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  string(1724) "Background
EH is an important goal of treatment in CD. Biologics approved for CD are required to demonstrate the ability to heal ulcers in the ileum and colon. There is growing evidence to suggest EH may not be linear across ileocolonic segments and the relative efficacy of biologics for segment EH has not been reported.
Objectives
This study aims to compare the efficacy of adalimumab, ustekinumab, infliximab, and vedolizumab on endoscopic outcomes at one year on each ileocolonic segment.
Study Design
The proposed study will be a post-hoc analysis of VERSIFY, UNITI, EXTEND, and CT-P13, which were all multicentre, randomized and double-blind trials. This post-hoc analysis aims to evaluate the relative efficacy of four biologics approved for use in CD on endoscopic outcomes for each ileocolonic segment.
Study Population
Participants with endoscopic data at baseline will be included in the analysis. For each segment assessed, patients with a segment SES-CD score of at least 3 will be included. . Participants must also receive adalimumab, ustekinumab, infliximab, and vedolizumab throughout the trial.
Outcomes
The primary outcome of the proposed study will be segment EH at one year, defined as segment SES-CD of 0 in the segment assessed. Secondary outcomes will use alternative definitions of EH, including absence of mucosal ulcerations (as defined by the SES-CD).
Statistical Analysis
Multivariable logistic regression models will be used to assess the likelihood of achieving segment EH at one year. Known confounders will be adjusted for, including, disease duration, concomitant corticosteroid use, and prior anti-TNF failure." ["project_brief_bg"]=> string(1060) "Crohn?s disease (CD) is a type of inflammatory bowel disease that is characterized by periods of relapse and remission and affects nearly 300,000 Canadians. CD affects any area of the gastrointestinal tract but is more common in the ileum and colon. Healing of ulcers is an important treatment target in CD, and is defined as endoscopic healing (EH). The Simple Endoscopic Score for CD (SES-CD) is a validated tool used to quantify mucosal inflammation in CD via endoscopy and is used to define EH. Biologics are medications used to treat patients with moderate to severe CD. To obtain regulatory approval, biologics must demonstrate the ability to heal ulcers in clinical trials of CD. Biologics approved for CD include adalimumab, ustekinumab, infliximab, and vedolizumab. Previous studies have demonstrated EH is not linear across the segments of the colon and the ileum and may be more difficult to achieve in the ileum and rectum. However, the comparative effectiveness of approved biologics for CD for achieving segment-specific EH has not been reported." ["project_specific_aims"]=> string(265) "The primary objective of this study is to compare the efficacy of four approved biologics for CD on EH of each ileocolonic segment at one year. The specific hypothesis to be tested is different biologics have varying degrees of effectiveness in the ileum and colon." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(0) { } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> string(0) "" ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(1128) "Study Design
This study will obtain participant-level data from the Yale University Open Data Access (YODA) Project and Vivli. Data from VERSIFY (ClinicalTrial.gov number: NCT02425111), UNITI-1 (ClinicalTrial.gov number: NCT01369329), UNITI-2 (ClinicalTrial.gov number: NCT01369342), IM-UNITI (ClinicalTrial.gov number: NCT01369355), and EXTEND (ClinicalTrial.gov number: NCT00348283) is being requested. Data requested from the YODA Project (UNITI-1, UNITI-2, and IM-UNITI) will be transferred to the Vivli platform for analysis.
Inclusion Criteria
Participants must have endoscopic data at baseline. For each segment analyzed, patients must have a SES-CD of at least 3 in the segment to be included in the analysis. Participants must have received adalimumab, ustekinumab, infliximab, and vedolizumab throughout the trial.
Exclusion Criteria
Participants who have missing baseline endoscopic data will be excluded. For segment-specific analyses, participants with a segment SES-CD score less than 3 will not be included. Participants who crossed over treatments at any time will be excluded." ["project_main_outcome_measure"]=> string(835) "Outcome Measures
Patients with endoscopic data available at baseline will be included. A cohort of patients in UNITI were enrolled in the endoscopic sub-study and underwent ileocolonoscopy at baseline, week 8, and week 52. In EXTEND, patients underwent ileocolonoscopy at baseline, week 12, and week 52. In CT-P13, patients underwent ileocolonoscopy at baseline, week 14, and week 52. In CT-P13, Ileocolonoscopy was performed at baseline and week 54. Therefore, the outcome of ?one year? includes week 52 and week 54 (in the case of CT-P13).
Primary Outcome
The primary outcome of the proposed study will be segment EH at one year, defined as SES-CD of 0 in the segment.
Secondary Outcome
The secondary outcomes of interest include segment EH (defined as absence of mucosal ulceration), at one year." ["project_main_predictor_indep"]=> string(209) "The independent variable in this study will be biologics at baseline (adalimumab, ustekinumab, infliximab, and vedolizumab), which will be determined based on the randomization arm assigned to the participant." ["project_other_variables_interest"]=> string(3) "N/A" ["project_stat_analysis_plan"]=> string(2056) "Descriptive statistics will be used to summarize baseline characteristics (e.g. distribution of endoscopic disease and patient demographics) as well as outcomes. Dichotomous variables will be presented as proportions or percentages. Continuous variables will be reported as means with standard deviations or medians with interquartile ranges.
The SES-CD is an endoscopic scoring tool used in clinical trials to quantify endoscopic burden in CD. Each of the five ileocolonic segments are scored using four parameters, which are each scored from a scale of 0-3, for a total segment SES-CD score totalling 0-12. The primary outcome (segment SES-CD of 0) will be determined based on the total segment SES-CD score. Additionally, one of the parameters of the SES-CD measures the size of ulcers (0: none, 1: small, 2: large , 3: very large). The secondary outcome (absence of mucosal ulcerations) will be determined based on this parameter. Participants with missing outcome data will be analyzed on an intention-to-treat basis (e.g. those with missing endoscopic data at one year will be assumed to not have achieved endoscopic healing (EH)).
Multivariable logistic regression models will be used to assess the relationship between treatments and segment EH at one year. Adjustment for known confounders, including disease duration, concomitant corticosteroid use, and prior anti-tumor necrosis alpha failure will be performed. Additionally, other socio-demographic factors that may influence the outcome will be assessed on univariate analysis, and those with a p < 0.05 will be included in the multivariable regression models. Planned exploratory analyses will stratify patients based on previous biologic exposure among other factors that are known predictors for the outcomes of interest. Sensitivity analyses will be conducted with alternative definitions of endoscopic healing (absence of mucosal ulcerations). Results will be presented as odds ratios with 95% confidence intervals and associated p-values. Data will be analyzed using Stata." ["project_timeline"]=> string(220) "Date to Start Project: November ? December 2021.
Date to Complete Analysis: December ? January 2022.
Date to Draft Manuscript: January ? February2022.
Date to Submit Manuscript: February? March 2022." ["project_dissemination_plan"]=> string(415) "Results arising from this study include presentations and abstracts to target audiences. These will be submitted to relevant conferences such as Canadian Digestive Diseases Week, Digestive Disease Week, and European Crohn?s and Colitis Organisation. A manuscript will also be submitted for publication. The YODA Project and Vivli will be acknowledged in all study products, which will be shared prior to submission." ["project_bibliography"]=> string(651) "

1. De Cruz P, Kamm MA, Prideaux L, Allen PB, Moore G. Mucosal healing in Crohn’s disease: a systematic review. Inflamm Bowel Dis. 2013;19(2):429-44.
2. Daperno M, D’Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc. 2004;60(4):505-12.
3. Narula N, Wong ECL, Aruljothy A, Dulai PS, Colombel JF, Marshall JK, et al. Ileal and Rectal Ulcer Size Affects the Ability to Achieve Endoscopic Remission: A Post hoc Analysis of the SONIC Trial. Am J Gastroenterol. 2020;115(8):1236-45.

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2021-4778

Research Proposal

Project Title: Comparative Effectiveness of Biologics for Endoscopic Healing of the Ileum and Colon in Crohn's Disease

Scientific Abstract: Background
EH is an important goal of treatment in CD. Biologics approved for CD are required to demonstrate the ability to heal ulcers in the ileum and colon. There is growing evidence to suggest EH may not be linear across ileocolonic segments and the relative efficacy of biologics for segment EH has not been reported.
Objectives
This study aims to compare the efficacy of adalimumab, ustekinumab, infliximab, and vedolizumab on endoscopic outcomes at one year on each ileocolonic segment.
Study Design
The proposed study will be a post-hoc analysis of VERSIFY, UNITI, EXTEND, and CT-P13, which were all multicentre, randomized and double-blind trials. This post-hoc analysis aims to evaluate the relative efficacy of four biologics approved for use in CD on endoscopic outcomes for each ileocolonic segment.
Study Population
Participants with endoscopic data at baseline will be included in the analysis. For each segment assessed, patients with a segment SES-CD score of at least 3 will be included. . Participants must also receive adalimumab, ustekinumab, infliximab, and vedolizumab throughout the trial.
Outcomes
The primary outcome of the proposed study will be segment EH at one year, defined as segment SES-CD of 0 in the segment assessed. Secondary outcomes will use alternative definitions of EH, including absence of mucosal ulcerations (as defined by the SES-CD).
Statistical Analysis
Multivariable logistic regression models will be used to assess the likelihood of achieving segment EH at one year. Known confounders will be adjusted for, including, disease duration, concomitant corticosteroid use, and prior anti-TNF failure.

Brief Project Background and Statement of Project Significance: Crohn?s disease (CD) is a type of inflammatory bowel disease that is characterized by periods of relapse and remission and affects nearly 300,000 Canadians. CD affects any area of the gastrointestinal tract but is more common in the ileum and colon. Healing of ulcers is an important treatment target in CD, and is defined as endoscopic healing (EH). The Simple Endoscopic Score for CD (SES-CD) is a validated tool used to quantify mucosal inflammation in CD via endoscopy and is used to define EH. Biologics are medications used to treat patients with moderate to severe CD. To obtain regulatory approval, biologics must demonstrate the ability to heal ulcers in clinical trials of CD. Biologics approved for CD include adalimumab, ustekinumab, infliximab, and vedolizumab. Previous studies have demonstrated EH is not linear across the segments of the colon and the ileum and may be more difficult to achieve in the ileum and rectum. However, the comparative effectiveness of approved biologics for CD for achieving segment-specific EH has not been reported.

Specific Aims of the Project: The primary objective of this study is to compare the efficacy of four approved biologics for CD on EH of each ileocolonic segment at one year. The specific hypothesis to be tested is different biologics have varying degrees of effectiveness in the ileum and colon.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.:

Software Used:

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Study Design
This study will obtain participant-level data from the Yale University Open Data Access (YODA) Project and Vivli. Data from VERSIFY (ClinicalTrial.gov number: NCT02425111), UNITI-1 (ClinicalTrial.gov number: NCT01369329), UNITI-2 (ClinicalTrial.gov number: NCT01369342), IM-UNITI (ClinicalTrial.gov number: NCT01369355), and EXTEND (ClinicalTrial.gov number: NCT00348283) is being requested. Data requested from the YODA Project (UNITI-1, UNITI-2, and IM-UNITI) will be transferred to the Vivli platform for analysis.
Inclusion Criteria
Participants must have endoscopic data at baseline. For each segment analyzed, patients must have a SES-CD of at least 3 in the segment to be included in the analysis. Participants must have received adalimumab, ustekinumab, infliximab, and vedolizumab throughout the trial.
Exclusion Criteria
Participants who have missing baseline endoscopic data will be excluded. For segment-specific analyses, participants with a segment SES-CD score less than 3 will not be included. Participants who crossed over treatments at any time will be excluded.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Outcome Measures
Patients with endoscopic data available at baseline will be included. A cohort of patients in UNITI were enrolled in the endoscopic sub-study and underwent ileocolonoscopy at baseline, week 8, and week 52. In EXTEND, patients underwent ileocolonoscopy at baseline, week 12, and week 52. In CT-P13, patients underwent ileocolonoscopy at baseline, week 14, and week 52. In CT-P13, Ileocolonoscopy was performed at baseline and week 54. Therefore, the outcome of ?one year? includes week 52 and week 54 (in the case of CT-P13).
Primary Outcome
The primary outcome of the proposed study will be segment EH at one year, defined as SES-CD of 0 in the segment.
Secondary Outcome
The secondary outcomes of interest include segment EH (defined as absence of mucosal ulceration), at one year.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: The independent variable in this study will be biologics at baseline (adalimumab, ustekinumab, infliximab, and vedolizumab), which will be determined based on the randomization arm assigned to the participant.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: N/A

Statistical Analysis Plan: Descriptive statistics will be used to summarize baseline characteristics (e.g. distribution of endoscopic disease and patient demographics) as well as outcomes. Dichotomous variables will be presented as proportions or percentages. Continuous variables will be reported as means with standard deviations or medians with interquartile ranges.
The SES-CD is an endoscopic scoring tool used in clinical trials to quantify endoscopic burden in CD. Each of the five ileocolonic segments are scored using four parameters, which are each scored from a scale of 0-3, for a total segment SES-CD score totalling 0-12. The primary outcome (segment SES-CD of 0) will be determined based on the total segment SES-CD score. Additionally, one of the parameters of the SES-CD measures the size of ulcers (0: none, 1: small, 2: large , 3: very large). The secondary outcome (absence of mucosal ulcerations) will be determined based on this parameter. Participants with missing outcome data will be analyzed on an intention-to-treat basis (e.g. those with missing endoscopic data at one year will be assumed to not have achieved endoscopic healing (EH)).
Multivariable logistic regression models will be used to assess the relationship between treatments and segment EH at one year. Adjustment for known confounders, including disease duration, concomitant corticosteroid use, and prior anti-tumor necrosis alpha failure will be performed. Additionally, other socio-demographic factors that may influence the outcome will be assessed on univariate analysis, and those with a p < 0.05 will be included in the multivariable regression models. Planned exploratory analyses will stratify patients based on previous biologic exposure among other factors that are known predictors for the outcomes of interest. Sensitivity analyses will be conducted with alternative definitions of endoscopic healing (absence of mucosal ulcerations). Results will be presented as odds ratios with 95% confidence intervals and associated p-values. Data will be analyzed using Stata.

Narrative Summary: Crohn?s disease (CD) is a type of inflammatory bowel disease that is characterized by periods of relapse and remission. CD affects any area of the gastrointestinal tract but is more common in the ileum and colon.(1) Healing of ulcers is an important treatment target in CD, and is defined as endoscopic healing (EH). Biologics are medications used to treat patients with moderate to severe CD. However, the comparative effectiveness of approved biologics for CD for achieving segment-specific EH has not been reported. The primary objective of this study is to compare the efficacy of four approved biologics for CD on endoscopic healing of the ileum and individual segments of the colon at week 52.

Project Timeline: Date to Start Project: November ? December 2021.
Date to Complete Analysis: December ? January 2022.
Date to Draft Manuscript: January ? February2022.
Date to Submit Manuscript: February? March 2022.

Dissemination Plan: Results arising from this study include presentations and abstracts to target audiences. These will be submitted to relevant conferences such as Canadian Digestive Diseases Week, Digestive Disease Week, and European Crohn?s and Colitis Organisation. A manuscript will also be submitted for publication. The YODA Project and Vivli will be acknowledged in all study products, which will be shared prior to submission.

Bibliography:

1. De Cruz P, Kamm MA, Prideaux L, Allen PB, Moore G. Mucosal healing in Crohn’s disease: a systematic review. Inflamm Bowel Dis. 2013;19(2):429-44.
2. Daperno M, D’Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc. 2004;60(4):505-12.
3. Narula N, Wong ECL, Aruljothy A, Dulai PS, Colombel JF, Marshall JK, et al. Ileal and Rectal Ulcer Size Affects the Ability to Achieve Endoscopic Remission: A Post hoc Analysis of the SONIC Trial. Am J Gastroenterol. 2020;115(8):1236-45.