosis of moderate to severe CD or UC (if not the same as previous); 
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 
Family history of IBD; 
 
Smoking habits; 
 
Medical History / Comorbidities (including prior TB and Hepatitis infection); 
 
Disease presentation [location, behavior, extraintestinal manifestations (EIM)]; 
 
Steroid behavior (dependent, refractory, not applicable); 
 
Colonoscopy in the previous 12 months suggestive of inadequate control of activity (yes/no) 
(qualitative data/Mayo subscore); 
 
Calprotectin levels in the previous 12 months suggestive of inadequate control of activity (i.e., 
calprotectin >200ug/g) (yes/no) (qualitative data); 
 
Disease activity (at Day 1) 
 
For CD patients: Harvey Bradshaw Index (HBI) score or Crohn’s Disease Activity Index (CDAI); 
 
For UC patients: 9-item partial Mayo Score (always collected) and the total Mayo score (when 
available).  
The Harvey Bradshaw Index (HBI) score considers five easily assessed dimensions (general well-
being, abdominal pain, number of liquid stools per day, abdominal mass, and complications). These 
dimensions are scored from the previous day (no diary cards are required). Patients with HBI ≥ 8 are 
classified as presenting moderate to severe active disease (22). 
The Crohn’s Disease Activity Index (CDAI) evaluates the severity of signs and symptoms of CD. 
Collected data include information on the number of liquid stools, intensity of abdominal pain, 
general well-being, presence of comorbid conditions, use of medications for diarrhea, physical 
examination, and laboratory findings (abdominal mass, hematocrit, body weight), yielding 8 items 
that are combined with data from a 7-day diary to obtain the total CDAI score. Higher scores indicate 
a greater disease severity. Moderate to severe active CD is defined as CDAI ≥ 220 (23). 
The Mayo score is composed of four categories (bleeding, stool frequency, physician assessment, and 
endoscopic appearance) rated from 0–3 that are summed to give a total score that ranges from 0–12. 
The partial Mayo Score (pMayo) was previously compared with the full Mayo score and categorizes 
patients as being in remission (score of 0–2), having mild disease (pMayo of 3 or 4) or moderate to 
severe disease (pMayo of ≥5) (24). 
 
 
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Health-Related Quality of Life and Work Productivity (at Day 1) 
 
36-item Short Form Health Survey (SF-36) 
 
5-dimensional EuroQoL measure (EQ-5D) 
 
Inflammatory Bowel Disease Questionnaire (IBDQ) - 32 items 
 
Work Productivity and Activity Impairment Questionnaire (WPAI) – 6 items 
 
The Short Form-36 (SF-36) evaluates 8 health dimensions: physical functioning, bodily pain, role 
physical (limitations due to physical problems), role emotional (limitations due to personal or 
emotional problems), mental health, social functioning, vitality, and general health perceptions. Based 
on these 8 scales, two weighted scores are generated: the physical component summary (PCS) and the 
mental component summary (MCS) score. Scores range between 0 and 100, with higher scores 
indicating a better quality of life (25). For additional information, please consult 
http://www.rand.org/health/surveys_tools/mos/mos_core_36item_survey_print.html. 
EuroQoL questionnaire (EQ-5D-5L) considers five attributes of quality of life evaluation, i.e. 
mobility, self-care, usual activity, pain/discomfort, and anxiety/depression. Each dimension has five 
possible levels, 1-no problems, 2 slight problems, 3-moderate problems, 4-severe problems, 5-
extreme problems, thus defining a total of 3125 possible health states, each one referred to in terms of 
a 5 digit code. EQ-5D also include an additional visual analogic scale (EQ-VAS), which ranges from 
0, worst imaginable health state, to 100, best imaginable health state (26). For more information, 
please consult http://www.euroqol.org/.  
The Inflammatory Bowel Disease Questionnaire (IBDQ) is a 32-item questionnaire that measures 4 
dimensions: bowel function, emotional status, systemic symptoms, and social function. Within 
dimensions, each question presents seven possible answers/points. The score for each dimension 
results from the sum of points. Hence, the total score ranges from 32 to 224, with higher scores 
representing better QoL (27). The IBDQ is not validated for patients with ostomies and therefore 
should 
not 
be 
applied 
for 
these 
patients. 
For 
more 
information, 
please 
consult 
http://www.flintbox.com/public/project/641. 
The Work Productivity and Activity Impairment questionnaire (WPAI) assesses the impact of IBD on 
work productivity and daily activities during the previous 7 days. In brief, the WPAI questions are: 1) 
if currently employed, 2) hours missed due to disease, 3) hours missed other reasons, 4) hours actually 
worked, 5) degree disease affected productivity while working, 6) degree disease affected regular 
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activities (7). WPAI generates four component scores: percentage of work time missed (absenteeism); 
percentage of impairment while working (presenteeism); percentage of overall work impairment 
(absenteeism and presenteeism combined); and percentage of activity impairment. Unemployed 
patients only answer to questions related to employment status and activity impairment. Scores for 
WPAI range from 0% (‘no impairment’) to 100% (‘total loss of work productivity/activity’). For more 
information, please consult http://www.reillyassociates.net/WPAI_General.html. 
 
Treatment 
 
Previous 
treatments 
or 
regimens 
(aminosalicylates, 
steroids, 
immunomodulators, 
immunossupressors, biologics, probiotics, antibiotics); start date; end date, dose, reason for 
discontinuation; 
 
First treatment after diagnosis of moderate to severe IBD (name, dose); 
 
Treatment started at Day 1 (name, dose); 
 
Previous surgeries for IBD. 
 
Other healthcare resources related with IBD management 
 
Imaging and laboratory testing; 
 
Surgeries; 
 
Hospitalizations; 
 
Consultations. 
 
8 Management and Reporting of Adverse Events 
8.1 Definitions 
Adverse Events  
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. An AE 
can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, a new disease or worsening in severity or frequency of a concomitant disease, temporally 
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associated with the use of a medicinal product, whether or not the event is considered causally related 
to the use of the product.  
Adverse Reactions 
An adverse drug reaction (ADR) is 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. This includes the following, regardless of 
whether adverse reactions arise from: use of a medicinal product within the terms of the marketing 
authorization; use outside the terms of the marketing authorization, including overdose, misuse, 
abuse, medication errors, use of falsified medicinal product, suspected transmission of an infectious 
agent, breast feeding: infant exposure from breast milk, lack of efficacy of a Takeda product and 
occupational exposure*. 
 
* This corresponds to the exposure to a medicinal product for human use as a result of one’s 
occupation, such as nurses who may handle products routinely in their occupational setting. 
 
Special Situation Reports and Product Quality Issues  
A Special Situation Report (SSR) includes any of the following events: 
 
Pregnancy: Any case in which a pregnancy patient is exposed to a Takeda Product or in 
which a female patient or female partner of a male patient becomes pregnant following 
treatment with Takeda Product. Exposure is considered either through maternal exposure or 
via semen following paternal exposure. 
 
Breastfeeding: Infant exposure from breast milk. 
 
Overdose: All information of any accidental or intentional overdose. 
 
Drug abuse, misuse or medication error: All information on medicinal product abuse, misuse 
or medication error (potential or actual). 
 
Suspected transmission of an infectious agent: All information on a suspected (in the sense of 
confirmed or potential) transmission of an infectious agent by a medicinal product. 
 
Lack of efficacy of Takeda Product. 
 
Occupational exposure. 
 
Use outside the terms of the marketing authorisation, also known as “off-label”. 
 
Use of falsified medicinal product. 
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A Product Quality Issue refers to defects related to the safety, identity, strength, quality, or purity of 
the product or with the physical characteristics, packaging, labeling, or design of the product. 
 
8.2 Classifications 
Seriousness 
A serious ADR or AE (SADR/SAE) is any ADR or AE which results in death, is life threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability or incapacity, or is a congenital anomaly or birth defect. 
Life-threatening in this context refers to a reaction/event in which the subject was at risk of death at 
the time of the reaction/event. It does not refer to a reaction/event 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, such as important medical events that might not be immediately life-threatening or 
result in death or hospitalisation but might jeopardise the subject 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 hospitalisation, or development of dependency or abuse.  
Any suspected transmission of an infectious agent via a medicinal product is considered a serious 
adverse reaction. 
 
Severity 
Severity is a clinical observation and describes the intensity of the event. 
 
Mild: Transient symptoms, no interference with the subject’s daily activities 
 
Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
 
Severe: Considerable interference with the subject’s daily activities. 
 
Causality 
The following definitions of Related should be used to characterize the suspected causality of an AE. 
This assessment should be based on the Investigator's consideration of all available information about 
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the event, including temporal relationship to drug administration, recognized association with drug 
product/class, pharmacological plausibility, and alternative etiology (e.g., underlying illness, 
concurrent conditions, concomitant treatments): 
 
Related (Yes): An AE that follows a reasonable temporal sequence from administration of the 
medication, vaccine or device (including the course after withdrawal of the medication), or for 
which a causal relationship is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out, although factors other than the medication, vaccine or device, such as underlying 
diseases, complications, concomitant drugs and concurrent treatments, may also be responsible. 
 
Not related (No): An AE that does not follow a reasonable temporal sequence from 
administration of the medication, vaccine or device and/or that can reasonably be explained by 
other factors, such as underlying disease, complications, concomitant drugs and concurrent 
treatments. The investigator must make an assessment of causality using the above definition. 
Causality cannot be assumed in the absence of the investigator’s assessment. 
 
Outcome  
 Fatal: The subject died due to the event. If the subject died due to other circumstances than the 
event the outcome should be stated as ‘Not recovered’ or ‘Recovering’ 
 Recovered/Resolved: The subject has fully recovered from the event or the condition has returned 
to the level observed at baseline. 
 Recovering/Resolving: The event is improving but the subject is still not fully recovered 
 Not Recovered/Not Resolved: The event is ongoing at the time of reporting and the subject has 
still not recovered. 
 Recovered with Sequelae/Resolved with Sequelae: As a result of the event, the subject suffered 
persistent and significant disability/incapacity (e.g. became blind, deaf or paralysed). 
 
Unknown: If Outcome is not known or not reported. 
 
8.3 Collection of Adverse Events, Special Situation Reports and Product 
Quality Issues 
If during the conduct of the study a member of the research team is spontaneously informed of an AE, 
ADR, SSR or product quality issue, where the event/issue pertains to a Takeda product (or unbranded 
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generic), such information should be reported to the Sponsor. As such reports are spontaneously 
notified, causality of any adverse events should be assumed unless there is evidence to the contrary. 
 
No data on AEs or ADRs will be collected as part of the study database.  
All safety-related data on study subjects collected in the study database or reported to Takeda 
according to the normal procedure for marketed drugs, e.g. serious and non-serious ADRs, must be 
summarized in the Non-Interventional Study Report. 
 
 
9 Data Quality Control and Assurance 
9.1 Quality Control 
The study will use electronic data collection, for which a set of automatic data checks with data 
queries will be programmed for data cleaning. Manual data monitoring will include on and off site 
visits and on site Source Data Verification will include the check of the signed ICF for all subjects. 
Source documents (e.g., medical records, original laboratory records) and signed ICF should be 
available to study monitors whenever possible, and consent to such access will be explicitly included 
in the ICF. 
Additional details will be specified in the Monitoring Plan.  
 
9.2 Audit from Quality Assurance Unit 
The Quality Assurance unit may audit the study to ensure that study procedures comply with the 
protocol and standard operating procedures, and that collected data is correct and complete. 
 
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9.3 Inspection by IEC or Competent Authority 
Representatives from IEC or Competent Authority may in rare cases wish to inspect the study on site. 
Upon receiving notification of such inspection, the Study Site Responsible must immediately contact 
Global Research and must make the records available as requested.  
 
9.4 Data Management 
Data management will be performed by the appointed CRO which must be written and approved 
before the design of the study database is finalized. The data management provider should approve all 
data formats before the data collection tools are made available to the sites. 
If the written informed consent of a subject is known not to be available in spite of it being required, 
data for this subject is not entered into or is deleted from the database.  
If a subject is erroneously included in the study more than once only the data relating to the first 
inclusion will be kept in the database and be available for analysis. Data from later inclusions will be 
transferred to the first dataset when relevant, i.e., if collected within the time frame of the first follow-
up period.  
The current Standard Coding Instructions for coding of medical history, concomitant illness 
(MedDRA) and concomitant medication (WHO-Drug) must be followed. 
The subjects will be identified in the database only by Study ID, Site ID, and subject number. 
 
9.4.1 
Data Collection Tools and Flow 
The Study Site will receive data collection tools (access to eCRFs and PRO tools) from Takeda or 
Designee. Whenever possible, complete data sets should be entered. Text field entries and any data 
collected on paper should be legible and follow the requested language standard. 
The Study Site Responsible must sign off the complete data set for each subject, confirming the 
collected data. ADR data reported according to section 8 and data on serious AE/ADR reactions 
collected according to section 8 should be signed off separately by a physician who may or may not 
be involved in the study. 
 
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All data collected for the purpose of this study will be entered, stored and retrieved with the use of an 
electronic eCRF specifically designed for the study. The system will comprise a web-based interface 
for use by investigators, and a central database for storage and retrieval. The database will be 
physically stored at a data center designated by Takeda or the appointed CRO, with appropriate 
measures for back-up of data and stability of the system. The system will ensure patient 
confidentiality, as well as security and confidentiality of the data for the duration of the study. Each 
Site Responsible or designee will receive from Takeda or the appointed vendor a login name and a 
password, and will hold the responsibility for data entry into the system. Investigators will be able to 
access the database for the whole duration of the study. The database will contain single-choice, 
multiple-choice and open-field options for the entry of patient demographic and clinical data. 
Moreover, the system will allow for automatic data checks and the negation of queries based on 
programming logic. A detailed Data Validation Plan that will identify missing data, out-of-range data, 
and other data inconsistencies will be implemented prior to study start. To resolve any questions 
arising from the data review process, data queries and/or site notifications will be created in the 
Electronic Data Capture (EDC) system for site resolution and closed by the sponsor reviewer. 
 
At any time during the course of the study, the investigator (or site staff) may contact the study 
monitor in order to clarify any study procedures. All source documentation supporting entries into the 
eCRF must be maintained and readily available. Given that source documents (institutional charts and 
reports of results from laboratory and imaging studies) will not necessarily be available for auditing in 
the future, the Site Responsible will ensure that data collection for the study be done in a proper way 
and by individuals who are under their direct supervision. Moreover, the Site Responsible will ensure 
data are attributable, accurate, complete, contemporaneous, and consistent. The Site Responsible must 
sign off the complete data set for each subject, confirming the collected data.  Serious and non-serious 
AE collected according section 8 should be signed off separately, in a specific form, by a study team 
member previously trained. 
 
 
10 Statistical Methods and Determination of Sample Size 
Statistical analyses will be performed by the designated CRO. This section describes the statistical 
analyses as foreseen at the time of planning the study. Any known deviations from the planned 
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analyses, the reason for such deviations and all alternative / additional statistical analyses that may be 
performed as well as the final statistical analysis must be described in a revised Statistical Analysis 
Plan (SAP) before completion of data collection. All later deviations and / or alterations will be 
summarised in the Clinical Study Report. 
 
10.1 Statistical Analysis Plan 
This study is observational and epidemiological methods will be employed for data analyses. Data 
analysis will be performed using SAS ® (version 9.4; SAS Institute Inc, Cary, USA - running under 
Windows 8). 
Descriptive analysis will be performed of all collected data except data collected only for the purpose 
of data cleaning, i.e., all data listed in section 7. 
 
10.1.1 Study Endpoints 
The main study endpoints are:  
Primary Endpoints: 
 
For Crohn’s Disease: Proportion of patients with active disease (HBI ≥8 or CDAI ≥220 points - 
based on criteria used by the site) at Day 1.  
 
For Ulcerative Colitis: Proportion of patients with active disease (9-point partial Mayo score ≥5) 
at Day 1. 
Secondary Endpoints: 
 
Distribution of age, gender, smoking habits, professional status, family history, educational level, 
subject income, by IBD type. 
 
Distribution of clinical variables (steroid behaviour, anthropometric information, medical history 
and comorbidities, clinical presentation of disease) by IBD type. 
 
 Therapies for IBD (aminosalicylates, steroids, immunomodulators, immunossupressors, biologics, 
antibiotics, probiotics, surgeries) and the length of these therapies during the previous 3 years. 
 
Proportion of biologic-experienced patients. 
 
Proportion of patients who have not responded previously to biologic therapies and reason. 
 
IBD treatment introduced at Day 1 (if applicable). 
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 
Socio-demographic, clinical and treatment-related variables in patients with moderate to severe 
activity of CD (HBI ≥ 8 or CDAI ≥ 220 points) versus patients with mild or no activity (HBI < 8 
or CDAI < 220 points). 
 
Socio-demographic, clinical and treatment-related variables in patients with moderate to severe 
activity of UC (partial Mayo score ≥5) versus patients with mild or no activity (partial Mayo <5). 
 
Mean score of EQ-5D by IBD type. 
 
Mean score of different components of SF-36 by IBD type. 
 
Mean total score of IBDQ and by domain (bowel symptoms, systemic symptoms, emotional 
function and social function).  
 
Mean total percentage of work impairment (WPAI). 
 
Mean work time missed (WPAI). 
 
Mean impairment while working (WPAI). 
 
Mean total activity impairment (WPAI). 
 
Proportion of patient who quit their job due to IBD and have not been able to return to work. 
 
Healthcare resources (previous 3 years) imaging and laboratory testing, surgeries, hospitalizations 
and consultations. 
 
10.1.2 Statistical analyses overview 
For each study endpoint, data will be summarized for total IBD patients and by IBD type (CD and 
UC). 
Statistical analysis will allow a characterization of the study population, the estimation of primary 
endpoints and to compare the subgroup of patients with mild or no activity of disease and those with 
moderate to severe activity. Hence, for each IBD type, the patients with disease activity will be 
compared with patients with mild or no activity regarding socio-demographic, clinical and treatment 
variables of interest. Chi-square or Fisher exact tests will be used to compare activity vs non-activity 
regarding qualitative variables and t-student / Mann-Whitney tests will be used for comparison of 
quantitative variables. If applicable, logistic regression will be used for evaluating associated 
variables. All tests will be two-sided considering a significance level of 5%. 
For further details of the statistical analyses to be performed, please refer to the SAP. 
 
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10.2 Primary Analyses 
For Crohn’s Disease (CD), the proportion of patients with active disease at Day 1 will be presented as 
percentage and calculated as: 
𝐶𝐷 𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠 𝑤𝑖𝑡ℎ 𝐻𝐵𝐼≥8 𝑜𝑟 𝐶𝐷𝐴𝐼≥220
𝑇𝑜𝑡𝑎𝑙 𝐶𝐷 𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠
 𝑥 100 
For Ulcerative Colitis (UC), the proportion of patients with active disease at Day 1 will be presented 
as percentage and calculated as: 
𝑈𝐶 𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠 𝑤𝑖𝑡ℎ 𝑝𝑎𝑟𝑡𝑖𝑎𝑙 𝑀𝑎𝑦𝑜 𝑠𝑐𝑜𝑟𝑒≥5 
𝑇𝑜𝑡𝑎𝑙 𝑈𝐶 𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠
 𝑥 100 
The 95% confidence intervals will be computed for each estimate. 
 
10.3 Secondary Analyses 
The following objectives will be addressed for all IBD patients: 
 
In order to characterize socio-demographic and clinical aspects of moderate to severe IBD, a 
summary table with the descriptive statistics of the selected variables, by CD and UC patients. 
 
Descriptive statistics will also be used to summarize treatment patterns for CD and UC in the 
previous 3 years, including the use of biologic therapies and failure to these therapies (if any), 
time between IBD diagnosis and initial treatment, first treatment after diagnosis of moderate to 
severe IBD, among other variables of interest. 
 
Within CD and UC groups, the patients with moderate to severe disease activity will be compared 
with patients with mild or no activity, regarding socio-demographic, clinical and treatment 
variables of interest: 
o Chi-square or Fisher exact tests will be used to compare qualitative variables, such as 
gender, smoking habits, professional status, family history of IBD, steroid behavior 
(dependent/refractory), previous treatment with biologic therapies, and previous surgery 
for IBD, among others. 
o The t-student or Mann-Whitney tests will be used for comparison of quantitative 
variables, such as age, time since diagnosis, and duration of treatment, among others. 
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o If applicable, logistic regression models (for CD and UC patients) will be used to identify 
independent variables associated with disease control at Day 1, and odds ratios (OR) with 
95% CI will be presented. 
 
Within CD and UC groups, the patients with moderate to severe disease activity will be compared 
with patients with mild or no activity, regarding socio-demographic, clinical and treatment 
variables of interest. 
 
For each IBD disease, descriptive statistics – mean, standard-deviation (SD), median, minimun, 
maximun – will be used to summarize patients’ QoL, overall and according to disease activity 
o The score of EQ-5D analog scale and responses to each item. 
 
Utilities will be configured such that 0.0 is associated with being dead and 1.0 is 
associated with perfect health; thus, a higher utility value is considered better. 
Mean (SD) utility index will be estimated for CD and UC patients, overall and 
according to disease activity. 
o The SF-36 uses 36 items to evaluate eight health dimensions: 
 Physical functioning (PF) – Average of Q3a, Q3b, Q3c, Q3d, Q3e, Q3f, Q3g, Q3h, 
Q3i and Q3j scores; 
 Role Physical (RP) – Average of Q4a, Q4b, Q4c and Q4d scores; 
 Body pain (BP) – Average of Q7 and Q8 scores; 
 General health (GH) – Average of Q1, Q11a, Q11b, Q11c and Q11d scores; 
 Vitality (VT) – Average of Q9a, Q9e, Q9g and Q9i scores; 
 Social Functioning (SF) – Average of Q6 and Q10 scores; 
 Role-Emotional (RE) – Average of Q5a, Q5b and Q5c scores; 
 Mental Health (MH) – Average of Q9b, Q9c, Q9d, Q9f and Q9h scores; 
 Based on SF-36 standardized scores, two summary scores are estimated, the 
Physical Component Score (PCS) and the Mental Component Score (MCS). 
o The IBDQ score and each of the four IBDQ domains: 
 Bowel systems – Add up scores of questions 01, 05, 09, 13, 17, 20, 22, 24, 26 and 
29 and divide by 10; 
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 Emotional health – Add up scores of questions 03, 07, 11, 15, 19, 21, 23, 25, 27, 
30, 31 and 32 and divide by 12; 
 Systematic systems – Add up scores of questions 02, 06, 10, 14 and 18 and divide 
by 5; 
 Social function – Add up scores of questions 04, 08, 12, 16 and 28 and divide by 
5; 
o The comparison of SF-36 scale scores or component summary scores, EQ-5D VAS scale 
and IBDQ domain scores or total score according to disease activity will be performed 
through the t-test for independent samples or Mann-Whitney test in case of non-normality 
of the quantitative variable distribution. The association between each EQ-5D dimension 
and disease activity will be determined for each IBD type using Chi-Square Test. 
 
To evaluate the work productivity impairment (WPAI) experienced by moderate to severe IBD 
patients, the following variables will be estimated and summarized, by CD or UC, overall and 
according to disease activity:  
o In brief, the WPAI questions are: 1) if currently employed, 2) hours missed due to 
disease, 3) hours missed other reasons, 4) hours actually worked, 5) degree disease 
affected productivity while working, 6) degree disease affected regular activities. 
o Mean (SD) total work productivity impairment (TWPI), defined as the mean of subjects 
total percentage of work impairment associated with IBD that results from both 
absenteeism and presenteeism, and assessed with specific WPAI for each IBD type. The 
TWPI due to IBD will be calculated as Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4)))x(Q5/10)]*100 
o Mean (SD) work time missed due to IBD. The percentage of work time missed due to 
IBD will be calculated for each subject as Q2/(Q2+Q4)*100 
o Mean (SD) impairment while working due to IBD. The percentage of impairment while 
working due to IBD will be calculated for each subject as Q5/10*100 
o Mean (SD) total activity impairment due to IBD. The percentage of total activity 
impairment due to IBD will be calculated for each subject as Q6/10 *100 
o Additionaly, the proportions of patients reporting some absenteeism, some work 
impairment, and some activity impairment due to IBD will be presented. 
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o Patients with moderate to severe disease will be compared with patients with no or mild 
disease regarding WPAI data (percent total work productivity impairment due to IBD, 
percent work time missed due to IBD, percent impairment while working due to IBD and 
percent total activity impairment due to IBD) through the t-test for independent samples 
or Mann-Whitney test in case of non-normality of the quantitative variable distribution. 
 
Healthcare resources (previous 3 years) will be described by IBD group and by disease activity, 
for the following events: drug therapies, number and type of imaging and laboratory testing, 
surgeries, number, reason and duration of hospitalizations, number and type of consultations with 
gastroenterologists or other medical specialists and adverse events. 
 
Healthcare resource costs: costs will be reported in total and on a per patient per month basis. 
Costs will be obtained by multiplying resource use with relevant unit costs. Unit costs for 
resource items will be collected in Argentine reliable administrative databases or other sources.  
o UC or CD-related health care costs. Consumer price index (CPI)-adjusted IBD-related 
health care costs will be computed as total costs, medical costs, drug costs, and other 
costs. 
o Treatment pattern costs. Treatment pattern costs will be calculated as total UC or CD-
related health care costs, stratified by the defined treatment patterns. In addition to the 
descriptive cost data, multivariate cost models may be developed where the observation 
time is divided into intervals of equal length.  
 
10.4 Interim Analyses 
No interim analyses are planned for this study.  
 
10.5 Handling of missing data 
Given that all analyses are descriptive in nature, no imputation of missing data will be performed, 
except when detailed in the SAP regarding the PRO tools. 
 
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10.6 Determination of Sample Size 
It is expected to include 246 patients regardless of IBD type. This sample size will allow estimates 
with 95% confidence interval and a margin of error less than 5% and assuming a rate of inadequate 
control of disease of 20% (conservative approach), regardless of IBD type. 
The following formula was used:  
𝑛= 1.962 × 𝑝× (1 −𝑝)
𝑀𝐸2
 
Rate of uncontrolled disease (p) = 20%  
Margin of error (ME) = 0.05 
 
11 Reports 
A Non-Interventional Study Report based on the results obtained will be prepared and submitted for 
distribution. This Study Report should be available within one year from collection of the last data 
point, and the participating sites should be informed about the results when the report is finalized. 
 
12 Publications 
Takeda aims to have the results of this study published. 
Takeda has the right to use the data and results for regulatory purposes and for internal presentation 
within the company and to partners. 
 
13 Archiving of Study Documentation 
During the course of the study the Study Site Responsible must as a minimum file the essential 
documents (Section 4.4), the protocol, any amendments, the list of participating subjects, the written 
informed consents, the CRFs and the progress reports in the Study Site File. After final database lock, 
the Study Site Responsible must keep a minimum store the list of participating subjects and the signed 
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ICFs on site for 5 years. The Study Site Responsible should store additional study documentation for a 
longer period of time as required by any local regulations and/or hospital requirement. 
 
14 References 
                                                     
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activity in Crohn’s disease and ulcerative colitis. World J Gastroenterol. 2012;18:872–81. 
3. Schirbel A, Reichert A, Roll S, Baumgart DC, Büning C, Wittig B, et al. Impact of pain on health-
related quality of life in patients with inflammatory bowel disease. World J Gastroenterol. 
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4. Yamamoto-Furusho J, Bosques-Padilla F, de-Paula J, Galiano M, Ibañez P, Juliao F, et al. 
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5. Gibson PR, Vaizey C, Black CM, Nicholls R, Weston AR, Bampton P, et al. Relationship between 
disease severity and quality of life and assessment of health care utilization and cost for ulcerative 
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disease in Europe. J Crohns Colitis. 2013;7(4):322-37. 
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10. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nature Reviews Gastroenterology & 
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