Real-world Data of Moderate to Severe Inflammatory Bowel Disease (UC and CD) in Mexico: a Multicenter, Non-interventional Study to Evaluate Disease Control, Treatment Patterns, Burden of Disease and Patient Reported Outcomes
Conditions: Inflammatory Bowel Diseases, Colitis, Ulcerative, Crohn Disease
Sponsor: Takeda

CLINICAL STUDY PROTOCOL 
NCT Number: 
Study Title: 
Study Number: 
NCT04873700 
Real-world Data of Moderate to Severe Inflammatory Bowel Disease 
(UC and CD) in Mexico: a Multicenter, Non-interventional Study to 
Evaluate Disease Control, Treatment Patterns, Burden of Disease 
and Patient Reported Outcomes  
IBD-5010
Protocol Version and Date: 
Version 2.0: 22-September-2020 
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Study RISE-MX 
IBD-5010 
Observational/Non-Interventional 
Study Protocol 
FINAL Version No 2.0 
22Sep2020 
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Non-Interventional Study Protocol 
 
 
Short title: Non-interventional Study of Moderate to Severe Inflammatory Bowel Disease (UC and 
CD) in Mexico (RISE-MX) 
 
 
Title: 
Real-world data of Moderate to Severe Inflammatory Bowel Disease (UC and CD) in 
Mexico: a multicenter, non-interventional study to evaluate disease control, treatment 
patterns, burden of disease and patient reported outcomes (RISE-MX) 
 
 
Study ID: 
IBD-5010 
 
 
Sponsor: 
Takeda México S.A. de C.V. 
Av. Primero de Mayo No 130, 
Col. Industrial Atoto, Naucalpan de Juarez, Edo de Mex, 53519 
Phone: +52 55 5387 9330 
Study phase: 
Medical Affairs, Non-registration Company Sponsored (Late Phase Observational) 
 
Date of version of protocol: 21 May 2019 
 
Administrative Amendment: 22 Sep 2020 
 
 
 
 
 
 
 
 
 
 
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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2.0 
22Sep20 
4.2 
Change in 
responsible 
2.0 
22Sep20 
4.2 
Change in 
responsible 
2.0 
22Sep20 
6.1 
Planned Start of Study: 
Q1 FY19 
Q3 FY20 
Planned Patient In: 
Q4 FY19 
Q1 FY21 
Planned collection of first data point: 
Q4 FY19 
Q1 FY21 
Planned End of Study: 
Q2 FY20 
Q2 FY22 
Planned Final Database Lock: 
Q3 FY20 
Q1 FY22 
Planned completion of the Study Report: Q1 FY21 
Q2 FY22 
Timeline 
Change 
2.0 
22Sep20 
6.1 
The Start of Study is defined as date of last protocol 
signature and planned to occur on June 2019 October 
2020. The collection of first data point (first patient 
in) will start during 4th 1st quarter 2019 2021. 
Timeline 
change 
 
 
 
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1.3 Approval 
 
REPRESENTATIVES OF TAKEDA 
 
This study will be conducted with the highest respect for the individual participants, in accordance with 
the requirements of this clinical study protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki; 
• 
The International Conference on Harmonisation (ICH) E6 Good Clinical Practice: Consolidated 
Guideline; 
• 
Guidelines for Good Pharmacoepidemiology Practices (GPP); 
• 
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
 
 
SIGNATURES 
 
 
 
  
 
Date 
 
Medical Operations 
 
Date 
 
Pharmacovigilance
Date 
 
, Global Biometrics Biostatistics 
Eurotrials Scientific Consultants, now a part of 
CTI Clinical Trial & Consulting Services 
Date 
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1.4 Summary 
 
Short Title of Study 
 
Non-interventional Study of Moderate to Severe Inflammatory Bowel Disease (UC and CD) in Mexico 
(RISE-MX). 
Study sites 
 
The study will be conducted in approximately 10-12 sites in Mexico. 
 
Objectives 
 
This study aims to understand the journey of UC and CD patients diagnosed with moderate to severe 
disease in Mexico and to describe their characteristics. In addition, it is essential to understand how 
patients are managed, the treatment patterns (particularly on the use of available biologic therapies) and 
obtain the patients' perspective on how the disease impacts on their quality of life (QoL) and work 
productivity. 
Primary Objective: 
 
• 
To evaluate the disease activity at Day 1 among UC and CD patients diagnosed with moderate 
to severe disease (i.e., to evaluate the proportion of patients with active Crohn’s Disease (CD) 
defined as Harvey Bradshaw Index (HBI) score ≥ 8 or Crohn’s Disease Activity Index (CDAI) 
≥ 220, and with active Ulcerative Colitis (UC) defined as 9-point partial Mayo ≥5). 
 
Secondary Objectives: 
 
• 
To characterize socio-demographic and clinical features of UC and CD patients, overall and by 
disease activity at Day 1. 
• 
To characterize treatment patterns for UC and CD in the 3 years prior to Day 1, including the 
use of biologic and conventional therapies and failure to these therapies (if any), overall and by 
disease activity at Day 1. 
• 
For UC and CD, to compare patients with moderate to severe disease activity with patients with 
no or mild activity, regarding socio-demographic and clinical variables and treatment patterns 
at Day 1. 
• 
To evaluate the QoL (36-item Short Form health Survey [SF-36] and Inflammatory Bowel 
Disease Questionnaire [IBDQ]) in UC and CD patients at Day 1, overall and by disease activity 
at Day 1. 
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• 
To evaluate the work productivity impairment (WPAI) experienced by UC and CD patients at 
Day 1, overall and by disease activity at Day 1. 
• 
To describe the burden of disease in terms of healthcare resources utilization and costs (direct 
and indirect) related to the management of UC and CD in the 3 years prior to Day 1. 
 
 
Methodology 
 
This is a multicenter, non-interventional, cross-sectional study aiming primarily to evaluate the UC and 
CD activity. 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 QoL will be collected from the patients’ medical records and 
patients will be asked to complete the Patient Report Outcome (PRO) questionnaires. PRO 
questionnaires include QoL (SF-36 and IBDQ) and WPAI questionnaires. Besides the cross-sectional 
data collection, the study will have an additional retrospective data collection referring to the three years 
prior to Day 1, regarding the previous IBD treatments (drug, dose, treatment duration and drug changes), 
and use of other healthcare resources (surgeries, hospitalizations, medical appointments, imaging and 
laboratory testing) related with the management of UC and CD. Direct costs calculation will be 
performed by a micro-cost analysis (i.e. identifying and quantifying each single resource and 
multiplying it by the corresponding unit cost) and indirect cost by human capital method for absenteeism 
and presenteeism (i.e. the amount of salary paid to the employee proportional to the hours of 
absence/productivity impairment at work) based on WPAI data collected. 
 
 
Number of subjects 
 
It is expected to include 335 patients regardless of IBD (UC or CD) type. 
 
Due to lack of information regarding the rate of UC and CD control in Mexico a rate of inadequate 
control of disease (i.e. the proportion of patients with moderately to severely active disease) of 50% will 
be assumed. Hence, a sample of 318 patients, regardless of IBD type (UC or CD), will allow estimates 
with 95% confidence interval (CI) and a margin of error (ME) less than 5.5%. The following formula 
was used: 
𝑛𝑛= 1.962 × 𝑝𝑝× (1 −𝑝𝑝)
𝑀𝑀𝑀𝑀2
 
Rate of uncontrolled disease (p) = 50%
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ME = 0.055 
 
To account for a non-evaluable rate of 5%, a total of 335 patients should be included in the study. No 
stratification sampling methods will be used. 
 
 
Diagnosis/Disease/Condition and main criteria for inclusion 
 
Subjects must meet all the following inclusion criteria: 
 
• 
Male or female subjects. 
• 
Subjects aged 18 years or older (at the time of diagnosis of moderate to severe UC or CD). 
• 
Diagnosis of moderate to severe CD or UC established for at least 6 months prior to Day 1 
appointment, based on clinical, endoscopic, or imaging criteria. 
• 
The subject or, when applicable, the subject’s legally acceptable representative signs and dates 
a written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures. 
Patients will be excluded if presenting at least one of the following: 
 
• 
Indeterminate or not classified colitis. 
• 
Current or previous participation in interventional clinical trials (within the previous 3 years). 
• 
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, sex, professional status (employed, unemployed, retired, student, other), educational level, 
subject income, smoking habits, anthropometric information, date of diagnosis of CD or UC, date of 
diagnosis of moderate to severe CD or UC (if not the same as previous), steroid dependence or 
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refractoriness, family history of IBD, comorbidity(ies), disease presentation (location, behavior, 
extraintestinal manifestations). 
Main outcome variables 
 
Primary Endpoints: 
 
• 
For CD: Proportion of patients with active disease (HBI ≥ 8 or CDAI ≥ 220 points) at Day 1. 
• 
For UC: Proportion of patients with active disease (9-point partial Mayo ≥5) at Day 1. 
 
Secondary Endpoints: 
 
• 
Distribution of age, sex, professional status, educational level, subject income. 
• 
Distribution of clinical variables (smoking habits, anthropometric information, duration and age 
at diagnosis, steroid dependence or refractoriness, family history, medical history and 
comorbidities, criteria used for diagnosis, calprotectin, extraintestinal manifestations and 
clinical presentation of IBD [CD - location, behavior, perianal disease, achievement of ileal 
disease; UC - extent of inflammation and severity]). 
• 
Therapies for IBD (UC or CD) (aminosalicylates, steroids, immunomodulators, 
immunosupressors, biologics, antibiotics, probiotics and surgeries) and the length of these 
therapies during the previous 3 years. 
• 
Proportion of biologic-experienced patients at Day 1. 
• 
Proportion of patients who have not responded to previous lines of biologic therapies and 
reason. 
• 
UC and CD treatment introduced at Day1 (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) at Day 1. 
• 
Socio-demographic, clinical and treatment-related variables in patients with moderate to severe 
activity of UC (partial Mayo [pMayo] score ≥5) versus patients with mild or no activity (partial 
Mayo <5). 
• 
Mean score of different components of SF-36. 
• 
Mean total score of IBDQ and by domain (bowel symptoms, systemic symptoms, emotional 
function and social function). 
• 
Mean total percentage of work impairment (WPAI) in hours, for patients with moderate to 
severe activity compared with patients with no or mild activity. 
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• 
Mean work time missed (WPAI), in hours, for patients with moderate to severe activity 
compared with patients with no or mild activity. 
• 
Mean productivity impairment while working (WPAI), in hours, for patients with moderate to 
severe activity compared with patients with no or mild activity. 
• 
Mean total activity impairment (WPAI). 
• 
Proportion of patients who quit their job due to IBD (UC or CD) and have not been able to 
return to work. 
• 
Distribution of surgeries, hospitalizations, medical appointments, imaging and laboratory 
testing in the 3 years prior to Day 1. 
• 
Direct medical costs: distribution of healthcare resources consumption and unitary cost per 
resource. 
• 
Indirect costs (only for active workers): mean number of workhours missed or with productivity 
reduced due disease and average salary/hour/person. 
 
 
Statistical methods 
 
All data will be summarized for total UC and CD patients and by IBD type (CD or UC). 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% CI will be 
computed whenever relevant. 
For each UC or CD 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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Table of Contents 
 
Administrative information .............................................................................................................. 2 
1.1 
Contacts ................................................................................................................................. 2 
1.2 
Amendments and updates ...................................................................................................... 2 
1.3 
Approval ................................................................................................................................ 4 
1.4 
Summary................................................................................................................................ 5 
Table of Contents .................................................................................................................................. 10 
List of Abbreviations and Definition of Terms ..................................................................................... 13 
Introduction .................................................................................................................................... 15 
2.1 
Study Rationale ................................................................................................................... 16 
Study Objectives ............................................................................................................................ 17 
Study Administrative Structure...................................................................................................... 18 
4.1 
Study Sites ........................................................................................................................... 18 
4.2 
Sponsor Personnel ............................................................................................................... 18 
4.3 
Contract Research Organisation (CRO) .............................................................................. 18 
4.4 
Essential Documents ........................................................................................................... 18 
Ethics ............................................................................................................................................. 19 
5.1 
Ethical conduct of the Study ................................................................................................ 19 
5.2 
Independent Ethics Committee ............................................................................................ 20 
5.3 
Subject Information and Written Informed Consent ........................................................... 21 
Study Design and Plan ................................................................................................................... 22 
6.1 
Study Schedule .................................................................................................................... 23 
6.2 
Discussion of Study Design ................................................................................................. 23 
6.3 
Selection of Study Population ............................................................................................. 25 
6.3.1 
Inclusion Criteria .................................................................................................. 25 
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6.3.2 
Exclusion Criteria................................................................................................. 25 
6.3.3 
Enrolment ............................................................................................................. 25 
6.4 
Treatments ........................................................................................................................... 26 
Conduct .......................................................................................................................................... 26 
7.1 
Data collection overview ..................................................................................................... 26 
7.2 
Study Variables ................................................................................................................... 27 
Management and Reporting of Adverse Events ............................................................................ 30 
8.1 
Definitions ........................................................................................................................... 30 
8.2 
Classifications...................................................................................................................... 32 
8.3 
Collection of Adverse Events, Special Situation Reports and Product Quality Issues ........ 34 
Data Quality Control and Assurance ............................................................................................. 35 
9.1 
Quality Control .................................................................................................................... 35 
9.2 
Audit from Quality Assurance Unit ..................................................................................... 35 
9.3 
Inspection by IEC or Competent Authority (CA) ................................................................ 35 
9.4 
Data Management ................................................................................................................ 35 
9.4.1 
Data Collection Tools and Flow ........................................................................... 36 
Statistical Methods and Determination of Sample Size ................................................................. 37 
10.1 Statistical Analysis Plan ...................................................................................................... 37 
10.1.1 
Study Endpoints ................................................................................................... 37 
10.1.2 
Statistical analyses overview ................................................................................ 40 
10.2 Primary Analyses ................................................................................................................. 41 
10.3 Secondary Analyses ............................................................................................................. 41 
10.4 Interim Analyses .................................................................................................................. 44 
10.5 Handling of missing data ..................................................................................................... 44 
10.6 Determination of Sample Size ............................................................................................. 45 
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Reports ........................................................................................................................................... 45 
Publications .................................................................................................................................... 45 
Archiving of Study Documentation ............................................................................................... 46 
References ...................................................................................................................................... 47 
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List of Abbreviations and Definition of Terms 
 
 
5-ASA 
5-aminosalicilic acid 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BMI 
Body Mass Index 
CA 
Competent Authority 
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 
CSR 
Clinical Study Report 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EIM 
Extraintestinal Manifestations 
GPP 
Good Pharmacoepidemiology Practices 
HBI 
Harvey Bradshaw Index 
IBD 
Inflammatory Bowel Disease 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
ME 
Margin of error 
MedDRA 
Medical Dictionary for Regulatory Activities 
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pMayo 
partial Mayo score 
 
PRO 
Patient Reported Outcomes 
 
QoL 
Quality of Life 
 
SAE 
Serious Adverse Event 
 
SAP 
Statistical Analysis Plan 
 
SF-36 
36-item Short Form health Survey 
SSR 
Special Situation Report 
TNF 
Tumor Necrosis Factor 
 
TWPI 
Total Work Productivity Impairment 
UC 
Ulcerative Colitis 
VAS 
Visual Analog Scale 
 
WPAI 
Work Productivity and Activity Impairment questionnaire 
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Introduction 
 
Inflammatory bowel diseases (IBD) comprise mainly Crohn’s disease (CD) and ulcerative colitis (UC) 
(1). Signs and symptoms of active UC and CD 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). UC and CD 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 prevalence of CD is reported to be from 0.9 - 322.0 per/105 inhabitants, while UC 
prevalence range is 2.42 - 505.0 per 105 inhabitants. On the other hand, the incidence reaches up to 
29.3/105 inhabitants and 0.15 – 57.9/105 inhabitants for CD and UC, respectively (8). Furthermore, the 
incidence of CD and UC have been increasing in several world regions, namely in developing countries 
(9,10). In South American countries, incidence of CD and UC seem to be lower than in Europe and 
North American countries but some studies have reported an increase in recent years (4,11). 
A Mexican consensus on the diagnosis and treatment of UC estimated a three-fold increase in the 
adjusted incidence rates in the last twenty years (12). A single center study in a referral hospital from 
Mexico City showed an increase of the UC incidence between 1987 and 2006, with a 2.6-fold increase 
when comparing the periods 1987-1996 and 1997-2006 (mean number of new cases per year: 28.8 vs. 
76.1, respectively) (13). Another single center study in the Northwest Mexico also reported an increase 
of the rate of new UC patients, from 2.3/1000 admissions in 2004 to 4.1/1000 admissions in 2008 (14). 
Of notice, there is no available estimates of the incidence and prevalence of CD in Mexico, even though 
some experts estimate that CD incidence would be approximately 2% (15). 
There are several strategies available for the treatment of UC and CD, which remains challenging 
(1,16). Corticosteroids are indicated to induce clinical remission in active UC of moderate to severe 
intensity and active CD of mild to severe intensity (4,17). However, resistance and dependence may 
occur, ranging from 8%-20% and from 15%-36%, respectively, among CD cases. In UC, 
corticosteroid-resistance and dependence can reach more than 20% for both outcomes (17,18). 
Furthermore, prolonged exposure with steroids is not recommended, given the lack of efficacy in the 
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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 (4,19,20). 
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 (4,19,20). 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 (21). 
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 CD patients who have never received anti-TNF therapy (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). If the first-line 
immunosuppressive maintenance therapy fails, several other factors should be taken into account when 
deciding the following treatment, including patient’s preferences, fecundity and patient age (16). 
 
 
2.1 Study Rationale 
 
No studies have been conducted in Mexico with large territorial coverage, to evaluate demographic and 
clinical aspects of IBD, namely the level of disease activity and the burden of both CD and UC. 
Therefore, it is pertinent to gather information regarding the characteristics of the population with 
moderate to severe IBD (UC and CD), the IBD (UC and CD) burden in terms of patient QoL and work 
productivity, consumption of healthcare resources, and to understand UC and CD treatment patterns, 
particularly on the use of available biologic therapies. 
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Study Objectives 
 
Primary Objective: 
 
• 
To evaluate the disease activity at Day 1 among UC and CD patients diagnosed with moderate 
to severe disease. 
 
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 (pMayo) score ≥5. 
 
Secondary Objectives: 
 
• 
To characterize socio-demographic and clinical features of UC and CD patients, overall and by 
disease activity at Day 1. 
• 
To characterize treatment patterns for UC and CD in the 3 years prior to Day 1, including the 
use of biologic therapies and failure to these therapies (if any), overall and by disease activity 
at Day 1. 
• 
For UC and CD, to compare patients with moderate to severe disease activity with patients with 
no or mild activity, regarding socio-demographic and clinical variables and treatment patterns 
at Day 1. 
• 
To evaluate the QoL (36-item Short Form health Survey [SF-36] and Inflammatory Bowel 
Disease Questionnaire [IBDQ]) in UC and CD patients at Day 1, overall and by disease activity 
at Day 1. 
• 
To evaluate the work productivity impairment (WPAI) experienced by UC and CD patients at 
Day 1, overall and by disease activity at Day 1. 
• 
To describe the burden of disease in terms of healthcare resources utilization and costs (direct 
and indirect) related to the management of UC and CD in the 3 years prior to Day 1. 
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Study Administrative Structure 
 
4.1 Study Sites 
 
The study is planned to be conducted in approximately 10-12 sites in Mexico. The selected sites are 
public/private reference hospitals from regions of Mexico, institutions recognized by their large 
experience in the IBD management, and that follow UC and CD patients in ambulatory care. 
 
 
4.2 Sponsor Personnel 
 
Takeda LOC will keep a record of all relevant sponsor personnel. 
 
Name 
Study Team Role 
 
Medical Operations 
 
 
Clinical Operations 
 
 
 
 
 
 
Regulatory Affairs 
 
 
Pharmacovigilance 
 
 
 
4.3 Contract Research Organisation (CRO) 
 
A CRO will be responsible for the development of electronic Case Report Form (eCRF), study 
implementation and monitoring, data management, data analysis and development of the final clinical 
study report (CSR). The CRO will keep a record of all involved CRO personnel. 
 
 
4.4 Essential Documents 
 
The following essential documents must be received by CRO before the study is initiated at a site: 
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• 
Written agreement between Takeda or appointed CRO and the selected Sites. 
• 
Signed and dated protocol agreement and amendment agreements, if any, with the original 
signature of the Site Responsible. 
• 
Informed Consent Form (ICF) 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. 
 
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 Outcomes 
(PRO) tools, to collect information about health related QoL and WPAI due to UC or CD (22). 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 with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have origin in the the Declaration of Helsinki (23), 
Guidelines for Good Pharmacoepidemiology Practices (GPP) (24). Each Investigator will conduct the 
study according to applicable Mexico regulatory requirements. A 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 ICF are submitted to 
the relevant IECs according to local requirements. 
Takeda, as the sponsor, is responsible for meeting the ICH requirement for yearly updates to the IECs, 
if applicable. 
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5.2 Independent Ethics Committee 
 
IEC 
 
IECs must be constituted according to the applicable Mexican regulations (Guidance from Comisión 
Nacional de Bioética). The sponsor or designee will require documentation noting all names and titles 
of members who make up the respective IEC. If any member of the IEC has direct participation in this 
study, written notification regarding his or her abstinence from voting must also be obtained. The 
sponsor or designee will supply relevant documents for submission to the respective IEC for the 
protocol’s review and approval. This protocol, a copy of the ICF and, if applicable, subject recruitment 
materials and/or advertisements and other documents required by all applicable laws and regulations, 
must be submitted to the local IEC for approval. The IEC’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before commencement of 
the study (ie, before study specific screening activity). The IEC approval must refer to the study by 
exact protocol title, number, and version date; identify versions of other documents (eg, informed 
consent form) reviewed; and state the approval date. 
Sites must adhere to all requirements stipulated by their respective IEC. This may include notification 
to the IEC regarding protocol amendments, updates to the ICF, recruitment materials intended for 
viewing by subjects, local safety reporting requirements, reports and updates regarding the ongoing 
review of the study at intervals specified by the respective IEC, and submission of the investigator’s 
final status report to IEC. All IEC approvals and relevant documentation for these items must be 
provided to the sponsor or its designee. 
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 regulatory authority Federal 
Commission for the Protection against Sanitary Risks (COFEPRIS). Sponsor will keep an updated list 
of submission and approval dates and a copy of all documents submitted. 
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5.3 Subject Information and Written Informed Consent 
 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all applicable 
laws and regulations. The ICF, describes the planned and permitted uses, transfers, and disclosures of 
the subject’s personal and personal health information (hereinafter referred to as personal data) for 
purposes of conducting the study. The ICF further explain the nature of the study, its objectives, and 
potential risks and benefits, as well as the date informed consent is given. The ICF details the 
requirements of the participant and the fact that he or she is free to withdraw at any time without giving 
a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IEC approval of the ICF. The ICF, must 
be approved by both the IEC and the sponsor prior to use. 
The ICF must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed appropriate 
by the IEC. In the event the subject is not capable of rendering adequate written informed consent, then 
the subject’s legally acceptable representative may provide such consent for the subject in accordance 
with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: (1) 
inquire about details of the study and (2) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and prior to the subject entering into the study. The subject or the 
subject’s legally acceptable representative should be instructed to sign using their legal names, not 
nicknames, using blue or black ballpoint ink. The investigator must also sign and date the ICF at the 
time of consent and prior to subject entering into the study; however, the sponsor may allow a designee 
of the investigator to sign to the extent permitted by applicable law. 
Once signed, the original ICF will be stored in the investigator’s site file. The investigator must 
document the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed informed consent form shall be given to the subject. 
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laboratory testing). Direct costs calculation will be performed by a micro-cost analysis (i.e. identifying 
and quantifying each single resource and multiplying it by the corresponding unit cost) and indirect cost 
by human capital method for absenteeism and presenteeism (i.e. the amount of salary paid to the 
employee proportional to the hours of absence/productivity impairment at work) based on WPAI data 
collected. 
 
 
6.1 Study Schedule 
 
 
Planned Start of Study: 
Q3 FY20 
Planned Patient In: 
Q1 FY21 
Planned collection of first data point: 
Q1 FY21 
Planned End of Study: 
Q2 FY22 
Planned Final Database Lock: 
Q1 FY22 
Planned completion of the Study Report: 
Q2 FY22 
 
 
 
The Start of Study is defined as date of last protocol signature and planned to occur on October 2020. 
The collection of first data point (first patient in) will start during 1st quarter 2021. 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, Sponsor might choose to terminate the study prematurely. In such case, 
the, study sites, IECs and COFEPRIS 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 QoL 
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among patients with UC and CD. 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 10-12 study sites will be 
selected among reference public/private institutions for IBD management in different districts in 
Mexico. It is expected that their patients will be representative in Mexico. In addition, the inclusion and 
exclusion criteria are not restrictive and will enable the assessment of real-world data about UC and CD 
control in Mexico. 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 previous 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 UC or CD 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 the following inclusion criteria: 
 
• 
Male or female subjects. 
• 
Subjects aged 18 years or older (at the time of diagnosis of moderate to severe UC or CD). 
• 
Diagnosis of moderate to severe CD or UC established for at least 6 months prior to Day 1 
appointment, based on clinical, endoscopic or image criteria (19,20). The subject or, when 
applicable, the subject’s legally acceptable representative signs and dates a written, informed 
consent form and any required privacy authorization prior to the initiation of any study 
procedures. 
 
 
6.3.2 Exclusion Criteria 
 
Subjects will be excluded if presenting at least one of the following: 
 
• 
Indeterminate or not classified colitis. 
• 
Current or previous participation in interventional clinical trials (within the last 3 years). 
• 
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 recruitment of study subjects is expected to occur during a 6-month period. A patient tracking log 
form will be used by each site. 
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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. 
 
 
6.4 Treatments 
 
This is a non-interventional study and, thus, no treatments/pharmacotherapy are predefined in the 
protocol. 
All clinical decisions will be full responsibility of the investigator. 
 
Conduct 
 
7.1 Data collection overview 
 
Table 1. Study Flow Chart 
 
Study variables 
Day 1 
Retrospective data, concerning the 3 years 
before 
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 
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 dependence or refractoriness 
X 
Family history of IBD 
X 
Medical history / Comorbidities 
X 
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Study variables 
Day 1 
Retrospective data, concerning the 3 years 
before 
Disease activity: CD (HBI score or CDAI); UC 
(partial/total Mayo score) 
X 
Clinical Characterization of Disease: location, 
behavior, EIM 
X 
SF-36 
X 
IBDQ 1 
X 
WPAI 
X 
Previous treatments or regimens 2 
X 
Treatment started at Day 1 (if applicable) 
X 
Previous surgeries for IBD (UC and CD) 
X 
IBD (UC and CD)-related hospitalizations 
X 
Previous medical appointments related with IBD 
(UC and CD) 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 Not applicable for patients who have a colostomy or ileostomy. 
2 Excludes new treatments prescribed at Day 1 visit. 
 
 
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; 
• 
Sex; 
• 
Professional status (employed, unemployed, retired, student, other); 
• 
Educational level; 
• 
Subject income. 
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Clinical variables 
 
• 
IBD type: CD or UC; 
• 
Smoking habits; 
• 
Anthropometric information (weigh, height, body mass index [BMI]); 
• 
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); 
• 
Steroid dependence or refractoriness or not applicable); 
• 
Family history of IBD; 
• 
Medical History / Comorbidities (including prior tuberculosis and hepatitis infection); 
• 
Disease presentation [location, behavior, extraintestinal manifestations (EIM)]; 
• 
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, if it 
is available (i.e., calprotectin >200ug/g) (yes/no) (qualitative data). 
Disease activity (at Day 1) 
 
• 
For CD patients: HBI score or CDAI; 
• 
For UC patients: 9-item pMayo score (always collected) and the total Mayo score (when 
available). 
Both HBI and CDAI are commonly used to assess CD activity. 
 
The 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 moderately 
to severely active CD (25). 
The 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 activity. Moderately to severely 
active CD is defined as CDAI ≥ 220 (26). 
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The Mayo score is composed of four categories (bleeding, stool frequency, physician assessment, and 
endoscopic appearance) rated from 0–3 that are summed into a total score ranging from 0–12. The 
pMayo score was previously compared with the full Mayo score and categorizes UC patients as being 
in remission (score of 0–2), having mild activity (pMayo of 3 or 4) or moderate to severe activity 
(pMayo of ≥5) (27). 
 
 
Health-Related Quality of Life and Work Productivity (at Day 1) 
 
• 
36-item Short Form Health Survey (SF-36) 
• 
Inflammatory Bowel Disease Questionnaire (IBDQ) - 32 items 
• 
Work Productivity and Activity Impairment Questionnaire (WPAI) – 6 items 
 
SF-36 is a general QoL-questionnaire, which 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 dimensions, two weighted scores are generated: the physical component 
summary score and the mental component summary score. Scores range between 0 and 100, with higher 
scores indicating a better quality of life (28). For additional information, please consult 
http://www.rand.org/health/surveys tools/mos/mos core 36item survey print.html. 
 
IBDQ is a disease-specific questionnaire with 32 items that measures four 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 (29). 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. 
Work Productivity will be measured by the WPAI, a patient-reported quantitative assessment of the 
amount of absenteeism, presenteeism and daily activity impairment attributable to general health 
(WPAI:GH) or a specific health problem (WPAI:SHP). It presents six questions that cover 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 
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impairment (absenteeism and presenteeism combined); and percentage of regular activity impairment. 
Unemployed patients only answer to questions related to employment status and regular activities 
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 UC or CD (name, dose); 
• 
Treatment started at Day 1 (name, dose); 
 
Other healthcare resources related with UC and CD management 
 
• 
Surgeries; 
• 
Hospitalizations; 
• 
Medical appointments; 
• 
Imaging and laboratory testing. 
 
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. 
Although abnormal laboratory values are typically not considered AEs, the following considerations 
may result in an abnormal laboratory value being considered an AE: 
• 
A laboratory test result that meets the criteria for an SAE 
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• 
A laboratory test result that requires the subject/patient to receive specific corrective therapy 
• 
A laboratory abnormality that leads to discontinuation of therapy 
• 
A laboratory abnormality that the health care provider considers to be clinically significant 
 
Serious Adverse Events 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
• 
Results in death. Note that death is an outcome of an event. The event(s) causing death should 
be recorded. 
• 
In the view of the Healthcare provider, places the subject/patient at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred in a more 
severe form, might have caused death 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Results in a congenital anomaly/birth defect 
 
A SAE may also be any other medically important event that, in the opinion of the Health care provider, 
may jeopardize the subject/patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
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 
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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. 
• 
Accidental exposure. 
• 
Use outside the terms of the marketing authorisation, also known as “off-label”. 
• 
Use of falsified medicinal product. 
• 
Unintended benefit 
• 
Drug-drug or drug-food interactions 
 
 
A SSR should be reported even if there is no associated AE. 
 
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. 
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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 
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. 
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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, 
SAE, SADR, SSR or product quality issue and that event pertains to a Takeda product, they, must be 
reported relevant Takeda Mexico Pharmacovigilance Department within 1 calendar day for deaths, 
within 4 calendar days for other SAES and within 7 calendar days for all other events in order to comply 
with local regulations. 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 pro-actively 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. 
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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. 
 
 
9.3 Inspection by IEC or Competent Authority (CA) 
 
Representatives from IEC or CA may in rare cases wish to inspect the study on site. Upon receiving 
notification of such inspection, the Study Site Responsible must immediately escalate (according to the 
escalation line information) and must make the records available as requested. 
 
 
9.4 Data Management 
 
Data management 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 despite 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 
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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 (Medical 
Dictionary for Regulatory Activities - 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. No 
personal identifiable data will be collected. 
 
 
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. 
All data collected for the purpose of this study will be entered, stored and retrieved with the use of an 
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 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 
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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. 
 
 
 
Statistical Methods and Determination of Sample Size 
 
This section describes the statistical analyses as foreseen at the time of planning the study. Any known 
deviations from the planned 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 CSR. 
 
 
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). 
Descriptive analysis will be performed of all collected data (listed in section 7.2) except data collected 
only for the purpose of data cleaning. 
 
 
10.1.1 Study Endpoints 
 
The main study endpoints are: 
 
Primary Endpoints: 
 
• 
Percentage of Participants with Active Crohn's Disease (CD) at Day 1 [Time Frame: Day 1] 
Percentage of participants with active CD observed, where active CD is defined as Harvey 
Bradshaw index (HBI) greater than or equal to (≥) 8 or Crohn's disease active index (CDAI) ≥ 
220 to total CD participants multiplied by 100. CDAI assesses CD based on clinical signs and 
symptoms such as number of liquid stools, intensity of abdominal pain, general wellbeing, 
presence of comorbid conditions, use of antidiarrheal, physical examination and laboratory 
findings. Total score ranges from 0 to 600 points. Higher score indicates more severe disease. 
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HBI consists of 5 clinical parameters: general well-being, abdominal pain, number of liquid 
stools per day, abdominal mass, and complications. Total score is sum of individual parameters. 
Score ranges from a minimum score of 0 to no pre-specified maximum score as it depends on 
number of liquid stools, where higher scores indicates more severe disease. 
• 
Percentage of Participants with Active Ulcerative Colitis (UC) at Day 1 [Time Frame: Day 1] 
Percentage of participants with active UC will be calculated as the ratio of UC participants with 
Mayo score ≥5 to the total UC participants multiplied by 100. Mayo score is an instrument used 
to measure disease activity. It consists of 3 sub scores: stool frequency, rectal bleeding, and 
physician global assessment of disease severity, each graded from 0 to 3 with higher scores 
indicating more severe disease. These scores are summed to give a total score range of 0 to 9; 
where higher scores indicating more severe disease. 
Secondary Endpoints: 
 
• 
Number of UC or CD participants based on socio-demographic variables [Time Frame: Day 1] 
(Socio-demographic variables age, sex, professional status, educational level, subject income). 
• 
Number of UC or CD participants based on smoking habits, anthropometric information and 
clinical variables. [Time Frame: from initial diagnosis until Day 1]- (Clinical variables include 
duration and age at diagnosis, steroid dependence or refractoriness, family history, medical 
history and comorbidities, criteria used for diagnosis, calprotectin, EIM). 
• 
Number of participants based on clinical presentation [CD - location, behavior, perianal disease, 
achievement of ileal disease; UC - extent of inflammation and severity]) [Time Frame: Day 1]. 
• 
Number of UC or CD participants based on IBD therapies and the duration of these therapies. 
[Time Frame: From 3 years prior to Day 1 until Day 1]. (IBD therapies include 
aminosalicylates, steroids, immunomodulators, immunossupressors, biologics, antibiotics, 
probiotics and surgeries) 
• 
Percentage of UC or CD participants with biologic-experience [Time Frame: From 3 years prior 
to Day 1 until Day 1] 
• 
Percentage of UC or CD participants who have not responded previously to biologic therapies 
and reason [Time Frame: From 3 years prior to Day 1 until Day 1]. 
• 
Number of UC or CD participants with IBD treatment introduced at Day 1 (if applicable) [Time 
Frame: Day 1]. 
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• 
Number of participants with HBI ≥ 8 or CDAI ≥ 220 points versus HBI < 8 or CDAI < 220 
points based on socio-demographic, clinical and treatment-related variables in CD participants 
[Time Frame: Day 1]. 
• 
Number of participants with pMayo score ≥5 versus pMayo <5 based on socio-demographic, 
clinical and treatment-related variables in UC patients [Time Frame: Day 1]. 
• 
Mean score of different components of SF-36 by IBD type [Time Frame: Day 1] The 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, where higher 
scores indicate a better quality of life. 
• 
Mean total score of IBDQ [Time Frame: Day 1] 
The 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. Each domain score is the sum of 8 responses each ranging from 
1 to 7, where 1 indicates worst function and 7 the best. The sub-score ranges from 8 to 56 and 
thus the total score ranges from 32 to 224, where higher score indicates better quality of life. 
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) in hours [Time Frame: Day 1]. 
The WPAI assess the impact of IBD on work productivity and daily activities during the 
previous 7 days. The WPAI includes 6 questions: 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). WPAI 
generates four component scores: percentage of work time missed (absenteeism); percentage of 
impairment while working (presentisms); percentage of overall work impairment (absenteeism 
and presentisms combined); and percentage of activity impairment. Unemployed participants 
only answer questions related to employment status and activity impairment. Scores for WPAI 
range from 0% to 100%, where 0 % indicates no impairment and 100% is total loss of work 
productivity/activity. 
• 
Mean work time missed (WPAI) [Time Frame: Day 1] 
• 
Mean impairment while working (WPAI) [Time Frame: Day 1]. 
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• 
Mean total activity impairment (WPAI) [Time Frame: Day 1] 
• 
Percentage of UC or CD participants who quit their job due to IBD and have not been able to 
return to work [Time Frame: Day 1]. 
• 
Percentage of UC or CD participants based on the use of surgeries, hospitalizations, medical 
appointments, imaging and laboratory [Time Frame: From 3 years prior to Day 1 until Day 1] 
• 
Number of healthcare resources used and unitary cost per resource (direct medical cost) [Time 
Frame: From 3 years prior to Day 1 until Day 1]. 
• 
Number of workhours missed or with productivity reduced due disease and average 
salary/hour/person (indirect costs applicable to active workers) [Time Frame: From 3 years 
prior to Day 1 until Day 1] 
 
 
10.1.2 Statistical analyses overview 
 
For each study endpoint, all data will be summarized for total UC and CD patients and by IBD type 
(UC or CD). 
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 (UC and CD), the patients with disease activity 
will be compared with patients with mild or no activity regarding socio-demographic, clinical and 
treatment variables of interest. 
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 (CI) will be computed whenever relevant. Chi-square or Fisher exact tests will be used to 
compare activity vs non-activity regarding qualitative variables and t-student or Mann-Whitney tests 
will be used for comparison of quantitative variables. If applicable, multivariable logistic regression 
model will be performed to evaluate association of independent variables with disease activity at Day 
1 with odds ratios (ORs) estimates and the respective 95% CI. All tests will be two-sided and 
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 CD, the percentage of patients with active disease at Day 1 will be calculated as: 
 
𝐶𝐶𝐶𝐶 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝐻𝐻𝐻𝐻𝐻𝐻≥8 𝑜𝑜𝑜𝑜 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶≥220
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐶𝐶𝐶𝐶 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
 𝑥𝑥 100
For UC, the percentage of patients with active disease at Day 1 will be calculated as: 
 
𝑈𝑈𝑈𝑈 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠≥5 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑈𝑈𝑈𝑈 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
 𝑥𝑥 100 
 
 
The 95% CIs will be computed for each estimate. 
 
10.3 Secondary Analyses 
 
In order to characterize socio-demographic and clinical aspects of UC and CD, 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 conventional and 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, time for of biologic from date of diagnosis of UC or CD, 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: 
• 
Chi-square or Fisher exact tests will be used to compare qualitative variables, such as sex, 
smoking habits, professional status, family history of IBD, steroid dependence or refractoriness, 
previous treatment with biologic therapies, and previous surgery for IBD (UC and CD), among 
others. 
• 
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. 
• 
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. 
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Descriptive statistics will also be summarized regarding patients’ QoL, overall and according to disease 
activity. For each score estimate, the 95% CI will be computed. 
• 
The SF-36 uses 36 items to evaluate the eight health dimensions. After the standard scoring 
(section 7.2) the dimension score will be calculated by averaging the score items of the same 
scale. 
 
Physical functioning – Average of Q3a, Q3b, Q3c, Q3d, Q3e, Q3f, Q3g, Q3h, Q3i and Q3j 
scores. 
 
Role Physical – Average of Q4a, Q4b, Q4c and Q4d scores. 
 
Body pain – Average of Q7 and Q8 scores. 
 
General health – Average of Q1, Q11a, Q11b, Q11c and Q11d scores. 
 
Vitality – Average of Q9a, Q9e, Q9g and Q9i scores. 
 
Social Functioning – Average of Q6 and Q10 scores. 
 
Role-Emotional – Average of Q5a, Q5b and Q5c scores. 
 
Mental Health – Average of Q9b, Q9c, Q9d, Q9f and Q9h scores. 
 
A summary score for each component will be obtained through a standardization of each scale 
score followed by the computation of aggregate scores for the physical and mental summaries 
using weights. The component summary will be scored from 0 to 100, with a high score 
denoting a more favorable health state: 
 
Physical Component Score 
 
Mental Component Score 
• 
The IBDQ questions have seven optional choices. In order to obtain a score, each question 
corresponds to the given number, with question 1 representing a worse status of quality of life 
and 7 a better, adding up the total of points in each dimension. The dimension score will be 
calculated by the average of the questions scores associates to each dimension. A higher score 
shows better function in that area. 
 
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. 
 
Social function – sum of questions 04, 08, 12, 16, 28. 
 
The comparison of SF-36 scale scores or component summary scores, EQ-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. 
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Descriptive statistics will be summarized regarding work productivity impairment (WPAI), experienced 
by IBD patients (overall, by IBD type (UC and CD) and according to disease activity): 
• 
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. 
• 
Percent total work productivity impairment (TWPI) due to UC or CD defined as the mean of 
subjects’ total percentage of work impairment associated with UC or CD that results from both 
absenteeism and presenteeism. The TWPI, assessed by each IBD (UC or CD), will be calculated 
as following: 
 
𝑄𝑄2
𝑄𝑄2 + 𝑄𝑄4 + [(1 −൬
𝑄𝑄2
𝑄𝑄2 + 𝑄𝑄4൰) ∗𝑄𝑄5
10] ∗100 
 
• 
Percent work time missed due to UC or CD will be calculated for each subject as following: 
𝑄𝑄2
𝑄𝑄2 + 𝑄𝑄4 ∗100 
• 
Percent impairment while working due to UC or CD will be calculated for each subject as 
following: 
𝑄𝑄5
10 ∗100 
• 
Percent total activity impairment due to UC or CD will be calculated for each subject as 
following: 
𝑄𝑄6
10 ∗100 
• 
Additionally, the proportions of patients reporting some absenteeism, some work impairment, 
and some activity impairment due to UC or CD will be presented. 
Patients with moderate to severe activity will be compared with patients with no or mild activity 
regarding WPAI data (percent TWPI due to UC or CD, percent work time missed due to UC or CD, 
percent impairment while working due to UC or CD and percent total activity impairment due to UC or 
CD) through the t-test for independent samples or Mann-Whitney test in case of non-normality of the 
quantitative variable distribution. 
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Healthcare resources (previous 3 years) will be described by IBD group (UC or CD) and by disease 
activity at Day 1, for the following events: drug therapies; surgeries; number, reason and duration of 
hospitalizations; number and type of medical appointments with gastroenterologists or other medical 
specialists; and number and type of imaging and laboratory testing. 
Healthcare resource costs will be reported in total and on a per patient per month basis. Direct costs 
will be obtained by multiplying resource use with relevant unit costs. Unit costs for each resource items 
will be collected in Mexican reliable administrative databases or other sources. 
• 
UC or CD-related health care costs: Consumer price index (CPI)-adjusted IBD (UC or CD)- 
related health care costs will be computed as total costs, medical costs, UC and CD drug costs, 
and other costs (sum of surgeries, hospitalization, medical appointments; imaging and 
laboratory testing costs). 
• 
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. 
The indirect costs will be reported as the cost of productivity loss by absenteeism and presenteeism per 
patient. In the present study it was considered relevant to consider the human capital method since it 
was understood that the disease is not incapacitating, and the period of absence would not be long 
enough to justify the replacement of the employee. 
• 
In the human capital method, the calculation considers exactly the cost of the salary paid to the 
employee proportionally to the hours of absence/ work impairment based on the average 
mexican incomes and the absence/impaired work hours reported during the study. 
 
 
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 335 patients regardless of IBD type (UC or CD). 
 
Due to lack of information regarding the rate of UC or CD control in Mexico, a rate of inadequate 
control of disease (i.e. the percentage of patients with moderately to severely active disease) of 50% 
will be assumed. Hence, a sample of 318 patients, regardless of IBD type (CD or UC), will allow 
estimates with 95% CI and a margin of error (ME) less than 5.5%. The following formula was used: 
𝑛𝑛= 1.962 × 𝑝𝑝× (1 −𝑝𝑝)
𝑀𝑀𝑀𝑀2
 
 
Rate of uncontrolled disease (p) = 50% ME = 0.055 
ME = 0.055 
To account for a non-evaluable rate of 5%, a total of 335 patients should be included in the study. No 
stratification sampling methods will be used. 
 
 
 
Reports 
 
A Non-Interventional Study Report based on the results obtained will be prepared and submitted for 
distribution. This Study Report should be available in compliance to Sponsor policies, and the 
participating sites should be informed about the results when the report is finalized. 
 
 
 
Publications 
 
The investigator is obliged to provide the sponsor all data derived by the investigator from the study. 
During and after the study, only the sponsor may make study information available to other study 
investigators or to regulatory agencies, except as required by law or regulation. Except as otherwise 
allowable in the clinical study site agreement, any public disclosure (including publicly accessible 
websites) related to the protocol or study results, other than study recruitment materials and/or 
advertisements, is the sole responsibility of the sponsor. 
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The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for any 
peer-reviewed publication will appropriately reflect contributions to the production and review of the 
document. All publications and presentations must be prepared in accordance with this section and the 
Clinical Study Site Agreement. In the event of any discrepancy between the protocol and the Clinical 
Study Site Agreement, the Clinical Study Site Agreement will prevail. 
Takeda aims to have the results of this study published. 
 
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 
ICFs on site for 5 years. The Study Site Responsible should store additional study documentation for a 
longer period if required by any local regulations and/or hospital requirement. 
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