Real-world Data of Moderate to Severe Inflammatory Bowel Disease in Brazil: a Non-interventional, Multicenter Study to Evaluate Disease Control, Treatment Patterns, Burden of Disease and Quality of Life (RISE BR)
Conditions: Inflammatory Bowel Disease
Sponsor: Takeda



•
Title: Real-world data of Moderate to Severe Inflammatory Bowel Disease in Brazil: a non-
interventional, multicenter study to evaluate the disease control, treatment patterns, burden of 
disease and the quality of life (RISE BR).
NCT Number: NCT02822235
Protocol Approve Date: 19 Apr 2016 
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.

Vedolizumab_4008 
Observational/Non-Interventional 
Study Protocol 
      Amendment 1 
Version 17 Oct 2016 
Page 1 of 51 
Non-Interventional Study Protocol 
Short title: 
Non-interventional Study of Moderate to Severe Inflammatory Bowel Disease 
in Brazil 
Title: 
Real-world data of Moderate to Severe Inflammatory Bowel Disease in Brazil: 
a non-interventional, multicenter study to evaluate disease control, treatment 
patterns, burden of disease and quality of life (RISE BR). 
Study ID: 
Vedolizumab_4008 
Sponsor: 
Takeda Pharma Ltda. 
Rua do Estilo Barroco, 721 
04709-011 - São Paulo/SP – Brasil 
Phone: + 55 11 5188 4400 
Fax: 
+ 55 11 5181 0081 
Study phase:  Medical Affairs, Non-registration Company Sponsored (Observational) 
Date of version of protocol: 19 Apr 2016 
Amendment # Sequence and type of amendment 
01 
 
1st Amendment, local, substantial 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Takeda except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered. Furthermore, the information is only meant for review and compliance by 
the recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable 
conduct of the study. 

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          Amendment 1 
Version 17 Oct 2016 
 
 
Page 4 of 51 
 
 
Criteria 
Criteria for 
Prospective Phase 
less restrict the 
criteria. 
9 
 
17Oct2016 
6.3.2 Exclusion 
Criteria 
Updated Exclusion 
Criteria 1. 
To clarify the text 
excluding also “not 
classified colitis”. 
10 
 
17Oct2016 
6.3.2 Exclusion 
Criteria 
Updated Inclusion 
Criteria 2. 
To clarify that is 
related only to 
interventional trials. 
11 
 
17Oct2016 
6.3.2 Exclusion 
Criteria 
Exclusion Criteria 
for Prospective 
Phase updated to 
become also 
exclusion criteria 
for the 
Retrospective Phase 
To be more 
consistent with the 
study design.  
12 
 
17Oct2016 
6.3.2 Exclusion 
Criteria 
Updated Exclusion 
Criteria for 
“Hospitalized 
Patients” 
To clarify that is 
related for Day 1 
only. 
13 
 
17Oct2016 
7.1 Data Collection 
Overview  
Table updated with 
information to be 
collected during the 
study. 
Clarify information 
to be consistent 
with the study 
design. 
14 
 
17Oct2016 
7.2 Study Variables  
Updated 
information to be 
consistent with the 
changes from this 
amendment in the 
item 6.3.2. 
Clarify information 
to be consistent 
with the changes 
from this 
amendment in the 
item 6.3.2. 
15 
 
17Oct2016 
1.4 Summary - 
Main outcome 
variables – Health 
Economics 
7.2 Study Variables 
10.1.1 Study 
Endpoints  
Included 
information about 
exclusion of the 
patients who have 
colostomy or 
ileostomy from the 
group to answer 
IBDQ since this 
questionnaire is not 
applicable. 
Clarify information 
to be consistent 
with the study 
design. 

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Version 17 Oct 2016 
 
 
Page 5 of 51 
 
 
16 
 
17Oct2016 
14. Reference 
Added references 
31 to 34 to support 
change in the item 
6.3.1. 
Added references 
31 to 34 to support 
change in the item 
6.3.1. 
17 
 
17Oct2016 
1.4 Summary – 
Number of subjects 
6.3.4 Enrollment 
10.1.2 Statistical 
Analysis Overview 
10.6 Determination 
of Sample Size 
Change the 
estimated 
proportion of type 
of disease from 
60%CD/40% UC to 
50%CD/50%UC 
since the original is 
not supported by 
the literature in 
Brasil. The 50% 
rate for each type of 
disease will be 
more reasonable for 
the study sample 
size. 
Clarify information 
to be consistent 
with the study 
design. 
18 
 
17Oct2016 
7 Conduct 
8 Management and 
Reporting of 
Adverse Events 
Updated 
information to be 
consistent with 
spontaneous 
reporting 
Updated 
information to be 
consistent with 
spontaneous 
reporting 
 
 

PPD

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1.4 
Summary 
 
Short Title of Study 
Non-interventional Study of Moderate to Severe Inflammatory Bowel Disease in Brazil. 
 
Study sites 
The study will be conducted in approximately 20 sites in Brazil. 
 
Objectives 
Knowledge regarding the control of disease activity in Inflammatory Bowel Disease (IBD) is 
limited in Brazil. Therefore, it is pertinent to gather information regarding the population with 
moderate to severe IBD, the burden of the disease, and understand their treatment patterns, 
particularly on the use of available biologic therapies. 
Primary Objective: 
• 
To evaluate the disease activity in moderate to severe IBD patients [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 in the previous 3 years, 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. 
• 
For patients with active IBD at study appointment (Day 1):   
a) To assess clinical activity after 12 months of follow up. 
b) To describe physician's drivers for therapeutic decision during the 12-month 
follow up period. 
• 
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. 

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• 
To describe the use of health resources related with the management of IBD in the 
previous 3 years. 
• 
To estimate UC or CD-related health care costs in data from the previous 3 years. 
 
Methodology 
This is a multicentre, non-interventional study to determine the rate of control of disease 
activity. At each site, eligible subjects will be identified consecutively as they attend 
scheduled clinical appointment (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 Patient Report Outcome 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), and use of other health resources related with the management of 
IBD. 
For patients with active disease at Day 1, a prospective period of 12 months will be 
conducted to follow up the course of the disease. Ulcerative colitis (UC) patients with no or 
mild disease activity at Day 1 will not continue to 12-month follow up. Crohn's Disease (CD) 
patients with no or mild disease activity at Day 1 but with colonoscopy or calprotectin levels 
(i.e, calprotectin >200ug/g) in the previous year suggestive of inadequate control of activity 
will progress to 12-month follow up. 
 
Number of subjects 
It is expected to include approximately 400 patients regardless of IBD type. This sample size 
will allow estimates with 95% confidence interval and a margin of error less than 5%.  
Based on the above and considering an expected ratio of CD/UC of approximately 
50%/50%, and that the rate of inadequate control of disease activity varies from 20-30% 
(regardless of the IBD type), it is expected to analyse 40-60 patients with CD and 30-50 
patients with UC during the 12-month follow up. 
 
Diagnosis/Disease/Condition and main criteria for inclusion 
Subjects must meet all of the following inclusion criteria: 1) male or female subjects, 2) aged 
18 years or older (at the time of diagnosis of moderate to severe UC or CD), 3) with 
diagnosis of moderate to severe CD or UC for at least 6 months prior to Day 1 appointment 
according the clinical or endoscopic criteria (23, 24, 25, 26, 27), 4) who provided the written 

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Page 9 of 51 
 
 
informed consent.Patients will be excluded if (1)presenting  indeterminate or not classified 
colitis, or (2) having current or previous participation in interventional clinical trials (within the 
last 3 years), or (3) presenting mental incapacity, unwillingness or language barriers 
precluding adequate understanding or cooperation, or (4) hospitalized patients at Day 1, or 
(5) in current off label treatment with Vedolizumab. 
 
 
Duration of data collection per subject 
Cross-sectional at Day 1, with retrospective data collection over the previous 3 years. For 
patients enrolled in the prospective phase, information will be collected at all clinical 
appointments occurring within 12 months. 
 
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  ( e.g.: type of IBD, steroid behavior, anthropometric 
information, medical history and comorbidities, clinical characterization of disease) by 
IBD type. 
• 
 Therapies for IBD (aminosalicylates, steroids, immunomodulators, immunosupressors 
biologics, antibiotics, probiotics, surgeries) within the previous 3 years. 
• 
Proportion of biologic-experienced patients. 

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• 
Proportion of patients who have not responded previously to biologic therapies and 
reason. 
• 
IBD treatment introduced at Day 1. 
• 
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). 
• 
Among patients who had moderately to severely active CD at Day 1:  HBI or CDAI score 
after 12 months. 
• 
Among patients who had moderately to severely active UC at Day 1: Partial Mayo score 
after 12 months. 
• 
Among patients who had moderately to severely active CD or UC at Day 1: Treatment 
after 12 months; In case of change of current treatment: reason for change. 
 
Health economics: 
• 
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 of subjects total percentage of work impairment (WPAI). 
• 
Mean work time missed (WPAI). 
• 
Mean impairment while working (WPAI). 
• 
Mean total activity impairment (WPAI). 
• 
Health resources (previous 3 years): drug therapies, imaging and laboratory testing, 
surgeries, hospitalizations, and consultations. 
 
Statistical methods 
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.  

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Data will be summarized by IBD type (Crohn’s Disease and Ulcerative Colitis).  
Cross-sectional analysis - For each IBD type, the patients with disease activity will be 
compared with patients with no or mild activity regarding socio-demographic and clinical 
variables of interest. Chi-square/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 
quantitative variables comparisons. The cross-sectional analysis will be conducted once all 
patients have completed the Day 1 assessment (expected to occur 6 months after start of 
enrolment). 
Longitudinal analysis - The proportion of controlled patients will be presented as well as the 
95%CI at the 12-month follow up assessment.  If applicable, logistic regression will be used 
for calculating odd ratios and 95% confidence intervals for the patient control at month 12 
determined by independent numerical/categorical variables.  All tests will be two-sided 
considering a significance level of 5%. Utility scores will be calculated from EQ-5D and SF-
36. The longitudinal analysis will be performed once all the concerned patients complete the 
12-month follow up. 
 
 
 
 

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Table of Contents 
1 
Administrative information................................................................................................ 2 
1.1 
Contacts ................................................................................................................. 2 
1.2 
Amendments and updates ...................................................................................... 3 
1.3 
Approval ................................................................................................................. 6 
1.4 
Summary ................................................................................................................ 7 
2 
Introduction .................................................................................................................... 16 
2.1 
Study Rationale .................................................................................................... 17 
3 
Study Objective(s) ......................................................................................................... 18 
4 
Study Administrative Structure ....................................................................................... 18 
4.1 
Study Sites ........................................................................................................... 19 
4.2 
Sponsor Personnel ............................................................................................... 19 
4.3 
Contract Research Organisation (CRO) ............................................................... 19 
4.4 
Essential Documents ............................................................................................ 19 
5 
Ethics ............................................................................................................................ 20 
5.1 
Ethical conduct of the Study ................................................................................. 20 
5.2 
Independent Ethics Committee ............................................................................. 20 
5.3 
Subject Information and Written Informed Consent ............................................... 21 
6 
Study Design and Plan .................................................................................................. 23 
6.1 
Study Schedule .................................................................................................... 24 
6.2 
Discussion of Study Design .................................................................................. 25 
6.3 
Selection of Study Population ............................................................................... 26 
6.3.1 
Inclusion Criteria ..................................................................................... 26 
6.3.2 
Exclusion Criteria .................................................................................... 27 
6.3.3 
Study Discontinuation Criteria ................................................................. 28 
6.3.4 
Enrolment ............................................................................................... 28 
6.4 
Treatments ........................................................................................................... 29 
7 
Conduct ......................................................................................................................... 30 
7.1 
Data collection overview ....................................................................................... 30 
7.2 
Study Variables .................................................................................................... 31 
8 
Management and Reporting of Adverse Events ............................................................. 34 
8.1 
Definitions............................................................................................................. 34 
8.2 
Collection and Recording of Adverse Events ........................................................ 35 
8.3 
Reporting of Adverse Reactions ........................................................................... 36 

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8.4 
Other Safety Information ....................................................................................... 36 
9 
Data Quality Control and Assurance .............................................................................. 37 
9.1 
Quality Control ...................................................................................................... 37 
9.2 
Audit from Quality Assurance Unit ........................................................................ 37 
9.3 
Inspection by IEC or Competent Authority ............................................................ 37 
9.4 
Data Management ................................................................................................ 37 
9.4.1 
Data Collection Tools and Flow ............................................................... 38 
10 Statistical Methods and Determination of Sample Size .................................................. 39 
10.1 Statistical Analysis Plan ........................................................................................ 39 
10.1.1 
Study Endpoints ...................................................................................... 39 
10.1.2 
Statistical analyses overview................................................................... 41 
10.2 Primary Analyses .................................................................................................. 42 
10.3 Secondary Analyses ............................................................................................. 42 
10.4 Interim Analyses ................................................................................................... 46 
10.5 Handling of missing data ...................................................................................... 46 
10.6 Determination of Sample Size .............................................................................. 46 
11 Reports .......................................................................................................................... 47 
12 Publications ................................................................................................................... 47 
13 Archiving of Study Documentation ................................................................................. 47 
14 References .................................................................................................................... 48 
 
 
 
 
 

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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 Organisation 
CV: 
 
Curriculum Vitae 
DSO:  
Drug Safety Officer 
eCRF:  
electronic Case Report Form  
EDC:  
Eletronic Data Capture 
EIM: 
 
Extraintestinal Manifestations 
EQ-5D: 
5-dimensional EuroQoL measure 
GCP:  
Good Clinical Practice 
GPP:  
Good Pharmacoepidemiology Practices 
HBI: 
 
Harvey Bradshaw Index 
IBD: 
 
Inflammatory Bowel Disease 
IBDQ:  
Inflammatory Bowel Disease Questionnaire 
ICH: 
 
International Conference on Harmonisation 
IDS: 
 
International Drug Safety 
IEC: 
 
Independent Ethics Committee 
MCS:  
Mental Component Summary 
PCS:  
Physical Component Summary 
pMayo: 
partial Mayo score 
PRO:  
Patient Reported Outcomes 
PSUR:  
Periodic Safety Update Report 
QA: 
 
Quality Assurance 
QoL:  
Quality of Life 

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SAE:  
Serious Adverse Event 
SAP:  
Statistical Analysis Plan 
SADR:  
Serious Adverse Drug Reaction 
SDV:  
Source Data Verification 
SF-36:  
36-item Short Form health Survey 
SPC:  
Summary of Product Characteristics 
UC: 
 
Ulcerative Colitis 
VAS:  
Visual Analog Scale 
WPAI:  
Work Productivity and Activity Imparment questionnaire 
 
 

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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). 
 
With episodes of relapse and remission, IBD presents relevant health and economic burden 
(4,5). In fact, IBD impact on patient quality of life is particularly relevant since it affects 
mainly young individuals, may present severe symptoms and disease flares are 
unpredictable (6). Alongside with loss of patient’s QoL, symptoms may also impact work 
productivity and increase the economic burden of these diseases (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; IBD prevalence is estimated to reach up to 
396 per 105 people (8). The incidence of inflammatory bowel disease (IBD) has been 
increasing in several world regions, namely in developing countries (9,10).  
 
In Brazil, epidemiologic and cost of illness information about IBD is scarce. Increased 
frequencies of outpatient visits and hospitalizations in the major urban centers of Brazil have 
been observed (11, 12,13). A retrospective hospital study in Piauí (North-eastern Brazil) with 
252 IBD patients, observed that 152 (60.3%) were UC patients and 100 (39.7%) CD 
patients (14). More recently, a cross-sectional study in two IBD treatment referral centers in 
Bahia (North-eastern Brazil) has described demographic and clinical characteristics of 267 
patients with UC, being observed that extensive colitis was positively associated with male 
gender, diarrhea, weight loss, and a younger age at diagnosis (15). And there are no 
studies describing the health care resources and costs of IBD in Brazil. 
 
Treatment of IBD remains challenging, with several strategies available (1,11). In Brazil, 
treatment options include salicylic derivatives [namely, sulfasalazine and mesalazine (5-
ASA)], corticosteroids, immunosuppressors (azathioprine, 6-mercaptourine, methotrexate, 
cyclosporine), and biological therapy (infliximab, adalimumab and, more recently, 
vedolizumab) (12,13,14).  

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Corticosteroids (oral prednisolone 0.75-1mg/kg/day) are indicated to induce clinical 
remission in patients with active UC or CD of mild and moderate intensity. Clinical remission 
is achieved in 70%-90% of cases after 4-6 weeks of treatment but endoscopic and histologic 
remission are only achieved in approximately 30% of cases. In addition, corticosteroid-
resistant and corticosteroid-dependent CD cases ranges from 8%-20% and from 15%-36%, 
respectively. In UC, reported frequencies of corticosteroid-resistance and dependence were 
29% and <10%, respectively (12).  
 
Regarding maintenance treatment, corticosteroids are not indicated due to side effects. 
Sulphasalazine and 5-ASA are recommended in the maintenance of remission of UC (11, 
12). Immunosuppressors are effective in maintaining remission in CD and UC and while 
promoting corticosteroid withdrawal in corticosteroid-dependent patients (12). However, 
methotrexate is nowadays a second-line immunosupressor for patients resistant or 
intolerant to azathioprine or 6-mercaptourine, and cyclosporine seems to have no 
therapeutic value in treatment of CD (11).  
 
Biological therapy has been increasingly used, namely for moderate to severe IBD or when 
there is no response to conventional treatments (12). In fact, infliximab (11,15), adalimumab 
(16,17) and vedolizumab (13,14) have shown to be effective in induction and maintenance 
of clinical remission of UC and CD. Side effects usually occur in less than 10% of cases, 
and it has been described that biological therapy can promote endoscopic and histologic 
improvement (12). Biologics have also the potential to improve QoL in IBD patients (18). 
 
In face of IBD complexity and heterogeneity, treatment decision should consider the activity 
and severity level, the extension of inflammatory process and corticoid dependency (12). 
Furthermore, if the first-line immunosuppressive maintenance therapy fails, several other 
factors should be taken into account, including patient’s wishes, fecundity and patient age 
(11). 
 
 
2.1 Study Rationale 
No studies have been conducted in Brazil with large territorial coverage, to evaluate 
demographic and clinical aspects of IBD, namely the level of disease activity and the burden 

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of disease. Therefore, it is pertinent to gather information regarding the population with a 
moderate to severe IBD, the burden of the disease, and understand their treatment patterns, 
particularly on the use of available biologic therapies. 
 
3 
Study Objective(s) 
 
Primary Objective: 
• 
To evaluate the disease activity in moderate to severe IBD patients (active CD defined 
as HBI ≥ 8 or CDAI ≥ 220 points at Day 1; active UC defined as 9-point partial Mayo 
score ≥5 at Day 1). 
 
Secondary Objectives: 
• 
To characterize socio-demographic and clinical aspects of moderate to severe IBD; 
• 
To characterize treatment patterns for IBD in the previous 3 years, 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 at Day 1, regarding socio-demographic and clinical 
variables of interest and treatment patterns; 
• 
For patients with active IBD at study appointment (Day 1): 
a) To assess clinical activity after 12 months of follow up; 
b) To describe physician's drivers for therapeutic decision during the 12-month 
follow up period; 
• 
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 health resources related with the management of IBD in the 
previous 3 years. 
• 
To estimate UC or CD-related health care costs in data from the previous 3 years. 
 
4 
Study Administrative Structure 
 

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          Amendment 1 
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Page 20 of 51 
 
 
• 
Signed and dated protocol agreement and amendment agreements, if any, with the 
original signature of the Site Responsible. 
• 
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 (ie, 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 
Brazilian 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 
According to applicable regulations, the appointed CRO or the Site Study 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, eg, 
Patient Report Outcome tools. 

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The appointed CRO or the Site Study 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. 
 
Global Research will keep an updated list of all submission and approval dates of all 
documents submitted to the IEC and will provide the Site Responsible with a copy of this list. 
Copies of the documents will be distributed upon request. 
 
 
Authorities 
Global Research or the appointed Contract Research Organization (CRO) will send required 
documents to the competent authority (CA) and/or other national or regional authorities. 
Global Research 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 Site Study 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 

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          Amendment 1 
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Page 22 of 51 
 
 
anonymous form to 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 it is stated that if consent is withdrawn, any data collected before 
withdrawal of consent will be kept. The original, signed Informed Consent Forms must be 
kept on the Site. 
 
For details, see the Subject Information Sheet and Informed Consent Form. 
 
 
 
 

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At each site, eligible subjects will be identified consecutively as they attend scheduled 
clinical appointment (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 health resources related with the management of IBD. 
 
UC patients with no or mild disease activity at Day 1 will not continue to 12-month follow up. 
CD patients with no or mild disease activity at Day 1 but with colonoscopy or calprotectin 
levels in the previous year suggestive of inadequate control of activity will progress to 12-
month follow up. 
 
6.1 Study Schedule 
Planned Start of Study: 
 
 
 
April 2016 
Planned collection of first data point: 
 
October 2016 
Planned End of Study: 
 
 
 
April 2018 
Planned completion of the Study Report: 
 
August 2018 
 
This study will have duration of 6 months for the cross-sectional phase, with an additional 
follow-up of 12 months for the patients included in the prospective phase. 
 
The Start of Study is defined as date of last protocol signature and planned to occur on April 
2016. The collection of first data point (first patient in) will start during October 2016. The 
recruitment period is expected to last up to 6 months. The End-of-Study is defined as the 
date when the last subject completed follow-up period.  
 
Takeda Brasil 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. 
 
Global Research will ensure that results are posted on “clinicaltrials.gov” and as required by 
local authorities.  

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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 designed to evaluate disease control, treatment patterns, 
burden of disease and health related quality 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. Furthermore, the inclusion of a prospective follow-
up for patients with active disease will enable an insight on how active CD or UC are 
managed in Brazil and what are the factors associated to achieving disease control. 
 
In terms of external validity, two major points should be considered. First, the 20 study sites 
will be selected among reference public and private institutions for IBD management. It is 
expected that their patients will be representative of patients with moderate to severe IBD in 
Brazil. In addition, the inclusion and exclusion criteria are not restrictive and will enable the 
assessment of real-world data about IBD control in Brazil. 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 and prospective 
evaluations. 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. 
 
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 6 
months. Disease control may be underestimated due to selection bias, since patients with 
active IBD are expected to have more medical appointments and may be more easily 
invited. Nevertheless, the 6-month period will also enable the inclusion of patients with no or 
mild active disease. 
 
 
 

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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.  
 
 
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; 
2) Subjects aged 18 years or older (at the time of diagnosis of moderate to severe UC 
or CD); 
3) Diagnosis of moderate to severe CD or UC for at least 6 months prior to Day 1 
appointment according the clinical or endoscopic criteria (23, 24, 25, 26, 27);  
 
4) Subjects who provided the written informed consent. 
 
In addition, for the prospective period, eligible patients should present at least one of the 
following criteria that will only be applied at Day 1: 
• 
For CD patients: 
o HBI ≥ 8 or  
o CDAI ≥ 220 or 

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Considering that for CD patients, the disease activity may not be clearly documented only 
with clinical data, some objective criteria may be considered as entry criteria for the 12-
month prospective period:  
o colonoscopy in the previous year suggestive of inadequate control of activity 
or 
o calprotectin levels in the previous year suggestive of inadequate control of 
activity (i.e, calprotectin >200ug/g) (28). 
 
For UC: partial Mayo Score ≥5 
Note 1: UC patients with no or mild disease activity at Day 1 will not continue to follow up. 
CD patient with no or mild disease activity at Day 1 but with colonoscopy or calprotectin 
levels (i.e, calprotectin >200ug/g) in the previous year suggestive of inadequate control of 
activity will progress to 12-month follow up. 
Patients that fulfill the above criteria (active disease) will be followed for 12 months, in order 
to explore patterns of care. 
 
Note 2: Patients with colostomy and prospective period:  
Although clinical scales defined above are impacted by colostomy these patients will not be 
excluded from the protocol to ensure the assessment of different clinical presentations of the 
IBD. In addition, patients with colostomy must follow the same criteria as above to be eligible 
to the prospective phase.  
 
Note 3: Patients who are eligible for the prospective period, it means, with active disease at 
Day 1 but who during the 12 months period presents disease remission and/or no activity 
disease condition, mustcontinue in the study. 
 
 
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. 

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4) Hospitalized patients at Day 1. 
5) Current off label treatment with Vedolizumab. 
 
6.3.3 Study Discontinuation Criteria 
 
It will be considered a premature termination the situation in which the subject discontinues 
the participation, i.e. they are withdrawn from the study before completing the 12 months of 
follow up period (365 days ± 14 days from Day 1), due to any of the reasons listed below: 
1. Withdrawal of consent: subjects who for any reason withdraw the free and informed 
consent; 
2. Lost to follow-up (no return of the subject on the expected date of visit - drop-out from 
the protocol); 
3. Death; 
4. Study termination; 
5. Any situation that places the subject within one of the exclusion criteria. 
 
Note: Patients who are eligible for the prospective period, it means, with active disease at 
Day 1 but who during the 12 months period presents disease remission and/or no activity 
disease condition, are allowed to continue the participation in the study. 
 
6.3.4 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. 
 
After 2 and 4 months of enrolment, the overall proportion of patients with CD and UC will be 
reviewed. In case the expected ratio of IBDs (50%CD/50%UC) is not attained at 2 and 4 
months of enrolment, the participating sites will be instructed to change future enrolments so 

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that this balance is achieved and that at least 30 UC patients and 30 CD patients with active 
disease enter the prospective follow-up. 
 
6.4 Treatments 
Non-interventional study – no treatments/pharmacotherapy are pre-defined in the protocol.  
All clinical decisions will be fully responsibility of the investigator. 
 
 

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7 
Conduct 
 
7.1 Data collection overview 
Table 1. Study Flow Chart 
Study variables 
Day 1 
Prospective period* 
(approx. 12 months) 
Collection data points 
Timing of data collection 
Day 1 visit 
 
3-months 
(90 days ± 
14 days) 
 
6-months 
(180 days 
± 14 days) 
.  
9-months 
(270 days 
± 14 days) 
End of  
fw-up (12 
months) 
(365 days 
± 14 days) 
Informed consent 
X 
 
 
 
 
Inclusion criteria  
X 
 
 
 
 
Exclusion criteria 
X 
 
 
 
 
Anthropometric Information (Weight, Height, BMI) 
X 
 
 
 
 
IBD type (CD or UC) 
X 
 
 
 
 
Socio-demographic variables  
X 
 
 
 
 
Smoking habits 
X 
 
 
 
 
Family history of IBD 
X 
 
 
 
 
Medical history / Comorbidities  
X 
 
 
 
 
Date of diagnosis of CD or UC 
X 
 
 
 
 
Date of diagnosis of moderate to severe CD or UC  
X 
 
 
 
 
Clinical Characterization of Disease – (location, 
behavior, EIM) 
X 
 
 
 
 
Steroid behavior 
X 
 
 
 
 
Disease activity: CD (HBI score or CDAI); UC 
(partial/total Mayo Score) 
X 
 
 
 
X 
Eligibility for 12-month follow up  
X 
 
 
 
 
SF-36 
X 
 
 
 
 
EQ-5D 
X 
 
 
 
 
IBDQ** 
X 
 
 
 
 
WPAI 
X 
 
 
 
 
Previous treatments or regimens 1, 2 
X 
 
 
 
 
Treatment started at Day 1 
X 
 
 
 
 
Treatment at follow-up 
 
X 
X 
X 
X 
Previous surgeries for IBD 
X 2 
 
 
 
 
Hospitalizations 
X 2 
 
 
 
 
Consumption of health resources related with IBD 
management 
X 2 
 
 
 
 
Previous imaging and laboratory testing form 
X 2 
 
 
 
 

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¹ Excludes new treatments prescribed at Day 1 visit. 2 Retrospective data collection (approx. 3 years)  
* Prospective follow-up only for patients with active IBD at Day 1. In this period, data collection is expected to occur quarterly for all 
registered medical appointments.  
** 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; 
• 
Date of diagnosis of moderate to severe CD or UC (if not the same as previous); 
• 
Family history of IBD; 
• 
Smoking habits; 
• 
Medical History / Comorbidities; 
• 
Disease presentation [location, behavior, extraintestinal manifestations (EIM)]; 
• 
Steroid behavior (dependent or refractory); 
• 
Colonoscopy in the previous year suggestive of inadequate control of activity (yes/no) 
(qualitative data/Mayo subscore); 
• 
Calprotectin levels in the previous year suggestive of inadequate control of activity (i.e., 
calprotectin >200ug/g) (yes/no) (qualitative data); 
• 
Eligibility for 12-month prospective follow up (yes/no). 
 
Disease activity (at Day 1 and 12 months follow up appointment) 
• 
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).  

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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 (29). 
 
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 (30). 
 
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) (31). 
 
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 (32). 

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For more 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 (33). 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 quality of life (34). A Portuguese (Brazil) 
version was already validated (35). 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 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 

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• 
Previous treatments or regimens (aminosalicylates, steroids, immunomodulators, 
immunossupressors, biologics, probiotics, antibiotics); start date; end date, dose, reason 
for discontinuation; 
• 
Treatment started at Day 1 (name, dose); 
• 
Previous surgeries for IBD. 
 
At follow up appointment only:  
• 
Therapeutic strategy: maintain current treatment vs discontinued;  
• 
If discontinued, new treatment (name, dose, start date), and reason for 
discontinuation. 
 
Other health care resources related with IBD management 
• 
Imaging and laboratory testing; 
• 
Surgeries; 
• 
Hospitalizations; 
• 
Consultations; 
• 
Adverse Events. 
 
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 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 reaction is an AE for which there is at least a reasonable suspicion of a causal 
relationship between an AE and a suspected medicinal product. 

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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 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: There is a reasonable possibility that the drug caused the event. There is a 
reasonable temporal relationship between the drug administration and the event, and no 
other obvious alternative explanation for the occurrence of the event. 
Not related: There is not a reasonable possibility that the drug caused the event. There 
is evidence for (an) alternative explanation(s) for the event (eg, the event is explained 
by one or more of the following: a) the subject’s medical condition (medical history, 
disease progress, indication), b) a concomitant medication for which the event is 
labelled, or c) AE occurrence prior to the introduction of the medicinal product. 
The investigator must make an assessment of causality using the above definition. Causality 
cannot be assumed in the absence of the investigator’s assessment. 
 
8.2 Collection and Recording of Adverse Events  
 
Collection and recording of AEs will commence after the study participant has provided 
informed consent. 
If during the conduct of the study a member of the research team is spontaneously informed 
of an AE, ADR, SSR, beneficial event or product quality issue, where the event/issue 
pertains to a Takeda/ Multilab product (or unbranded generic which active principle is also 
manufactured by Multilab), such information should be reported to the Sponsor within 24 
hours of Investigator´s team awareness, including the Investigator itself. The investigator 
should assess the causality for the adverse events and the causality should not be assumed 
if there is no investigator’s assessment. 
 
Follow-up information 

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After notification of the initial AE Report form, the Investigator may be contacted by the 
Sponsor to obtain additional information on the event or for data clarification. The 
investigator shall make best effort to obtain the requested additional information. All new 
additional information obtained on the event should be recorded on an AE Report form and 
notified to the Sponsor within 24 hours of Investigator awareness of the new information. 
 
8.3 Reporting of Adverse Reactions  
The Sponsor is responsible for submission of adverse reactions to regulatory authorities in 
accordance with local reporting requirements or the Sponsor’s post marketing commitments, 
with the exception of Individual Case Safety Reports s not collected as part of the study and 
reported spontaneously by investigator or study participant to national competent authorities 
as in 12.2 above. 
 
8.4 Other Safety Information 
If the investigator becomes aware of any of the following events associated with a Takeda 
product during the study, whether or not associated with an AE, the event should be 
recorded on an AE Report form /Pregnancy Report form and submitted to the Sponsor within 
24 hours of investigator awareness. 
 
• 
Use during pregnancy 
• 
Overdose: This refers to the administration of a quantity of a drug given per 
administration or cumulatively, which is above the maximum recommended dose 
according to the authorised product information. Clinical judgement should always be 
applied.  
• 
Off-label use: This relates to situations where the drug is intentionally used for a 
medical purpose not in accordance with the authorised product information.  
• 
Misuse: This refers to situations where the drug is intentionally and inappropriately 
used not in accordance with the authorised product information.  
• 
Abuse: This corresponds to the persistent or sporadic, intentional excessive use of a 
drug, which is accompanied by harmful physical or psychological effects. 

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Page 40 of 51 
 
 
• 
 Therapies for IBD (aminosalicylates, steroids, immunomodulators, immunossupressors, 
biologics, antibiotics, probiotics, surgeries) within 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. 
• 
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 light 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 light or no activity 
(partial Mayo <5). 
• 
Among patients who had moderately to severely active CD at Day 1:  HBI or CDAI score 
after 12 months. 
• 
Among patients who had moderately to severely active UC at Day 1: Partial Mayo score 
after 12 months. 
• 
Among patients who had moderately to severely active CD or UC at Day 1: Treatment 
after 12 months; in case of change of current treatment: reason for change 
• 
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). The IBDQ is not validated for patients with 
ostomies and therefore should not be applied for these patients. 
• 
Mean of subjects total percentage of work impairment (WPAI). 
• 
Mean work time missed (WPAI). 
• 
Mean impairment while working (WPAI). 
• 
Mean total activity impairment (WPAI). 
• 
Health resources (previous 3 years) imaging and laboratory testing, surgeries, 
hospitalizations, consultations and adverse events. 
 

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Page 41 of 51 
 
 
10.1.2 Statistical analyses overview 
Descriptive statistics will be calculated for all variables, including mean, median, standard 
deviation and range for numerical variables and absolute and relative frequencies for 
categorical variables. Whenever relevant, 95% confidence intervals (CI) will be computed.  
For each study endpoint, data will be summarized by IBD type (CD and UC).  
 
Cross-sectional analysis 
The cross-sectional analysis will be conducted once all patients have completed the Day 1 
assessment (expected to occur 6 months after start of enrolment).  
This analysis will allow a characterization of the study population, the estimation of primary 
endpoints and to compare the subgroup of patients with no or light 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 no or light 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%. 
 
Longitudinal analysis 
The longitudinal analysis will be performed once all the patients that were included in the 
prospective period have completed the 12-month follow up. 
The proportion of controlled patients will be presented as well as the 95%CI at the 12-month 
follow up assessment. If applicable, logistic regression will be used for calculating odd ratios 
and 95% confidence intervals for the patient control at month 12 determined by independent 
variables. All tests will be two-sided considering a significance level of 5%. 
 
In case the expected ratio of IBDs (50%CD/50%UC) is not attained at 2 and 4 months of 
enrolment, the participating sites will be instructed to change future enrolments so that this 
balance is achieved and that at least 30 UC patients and 30 CD patients with active disease 
enter the prospective follow-up. 
 
For details of the statistical analyses please refer to the Statistical Analysis Plan. 
 

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Page 42 of 51 
 
 
 
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: 
 
𝐶𝐶𝐶𝐶 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝐻𝐻𝐻𝐻𝐻𝐻≥8 𝑜𝑜𝑜𝑜 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶> 220
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐶𝐶𝐶𝐶 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
 𝑥𝑥 100 
 
For Ulcerative Colitis (UC), the proportion of patients with active disease at Day 1 will be 
presented as percentage and calculated as: 
 
𝑈𝑈𝑈𝑈 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠≥5 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑈𝑈𝑈𝑈 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
 𝑥𝑥 100 
 
The 95% confidence intervals will be computed for each estimate. 
 
 
10.3 Secondary Analyses 
 
At the cross-sectional analysis, 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 no or light 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. 

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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. 
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 no or light 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’ quality of life, 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 (raw score) - sum of Q3a, Q3b, Q3c, Q3d, Q3e, Q3f, 
Q3g, Q3h, Q3i, Q3J 
 
Role Physical (raw score) - sum of Q4a, Q4b, Q4c, Q4d 
 
Body Pain (raw score) - sum of Q7,Q8 
 
General Health (raw score) - sum of Q1, Q11a, Q11b, Q11c, Q11d 
 
Vitality (raw score) - sum of Q9a, Q9e, Q9g, Q9i 
 
Social Functioning (raw score) - sum of Q6, Q10 
 
Role-Emotional (raw score) - sum of Q5a, Q5b, Q5c 
 
Mental Health (raw score) - sum of Q9b,Q9c,Q9d,Q9f,Q9h 
 
Based on SF-36 standardized scores, two summary scores are estimated, 
the Physical Component Score and the Mental Component Score 
o The IBDQ score and each of the four IBDQ domains: 
 
Bowel function – sum of questions 01, 05, 09, 13, 17, 20, 22, 24, 26, 29. 
 
Emotional status – sum of questions 03, 07, 11, 15, 19, 21, 23, 25, 27, 30, 
31, 32. 
 
Systemic symptoms – sum of questions 02, 06, 10, 14, 18. 

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 
Social function – sum of questions 04, 08, 12, 16, 28. 
• 
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. 
• 
Health 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. 
• 
Health Care 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 by in Brazilian reliable administrative databases or other sources. 
 
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.  

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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.  
 
For patients with active IBD at study appointment (Day 1), and included in the prospective 
period, the following analysis will be conducted: 
• 
Descriptive statistics will be presented in a summary table, for the main socio-
demographics, clinical characteristics and treatment regimen of the included patients at 
Day 1 (baseline), by IBD disease. 
• 
The proportion of patients with active CD after 12 months among patients who had 
moderately to severely active CD at Day 1 (baseline) will be expressed as percentage 
and determined as 
 
𝐶𝐶𝐶𝐶 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝐻𝐻𝐻𝐻𝐼𝐼≥8 𝑜𝑜𝑜𝑜 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶> 220 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 12 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑠𝑠
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐶𝐶𝐶𝐶 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝐻𝐻𝐻𝐻𝐻𝐻≥8 𝑜𝑜𝑜𝑜 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶> 220 𝑎𝑎𝑎𝑎 𝐷𝐷𝐷𝐷𝐷𝐷 1  𝑥𝑥 100 
 
• 
Similarly, the proportion of patients with active UC after 12 months among those who 
had moderately to severely active UC at Day 1 (baseline) will be expressed as 
percentage and determined as: 
 
𝑈𝑈𝑈𝑈 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 ≥5 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 12 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑠𝑠 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑈𝑈𝑈𝑈 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 ≥5 𝑎𝑎𝑎𝑎 𝐷𝐷𝐷𝐷𝐷𝐷 1  𝑥𝑥 100 
 
• 
Patients that had light or no activity of disease at the end of the 12-month follow-up will 
be compared with patients that remained with active disease, regarding socio-
demographic, clinical and treatment variables of interest. Similarly to the cross-sectional 
analysis, the comparison of categorical variables will be conducted with Chi-square or 
Fisher exact tests and t-student or Mann-Whitney tests will be used to compare 
quantitative variables. 
• 
If applicable, variables associated with having light or no activity 12 months after 
baseline will be identified through logistic regression models for each IBD disease and 
OR (95%CI) will be presented. 

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• 
In addition, survival analysis with Kaplan Meier curves and Cox regression models will 
be used (if applicable) to identify factors associated with achieving light or no activity with 
baseline treatment (continued or initiated at baseline), during follow-up. In this analysis, 
patients that remained with active disease or that change treatment due to lack of 
disease control will be censored and, conversely, success will be defined as having light 
or no active disease. Time to success will be considered as dependent variable in 
survival analysis methods. 
• 
The number and reason for treatment changes during follow-up will be summarized and 
treatment patterns during prospective period will also be described. Patients with 
treatment changes will be compared with those without changes, regarding main socio-
demographic, clinical and treatment baseline variables. The comparison of categorical 
variables will be conducted with Chi-square or Fisher exact tests and t-student or Mann-
Whitney tests will be used to compare quantitative variables. 
• 
If aplicable, Poisson regression models based on generalized linear equations will be 
used to examine the relationship between variables of interest and the incidence of the 
treatment changes during follow-up. 
 
10.4 Interim Analyses 
No interim analyses are planned for this study. The planned analyses will be conducted in 
two moments, at the end of the cross-sectional study and at the end of the 12-month follow-
up period. 
 
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. 
 
10.6 Determination of Sample Size 
It is expected to include approximately 400 patients regardless of IBD type. This sample size 
will allow estimates with 95% confidence interval and a margin of error less than 5%.  
Based on the above and considering an expected ratio of CD/UC of approximately 
50%/50%, and that the rate of inadequate control of disease activity varies from 20-30% 
(regardless of the IBD type), it is expected to analyze 40-60 patients with CD and 30-50 
patients with UC during the 12-month follow up. 
 

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11 Reports 
A Non-Interventional Study Report based on the results obtained will be prepared and 
submitted to Global Research for distribution. The Final 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 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 Site Responsible must as a minimum store the list of participating 
subjects and the signed Informed Consent Forms on site for 5 years. The Site Responsible 
should store additional study documentation for a longer period of time as required by any 
local regulations and/or hospital requirement. 
 
 
 

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