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  string(676) "Given the clinical importance of endoscopic disease activity in CD and potential to reduce placebo effect in clinical trials, it is important to understand operating properties of endoscopic indices and to use optimal outcome measures in clinical trials . Our primary objective is to assess the operating characteristics of (a) PRO2, (b) optimized CDEIS, and (c) optimized SES-CD using SONIC trial data.  Operating characteristics will include sensitivity (responsiveness to treatment effect) and correlation with other measures of disease activity.  We aim to evaluate these tools for possible outcome measurement as well as eligibility assessment for future clinical trials."
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  string(1621) "Background: Given the clinical importance of endoscopic disease activity in Crohn's disease (CD) and potential to reduce placebo effect in clinical trials, it is important to understand operating properties of endoscopic indices (EIs) and to use optimal outcome measures in clinical trials.
Objective: To assess the operating characteristic of (a) PRO2, (b) optimized CDEIS, and (c) optimized SES-CD using the week 0, week 26, and week 50 SONIC study data.
Study Design: This study involves using scores for optimized EIs, assessed by central adjudicators in a parallel study, and comparing scores to existing SONIC study clinical data to determine operating characteristics of these optimized EIs (CDEIS and SES-CD). Additionally, the properties of a clinical index derived from existing CDAI data (PRO-2) will be analyzed using exploratory techniques.
Participants: Data from the completed SONIC trial that randomized 508 TNF and azathioprine-naive patients with moderate to severe CD to AZA monotherapy (n=170), IFX monotherapy (n=169), or IFX and AZA combination therapy (n=169). All data would be used for PRO2 analyses. For analysis of EIs, the subset of data where endoscopy video was collected would be used.
Main Outcome Measures: 1.) Operating Properties of EIs including, a.) Sensitivity/Responsiveness of EIs b.) Correlation of EIs with other clinical measures; 2.) Exploratory impact of alternate outcome measures and eligibility definitions using a.) Optimized EIs and PRO2, b.) PRO2.
Statistical Analysis: Responsiveness, correlation and exploratory methods, as below." ["project_brief_bg"]=> string(2911) "Several EIs are currently available to assess disease activity in Crohn?s disease (CD).[1-3] The Crohn?s Disease Endoscopic Index of Severity (CDEIS) [1] and the Simple Endoscopic Score for Crohn?s Disease (SES-CD) [2] are commonly used EIs to assess disease activity. Both indices score endoscopic lesions in 5 colonic segments to obtain a composite score. A recent study identified common sources of disagreement among endoscopists when using these EIs, and created standardized rules to minimize variability in scoring these problematic lesions [4]. These rules are termed the ?optimized? EIs which further enhanced the reliability of these evaluative instruments.
In response to a new regulatory decision that mandates the use of both patient reported outcomes (PROs) and endoscopic assessment as efficacy criteria in Inflammatory Bowel Disease (IBD) registration trials, Robarts adapted a 2-item PRO (PRO2) from the Crohn?s Disease Activity Index (CDAI) as an interim measure, until a fully validated PRO can be developed.
The operating properties (reliability, responsiveness, correlation with other measures of disease activity) of these optimized EIs and PRO2 are poorly defined. Understanding these properties is critical to the development of trials for the evaluation of new treatments for CD. Based on the clinical importance of endoscopic disease activity and the potential to reduce the placebo effect in clinical trials, it is imperative to understand the operating properties of the EIs to identify the optimal outcome measure. A subsequent post hoc sub-group analysis of SONIC attempted to address this question and demonstrated that week 26 mucosal healing and endoscopic response, defined as a decrease from baseline in SES-CD or CDEIS of at least 50%, identified those patients most likely to be in corticosteroid-free remission (CFREM) at week 50 [5]. Although these data established that EIs are responsive to clinical changes in CD, the degree of responsiveness has not been quantified and the responsiveness of optimized EIs have not yet been assessed. Additionally, the responsiveness of PRO2 has not been confirmed.
Accordingly, our aim is to determine the operating properties of central endoscopic scoring of optimized EIs and PRO2 for CD within a population of patients with moderate to severe CD. Since these patients received a treatment of known efficacy and demonstrated various degrees of improvement in disease status over the study period, EIs and PRO2 should reflect these changes. Recognizing that the validity of EIs also depends on their correlation with patient reported outcomes, we also aim to investigate the effect of co-primary end points, including EIs and PRO2, on the effect size estimates using the original study definitions. We anticipate this study will help to define the optimal endoscopic endpoints for use in clinical trials." ["project_specific_aims"]=> string(1174) "Our goal is to assess the operating characteristics of optimized CDEIS, optimized SES-CD and PRO2 as outcome and eligibility criteria in clinical trials. To meet this goal, we will analyze the effects of different scoring tools (EIs or PRO2) on response and remission definitions on the estimates of effect size in the SONIC trial. Additional objectives are to examine the effects of various PRO2 and optimized SES-CD/CDEIS eligibility criteria on patient recruitment/trial feasibility.
Primary objective: To assess the operating characteristics of (a) PRO2, (b) optimized CDEIS, and (c) optimized SES-CD using the week 0, week 26, and week 50 SONIC study data.
Specific objectives include:
a. To evaluate the sensitivity/responsiveness of the optimized CDEIS and optimized SES-CD in patients who received a treatment of known efficacy.
b. To assess the correlation of optimized CDEIS and optimized SES-CD with other clinical measures.
c. To explore outcome measurement and eligibility criteria definitions with optimized EIs and PRO2.
d. To explore outcome measurement and eligibility criteria definitions with PRO2." ["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(678) "Both data from the original SONIC study and new data based on expert endoscopist assessment of optimized EIs (from a parallel study using SONIC endoscopy videos) will be used.
For objectives a, b and c related to operating characteristics of optimized EIs, only data from a subgroup of SONIC subjects would be used and combined with expert endoscopist assessments (from parallel study). It is expected a that this subset will include approximately 172 subjects that had endoscopic lesions at baseline, and underwent repeat endoscopy at week 26.
For objective d, relating also to characteristics of PRO2 only, outcome data from all SONIC subjects would be used." ["project_main_outcome_measure"]=> string(874) "The main outcome measure will be CDAI from the original SONIC study.
The magnitude of treatment effect will be quantified using the optimized SES-CD, optimized CDEIS and GELS. These effect sizes will be compared with the estimates for the original CDAI-derived outcome measures (response and remission) in subjects, with and without objective evidence of inflammation at baseline (based on CRP), between study interventions (AZA monotherapy, IFX monotherapy, IFX and AZA combination therapy).
Correlations between changes in EIs, PRO2, CRP, and CDAI will be assessed. The relationship between clinical response (decrease in CDAI ? 100 points from baseline, decrease in CDAI ? 70 points from baseline), clinical remission (CFREM), deep remission (no endoscopic ulcers and normal CRP), and optimized EI (optimized SES-CD, optimized CDEIS), PRO2 will be assessed." ["project_main_predictor_indep"]=> string(545) "Optimized SES-CD, Optimized CDEIS and GELS scoring will be defined based on the recent publication of created standardized rules to minimize variability in scoring of the original EIs[4]. Summarized rules for scoring are based on the January 31st, 2014 Delphi Consensus for Optimized SES-CD and Optimized CDEIS. This scoring is being completed in a parallel research study, and for this proposal, data would be used in combination with clinical data from SONIC
PRO2 will be derived from components of the existing SONIC study CDAI data." ["project_other_variables_interest"]=> string(468) "Other variables of interest include CRP, treatment group assignment, corticosteroid use (for corticosteroid free remission), as defined in the original SONIC study.
If available, demographic data (age, gender, race, smoking status, duration of CD, location of disease, presence of fistula) would be valuable to describe the subset of ~172 with endoscopic data.
CDAI data for screen failure subjects, if available, for exploratory entry criteria analysis." ["project_stat_analysis_plan"]=> string(1594) "For PRO2, score will be quantified from CDAI data (pain and stool frequency) at week 0, 26 and 50. The magnitude of responsiveness will be determined in patients with and without objective evidence of inflammation between study interventions (AZA monotherapy, IFX monotherapy, IFX and AZA combination therapy) in the complete randomized population of 508 patients.
EI responsiveness will be quantified by calculation of indices discussed by Deyo et al. [6] We will also explore the possibility of using mixed effects to account for repeated measures in estimating responsive indices. Two-sided 95% confidence intervals will be obtained for estimated indices. For each index (optimized SES-CD, optimized CDEIS, GELS, PRO2), we will calculate: Effect Size and Guyatt Responsiveness Statistic.
Correlations between changes in optimized EIs, PRO2, CRP, and CDAI will be assessed. The relationships between clinical response (decrease in CDAI ? 100 points from baseline, decrease in CDAI ? 70 points from baseline), clinical remission (CFREM), deep remission (no endoscopic ulcers and normal CRP), optimized EIs (SES-CD and CDEIS), and PRO2 will be assessed.
Exploratory analysis will be performed to compare hypothetical PRO2 entry criteria, assessed as a discrete cut-offs and as a continuous (combined) measures (tested against optimized SES-CD and optimized CDEIS criteria). As one example, the impact (loss of eligible patients) with hypothetical entry criteria of PR02 >14 and an elevated CRP, compared to the criteria used in the original SONIC trial, will be explored." ["project_timeline"]=> string(346) "Projected Start Date: 10-Sep-2015
(Central Endoscopic Data Review Complete from Parallel Study: 10-Sep-2015)
Data mapping: 17-Sep-15
Data analysis: 18-Sep-15 to 30-Oct-15
Manuscript drafted: 01-Dec-15
Results reported back to YODA Project: 01-Dec-15
Manuscript first submitted for publication: 23-Dec-15" ["project_dissemination_plan"]=> string(143) "Dissemination Plan:
- Conference presentation: DDW, EUGW
- Peer-reviewed journal publication: Gastroenterology or Gut or similar." ["project_bibliography"]=> string(1237) "

1. Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989;30:983-9.
2. Daperno M, D’Haens G, Van Assche G, et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc 2004;60:505-12.
3. Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990;99:956-63.
4. Khanna R, D’Haens G, Rutgeerts P, et al. Reliability of Central Readers in the Evaluation of Endoscopic Disease Activity in Crohn?s Disease. Inflamm Bowel Dis 2013;in press (Abstract).
5. Ferrante M, Colombel JF, Sandborn WJ, et al. Validation of endoscopic activity scores in patients with Crohn’s disease based on a post hoc analysis of data from SONIC. Gastroenterology 2013;145:978-986.e5.
6. Deyo RA, Diehr P, Patrick DL. Reproducibility and responsiveness of health status measures. Statistics and strategies for evaluation. Control Clin Trials 1991;12:142S-158S.

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2015-0556

General Information

How did you learn about the YODA Project?: Data Holder (Company)

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT00094458 - Multicenter, Randomized, Double-Blind, Active Controlled Trial Comparing REMICADE® (infliximab) and REMICADE plus Azathioprine to Azathioprine in the Treatment of Patients with Crohn’s Disease Naive to both Immunomodulators and Biologic Therapy (Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease)
What type of data are you looking for?: Individual Participant-Level Data, which includes Full CSR and all supporting documentation

Request Clinical Trials

Data Request Status

Status: Withdrawn/Closed

Research Proposal

Project Title: Operating Characteristics of Centrally-Read Endoscopic Indices and a Novel Patient Reported Outcome Measure for Crohn's Disease

Scientific Abstract: Background: Given the clinical importance of endoscopic disease activity in Crohn's disease (CD) and potential to reduce placebo effect in clinical trials, it is important to understand operating properties of endoscopic indices (EIs) and to use optimal outcome measures in clinical trials.
Objective: To assess the operating characteristic of (a) PRO2, (b) optimized CDEIS, and (c) optimized SES-CD using the week 0, week 26, and week 50 SONIC study data.
Study Design: This study involves using scores for optimized EIs, assessed by central adjudicators in a parallel study, and comparing scores to existing SONIC study clinical data to determine operating characteristics of these optimized EIs (CDEIS and SES-CD). Additionally, the properties of a clinical index derived from existing CDAI data (PRO-2) will be analyzed using exploratory techniques.
Participants: Data from the completed SONIC trial that randomized 508 TNF and azathioprine-naive patients with moderate to severe CD to AZA monotherapy (n=170), IFX monotherapy (n=169), or IFX and AZA combination therapy (n=169). All data would be used for PRO2 analyses. For analysis of EIs, the subset of data where endoscopy video was collected would be used.
Main Outcome Measures: 1.) Operating Properties of EIs including, a.) Sensitivity/Responsiveness of EIs b.) Correlation of EIs with other clinical measures; 2.) Exploratory impact of alternate outcome measures and eligibility definitions using a.) Optimized EIs and PRO2, b.) PRO2.
Statistical Analysis: Responsiveness, correlation and exploratory methods, as below.

Brief Project Background and Statement of Project Significance: Several EIs are currently available to assess disease activity in Crohn?s disease (CD).[1-3] The Crohn?s Disease Endoscopic Index of Severity (CDEIS) [1] and the Simple Endoscopic Score for Crohn?s Disease (SES-CD) [2] are commonly used EIs to assess disease activity. Both indices score endoscopic lesions in 5 colonic segments to obtain a composite score. A recent study identified common sources of disagreement among endoscopists when using these EIs, and created standardized rules to minimize variability in scoring these problematic lesions [4]. These rules are termed the ?optimized? EIs which further enhanced the reliability of these evaluative instruments.
In response to a new regulatory decision that mandates the use of both patient reported outcomes (PROs) and endoscopic assessment as efficacy criteria in Inflammatory Bowel Disease (IBD) registration trials, Robarts adapted a 2-item PRO (PRO2) from the Crohn?s Disease Activity Index (CDAI) as an interim measure, until a fully validated PRO can be developed.
The operating properties (reliability, responsiveness, correlation with other measures of disease activity) of these optimized EIs and PRO2 are poorly defined. Understanding these properties is critical to the development of trials for the evaluation of new treatments for CD. Based on the clinical importance of endoscopic disease activity and the potential to reduce the placebo effect in clinical trials, it is imperative to understand the operating properties of the EIs to identify the optimal outcome measure. A subsequent post hoc sub-group analysis of SONIC attempted to address this question and demonstrated that week 26 mucosal healing and endoscopic response, defined as a decrease from baseline in SES-CD or CDEIS of at least 50%, identified those patients most likely to be in corticosteroid-free remission (CFREM) at week 50 [5]. Although these data established that EIs are responsive to clinical changes in CD, the degree of responsiveness has not been quantified and the responsiveness of optimized EIs have not yet been assessed. Additionally, the responsiveness of PRO2 has not been confirmed.
Accordingly, our aim is to determine the operating properties of central endoscopic scoring of optimized EIs and PRO2 for CD within a population of patients with moderate to severe CD. Since these patients received a treatment of known efficacy and demonstrated various degrees of improvement in disease status over the study period, EIs and PRO2 should reflect these changes. Recognizing that the validity of EIs also depends on their correlation with patient reported outcomes, we also aim to investigate the effect of co-primary end points, including EIs and PRO2, on the effect size estimates using the original study definitions. We anticipate this study will help to define the optimal endoscopic endpoints for use in clinical trials.

Specific Aims of the Project: Our goal is to assess the operating characteristics of optimized CDEIS, optimized SES-CD and PRO2 as outcome and eligibility criteria in clinical trials. To meet this goal, we will analyze the effects of different scoring tools (EIs or PRO2) on response and remission definitions on the estimates of effect size in the SONIC trial. Additional objectives are to examine the effects of various PRO2 and optimized SES-CD/CDEIS eligibility criteria on patient recruitment/trial feasibility.
Primary objective: To assess the operating characteristics of (a) PRO2, (b) optimized CDEIS, and (c) optimized SES-CD using the week 0, week 26, and week 50 SONIC study data.
Specific objectives include:
a. To evaluate the sensitivity/responsiveness of the optimized CDEIS and optimized SES-CD in patients who received a treatment of known efficacy.
b. To assess the correlation of optimized CDEIS and optimized SES-CD with other clinical measures.
c. To explore outcome measurement and eligibility criteria definitions with optimized EIs and PRO2.
d. To explore outcome measurement and eligibility criteria definitions with PRO2.

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: Both data from the original SONIC study and new data based on expert endoscopist assessment of optimized EIs (from a parallel study using SONIC endoscopy videos) will be used.
For objectives a, b and c related to operating characteristics of optimized EIs, only data from a subgroup of SONIC subjects would be used and combined with expert endoscopist assessments (from parallel study). It is expected a that this subset will include approximately 172 subjects that had endoscopic lesions at baseline, and underwent repeat endoscopy at week 26.
For objective d, relating also to characteristics of PRO2 only, outcome data from all SONIC subjects would be used.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: The main outcome measure will be CDAI from the original SONIC study.
The magnitude of treatment effect will be quantified using the optimized SES-CD, optimized CDEIS and GELS. These effect sizes will be compared with the estimates for the original CDAI-derived outcome measures (response and remission) in subjects, with and without objective evidence of inflammation at baseline (based on CRP), between study interventions (AZA monotherapy, IFX monotherapy, IFX and AZA combination therapy).
Correlations between changes in EIs, PRO2, CRP, and CDAI will be assessed. The relationship between clinical response (decrease in CDAI ? 100 points from baseline, decrease in CDAI ? 70 points from baseline), clinical remission (CFREM), deep remission (no endoscopic ulcers and normal CRP), and optimized EI (optimized SES-CD, optimized CDEIS), PRO2 will be assessed.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Optimized SES-CD, Optimized CDEIS and GELS scoring will be defined based on the recent publication of created standardized rules to minimize variability in scoring of the original EIs[4]. Summarized rules for scoring are based on the January 31st, 2014 Delphi Consensus for Optimized SES-CD and Optimized CDEIS. This scoring is being completed in a parallel research study, and for this proposal, data would be used in combination with clinical data from SONIC
PRO2 will be derived from components of the existing SONIC study CDAI data.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Other variables of interest include CRP, treatment group assignment, corticosteroid use (for corticosteroid free remission), as defined in the original SONIC study.
If available, demographic data (age, gender, race, smoking status, duration of CD, location of disease, presence of fistula) would be valuable to describe the subset of ~172 with endoscopic data.
CDAI data for screen failure subjects, if available, for exploratory entry criteria analysis.

Statistical Analysis Plan: For PRO2, score will be quantified from CDAI data (pain and stool frequency) at week 0, 26 and 50. The magnitude of responsiveness will be determined in patients with and without objective evidence of inflammation between study interventions (AZA monotherapy, IFX monotherapy, IFX and AZA combination therapy) in the complete randomized population of 508 patients.
EI responsiveness will be quantified by calculation of indices discussed by Deyo et al. [6] We will also explore the possibility of using mixed effects to account for repeated measures in estimating responsive indices. Two-sided 95% confidence intervals will be obtained for estimated indices. For each index (optimized SES-CD, optimized CDEIS, GELS, PRO2), we will calculate: Effect Size and Guyatt Responsiveness Statistic.
Correlations between changes in optimized EIs, PRO2, CRP, and CDAI will be assessed. The relationships between clinical response (decrease in CDAI ? 100 points from baseline, decrease in CDAI ? 70 points from baseline), clinical remission (CFREM), deep remission (no endoscopic ulcers and normal CRP), optimized EIs (SES-CD and CDEIS), and PRO2 will be assessed.
Exploratory analysis will be performed to compare hypothetical PRO2 entry criteria, assessed as a discrete cut-offs and as a continuous (combined) measures (tested against optimized SES-CD and optimized CDEIS criteria). As one example, the impact (loss of eligible patients) with hypothetical entry criteria of PR02 >14 and an elevated CRP, compared to the criteria used in the original SONIC trial, will be explored.

Narrative Summary: Given the clinical importance of endoscopic disease activity in CD and potential to reduce placebo effect in clinical trials, it is important to understand operating properties of endoscopic indices and to use optimal outcome measures in clinical trials . Our primary objective is to assess the operating characteristics of (a) PRO2, (b) optimized CDEIS, and (c) optimized SES-CD using SONIC trial data. Operating characteristics will include sensitivity (responsiveness to treatment effect) and correlation with other measures of disease activity. We aim to evaluate these tools for possible outcome measurement as well as eligibility assessment for future clinical trials.

Project Timeline: Projected Start Date: 10-Sep-2015
(Central Endoscopic Data Review Complete from Parallel Study: 10-Sep-2015)
Data mapping: 17-Sep-15
Data analysis: 18-Sep-15 to 30-Oct-15
Manuscript drafted: 01-Dec-15
Results reported back to YODA Project: 01-Dec-15
Manuscript first submitted for publication: 23-Dec-15

Dissemination Plan: Dissemination Plan:
- Conference presentation: DDW, EUGW
- Peer-reviewed journal publication: Gastroenterology or Gut or similar.

Bibliography:

1. Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989;30:983-9.
2. Daperno M, D’Haens G, Van Assche G, et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc 2004;60:505-12.
3. Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990;99:956-63.
4. Khanna R, D’Haens G, Rutgeerts P, et al. Reliability of Central Readers in the Evaluation of Endoscopic Disease Activity in Crohn?s Disease. Inflamm Bowel Dis 2013;in press (Abstract).
5. Ferrante M, Colombel JF, Sandborn WJ, et al. Validation of endoscopic activity scores in patients with Crohn’s disease based on a post hoc analysis of data from SONIC. Gastroenterology 2013;145:978-986.e5.
6. Deyo RA, Diehr P, Patrick DL. Reproducibility and responsiveness of health status measures. Statistics and strategies for evaluation. Control Clin Trials 1991;12:142S-158S.