Impact of Co-morbidities on Treatment Response in Inflammatory Bowel Disease: VERNE Study
Conditions: Inflammatory Bowel Disease
Sponsor: Takeda

This may include, but is not limited to, redaction of the following: 
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Title: Impact of co-morbidities on treatment response in inflammatory bowel disease: VERNE study
NCT Number: NCT02861118
Protocol Approve Date:  13th of April of 2016
Certain information within this protocol has been redacted (ie, specific content is masked 
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information or company confidential information. 
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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.

1
 
Impact of co-morbidities on treatment response in inflammatory bowel disease 
Takeda | Apices | Version 1.1, 13th of April of 2016  
Impact of co-morbidities on treatment response in 
inflammatory bowel disease: VERNE study 
Project number: 
1049806 
Contact: 
 
Date: 
13th of April of 2016 
Version: 
1.1 
Confidential: 
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confidential information that must not be distributed or 
published without permit. Copying, reproducing or transferring 
this documents content is forbidden. 
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Impact of co-morbidities on treatment response in inflammatory bowel disease 
Takeda | Apices | Version 1.1, 13th of April of 2016  
Table of contents 
Table of contents ........................................................................................... 3 
1.
Figures ................................................................................................ 6
2.
List of abbreviations ............................................................................. 6
3.
Study Summary ................................................................................... 7
3.1. 
Sponsor ........................................................................................... 7 
3.2. 
Title ................................................................................................. 7 
3.3. 
Study code ....................................................................................... 7 
3.4. 
Scientific committee .......................................................................... 7 
3.5. 
Participating centers and investigators ................................................. 7 
3.6. 
Research ethics committee ................................................................. 7 
3.7. 
Study objectives ............................................................................... 7 
3.8. 
Study design .................................................................................... 8 
3.9. 
Study disease ................................................................................... 8 
3.10. 
Study population ............................................................................ 8 
3.11. 
Study calendar ............................................................................... 8 
3.12. 
Coordination and monitoring ............................................................ 8 
3.13. 
Study sponsor ................................................................................ 8 
4.
Rationale and background ..................................................................... 9
5.
Study objectives .................................................................................. 11
5.1. 
Primary objective ............................................................................. 11 
5.2. 
Secondary objectives ........................................................................ 11 
6.
Methodology ....................................................................................... 11
6.1. 
Study design ................................................................................... 11 
6.1.1. 
Study Scheme ........................................................................... 12 
6.1.2. 
Study calendar ........................................................................... 12 
6.2. 
Investigator recruitment, training and site selection ............................. 12 
6.2.1. 
Investigator recruitment ............................................................. 12 
6.2.2. 
Investigator training ................................................................... 13 
6.3. 
Patient selection ............................................................................... 13 
6.3.1. 
Study population ........................................................................ 13 

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6.3.2. 
Inclusion criteria ........................................................................ 13 
6.3.3. 
Exclusion criteria ........................................................................ 13 
6.3.4. 
Discontinuation criteria ............................................................... 14 
As it is a retrospective study, there is no possibility of early termination, hence 
no discontinuation criteria are considered. ....................................................... 14 
6.3.5. 
Informed consent ....................................................................... 14 
6.4. 
Study procedure............................................................................... 14 
6.4.1. 
Study visits ............................................................................... 14 
6.4.2. 
Study site monitoring ................................................................. 14 
6.4.3. 
Data collection ........................................................................... 14 
6.4.4. 
Study variables .......................................................................... 15 
6.4.5. 
Main outcome ............................................................................ 20 
7. 
Statistical Analysis ............................................................................... 20 
7.1. 
Sample size calculation ..................................................................... 20 
7.2. 
Analysis population ........................................................................... 20 
7.3. 
General statistical analysis considerations ........................................... 20 
7.4. 
Assessment of the primary objective: Evaluate the impact of the co-
morbidities profile in IBD patients on treatment response to biological 
therapy .................................................................................................... 21 
7.5. 
Percentage of IBD patients exhibiting co-morbidities ............................. 22 
7.6. 
Co-morbidities profile according to the level of IBD severity................... 22 
8. 
Data management ............................................................................... 22 
9. 
Practical considerations ........................................................................ 23 
9.1. 
Electronic case report form ................................................................ 23 
9.2. 
Monitoring and quality of data ............................................................ 23 
10. 
Ethical considerations .......................................................................... 24 
11. 
Confidentiality ..................................................................................... 25 
11.1. 
Patient confidentiality .................................................................... 25 
11.2. 
Data confidentiality........................................................................ 25 
12. 
Study administration............................................................................ 25 
13. 
Investigators compliance ...................................................................... 26 
14. 
Management and reporting of adverse events or adverse reactions ........... 26 
14.1. 
Definitions .................................................................................... 26 

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Impact of co-morbidities on treatment response in inflammatory bowel disease  
Takeda | Apices | Version 1.1, 13th of April of 2016   
14.1.1. 
Definition of Adverse Event ...................................................... 26 
14.1.2. 
DefinItion of Adverse Drug Reaction .......................................... 26 
14.1.3. 
DefinItion of Serious Adverse Event ........................................... 27 
14.1.4. 
Special Situations .................................................................... 27 
14.1.5. 
Criteria for Causal Relationship to the (Study) Drug..................... 28 
14.2. 
Handling of Adverse Events ............................................................ 29 
14.2.1. 
Reporting of Adverse Reactions ................................................. 29 
14.2.2. 
Collection and Recording of Adverse Events ................................ 29 
Appendix 1: Patient’s information sheet .......................................................... 31 
Appendix 2: Patient’s written informed consent ................................................ 34 
Appendix 5: Adverse event reporting form ....................................................... 36 
References................................................................................................... 37 
 
 
 

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Impact of co-morbidities on treatment response in inflammatory bowel disease  
Takeda | Apices | Version 1.1, 13th of April of 2016   
1. Figures 
Figure 1. Study Scheme
 
 ............................................................................................. 12
Figure 2. Study calendar
 
 ............................................................................................ 12
 
2. List of abbreviations 
 
Abbreviation 
Description 
ADR 
Adverse Drug Reaction  
AE 
Adverse event 
AEMPS 
Agencia Española del Medicamento y Productos Sanitarios 
AR 
Adverse Reaction 
CD 
Crohn’s Disease 
CDAI 
Crohn's Disease Activity Index  
eCRF 
Electronic Case Report Form 
EQ-5D 
EuroQoL Questionnaire 
HBI 
Harvey-Bradshaw Index  
HRQoL 
Health Related Quality of Life 
IBD 
Inflammatory Bowel Disease  
PMS 
Partial Mayo Score 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event  
SIBDQ 
Short Inflammatory Bowel Disease Questionnaire 
UC 
Ulcerative Colitis 
UCDAI 
Ulcerative Colitis Disease Activity Index 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. Study Summary 
3.1.  Sponsor 
Takeda Farmacéutica España S.A. 
3.2. Title 
Impact of co-morbidities on treatment response in inflammatory bowel disease: VERNE 
study 
3.3. Study code 
Vedolizumab-5016 (MACS-2015-101162) 
3.4. Scientific committee 
3.5. Participating centers and investigators 
It is estimated that 25 gastroenterology sites will participate in the study in order to 
ensure representativeness of all the Spanish territory.  
3.6. Research ethics committee 
The study protocol and other relevant documents will be submitted to Hospital 
Universitario y Politécnico La Fe de Valencia ethic committee.  
3.7. Study objectives 
The main objective of the present study is to evaluate the impact of the co-morbidities 
profile on treatment response in Inflammatory Bowel Disease (IBD) patients. The study 
also aims to describe the percentage of IBD patients exhibiting co-morbidities as well as 
the level of IBD severity according to the co-morbidities profile. 
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Impact of co-morbidities on treatment response in inflammatory bowel disease  
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3.8. Study design 
A retrospective, non-interventional, multicentre, observational study that will include 
consecutive patients diagnosed with Ulcerative Colitis (UC) or Crohn’s Disease (CD) who 
started treatment with biologics between June 2011 and June 2013. 
3.9. Study disease 
Patients with IBD: UC and CD. 
3.10. Study population 
Consecutive UC and CD patients that started treatment with biologics between June 
2011 and June 2013 that attend a regular visit to the gastroenterology site will 
participate in the study. A minimum estimated sample of 200 UC patients and 200 CD 
patients is required. In order to avoid a biased sample (specially selection bias), 
patients will be recruited consecutively.  
3.11. Study calendar 
In order to achieve the desired estimated sample, the work filed corresponding to the 
patients inclusion is estimated at four months. Also, time required for conducting data 
management, statistical analysis and preparation of the final report is estimated at 
three months after the inclusion of the last patient.  
3.12. Coordination and monitoring 
The study will be coordinated by Apices Soluciones SL. 
3.13. Study sponsor 
This study is funded by Takeda Farmacéutica España S.A. 
 
 
 
 
 
 
 

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4. Rationale and background  
Inflammatory Bowel Disease (IBD) is a group of inflammatory disorders of the 
gastrointestinal tract whose etiology is believed to be a combination of genetic predisposition 
to gastrointestinal immune system dysregulation and environmental factors.1 Crohn’s 
Disease (CD) and Ulcerative Colitis (UC) are IBD major forms and have been empirically 
defined by clinical, pathological, endoscopic and radiological features, exhibiting a very 
heterogeneous clinical profile; particularly, CD has different clinical courses and a broad 
spectrum of patterns, thus making it difficult to choose the best treatment. The course of 
IBD is characterized by two phases: relapse and remission.2
UC is a relapsing non-transmural inflammatory disease that is restricted to the colon and, 
depending on anatomic extent, can be classified as proctitis, left-sided colitis, or pancolitis.
  
3 
In gastroenterology clinical practice it is usually defined as mild, moderate or severe, 
depending on the frequency of bloody stools.4 Many tools have been developed to assess UC 
severity.5 Mayo score and Ulcerative Colitis Disease Activity Index (UCDAI or Sutherland 
Index) were developed in the early 1980s as simplified indexes to classify UC severity and 
considers three clinical variables and an endoscopy score.6,7
On the other hand, CD is a relapsing, transmural inflammatory condition that can affect the 
entire gastrointestinal tract, and is usually presented as discontinuous involvement of the 
different sections of the gastrointestinal tract which can lead to several complications (i.e. 
strictures, abscesses and fistulas). CD phenotype can be classified according to the Vienna 
criterion which is based on anatomical location and behavior of the disease.3,
 
8 Also, the 
Crohn's Disease Activity Index (CDAI) was developed to quantify the symptoms of patients 
with CD and has been broadly used in order to define response or disease remission when 
assessing therapeutic options. Index values of 150 and below are associated with quiescent 
disease; values above that indicate active disease, and values above 450 are reported for 
extremely severe disease.9
In terms of diagnosis, UC can be confirmed through endoscopic and histological studies, 
whereas CD has no definitive diagnostic, and it is usually conducted based on history, 
physical examination and findings from endoscopic, radiological, laboratory and histological 
studies.3  
  
In terms of epidemiology, some of the CD and UC highest-incidence areas of the world are 
northern European countries, the United Kingdom and North America.1,10 Although the 
incidence and prevalence of UC and CD are beginning to stabilize in these high-incidence 
areas, they continue to rise in low-incidence regions (i.e: southern Europe and Asia).1 It is 
estimated that 1.4 million and 2.2 million people in the United States and Europe, 
respectively, suffer from IBD.1 Spanish incidence of IBD seems to have increased in the last 
years, and is also variable across regions;11 UC incidence is estimated at 0.6-8 patients per 
100,000 inhabitants per year, whereas there seems to be 0.4-5.5 CD patients per 100,000 

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inhabitants per year. Spanish IBD prevalence, albeit very difficult to establish, is estimated 
at 87-110 cases per 100,000 inhabitants per year.12,13
The onset of IBD typically occurs in the late adolescence and beginning of adult stages of life 
and patients tend to progress to relapsing and chronic disease conditions.
  
14 IBD is known to 
exert a negative impact in patient’s life both in terms of Health Related Quality of Life 
(HRQoL) and productivity, overall representing a major burden for society and health 
services.15,16,17,18,19
In the recent years, the aim of IBD treatment has evolved from symptomatic control to deep 
remission, which is defined as the absence of symptoms, markers of inflammatory activity, 
and endoscopic lesions, and is associated with fewer admissions to hospital, surgeries and 
better HRQoL.
 
20,21 Main current treatment modalities for UC and CD include 5-
aminosalicates, corticosteroids, immunomodulators (including thiopurines, methotrexate, 
tacrolimus, cyclosporine, and biological therapies), and surgery. Conventional treatment with 
corticosteroids and immunomodulators has not been able to reduce the complications of the 
disease or modify its course.22,23 Over the last decade, biologic treatments, such as 
infliximab, adalimumab, certolizumab pegol, golimumab and vedolizumab has been used in 
patients with moderate to severe CD, and in those with acute severe UC who failed to 
respond to corticosteroids.24
At present, early introduction of immunomodulatros and biologic agents in patients with 
more serious disease is probably the most widely accepted management strategy.18-
  
25 
Treatment of IBD with anti-TNFα since IBD diagnosis, albeit capable of inducing and 
maintaining mucosal healing and reducing surgery and hospitalization rates, may imply 
overtreatment of patients with milder forms of disease, thus emphasizing the need for 
accurate prognostic markers to guide patient selection.18,20 It is worth mentioning that 
although anti-TNFα therapy is thought to be an effective approach for IBD, up to 30% of 
patients do not respond to induction therapy (primary non-response) and a significant 
proportion loses response over time (secondary non-response).26,27 Very often patients 
profile in randomized controlled trials is quite restrictive and not representative of patients 
routinely treated under usual clinical conditions, especially, in terms of presence co-
morbidities, concomitant treatments and previous use of biologics.28
Previous studies and reviews have been conducted in order to determine the impact of co-
morbidities on treatment response in diseases like chronic obstructive pulmonary 
disease.
  
29,30 However, to the best of our knowledge, this type of correlation has not been 
subject of study in IBD patients. Varkas et al.31 evaluated the impact of spondyloarthritis on 
IBD patients, but the co-morbidities profile was not analyzed. Also, Ha et al.32 conducted a 
study aiming to evaluate IBD management within aging population and identified previous 
co-morbidities as a variable related to disease progression but, again, the impact of co-
morbidities profile on treatment response was not assessed.  

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In this context, the present study aims to study the effect of certain co-morbidities profile on 
treatment response by developing a co-morbidity scale to predict response to biological 
treatment in UC and CD patients. 
 
5. Study objectives 
5.1.  Primary objective 
• 
Evaluate the impact of the co-morbidities profile in IBD patients on treatment response 
to biological therapy.  
5.2.  Secondary objectives 
• 
Evaluate the impact of Extraintestinal Manifestations profile in IBD patients on treatment 
response to biological therapy.  
• 
Describe the percentage of IBD patients exhibiting co-morbidities. 
• 
Determine the co-morbidities profile according to the level of IBD severity.  
6. Methodology 
6.1.  Study design 
In order to meet the objectives of the present study, a retrospective, non-
interventional, multicentre observational study including 25 gastroenterology sites from 
all 
around 
Spain 
has 
been 
designed. 
Participating 
investigators 
will 
be 
gastroenterologists and will include consecutive patients diagnosed with UC or CD that 
started treatment with biologics between June 2011 and June 2013, after giving written 
informed consent. The study will consist of one only visit in which investigators will 
collect patients’ sociodemographic (age, gender, race, level of education, smoking 
habits alcohol intake) and clinical (concomitant diseases, date of diagnosis, previous 
treatment, current treatment, disease activity when starting treatment with biologics 
and at the study visit, current situation in terms of treatment with biologics) data from 
medical charts or directly from patients (in case of discrepancy, the information coming 
from medical charts will be preferable). Time since patients started biological treatment 
until study visit or until lack of treatment response or until treatment change will 
constitute the reference period for the study. In order to fulfill current legislations 
regarding non-interventional studies, investigators will commit to follow usual clinical 
practice.  

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Impact of co-morbidities on treatment response in inflammatory bowel disease  
Takeda | Apices | Version 1.1, 13th of April of 2016   
fulfillment of the objectives of the study. The study will be conducted among hospital- 
and office-based gastroenterologists specialized in UC and CD care management.  
6.2.2. Investigator training 
A training phone call will be performed to all participant investigators in order to explain 
the protocol and to train them and their personnel in the eCRF. 
6.3. Patient selection 
6.3.1. Study population 
The present study will include patients diagnosed with UC or CD that started biological 
treatment between June 2011 and June 2013, attending physician gastroenterology 
services in Spain. In order to avoid a biased sample, investigators will recruit 
consecutive patients. It is estimated that a period of 4 months will be necessary to 
achieve the desired sample of 200 UC and 200 CD patients.  
6.3.2. Inclusion criteria 
• 
Adult patients (aged ≥18) 
• 
Patients diagnosed with UC or CD according to the “World Gastroenterology 
Organization Practice Guidelines for the Diagnosis and Management of IBD in 2010”33
• 
Patients naive to biologics that started treatment with biologics between June 2011 
and June 2013  
  
• 
Patients in whose biological treatment was prescribed according to daily clinical 
practice. 
• 
Patients that gave written informed consent  
6.3.3. Exclusion criteria 
• 
Patients that were participating in a clinical trial during the study reference period.  
• 
Patients that, according to investigator’s criteria is not capable to understand and fill 
in the study questionnaires or to give written informed consent 

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Impact of co-morbidities on treatment response in inflammatory bowel disease  
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6.3.4. Discontinuation criteria 
As it is a retrospective study, there is no possibility of early termination, hence no 
discontinuation criteria are considered. 
6.3.5. Informed consent   
Following the current local regulations, patients will be informed on study objective and 
methodology through a patient’s information sheet (appendix 1) and will also have to 
give written informed consent before data collection begins (appendix 2). 
6.4. Study procedure 
6.4.1. Study visits 
The study will consist of  only one visit in which investigators will inform patients about 
the study objective and methodology and the possibility to take part of it. All data will 
be collected during the study visit or retrospectively from patients’ clinical chart after 
giving written informed consent. More detail on data collection is given on sections 
6.4.3, 6.4.4 and 6.4.5.   
6.4.2. Study site monitoring  
Regular fortnightly phone calls will be made by study monitors in order to check 
inclusion status, solve any potential recruitment issues, check data plausibility etc. 
As the CRFs will be electronic, filters in the eCRF design may limit the number of 
queries. Nevertheless, study monitors will check the entered data and deal with any 
possible queries which may arise in relation with the core data set. If electronic queries 
are subsequently generated, these will be resolved with physicians by study monitors 
before completion and validation of the database. The corrections to data will be 
included in the eCRF either by the investigators or the study monitors. Any correction to 
data will be recorded in the system together with the automatic identification of the 
person who performed it and the corresponding date (audit trail). Ongoing eCRF review 
will be done by the CRO during the study field work. 
6.4.3. Data collection 
25 gastroenterology centers (one investigator per center) from all around Spain will 
participate in the study. In order to achieve the minimum sample, each 
gastroenterology specialist will have 4 months to include approximately 8 UC and 8 CD 
consecutive patients that fulfill the inclusion/exclusion criteria specified on sections 
6.3.2 and 6.3.3. Investigators will inform patients about the study objectives and 

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methodology and patients will have to give written informed consent before inclusion in 
the study as specified on section 6.3.5.  
Investigators will collect sociodemographic and clinical data from patients’ records 
specified on section 6.4.3 and will introduce it in the eCRF.  
6.4.4. Study variables 
The following sociodemographic variables will be collected from patients’ medical 
records or directly from patients during the study visit, straight after their inclusion in 
the study: 
• 
Age 
• 
Gender 
• 
Race (caucasian, asiatic, latin, black, other) 
• 
Level of education (uneducated, primary education, secondary education, university 
education) 
• 
Working status (student, self-employed, employed by other, retired, hosework, 
unemployed, temporarily unable to work, permanently unable to work, other) 
• 
Smoking habits (non-smoker, ex-smoker, smoker, number of cigarrtes per day) 
• 
Alcohol intake (units per week). 
The following clinical variables will be collected from patients’ medical records (when 
available) or directly from patients during the study visit, straight after their inclusion in 
the study: 
• 
Date of diagnosis (UD or CD). 
• 
Disease activity at the begining of the reference period and at the study visit through 
collection of the following variables: 
• 
For UC patients: 
 
 
Partial Mayo Score (PMS) (9 point scale that excludes the endoscopic 
appearance of the mucosa)34
 
General disease activity:2  
  
 
Mild: up to four bloody stools daily and no systemic toxicity   
 
Moderate: four to six bloody stools daily and minimal toxicity 
 
Severe: more than six bloody stools daily and signs of toxicity, such 
as fever, tachycardia, anaemia, raised erythrocyte sedimentation 
rate. 
 
Fulminant: More than ten bloody stools daily, continuous bleeding, 
anaemia requiring blood transfusion, abdominal tenderness and 
colonic dilatation on plain abdominal radiographs. 
 
Disease anatomic extent: proctitis, left-sided colitis or pancolitis. 
 
Endoscopy findings:  

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 
Normal or inactive disease 
 
Mild disease (erythema, decreased vascular pattern, mild friability) 
 
Moderate disease (marked erythema, lack of vascular pattern, 
friability erosions)  
 
Severe disease (spontaneous bleeding, ulceration). 
• For CD patients: 
 
Harvey-Bradshaw Index (HBI) (a simplified version of CDAI)35
 
General disease activity:2  
 
 
Mild to moderate: ambulatory patients able to tolerate oral 
alimentation 
without 
manifestations 
of 
dehydration, 
toxicity, 
abdominal tenderness, painful mass, obstruction or >10% weith loss.  
 
Moderate to severe: failure to respond to treatment for mild disease, 
more prominent symptoms of fever, weight loss, abdominal pain or 
tenderness, intermittent nausea and vomiting without obstruction, or 
significant anemia. 
 
Severe to fulminant: persisting symptoms on corticosteroids, high 
fevers, persistent vomiting, evidence of intestinal obstruction, 
rebound tenderness, cachexia, or evidence of abscess. 
 
Disease behaviour: non-stricting and non-penetrating, stricting and 
penetrating (fistulas and abscesses), 
 
Disease location: terminal ileum.  
• 
For CD and UC patients:2,33 
 
Stool frequency (normal number for this patient, 1-2 stools more than 
normal, 3-4 more stools than normal, 5 or more stools than normal) 
 
Rectal bleeding (no blood seen, streaks of blood with stool less than half the 
time, obvious blood with stool most of the time, blood alone passes) 
 
Urgency (hurry, immediately, incontinence) 
 
Nocturnal stools (yes/no) 
 
Need for antidiarrheal drugs (yes/no) 
 
Constipation (yes/no) 
 
Abdominal tenderness (none, mild and localized, mild to moderate and 
diffuse, severe or rebound) 
 
Abdominal pain or cramping (none, mild, moderate, severe) 
 
Anorexia (yes/no) 
 
Nausea (yes/no) 
 
Vomiting (yes/no) 
 
Fever (yes/no) 
 
Appetite loss 
 
Weight loss (yes/no) 
 
Fatigue (yes/no) 
 
Night sweats (yes/no) 

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 
Stunted growth (yes/no) 
 
Primary amenorrhoea (yes/no) 
 
General well-being (generally poor, fair, poor, terrible)  
 
Physician’s global assessment (normal or quiescent disease severity, mild 
disease activity, moderate disease activity, severe disease activity) 
 
Other complications: severe profuse bleeding, massive bleeding due to 
ulceration, presence of stomach or duodenum ulceration, intestinal 
perforation, intraabdominal abscesses, estenosis, obstruction, fistulas, 
megacolon, others. 
• 
Extraintestinal manifestations in UC and CD patients to be choosen from the 
following list according to ECCO guidelines:33 
 
Arthropathy and arthritis 
 
Metabolic bone disease 
 
Eye disease 
 
Oral, aural and nasal disease 
 
Skin disease 
 
Hepato-pancreato-biliary disease 
 
Neurological disease 
 
Cardiovascular manifestations of IBD 
 
Pulmonary manifestations of IBD 
• 
Urogenital manifestations of IBDComorbidies in UC and CD patients (defined as the 
coexistence of another medical condition alongside IBD, and does not imply 
causation) at the time of diagnosis and at the study visit, will be listed according to 
chosen according to the Charlson index:36
 
 
  

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Comorbidity Component 
Score  
Myocardial Infarction  
1 
Congestive Heart Failure 
1 
Peripheral Vascular Disease 
1 
Cerebrovascular Disease 
1 
Dementia 
1 
Chronic Obstructive Pulmonary Disease 
1 
Connective Tissue Disease 
1 
Peptic Ulcer Disease 
1 
Diabetes Mellitus 
1 (mild), 2 (moderate- severe) 
Moderate-Severe 
Chronic 
Kidney 
Disease  
2 
Hemiplegic 
2 
Leukemia 
2 
Malignant Lymphoma 
2 
Solid Tumor 
2 (tumor), 6 (if metastasis) 
Liver Disease 
1 (mild), 3 (moderate-severe) 
Acquired immunodeficiency syndrome 
(AIDS) 
6 
 

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• 
Biological treatment/s for UC or CD followed during the reference period: 
 
Starting date 
 
Posology 
 
Intensification of biological treatment: date and type of intensification 
 
Continuing with the treatment  
 
Date and reason for discontinuation, if applicable  
 
New biological treatment prescribed after discontinuation, starting date, 
posology, 
continuing 
with 
the 
treatment, 
date 
and 
reason 
for 
discontinuation.    
• 
Concomitant treatment with corticosteroids (e.g. prednisone, hydrocortisone, 
betamethasone, methylprednisolone, etc,) or immunosuppressives (e.g. Ciclosporin, 
Methotrexate, etc) during induction phase  
 
Starting date, number of cycles 
Other treatments followed before the reference period to be chosen from the following 
list: 
 
Aminosalicylates (e.g. mesalazine, Sulfasalazine, 5-ASA, etc), oral, 
enema, suppository. 
 
Corticosteroids 
(e.g. 
prednisone, 
hydrocortisone, 
betamethasone, 
methylprednisolone, etc), oral, enema, suppository. 
 
Thiopurines (e.g. azathioprine, mercaptopurine, etc). 
 
Immunosuppressives (e.g. Ciclosporin, Methotrexate, etc). 
 
Anti-diarrheal drugs. 
 
Pain medications. 
 
Antidepressants. 
 
Antibiotics. 
 
Use of alternative medicine (e.g. acupuncture, relaxation therapy, 
Qigong, herbal therapy, etc). 
 
Other (specify) 
• 
Other treatments followed during the reference period to be chosen from the 
following list: 
 
Aminosalicylates (e.g. mesalazine, Sulfasalazine, 5-ASA, etc), oral, 
enema, suppository. 
 
Corticosteroids 
(e.g. 
prednisone, 
hydrocortisone, 
betamethasone, 
methylprednisolone, etc), oral, enema, suppository. Number of cycles 
 
Thiopurines (e.g. azathioprine, mercaptopurine, etc). 
 
Immunosuppressives (e.g. Ciclosporin, Methotrexate, etc). 
 
Anti-diarrheal drugs. 
 
Pain medications. 

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 
Antidepressants. 
 
Antibiotics. 
 
Use of alternative medicine (e.g. acupuncture, relaxation therapy, 
Qigong, herbal therapy, etc). 
 
Other (specify) 
  
All patients’ data will be handled in a manner that preserves confidentiality. 
6.4.5. Main outcome  
Non responders will be those patients not achieving a reduction in HBI of at least 2 
points from baseline for CD,35 and a decrease in the PMS of at least 2 points for UC34.37
Reasons to stop the drug will be classiﬁed as follows: PNR, LOR, side effects (SE), 
remission and other37. 
. 
In the cases where these indexes are not available, clinical response will be evaluated 
according to physician criteria at short term (10 weeks after starting the anti-TNF) and 
at long term (at least 6 months after starting the anti-TNF). Primary non-responders 
(PNR) were deﬁned as patients with no clinical response at short term. Loss of response 
(LOR) was deﬁned as loss of the effect of the drug along the follow up in a patient with 
initial response37.  
 
7. Statistical Analysis  
7.1. Sample size calculation 
Response to treatment with biologics is estimated at 50%, meaning that half of 
included patients are expected to be non-responders. Considering a minimal sample of 
10 patients that present the event of interest per independent variable included in the 
logistic regression model and a maximum of 10 independent variables per model, a 
minimum estimated sample of 200 UC patients and 200 CD patients is required.  
7.2. Analysis population  
All patients participating in the study that fulfill inclusion criteria, not presenting a 
major deviation of the study protocol will be included in the analysis. 
7.3. General statistical analysis considerations 
This section describes the main analyses that will be performed. Further information 
about detailed analyses, the methods of handling missing data, analysis methods and a 
list of table shells will be documented in a Statistical Analysis Plan (SAP) that will be 

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agreed with Takeda. All data analyses will be performed using SAS statistics software 
version 9.1 (SAS Institute Inc., Cary, NC) or SPSS for Windows version 19. All analyses 
will be performed in a manner consistent with the Strengthening the Reporting of 
Observational Studies in Epidemiology (STROBE) guidelines24 and applicable sections of 
the Consolidated Standards of Reporting Trials (CONSORT) guidelines25. 
All analyses will be primarily performed by descriptive statistical methods.  
Continuous variables will be described with number of patients with valid / missing 
observations, mean, standard deviation, median, minimum and maximum. Additional 
descriptive statistics may be calculated as needed (e.g. quartiles other than the 
median, coefficient of variation, etc.). In particular, for non-normally distributed data, 
the median and interquartile range will be calculated. Categorical variables will be 
described by frequencies and related percentages per class level. Summaries will be 
reported overall. 
In addition to descriptive analysis, many of the endpoints will undergo statistical testing 
to provide inferential summaries of subgroup comparisons (i.e. p-values, confidence 
limits). 
Inter-individual comparisons will be performed: 2 sample t-test, Mann-Whitney test, 
ANOVA or Kruskall-Wallis test will be used to compare quantitative variables between 
study groups or categories or categorical variables; chi-square test or the exact Fisher 
test will be used to compare categorical variables between them.  
7.4. Assessment of the primary objective: Evaluate the impact of the co-
morbidities profile in IBD patients on treatment response to biological 
therapy  
In order to determine the level of correlation between the co-morbidities profile and 
treatment response, adjusting for sociodemographic and clinical profile of patients, two 
logistic regression models will be conducted. The dependent variable of the models will 
be the lack of response during the induction phase (primary non response) and the loss 
of response during the maintenance phase (secondary loss of response) (see section 
6.4.6). In both models independent variables will include all comoborbidities included in 
the study, as well as sociodemographic and clinical variables as covariates. The 
maximum number of independent variables included in the model will be defined 
according to the number of patients per response category in the dependent variable. 
The maximum number of variables will be defined to ensure a minimum of 10 patients 
per independent variable and response category in the dependent one.  
Depending on the volume of patients that have discontinued a biological treatment and 
started treatment with a different biologic during the reference period, this sample may 
be separately analyzed.  

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7.5. Percentage of IBD patients exhibiting co-morbidities  
The number, percentage, and 95% confidence interval of IBD patients with each co-
morbidity will described.  
7.6. Co-morbidities profile according to the level of IBD severity 
The percentage of patients reporting each co-morbidity at treatment initiation will be 
compared according to the IBD severity assessed using the PMS and the general 
disease activity for UC patients and the HBI and the general disease activity for CD 
patients. Multivariable regression models will be used to assess the relationship 
between the co-morbidities profile and the level of IBD severity.  
 
8. Data management 
Patients’ data will be collected through an eCRF specially designed for this study. The 
eCRF will constitute the analysis data source and will consist of a web application 
accessible from any computer with internet access. The SSL (128 bites) protocol will be 
used for web communication, ensuring confidentiality for all communication between 
servers and investigators computers by encrypting all data sent (safe connection).  
Each investigator will have a user name and password to guarantee that data is not 
accessible to anyone else. Each investigator or designated person will be responsible for 
registering and verifying accuracy of patients’ data introduced in the eCRF. By signing 
this protocol, investigators accept their digital signature to be legally equivalent and 
binding to its written form. When introducing their digital signature, investigators 
confirm all data has been reviewed and is considered accurate.  
All data recorded by investigators will be reviewed by CRO personnel to detect missing 
information and data inconsistencies and indicate the corresponding queries in the 
monitoring reports. If any inconsistency is detected and resolved before locking the 
database, corrections will be included in the database. 
Once the field work has been completed data collected will be validated for quality 
control and the statistical analysis of the results will be performed by the CRO. 
The eCRF will allow defining filters in collected variables in order to avoid mistakes, as 
well as to obtain statistics about the main outcomes in real time. The eCRF will include 
specific logic checks and filters for collected variables in an effort to minimize errors in 
data entry. The eCRF will also allow the study team to obtain statistics on recruitment 
and eCRF completion progression in ‘real-time’. The web application will be developed 
with the following technology:  
 

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• ASP.NET 2.0  
• RDBMS My SQL v.5.0  
• IIS 6.0  
• SSL (128bits) validated by Verisign  
• WEB server O.S. Windows 2003  
The SSL technology implemented guarantees that all data transferred to the CRO 
database server will be encrypted and protected from external attacks. An audit trail 
process will ensure control of every movement made to the data stored. Information 
registered for every value stored in the database includes: the event date, responsible 
party, variable, old value, new value, and the type of action taken (creation, updating 
or deleting). This audit process provides an additional security mechanism for stored 
data and may also be useful in answering data entry questions by site personnel. 
The two questionnaires to be filled in by patients during the study visit will be sent to 
investigators together with all the study documents. Investigators will have to send all 
questionnaires completed by included patients at their site to the CRO.  
9. Practical considerations 
9.1. Electronic case report form 
An eCRF will be specifically designed for the present study and will include all the study 
variables required to meet the primary and secondary objectives of the study. The eCRF 
will consist of a web application accessible from any computer with internet access. 
Each investigator will have a unique access code to introduce patients’ information in 
the eCRF.   
Each patient will be assigned a 4-digit code: the two first digits will correspond to the 
site in which the patient has been recruited and the two last digits will be consecutively 
assigned after patient’s inclusion in the study. 
9.2. Monitoring and quality of data 
On-site monitoring will not be conducted in the context of this study. Regular fortnightly 
phone calls will be made by study monitors in order to check inclusion status, solve any 
potential recruitment issues, check data plausibility etc. Investigators will receive all 
documents before the study begins. The CRO will provide instructions to investigators 
on how to introduce data in the eCRF when data collection starts; these instructions will 
also be briefly reminded to investigators every time they access the eCRF. During the 

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entire duration of the study, The CRO will provide technical support to investigators 
participating in the study.  
Each investigator will be responsible for ensuring the accuracy of data entered in the 
eCRF as well as for completing all sections included in the eCRF. Each investigator 
commits to enter all data following their usual clinical practice.   
The CRO will be responsible for supervising patients’ recruitment through eCRF. During 
data collection period, standard monthly emails will be sent to investigators to inform 
about its progression, deal with any issues and remind investigators on their 
responsibilities. The CRO will guarantee database quality, compliance and accuracy of 
data introduced in the eCRF. The CRO will review the information entered through the 
web application weekly to guarantee data is being introduced correctly. If an 
inconsistency is detected during eCRF data review, the CRO will contact investigators 
via fax or email so that information can be clarified.  
Investigators will guard original documents from each patient. All the information 
introduced in the eCRF will need to be traceable from original medical charts. 
Participating investigators from each site will keep a patient tacking sheet that will 
contain patients name together with assigned consecutive numbers and date of birth to 
allow identification. Investigators must also keep the original signed written informed 
consent from all patients included in the study.    
When the CRO receives the completed questionnaires they will be handed to data entry 
department personnel that will introduce questionnaire answers in the study data base. 
Patients’ questionnaires will be kept in the CRO office until statistical final report is 
completed. After that, they will be kept by the study sponsor.  
10. Ethical considerations 
Investigators participating in the study will follow the principles described in the latest 
version of the Helsinki Declaration.  Copies of the Helsinki Declaration and subsequent 
revisions will be supplied on request or can be obtained from the World Medical 
Association website (http://www.wma.net/e/policy/17-c.html). The study will follow the 
International Guidelines for Ethical Review of Epidemiological Studies (Council for the 
International Organizations of Medical Sciences-CIOMS-Ginebra, 2009) and local 
recommendations.  
The study will be reviewed and approved by the appropriate Ethics Committee(s) 
according to their specific legal requirements. The study follows Spanish data protection 
laws; patient and data confidentiality will be respected. 
The type of approvals required and the estimated time to receive approvals depends on 
requirements of the local ethical committees. 

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11. Confidentiality 
11.1. 
Patient confidentiality 
Information on patients’ identity shall be considered as confidential for all effects and 
purposes. Each site and patient will have a study code. Sites will be automatically coded 
in the study website through the identification code and password assigned to each 
investigator. Patients will be assigned a sequential number by the study website upon 
meeting all inclusion and no exclusion criteria. Confidential patient tracking sheets, 
listing patient sequential numbers together with patient name and date of birth, will be 
kept by investigators at the study site for identification. 
Patients’ identity should not be revealed nor published under any circumstances. Patient 
data recorded in the eCRF will be documented anonymously, coded with a patient 
number in such a way that only the investigator and site staff may associate particular 
data with an identified or identifiable individual or his/her medical record. All other 
parties involved in data management, analysis and storage will receive, and 
subsequently analyze, non-identifiable patient data. 
11.2. 
Data confidentiality 
By signing the investigator’s confidentiality agreement, the investigator affirms to 
Takeda that information furnished by Takeda to the investigator will be kept in 
confidence and such information will be divulged to any expert committee, affiliated 
institution, and employees only under an appropriate understanding of confidentiality 
with such committee, affiliated institution and employees.  
Data security will be maintained by data being recorded in a central database and 
tracked using an audit trail. The system will allow retrieving all entered data at any 
time, and will include security elements to prevent others than authorized staff from 
accessing data. Each user will have a specific profile which will limit his/her use of the 
database. A security copy of the database and the application files will be made outside 
the server housing the web-based study. Security copies will be periodically made and 
stored outside this server. A copy of the data stored in the database will be transferred 
to Takeda at the end of the study. 
12. Study administration  
The entire study will be managed by a project coordinator at the CRO who will 
coordinate the project and maintain fluid communication with the study sponsor and the 
study team at the CRO. 

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As part of the monitoring plan, regular phone calls (at least every two weeks) will be 
made by local study monitors in order to check inclusion status, resolve any issues, 
check data plausibility, etc.  
 
13. Investigators compliance  
By signing the investigator’s agreement, the investigator agrees to conduct the study in 
an efficient and diligent manner and in conformance with this protocol, generally 
accepted standards of good clinical practice and all applicable laws, rules and 
regulations relating to the conduct of the study. 
The 
investigator 
shall 
prepare 
and 
maintain 
complete 
and 
accurate 
study 
documentation in compliance with applicable national and local laws, rules and 
regulations and, for each patient participating in the study, promptly record all data in 
the eCRF as required by this protocol. 
 
14. Management and reporting of adverse events or 
adverse reactions  
14.1. 
Definitions 
14.1.1. Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a 
drug or has undergone procedures and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.   
 
14.1.2. DefinItion of Adverse Drug Reaction 
An Adverse Drug Reaction (ADR) is defined as ‘Any noxious and unintended 
response associated with the use of a drug in humans, at any dose, where a 
causal relationship (drug-event) is at least a reasonable possibility’. x  Adverse 
reactions may arise from use of the product within or outside the terms 
of the marketing authorization or from occupational exposure.  
Conditions of use outside the marketing authorization include off-label 
use, overdose, misuse, abuse and medication errors. 

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14.1.3. DefinItion of Serious Adverse Event 
An adverse event is considered “serious” if, in the view of either the investigator 
or Sponsor, it results in any of the following outcomes:  
• Results in death  
• Is life threatening (an adverse event is considered “life-threatening” if, in the 
view of either the investigator or Sponsor, its occurrence places the patient at 
immediate risk of death. It does not include an adverse event that, had it 
occurred in a more severe form, might have caused death) 
• Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions  
• Results in congenital anomaly, or birth defect 
•  Requires inpatient hospitalization or leads to prolongation of existing 
hospitalization (hospitalization for treatment/observation/examination caused 
by AE is to be considered as serious)  
•   Other medically important events (Including transmission of an infectious 
agent) 
Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above. These events, including those that may 
result in disability/incapacity, should also usually be considered serious. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.  
 
14.1.4. Special Situations  
The following special situations, although not necessarily considered to be AEs or 
ADR must be reported in the same way as ADR, or even in the same way as 
SAEs.  
• Off-label use: situations where a medicinal product is intentionally used for a 
medical purpose not in accordance with the authorized product information.  
• Overdose (accidental or intentional): administration of a quantity of a 
medicinal product given per administration or cumulatively which is above 

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the maximum recommended dose according to the authorized product 
information.  
• Misuse of a medicinal product: situations where the medicinal product is 
intentionally and inappropriately used not in accordance with the authorized 
product information.  
• Abuse of a medicinal product: persistent or sporadic, intentional excessive 
use of medicinal products which is accompanied by harmful physical or 
psychological effects.  
• Drug exposure during pregnancy and/or breast-feeding. Exposure during 
pregnanacy is considered either through maternal exposure or via semen 
following paternal exposure. 
• Lack of efficacy/effectiveness 
• Medication errors: are broadly defined as any error in the prescribing, 
dispensing, or administration of a drug, irrespective of whether such errors 
lead to adverse consequences or not.  
• Occupational exposure: this refers to the exposure to a medicinal product, as 
a result of one’s occupation, such as nurses who may handle products 
routinely in their occupational setting 
• 
Falsified  product:  this refers to the use of a fake or counterfeit medicine, 
that passes itself off as a real, authorized medicine 
 
14.1.5. Criteria for Causal Relationship to the (Study) Drug  
 
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 (eg, 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 

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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. 
14.2. 
Handling of Adverse Events 
14.2.1. Reporting of Adverse Reactions 
According to the Order SAS/3470/2009, of 16 December, with published guidelines on 
post-authorization studies of drugs for human use, those studies in which it is not 
possible or not appropriate to do an individual assessment of the causal relation 
between clinical events and drugs of interest, individual reporting of suspected adverse 
reactions is not required. Studies labelled PAS-OD fall into this category and they do not 
require expedited reporting of suspected adverse reactions, unless otherwise specified 
by the AEMPS at the time of registration of the study. 
In addition to that specified in the preceding paragraph, any relevant safety problem 
found during the course of the study will be made known to the AEMPS and the 
competent bodies of the Autonomous Communities involved, regardless of study design 
and documentation. 
However, it is the responsibility of the investigator to report suspected serious adverse 
reactions that are detected during the course of the study to the contact point 
designated by the competent body on pharmacovigilance of the autonomous 
community in which the investigator reporting the case operates. 
14.2.2. Collection and Recording of Adverse Events 
Collection and recording of AEs will commence after the patient has provided informed 
consent. 
Information on all AEs or special situations, associated with the use of any product 
marketed by Takeda, whether initial or follow-up, serious or non-serious, that come to 
the attention of the investigator during the study visit should be recorded on 
the Takeda AE reporting form (see APPENDIX 5) and notified to the Sponsor 
within 24 hours of the Investigator's first awareness, using the following email 
address: farmacovigilancia@takeda.com   
In case the CRO is aware of any AE or special situation associated with the use of any 
product marketed by Takeda, it shall be the responsibility of the CRO to send such 
information recorded on the Takeda AE reporting form (see APPENDIX 5) to the 
pharmacovigilance department at Takeda within 24 hours from reception through the 
email address farmacovigilancia@takeda.com 

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On a quarterly basis Takeda Pharmacovigilance will send a list of the adverse events 
received to the CRO in order to perform the corresponding reconciliation process. Then 
the CRO will send back the discrepancies to Takeda Pharmacovigilance for resolution.  
 
 
 
 
 

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