Perianal Fistula Procedure Validation, Matched Case Control, and Patient Journey Study
Conditions: Inflammatory Bowel Disease, Perianal Fistula, Crohns Disease
Sponsor: Takeda




Title: Perianal Fistula Procedure Validation, Matched Case Control, and Patient Journey Study 
NCT Number: NCT03981939
Protocol Approve Date: 14 May 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

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20181113 – PAF Validation and Burden of Illness Study 
PAFBOI 
Study Protocol Ver. 2.0, 3 DEC 2018 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
STUDY SUMMARY 
Name of Sponsor(s): 
Jefferson Tea, Vice-President Medical & 
Scientific Affairs, Takeda Canada 
Compound/Product: 
Not applicable 
Title of Protocol: Perianal Fistula Procedure Reoccurrence Rate and Patient Journey Study 
Study Number: IBD-5009 
Phase: Not applicable 
Study Design: 
This is an observational databases study of patients who underwent surgery for perianal fistulas in 
Ontario.   
 
Study Aim: 
This study aims to provide a better understanding of the disease burden of perianal fistulas within 
Crohn’s disease in Ontario. 
 
Study Objectives: 
1. To validate the use of procedure codes to identify patients with PAFs in administrative 
databases 
2. To compare Crohn’s patients with a PAF (cases) to matched Crohn’s patients without a PAF 
(controls) to determine the disease burden and healthcare resource utilization of Crohn’s 
related-related PAF in Ontario 
3. To describe the patient journey among Crohn’s patients following their first diagnosis of 
perianal fistula 
 
Subject Population: Subjects aged >18 inclusive, with Crohn’s related perianal fistulas 
Number of Subjects: 
All patients in the study databases who meet all 
of the inclusion criteria for and none of the 
exclusion criteria for each objective will be 
used in this study. 
 
Study Sites:  
Ontario health administrative data 
Dose Level(s): 
Not applicable 
 
Route of Administration: 
Not applicable 
Duration of Study: 
Overall Study Duration: Apr 2002 – Mar 2017 
 
Main Criteria for Inclusion: 
All patients who meet the validated case definition (as described in section 6.1) will be selected from 
the administrative databases under study. 
 
Main Criteria for Exclusion: 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
Patients who are below the age of 18 on the date of their procedure, or those who have missing data 
will be excluded. Patients who are not eligible for universal Ontario Health Insurance Plan OHIP 
coverage through the follow up period will also be excluded e.g., due to termination of OHIP 
coverage, or death. 
 
Main Criteria for Evaluation and Analyses: 
This study aims to identify the unmet need in the PAF patient population. The population will be 
described (n, %) by age, sex, and local health integration network of residence. In addition, disease 
burden, (as measured by direct costs, overall and by sector), as well as healthcare resource utilization 
(emergency department visits, hospitalizations and outpatient visits), will be evaluated. 
 
Statistical Considerations: 
Objective 1: This study will be descriptive in nature. Therefore no statistical tests will be conducted. 
Objective 2: This study will use statistical tests, adjusting for variable follow-up periods, to compare 
mean costs and healthcare resource utilization between cases and controls at pre-specified time points. 
If the test assumptions are violated, then alternative methods will be used as appropriate. 
Objective 3: This study will be descriptive in nature. Therefore no statistical tests will be conducted. 
 
Sample Size Justification:  
This study is a retrospective database study. All patients who meet all inclusion and none of the 
exclusion criteria will be included in the study.  
 
 
 
 
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PAFBOI 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
Table of Contents 
Section 1.0 
Administrative information .......................................................................... 2 
1.1 
Contacts ...................................................................................................................... 2 
1.2 
Approval ..................................................................................................................... 3 
Section 2.0 
Introduction................................................................................................. 13 
Section 3.0 
Study Objective(s) and Endpoint(s)............................................................ 16 
3.1 
Study Aim ................................................................................................................. 16 
3.1.1 
Study Objectives ......................................................................................... 16 
3.2 
Endpoint(s) ................................................................................................................ 16 
Section 4.0 
Study Administrative Structure .................................................................. 17 
4.1 
Study Sites ................................................................................................................ 17 
4.2 
Sponsor Personnel ..................................................................................................... 17 
4.3 
Contract Research Organisation (CRO) ................................................................... 17 
Section 5.0 
Ethics .......................................................................................................... 18 
5.1 
Ethical conduct of the Study ..................................................................................... 18 
5.2 
Independent Ethics Committee / Institutional Review Board and Authorities ......... 18 
Section 6.0 
Study Design and Plan ................................................................................ 20 
6.1 
Objective 1: Validation Study ................................................................................... 20 
6.1.1 
Study Design ............................................................................................... 20 
6.1.2 
Selection of Study Population .................................................................... 20 
6.1.3 
Inclusion Criteria ........................................................................................ 22 
6.1.4 
Exclusion Criteria ....................................................................................... 22 
6.1.5 
Statistical Analysis...................................................................................... 22 
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PAFBOI 
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6.2 
Objective 2: Matched Case Control Study ............................................................... 23 
6.2.1 
Study Design ............................................................................................... 23 
6.2.2 
Selection of Study Population .................................................................... 23 
6.2.3 
Inclusion Criteria ........................................................................................ 25 
6.2.4 
Exclusion Criteria ....................................................................................... 25 
6.2.5 
Statistical Analysis...................................................................................... 25 
6.3 
Objective 3: Patient Journey Study ........................................................................... 26 
6.3.1 
Study Design ............................................................................................... 26 
6.3.2 
Selection of Study Population .................................................................... 26 
6.3.3 
Inclusion Criteria ........................................................................................ 27 
6.3.4 
Exclusion Criteria ....................................................................................... 28 
6.3.5 
Statistical Analysis...................................................................................... 28 
6.4 
Study Schedule ......................................................................................................... 28 
6.5 
Treatments ................................................................................................................ 29 
6.6 
Premature Termination or Suspension of Study or Investigational Site ................... 29 
6.7 
Study Plan ................................................................................................................. 30 
Section 7.0 
Safety Reporting ......................................................................................... 31 
Section 8.0 
Data Quality Control and Assurance .......................................................... 32 
8.1 
Quality Control ......................................................................................................... 32 
8.2 
Data Management ..................................................................................................... 32 
Section 9.0 
Statistical Methods and Determination of Sample Size ............................. 33 
9.1 
Statistical Analysis Plan ............................................................................................ 33 
9.1.1 
Variables and Epidemiological Measurements .......................................... 33 
9.1.1.1 
Age .................................................................................................................. 33 
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9.1.1.2 
Sex .................................................................................................................. 33 
9.1.1.3 
Procedure and Diagnosis Codes ..................................................................... 33 
9.1.1.4 
Patient Local Health Integration Network (LHIN) ......................................... 34 
9.1.1.5 
Index Date ....................................................................................................... 34 
9.1.1.6 
Neighbourhood Income Quintile .................................................................... 35 
9.1.1.7 
Date of Diagnosis ........................................................................................... 35 
9.1.1.8 
Lookback Period ............................................................................................. 35 
9.1.1.9 
Follow-Up Period ........................................................................................... 35 
9.1.1.10 
Cost ................................................................................................................. 35 
9.2 
Interim Analyses ....................................................................................................... 36 
9.3 
Determination of Sample Size .................................................................................. 36 
Section 10.0 
Reports ........................................................................................................ 36 
Section 11.0 
Publication, Disclosure, and Clinical Trial Registration Policy ................. 36 
Section 12.0 
Archiving of Study Documentation ............................................................ 36 
Section 13.0 
References................................................................................................... 38 
Section 14.0 
Appendices ................................................................................................. 41 
 
 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
APPENDICES 
1. 
Sample Output Tables (dated December 3, 2018, 18 pages) 
 
 
 
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PAFBOI 
Study Protocol Ver. 2.0, 3 DEC 2018 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
List of Abbreviations and Definition of Terms 
 
ADR:   
Adverse Drug Reactions 
CA: 
 
Competent Authority 
CD: 
 
Crohn’s disease 
CHMP: 
Committee for Medicinal Products for Human Use 
CIHI:  
Canadian Institute of Health Information 
CRO:  
Contract Research Organisation 
DAD:  
Discharge Abstracts Database  
ED: 
 
Emergency Department  
EMA:  
European Medicines Agency 
GPP:  
Good Pharmacoepidemiology Practices 
HCRU: 
Healthcare resource utilization 
ICES:  
Institute for Clinical Evaluative Sciences 
ICH:  
International Conference on Harmonisation 
IEC: 
 
Independent Ethics Committee 
IRB:  
Institutional Review Board 
LHIN:  
Local Health Integration Network 
NACRS: 
National Ambulatory Care Reporting System 
OCCC: 
Ontario Crohn’s and Colitis Cohort 
OHIP:  
Ontario Health Insurance Plan  
PAF:  
Perianal Fistula 
PQI:   
Product Quality Issues 
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PAFBOI 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
RIW:  
Resource Intensity Weight 
RPDB: 
Registered Persons Database  
SAP:  
Statistical Analysis Plan 
SSR:   
Special Situation Reports 
TNF-α: 
Anti-tumour necrosis factor alpha 
TOH  
The Ottawa Hospital 
 
 
 
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PAFBOI 
Study Protocol Ver. 2.0, 3 DEC 2018 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
Section 2.0 Introduction 
Perianal fistulas (PAFs) can develop following an anorectal abscess, and can be debilitating for 
patients1,2. PAFs are common complications in patients with Crohn’s disease (CD), resulting in a 
higher cost burden due to increased healthcare resource use (HCRU)3. 
 
Globally, the incidence and prevalence of CD is higher in developed countries as compared to 
developing countries. The annual incidence ranges from 5 per 100,000 person-years in Asia and 
the Middle East to 20.2 per 100,000 person-years in North America, while prevalence ranges 
from 67.9 per 100,000 population in Asia and Middle East to 322 per 100,000 population in 
Europe4. Canada, in particular, has one of the highest incidence and prevalence of CD 
worldwide4, with an estimated 0.7% (approximately 129,000) Canadians affected with CD5. 
Considerable differences in the incidence and prevalence of CD across the Canadian provinces 
have been noted. The highest incidence and prevalence were reported in Nova Scotia (annual 
incidence of 20.2 per 100,000 person-years and prevalence of 319 per 100,000 population) and 
the lowest in British Columbia (annual incidence of 8.8 per 100,000 person-years and prevalence 
of 161 per 100,000 population)6. One-third of patients with CD suffer from fistulas during their 
disease course with low remission rate7. While therapies and treatments do exist, they are 
associated with a range of side effects which impacts quality of life. 
 
Several surgical and medical therapies exist for the treatment of PAF. The surgical therapies 
range in terms of invasiveness, and can be tailored depending on the risk of reoccurrence and 
side-effects1,8. While a draining seton is generally used first, side effects include reoccurrence 
and fecal incontinence8. The reoccurrence rate following a seton can be as high as 83% in 
patients with CD9. Examples of available surgical treatment options include advancement flaps, 
anal fistula plugs, and fibrin sealants1,8.  Medical therapies include anti-tumor necrosis factor 
alpha (TNF-α) agents, antibiotics, immunomodulators and immunosuppressive drugs10. In CD 
patients, a combined medical and surgical approach has been shown to be more effective in 
treating PAF than single therapy alone11. Despite the availability of multiple treatment options, 
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PAFBOI 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
perianal fistulizing CD is difficult to treat, as existing therapies have limited efficacy and are 
associated with complications9,10,12. This, in turn, affects a patient’s quality of life13. 
 
Cx601, an allogenic expanded adipose-derived mesenchymal stem cells (eASCs), is a minimally 
invasive treatment option under development for PAF patients. A phase 3, randomized, double-
blind, placebo-controlled study of Cx601 (ADMIRE-CD) was conducted by TiGenix (now 
owned by Takeda) across 49 hospitals in seven European countries and Israel. This study 
included 212 patients with CD and treatment-refractory PAF14,15. Results from the study 
indicated that Cx601 is a safe and effective treatment option in closing external openings 
compared to placebo. The primary endpoint of combined remission at 24 weeks was significantly 
higher among patients taking Cx601 compared to placebo (51% vs. 36%; p=0.021)15. The effect 
was maintained at Week 52 when a greater proportion of patients achieved combined remission 
with Cx601 compared to placebo (56% vs. 39%; p=0.010)14.  
 
In December 2017, the European Medicines Agency (EMA) Committee for Medicinal Products 
for Human Use (CHMP) granted a positive opinion for Cx60116. Shortly after, Takeda 
announced the approval of Cx601 in Europe for the treatment of perianal fistulas in adult patients 
with Crohn’s disease with an inadequate response to at least one conventional or biologic 
therapy17. This new treatment option marks the first allogeneic stem cell therapy to receive 
central marketing authorization approval in Europe.  
 
The Institute for Clinical Evaluative Sciences (ICES), is an independent, non-profit corporation 
in Ontario, Canada that uses data collected through the administration of Ontario's system of 
publicly funded health care. As a “prescribed entity” in Ontario under the Personal Health 
Information Protection Act (PHIPA), ICES is allowed to collect and use administrative data for 
the purposes of monitoring and evaluating the provincial health system, a process that is renewed 
every three years. As a result, the ICES data repository consists of record-level, coded and 
linkable health data sets. It encompasses much of the publicly funded administrative health 
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Study Protocol Ver. 2.0, 3 DEC 2018 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
services records for the Ontario population eligible for universal health coverage since 1986 and 
is flexible to integrate research-specific data, registries and surveys. Currently, this includes 
health service records for as many as 13 million people.. In addition to health data from the 
Ontario Ministry of Health and Long Term Care, it also securely links data from a variety of 
health surveys and registries to provide a holistic understanding of patient health outcomes 
across the province. This provides a unique opportunity to follow patients over time to 
understand the burden of illness of PAF among Crohn’s patients. 
 
The current study aims to provide a better understanding of the disease burden and unmet need 
of perianal fistulas within Crohn’s disease in Ontario. It will accomplish this by first validating 
the use of procedure codes to reliably identify patients with PAF in administrative databases. It 
will then compare the burden of disease and healthcare resource utilization of Crohn’s patients 
with a perianal fistula (cases), to matched control patients without a diagnosis of perianal fistula. 
Finally, it will capture the five-year journey of patients following their first diagnosis of perianal 
fistula, stratifying them by the number and order of interventions received in their follow-up 
period. Burden of disease as measured by direct costs incurred by patients and healthcare 
resource utilization by patients will be measured. 
 
 
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GMA NIS Protocol Template for Takeda Sponsored Studies, version 1.0 (02-Mar-2018) 
Section 3.0 Study Objective(s) and Endpoint(s) 
3.1 
Study Aim 
This study aims to provide a better understanding of the disease burden of perianal fistulas 
within Crohn’s disease in Ontario. 
 
3.1.1 Study Objectives  
1. To validate the use of procedure codes to identify patients with PAFs in administrative 
databases 
2. To compare Crohn’s patients with a PAF (cases) to matched patients without a PAF 
(controls) to determine the impact of a PAF on disease burden, as measured by direct 
costs and healthcare resource utilization 
3. To describe the patient journey among Crohn’s patients following their first diagnosis of 
perianal fistula 
 
3.2 
Endpoint(s) 
Objective 1 is a validation study, and will measure the sensitivity, specificity, positive predictive 
value and negative predictive value of various diagnosis and administrative code combinations. 
Objective 2 will describe cases and controls by the following variables: 
 Frequencies of covariates, such as sex, age group, LHIN of residence,  
 Burden of disease, as measured by direct costs, and 
 Healthcare resource utilization 
Objective 3 will describe five different patient journeys (see pg 53, table 5, ‘Pathway Group’ 
column): 
 Frequencies of covariates, such as sex, age group, LHIN of residence,  
 Burden of disease, as measured by direct costs, and 
 Healthcare resource utilization 
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Section 5.0 Ethics 
Objective 1: Research ethics approval to conduct the retrospective chart review and validation 
study will be granted by the Research Ethics Board at the Ottawa Hospital.  
Objectives 2 and 3: This is  a secondary analysis of aggregated, deidentified data. Individual 
consent is not required as this is a retrospective study with a large number of patients and all data 
made available to the investigators will be anonymized. Patient risk will not be increased by the 
usage of these data. 
 
5.1 
Ethical conduct of the Study 
This study will be conducted in accordance with the protocol, the current version of the 
Declaration of Helsinki, Good Pharmacoepidemiology Practices (GPP), ISPE GPP guideline and 
any local regulations.  
 
The Sponsor and/or the appointed CRO will ensure that the protocol, any amendments and the 
Subject Information Sheet/Informed Consent Form are submitted to the relevant Independent 
Ethics Committees (IECs)/Institutional Review Boards (IRBs) according to local requirements. 
 
The sponsor is responsible for meeting the ICH requirement for yearly updates to the IECs/IRBs, 
if applicable. 
 
5.2 
Independent Ethics Committee / Institutional Review Board and Authorities 
IEC/ IRB 
According to applicable regulations, the appointed CRO or the Site Study Responsible will: 
 Notify or obtain approval from the relevant IEC/IRB of the protocol and any amendments 
 Ethics approval will be sought from Institutional Review Board Services, as per ICES study 
requirements. 
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The Sponsor or the appointed CRO will keep an updated list of all submission and approval dates 
of all documents submitted to the IEC / IRB and will provide the Site Responsible with a copy of 
this list. Copies of the documents will be distributed upon request. 
 
 
 
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Section 6.0 Study Design and Plan 
This study is a ‘non-interventional study’ as defined in Directive 2001/20/EC and will follow the 
guidelines for GPP.  
 
This means that: 
 The assignment of a subject to a particular therapeutic strategy is not decided in advance by 
the study protocol but falls within current practice. 
 No additional diagnostic or monitoring procedures shall be applied to the subjects. 
 Epidemiological methods shall be used for the analysis of collected data. 
 
6.1 
Objective 1: Validation Study 
6.1.1 Study Design 
This study aims to verify the potential of using procedure codes to reliably identify patients with 
PAF.  
 
6.1.2 Selection of Study Population 
Study subjects will be identified from The Ottawa Hospital (TOH) data warehouse. We will 
begin by performing a search for patients with CD based on ICD-10 coding. A chart review will 
be performed to confirm the diagnosis of CD and to identify patients with and without perianal 
fistulas. We will select approximately 300 patients with perianal CD and 300 patients with CD 
but without perianal fistulas. If they have a PAF at any time, they will be categorized as “PAF 
positive,” whereas if no PAF is found, they will be categorized as “no PAF”.  
 
The reference database will be linked to administrative data from the Institute for Clinical 
Evaluative Sciences’ Discharge Abstract Database (DAD), National Ambulatory Care Reporting 
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System (NACRS) and Ontario Health Insurance Plan (OHIP) datasets. ICES captures all medical 
claims submitted to the Ontario Health Insurance Plan (OHIP). Therefore, 100% of out-patient, 
in-patient, and clinic visits in Ontario are captured by ICES. The ICES data repository comprises 
most of the Ontario publicly funded administrative health service records since 1986.  
 
The Ontario DAD and NACRS databases are provided to ICES by CIHI. CIHI captures data 
across Canada (excluding Quebec) for inpatient and same-day surgery visits through DAD,18 as 
well as emergency department visits and same-day surgery through NACRS19. DAD and 
NACRS contain a range of data including hospitalizations, day surgery, emergency department 
visits, and outpatient clinics20,21. These datasets will be linked to the Registered Person’s 
Database (RPDB), which records demographic characteristics for patients in Ontario such as age 
and sex. Further, the ICES Ontario Crohn’s and Colitis Cohort (OCCC) will be used; a validated 
dataset of Ontarians who have a diagnosis of either disease. 
 
Each ICES dataset contributes unique information towards understanding the complete picture of 
PAF patient care in Ontario. The databases are completely integrated and provide end-to-end 
patient interactions within the Ontario public healthcare system. However, they lack visibility 
regarding privately reimbursed medications as well as patients who change their province of 
residence. For this study, all data sources will be linked at the patient-level to develop 
longitudinal patient-level perspectives. For all patients, relevant intervention and diagnosis codes 
for these patients will be extracted to construct the 12 case definitions of interest (Table 1). 
Patients have to have a PAF diagnosis at or after their OCCC inclusion date. If they enter the 
OCCC after their PAF diagnosis, their Crohn’s diagnosis date in this study will set to their index 
date. Finally, since this is administrative data that uses an inferred algorithm, it cannot be 
determined whether fistula are simple or complex in nature. However, ~80% of fistula are 
complex, and this study will be limited to patients in a validated cohort Crohn’s disease patients2. 
 
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6.1.3 Inclusion Criteria 
The inclusion criteria for this study will include:  
 Inclusion in TOH “reference” database AND 
 Aged 18-105 inclusive at date of index AND 
 Patient can be linked between TOH “reference” database to the ICES databases based on 
health card number (validated using sex and date of birth) AND 
 Incident inclusion in the OCCC between April 1 2002 to July 1, 2013 AND 
 Incident diagnosis of PAF in TOH database between April 1 2004 to July 1, 2015 
 
6.1.4 Exclusion Criteria 
The exclusion criteria will include:  
 Missing demographics at index date (sex, age, LHIN, income quintile) in all databases  
 Death date in the ICES data prior to TOH PAF incidence date 
 
The total number of patients excluded using each exclusion criteria will be reported in the final 
deliverable in a waterfall chart (Table 2). Subjects should be included in the study only once. 
 
6.1.5 Statistical Analysis 
All patients identified from the TOH data warehouse with and without PAF will be included in 
the analysis. The cohort will be profiled by age, sex, neighbourhood income quintile, and LHIN 
of residence (Table 3). Analyses will then be performed using the concepts of diagnostic test 
evaluation, following methods used in previous ICES cohort validation studies22–28. Sensitivity 
tables will be created with each of the 12 case definitions to maximize sensitivity, specificity, 
PPV, NPV, and AUC. Finally, positive and negative likelihood ratios will be calculated (Table 
4). The case definition with the highest sensitivity will be selected, and if there is a tie, the case 
definition with the higher PPV will be selected. Equations for each are provided below: 
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 Sensitivity = true positive / (true positive + false negative) 
 Specificity = true negative / (true negative + false positive) 
 Positive predictive value (PPV) = true positive / (true positive + false positive) 
 Negative predictive value (NPV) = true negative / (true negative + false negative) 
 Positive likelihood ratio = sensitivity / 1 – specificity 
 Negative likelihood ratio = 1 – sensitivity / specificity 
 
6.2 
Objective 2: Matched Case Control Study 
6.2.1 Study Design 
The objective of this study is to compare Crohn’s patients with a PAF (cases) to matched patients 
without a PAF (controls) to determine the impact of a PAF on disease burden and healthcare 
resource utilization. 
 
6.2.2 Selection of Study Population 
Databases from the Institute for Clinical Evaluative Sciences (ICES) will be used to follow 
patients over time. All patients who meet the case definition will be considered PAF positive. 
Their index date (i.e., onset of PAF) will be selected based on the first time they meet the first 
code in the case definition identified in Objective 1 between April 1, 2007 to March 31, 2012. 
Using the Ontario Crohn’s and Colitis Cohort (OCCC), their date of entry into the OCCC with a 
Crohn’s diagnosis will be ascertained. For patients who enter the OCCC after their PAF index 
date, their lookback time will be set to 0 days for matching purposes; the actual difference will 
be reported in the output tables. If the proportion of patients who enter the OCCC after their PAF 
index date is less than 5% of the total sample, these patients will be excluded from the study. 
Patients will then be followed forward until the end of the study (March 31, 2017). Controls will 
be assigned the same index date as their cases, and will be matched to PAF patients on the 
following (Figure 1): 
1. Age on index (± 5 years) 
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2. Sex  
3. Geographic region (LHIN) 
4. Match on Charlson Comorbidity Index 
5. Year of inclusion in the OCCC 
6. Maximum of duration from the OCCC to index date, or 0 days if OCCC entry is after the 
index date 
7. Duration of follow-up 
 
 
Figure 1: Case-control study design. Controls will be matched to cases on age on index, sex, 
geographic region (LHIN), Charlson Comorbidity Index, year of inclusion in the OCCC, duration 
from the OCCC to index date, and duration of follow-up 
 
Each case will be matched to up to 4 controls. In the event that the matching criteria are too 
strict, the exact match for the year of inclusion in the OCCC will be modified to ±1 year. Cases 
for whom a matched control cannot be found will be excluded from the analysis. If this is not 
successful, or a large percentage of cases are excluded, propensity score matching will be used to 
match patients. If propensity score matching is used, duration of follow-up will not be included 
as a matching criterion, however, the same matching criteria as the exact matching will be used 
to create the propensity score match (i.e., age, sex, geographic region, CCI, and year of index). 
 
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6.2.3 Inclusion Criteria 
The inclusion criteria for this study will include:  
 Patients were incident in the OCCC from April 1, 2002 to March 31, 2012 AND 
 The case meets the PAF case definition identified in Objective 1 in the selection period 
(April 1, 2005 to March 31, 2012) AND 
 Aged 18-105 inclusive at date of index  
 
6.2.4 Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
 Missing demographics at index date (sex, age, neighbourhood income quintile, LHIN) 
 Death during 5-year analysis period 
 OHIP coverage is terminated during the follow-up e.g., if the patient moves to another 
province 
 Meeting the case definition during the lookback period 
 Cases for whom a matched control cannot be found 
 
The total number of patients excluded using each exclusion criteria will be reported in the final 
deliverable in a waterfall chart (Table 5). Subjects should be included in the study only once.  
 
6.2.5 Statistical Analysis 
All eligible cases and controls will be used in this analysis. First, for cases and controls 
separately, their demographic characteristics on index, such as age, sex, neighbourhood income 
quintile, and LHIN of residence will be reported. In addition, for cases only, the average time 
from OCCC inclusion to case definition for PAF being met, and the calendar year in which the 
case definition was met will also be recorded (Table 6). If the percentage of patients who met the 
case definition for PAF prior to inclusion in the OCCC is above 5%, Table 6 will be duplicated, 
but only for patients who were already included in the OCCC when they met the case definition 
for PAF. 
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Next, the mean will be calculated for disease burden, as measured by total cost, cost by sector, 
and healthcare resource utilization for cases and controls. This will be done for years 0-10, 0-5 
and 0-1 prior to meeting the PAF case definition, inclusive. Patients will be censored at OCCC 
inclusion in the lookback period. For each of these three time periods, the mean difference 
between cases and controls will be calculated with standard deviations, and the statistical 
significance of the difference evaluated (Table 7). Inverse probability weighting will be used to 
account for loss to follow-up in patient counts. This will then be repeated after the cases met the 
case definition for a PAF for years 0-1, 0-5, and 0-10, inclusive (Table 8). By design, trends over 
time cannot be compared as each time period may utilize different cohorts.  
 
Finally, procedures will be categorized as EUA ± seton, advanced interventions, diversions, and 
proctectomy (Table 9). For each year of follow up, the total number of patients, and total number 
of cumulative procedures performed will be tabulated (Table 10). 
 
6.3 
Objective 3: Patient Journey Study 
6.3.1 Study Design 
The objective of this study is to describe the patient journey among Crohn’s patients following 
their first diagnosis of perianal fistula 
 
6.3.2 Selection of Study Population 
As per Objective 2, databases from the Institute for Clinical Evaluative Sciences (ICES) will be 
used to follow patients over time. All patients incident in the OCCC from Jan 1, 2002 to March 
31, 2012 will be selected. All patients who meet the case definition will be considered PAF 
positive. Their index date (i.e., onset of PAF) will be selected based on the first time they meet 
the first code in the case definition identified in Objective 1 between April 1, 2005 to March 31, 
2012. Using the Ontario Crohn’s and Colitis Cohort (OCCC), their date of entry into the OCCC 
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with a Crohn’s diagnosis will be ascertained. For patients who enter the OCCC after their PAF 
index date, their lookback time will be set to 0 days for matching purposes; the actual difference 
will be reported in the output tables. If the proportion of patients who enter the OCCC after their 
PAF index date is less than 5% of the total sample, these patients will be excluded from the 
study. Patients will then be followed forward until the end of the study (March 31, 2017). 
Patients will then be followed forward for five years, and all relevant procedures identified in the 
follow-up period (Table 9).  
 
Based on the order and number of procedures received, patients will be assigned into one of five 
groups (Table 11). These are: 
1. No intervention: These patients receive none of the listed interventions following their 
first diagnosis of PAF in the five-year follow-up period 
2. ≥1 EUA ± seton: Patients in this group received only EUA ± seton as part of their 
treatment, with no additional procedures administered 
3. 2 EUA ± seton AND Advanced Intervention: These patients received 2 x EUA ± seton, 
followed by an advanced intervention or diversion procedure. 
4. 1 EUA ± seton AND Advanced Intervention: Similar to group 2, these patients received a 
single EUA ± seton, followed by an advanced intervention or diversion procedure. They 
may have received additional procedures after this intervention. 
5. Other: These patients received an advanced intervention or diversion as their 1st line 
treatment. 
 
6.3.3 Inclusion Criteria 
The inclusion criteria for this study will include:  
 Inclusion in the OCCC at or prior to index visit with a diagnosis of Crohn’s disease AND 
 The case meets the PAF case definition identified in Objective 1 in the selection period 
AND 
 Aged 18-105 inclusive at date of index AND 
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 Have to have 5 years of follow-up 
 
6.3.4 Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
 Missing demographics at index date (sex, age, neighbourhood income quintile, LHIN) 
 Death during 5-year analysis period 
 OHIP coverage is terminated during the 5-year analysis period e.g., if the patient moves 
to another province 
 Meeting the case definition during the lookback period 
 
The total number of patients excluded using each exclusion criteria will be reported in the final 
deliverable in a waterfall chart (Table 11). Subjects should be included in the study only once.  
 
6.3.5 Statistical Analysis 
First, for each of the five patient pathway groups, their demographic characteristic, such as age, 
sex, neighbourhood income quintile, and LHIN of residence will be reported. (Table 13). 
 
Next, the mean and standard deviation will be calculated for total burden of disease, as measured 
by cost, cost by sector, and healthcare resource utilization for each patient group. This will be 
done for the entire 5-year follow-up period (Table 14), and annualized (i.e., divided by 5) to get 
the average cost and HCRU per year of follow-up (Table 15). 
 
6.4 
Study Schedule 
Planned Start of Study: 
 Apr 2002 
Planned End of Study: 
Dec 2017/latest data available in ICES 
Planned collection of first data point: 
 Jan 2018 
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Planned collection of the last data point: 
 Aug 2019 
Planned completion of the study report: 
Sep 2019 
 
6.5 
Treatments 
Non-interventional/observational – no treatments/pharmacotherapy are instructed by the study 
protocol. 
 
6.6 
Premature Termination or Suspension of Study or Investigational Site 
As this study is a retrospective observational database study with no investigational sites there 
are no requirements for premature termination or suspension of the study. 
 
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Section 7.0 Safety Reporting 
As this study is a retrospective observational database study with no investigational sites, and 
the study sponsors and CRO have no access to patient-level data there are no requirements 
for safety reporting in this study. No Takeda pharmaceutical products will be studied and no 
product-related or –unrelated adverse events will be collected.  Health Canada adverse event 
reporting is not relevant to this study. 
If during the conduct of the study the investigator(s) or a member of the research team is 
spontaneously informed by a healthcare professional or patient of an SAE, AE, ADR, SSR or 
PQI where the event/issue pertains to a Takeda product (or unbranded generic), such 
information should be forwarded to the relevant Takeda Pharmacovigilance department 
within 1 working day for fatal or life-threatening SAEs, within 4 calendar days for other 
SAEs, and within 7 calendar days for all other events.  This included events spontaneously 
notified to the investigators(s) or research team which are study endpoints and also events 
spontaneously notified which are not study endpoints.  As such reports are spontaneously 
notified, causality of any adverse events should be assumed unless there is evidence to the 
contrary. 
 
 
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Section 8.0 
Data Quality Control and Assurance 
8.1 
Quality Control 
The diagnosis codes and procedures entered into the DAD and NACRS databases have been 
entered by an abstractor at each hospital site and have been quality checked via several 
mechanisms outlined in Figure 3 below20,21. 
 
Figure 2. Discharge Abstract Database—Information Flow 
 
8.2 
Data Management 
Data will be housed within secure servers at ICES, the management of which have been 
approved by the Office of the Information and Privacy Commissioner of Ontario under 
section 45 of Ontario’s Personal Health Information Protection Act since 2005. Access to 
information is restricted by role, and is project specific. Data are analysed on these secure 
servers, and only the output may be extracted. The study sponsors and CRO will not have 
access to these data, and as such all data management and data privacy policies will be as per 
ICES internal protocols.    
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Section 9.0 
Statistical Methods and Determination of Sample Size 
This section describes the variables and epidemiological measurements as foreseen at the 
time of planning the study. Each study has an included statistical analysis section (Objective 
1: Section 6.1.5, Objective 2: Section 6.2.5, Objective 3: 6.3.5). 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.  
 
9.1 
Statistical Analysis Plan 
Epidemiological methods will be employed for data analyses. As noted in Section 7.0 there is 
no requirement to collect or report ASRs. 
 
9.1.1 Variables and Epidemiological Measurements 
9.1.1.1 Age 
Patient age at index will be categorized into the following groups:  
 18-44  
 45-64, and  
 ≥65 
 
9.1.1.2 Sex 
Patient sex at index will be extracted. Sex will be categorized as male or female. 
 
9.1.1.3 Procedure and Diagnosis Codes 
The following procedure and diagnosis codes will be captured in this study: 
1. K60.x – Fissure and fistula of anal and rectal regions 
2. 565 Fistula and Fissure 
3. S251: Excision – fistula in ano (EUA + seton) 
4. 3.NQ.^^.^^ Diagnostic Imaging Interventions on the Rectum 
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5. 3.NQ.10.^^ Xray, rectum 
6. 1.NQ.86.MB for fistula terminating at skin or subcutaneous tissue [e.g. anorectal] 
with simple excision (with or without closure) 
7. 1.NQ.86.MB-W3 using fibrin glue 
8. 1.NQ.86.MB-XX-E using local transposition flap [e.g. mucosal advancement flap] 
9. 1.NQ.86.MB-XX-F using free (myocutaneous) flap 
10. 1.NQ.86.MB-XX-G using distant pedicled flap 
11. 1.NT.86.MB open approach for fistula terminating at skin 
12. 1.NT.86.MB-FA using open approach and encirclage device [e.g. seton or rubber 
band] 
13. 1.NT.86.MB-W3 using open approach using fibrin glue 
14. 1.NT.86.MB-XX-G using pedicled flap [e.g. endorectal advancement muscle flap] 
15. 1.NT.86.MB-XX-L using xenograft [e.g. Surgisis anal plug] 
16. 1.NM.76.^^ Colocolostomy (for exclusion and diversion) 
17. 1.NM.77.^^ Colostomy (permanent, terminal, transverse loop, double barreled) 
18. 1.NM.82.^^ Colostomy [any type] 
19. 1.NK.77.^^  terminal, loop, end or Brooke 
20. 1.NK.84.^^ Ileostomy, Continent [e.g. Kock or Barnett pouch] 
a. Note that this include 1.NK.84.^^ Proctectomy with conversion from 
ileostomy to continent ileostomy 
 
9.1.1.4 Patient Local Health Integration Network (LHIN) 
Patient LHIN will be extracted at index. LHIN is the geographic partition of Ontario into 
healthcare regions, where each region has its own set of healthcare providers and 
administration to coordinate care and distribute funds. There are 14 regions (Central, Central 
East, Central West, Champlain, Erie St. Clair, Hamilton Niagara Haldimand Brant, 
Mississauga Halton, North East, North Simcoe Muskoka, North West, South East, South 
West, Toronto Central, and Waterloo Wellington).  
 
9.1.1.5 Index Date 
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The date of the first time a patient meets the case definition (Section 6.1) within the selection 
period will be considered the index date for cases in Objective 2, and patients in Objective 3. 
An index date will be assigned to controls in Objective 2 based on their matched case. 
 
9.1.1.6 Neighbourhood Income Quintile 
Neighbourhood income quintile is calculated using the postal code associated with each 
patient’s health card number, and linking this to Census data. Within the Census data, the 
median income in each dissemination area (which contains 400 to 700 persons) will be 
calculated, and neighborhoods will be divided into income quintiles, with quintiles 1 and 5 
having the lowest and highest median incomes, respectively. 
 
9.1.1.7 Date of Diagnosis 
The date of Crohn’s disease diagnosis (i.e., patient entry) into the OCCC will be considered 
their Crohn’s diagnosis date. 
 
9.1.1.8 Lookback Period 
The number of days from date of diagnosis of Crohn’s disease in the OCCC to the index date. 
 
9.1.1.9 Follow-Up Period 
The number of days from the index date to the end of the study (Objective 2), or five years 
following the index date (Objective 3). 
 
9.1.1.10 Cost 
The cost of each visit will be calculated using the resource intensity weight (RIW) 
methodology from the Canadian MIS Database (CMDB), which attributes a hospital specific 
cost to the resource intensity of each visit29,30. 
 
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9.2 
Interim Analyses 
No interim analyses are planned for this study.  
 
9.3 
Determination of Sample Size 
This study is a retrospective database study, and therefore all patients who meet all of the 
inclusion and exclusion criteria will be included in the study.  
 
Section 10.0 Reports 
A Non-Interventional Study Report based on the results obtained will be prepared and 
submitted to Global Research for distribution. The Final Study Report should be available 
within one year from collection of the last data point, and as there are no participating sites 
there is no need to inform them about the results when the report is finalised. 
 
Section 11.0 Publication, Disclosure, and Clinical Trial Registration Policy 
The Sponsor aims to have the results of this study published. 
 
The Sponsor has the right to use the data and results for regulatory purposes and for internal 
presentation within the company and to partners. 
 
Takeda may post the results of the study on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws and/or 
regulations. 
 
Section 12.0 Archiving of Study Documentation 
During the course of the study the Site Responsible must as a minimum file the below 
essential documents in the Study Site File: 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use

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Section 13.0 References 
1.  
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Force of the American Society of Colon and Rectal Surgeons. Practice parameters for 
the management of perianal abscess and fistula-in-ano. Dis Colon Rectum. 
2011;54(12):1465-1474. doi:10.1097/DCR.0b013e31823122b3 
2.  
Aguilera-Castro L, Ferre-Aracil C, Garcia-Garcia-de-Paredes A, Rodriguez-de-Santiago 
E, Lopez-Sanroman A. Management of complex perianal Crohn’s disease. Ann 
Gastroenterol. 2017;30(1):33-44. doi:10.20524/aog.2016.0099 
3.  
Bubbers EJ, Cologne KG. Management of Complex Anal Fistulas. Clin Colon Rectal 
Surg. 2016;29(1):43-49. doi:10.1055/s-0035-1570392 
4.  
Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the 
inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 
2012;142(1):46-54.e42; quiz e30. doi:10.1053/j.gastro.2011.10.001 
5.  
Rocchi A, Benchimol EI, Bernstein CN, et al. Inflammatory bowel disease: a Canadian 
burden of illness review. Can J Gastroenterol. 2012;26(11):811-817. 
6.  
Bernstein CN, Wajda A, Svenson LW, et al. The epidemiology of inflammatory bowel 
disease in Canada: a population-based study. Am J Gastroenterol. 2006;101(7):1559-
1568. doi:10.1111/j.1572-0241.2006.00603.x 
7.  
Scharl M, Rogler G, Biedermann L. Fistulizing Crohn’s Disease. Clin Transl 
Gastroenterol. 2017;8(7):e106. doi:10.1038/ctg.2017.33 
8.  
Dudukgian H, Abcarian H. Why do we have so much trouble treating anal fistula? 
World J Gastroenterol. 2011;17(28):3292-3296. doi:10.3748/wjg.v17.i28.3292 
9.  
de Groof EJ, Sahami S, Lucas C, Ponsioen CY, Bemelman WA, Buskens CJ. Treatment 
of perianal fistula in Crohn’s disease: a systematic review and meta-analysis comparing 
seton drainage and anti-tumour necrosis factor treatment. Colorectal Dis. 
2016;18(7):667-675. doi:10.1111/codi.13311 
10.  Taxonera C, Schwartz DA, García-Olmo D. Emerging treatments for complex perianal 
fistula in Crohn’s disease. World J Gastroenterol. 2009;15(34):4263-4272. 
11.  Yassin NA, Askari A, Warusavitarne J, et al. Systematic review: the combined surgical 
and medical treatment of fistulising perianal Crohn’s disease. Aliment Pharmacol Ther. 
2014;40(7):741-749. doi:10.1111/apt.12906 
12.  Chung W, Ko D, Sun C, Raval MJ, Brown CJ, Phang PT. Outcomes of anal fistula 
surgery in patients with inflammatory bowel disease. Am J Surg. 2010;199(5):609-613. 
doi:10.1016/j.amjsurg.2010.01.007 
13.  Riss S, Schwameis K, Mittlböck M, et al. Sexual function and quality of life after 
surgical treatment for anal fistulas in Crohn’s disease. Tech Coloproctol. 2013;17(1):89-
94. doi:10.1007/s10151-012-0890-x 
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14.  Panés J, García-Olmo D, Van Assche G, et al. Long-term Efficacy and Safety of Stem 
Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn’s Disease. 
Gastroenterology. 2018;154(5):1334-1342.e4. doi:10.1053/j.gastro.2017.12.020 
15.  Panés J, García-Olmo D, Van Assche G, et al. Expanded allogeneic adipose-derived 
mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a 
phase 3 randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281-1290. 
doi:10.1016/S0140-6736(16)31203-X 
16.  Takeda. TiGenix and Takeda announce Alofisel receives approval in Europe. 
https://www.takeda.com/newsroom/newsreleases/2018/tigenix-and-takeda-announce-
alofisel-receives-approval-in-europe/. Accessed January 29, 2019. 
17.  European Medicines Agency. New medicine to treat perianal fistulas in patients with 
Crohn’s disease | European Medicines Agency. 
https://www.ema.europa.eu/en/news/new-medicine-treat-perianal-fistulas-patients-
crohns-disease. Accessed January 29, 2019. 
18.  Canadian Institutes for Health Information. Discharge Abstract Database Metadata 
(DAD) | CIHI. https://www.cihi.ca/en/discharge-abstract-database-metadata. Published 
December 18, 2018. Accessed January 29, 2019. 
19.  Canadian Institutes for Health Information. National Ambulatory Care Reporting 
System Metadata (NACRS) | CIHI. https://www.cihi.ca/en/national-ambulatory-care-
reporting-system-metadata. Published October 2, 2018. Accessed January 29, 2019. 
20.  Canadian Institutes for Health Information. Data Quality Documentation, Discharge 
Abstract Database — Current-Year Information, 2016–2017. :18. 
21.  Canadian Institutes for Health Information. Data Quality Documentation, National 
Ambulatory Care Reporting System — Current-Year Information, 2016–2017. :20. 
22.  Benchimol EI, Guttmann A, Mack DR, et al. Validation of international algorithms to 
identify adults with inflammatory bowel disease in health administrative data from 
Ontario, Canada. J Clin Epidemiol. 2014;67(8):887-896. 
doi:10.1016/j.jclinepi.2014.02.019 
23.  Gershon AS, Wang C, Guan J, Vasilevska-Ristovska J, Cicutto L, To T. Identifying 
patients with physician-diagnosed asthma in health administrative databases. Can Respir 
J. 2009;16(6):183-188. 
24.  Gershon AS, Wang C, Guan J, Vasilevska-Ristovska J, Cicutto L, To T. Identifying 
individuals with physcian diagnosed COPD in health administrative databases. COPD. 
2009;6(5):388-394. 
25.  Lee TM, Tu K, Wing LL, Gershon AS. Identifying individuals with physician-
diagnosed chronic obstructive pulmonary disease in primary care electronic medical 
records: a retrospective chart abstraction study. NPJ Prim Care Respir Med. 2017;27. 
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26.  Rezaie A, Quan H, Fedorak RN, Panaccione R, Hilsden RJ. Development and validation 
of an administrative case definition for inflammatory bowel diseases. Can J 
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27.  McAuliffe ME, Lanes S, Leach T, et al. Occurrence of adverse events among patients 
with inflammatory bowel disease in the HealthCore Integrated Research Database. Curr 
Med Res Opin. 2015;31(9):1655-1664. doi:10.1185/03007995.2015.1065242 
28.  Herrinton LJ, Liu L, Levin TR, Allison JE, Lewis JD, Velayos F. Incidence and 
mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease 
from 1998 to 2010. Gastroenterology. 2012;143(2):382-389. 
doi:10.1053/j.gastro.2012.04.054 
29.  Canadian Institutes for Health Information. Patient Cost Estimator: Methodology Notes 
and Glossary. https://www.cihi.ca/en/pce_methodology_notes_en.pdf. Accessed 
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30.  Manitoba Centre for Health Policy. Concept: Calculating Hospital Costs Using Cost Per 
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