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  ["property_scientific_abstract"]=>
  string(368) "Background: Biologic monoclonal antibody drugs (?Biologics?) are efficacious for Crohn?s disease (CD) and ulcerative colitis (UC), but there are no systematic assessments of their efficacy if administered early after disease onset as opposed to later in the course of disease.  Objective: to compare clinical response to biologics between patients with early-disease ("
  ["project_brief_bg"]=>
  string(2190) "Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-driven inflammatory diseases of the gut, collectively known as inflammatory bowel disease (IBD).  Understanding of the progressive structural damage to the gut caused by incessant and/or recurrent bouts of inflammation in CD has led to the hypothesis that early initiation of biologic therapy (Top-down strategy) may better control underlying inflammation and prevent disease progression, compared with a later initiation of these drugs (Step-up approach) [1,2]. This contention has been supported by the SUTD trial which showed clinical benefit for top-down versus step-up treatment with infliximab in patients with CD [3]. REACT, a non-blinded controlled cluster randomized trial, did not show clinical benefit but did find lower rate of disease complications among CD patients treated by top-down compared to step-up approach [4]. However, no trial has directly compared efficacy of biologics in patients with early versus late disease. Such comparison is only available through some post-hoc sub-analyses of clinical trials and uncontrolled observations in retrospective cohorts. Some [5-7], albeit not all [8], of these studies seemed to indicate a better response rate to anti-TNF agents among CD patients with early as opposed to late-disease. Nonetheless, the impact of duration of CD on the response to biologic therapy has hitherto not been systematically investigated. Furthermore, whether such correlation exists in patients with UC has not been specifically explored.
Therefore, the primary objectives of the present study are to investigate the impact of disease duration on the rate of remission induction in CD and in UC, separately analyzed. To this end, we will compare the efficacy of FDA-approved biologics? in patients with early short-term disease versus those with a long-duration of disease. This first-of-its-kind meta-analysis at IPD level of interaction of disease duration with the response to biologics in UC and CD may elucidate the impact of early initiation of biologics, which is of paramount importance for clinical practice and management strategies of inflammatory bowel disease." ["project_specific_aims"]=> string(1017) "We will analyze the following secondary endpoints in a comparative analysis of patients with short versus long-duration of disease:
- The proportion of induction of response. Clinical response is defined as CDAI reduction of 100 points from baseline for CD and as a total Mayo Drop ?30% AND ? 3 points with either bleeding score of 0 or 1 OR drop of bleeding score?1, for UC trials. When these are not available, the response is defined as per the clinical trial's designated response definition.
- The proportion of response and remission at the end of the maintenance phase of the trial (when applicable), at specific time-period between week 16-54 designated for assessment of the maintenance treatment by the trial.
- in UC patients: the proportion of colectomy for patients with short versus long-duration of disease at the end of the trial.
-- Rate of intestinal surgeries and rate of hospitalizations for patients with short versus long-duration of disease at the end of the trial." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(0) { } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> array(2) { ["value"]=> string(86) "not_analyzing_participant_level_data__plan_to_use_another_secure_data_sharing_platform" ["label"]=> string(92) "I am not analyzing participant-level data / plan to use another secure data sharing platform" } ["project_software_used_exp"]=> string(101) "the data will be analysed on the Vivli platform using software suggested by the Vivli site (R or SAS)" ["project_research_methods"]=> string(927) "Electronic databases (MEDLINE, EMBASE/EMBASE classic Cochrane CENTRAL register of controlled trials, the Cochrane IBD Group Specialized Trials Register, and Clinicaltrials.gov registry) were searched to identify all randomized placebo-controlled clinical trials of FDA-approved biologics for CD and UC (by March 2016). Patients over 18 years old were included in the study. Inclusion and Exclusion criteria of these trials defined the study population. The following is the list of studies' ID in addition to those requested from YODA :
NCT00783718 (C13006)
NCT00783692 (C13007) GEMINI 2
NCT01224171 (C13011) GEMINI 3
JAPIC CTI-060298 Japan Kobayashi,
PMID 25844841 Jiang XL
NCT00032799 ENACT-1
NCT00032786 ENACT-2
NCT00078611 ENCORE
NCT00077779
NCT00445939 (M04-729)
NCT00445432 (M06-437)
NCT00055497 (M02-433)
NCT00853099 (M10-447)" ["project_main_outcome_measure"]=> string(567) "The primary outcome in the study is induction of remission defined as remission at the end of induction as per the study-specific pre-defined timepoint and within 4-14 weeks following initiation of treatment by biologics approved by the FDA for IBD at the time of launching of this study (November 2015). A Crohn's Disease Activity Index (CDAI) 1 is the primary remission outcome for UC trials. If these scores were unavailable, the remission/response measures are based on the specific clinical score and outcome definition employed by the respective clinical trial." ["project_main_predictor_indep"]=> string(113) "Biologics treatment in interaction with duration of disease (before and after 18 months from the disease onset)." ["project_other_variables_interest"]=> string(428) "Exposure to prior anti-TNF, use of concomitant immunomodulators, prior surgery, disease phenotype and extent for CD, disease extent for UC, age, gender, BMI, smoking status, CRP (elevated or not at baseline as per the laboratory normal range in the respective trial ), albumin (below normal or not), difference in clinical scores used to measure the efficacy outcomes, and the class of the biologic (anti-TNF vs. anti-integrins)" ["project_stat_analysis_plan"]=> string(710) "Secondary analyses include analyses of the response to induction, the maintenance of response, maintenance of remission, and the proportion of colectomy (for UC patients only), as well as the sub-group analysis of the primary outcome within the strata of patients treated with anti-TNF class of drugs and patients treated by anti-integrins.
Pre-planned sensitivity analyses will assess the primary outcome by:
1) including also trials with high risk of bias;
2) including only the studies employing the pre-defined clinical score criterion for remission induction (CDAI1 for CD and UC, respectively);
3) Using a fixed-effect model to pool data if heterogeneity assessment reveals I2" ["project_timeline"]=> string(830) "We will analyze the data within 6 months after data become available to the researchers. Most of the analysis has been performed in the YODA trails platform, separately from other companies' trials. The analysis included data cleaning, variables definitions and a meta-analysis based on the separate YODA trials.
The proposed analysis will be conducted within the Vivli platform. Full approval for #2019-4107 will be contingent upon closing out #2015-0677. We would like the datasets derived under #2015-0677 (or at least the sascodes used by us for creating those datasets) be made available to us under #2019-4107, to save months of work while cleaning and defining the working variables. Upon completion of analyses we will summarize the findings in a manuscript (additional 2-3 months) and submit for publication." ["project_dissemination_plan"]=> string(214) "Findings will be published in a peer-reviewed journal and disseminated via presentations at scientific meetings and links with patients groups and organizations. BMJ is one of the optional journals for publication." ["project_bibliography"]=> string(9747) "

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2. D’Haens GR, Panaccione R, Higgins PD, Vermeire S, Gassull M, Chowers Y, Hanauer SB, Herfarth H, Hommes DW, Kamm M, Lfberg R, Quary A, Sands B, Sood A, Watermeyer G, Lashner B, Lmann M, Plevy S, Reinisch W, Schreiber S, Siegel C, Targan S, Watanabe M, Feagan B, Sandborn WJ, Colombel JF, Travis S. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011; 106:199-212
3. D’Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, De Vos M, van Deventer S, Stitt L, Donner A, Vermeire S, Van de Mierop FJ, Coche JC, van der Woude J, Ochsenkhn T, van Bodegraven AA, Van Hootegem PP, Lambrecht GL, Mana F, Rutgeerts P, Feagan BG, Hommes D; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial Lancet. 2008 Feb 23;371(9613):660-7
4. Khanna R, Bressler B, Levesque BG, Zou G, Stitt LW, Greenberg GR, Panaccione R, Bitton A, Par P, Vermeire S, D’Haens G, MacIntosh D, Sandborn WJ, Donner A, Vandervoort MK, Morris JC, Feagan BG. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomised controlled trial. Lancet 2015 ;386:1825-34
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13. Schreiber S, Colombel JF, Bloomfield R, Nikolaus S, Schlmerich J, Pans J, Sandborn WJ; PRECiSE 2 Study Investigators. Increased response and remission rates in short-duration Crohn’s disease with subcutaneous certolizumab pegol: an analysis of PRECiSE 2 randomized maintenance trial data Am J Gastroenterol. 2010 Jul;105(7):1574-82
14. Ananthakrishnan AN, Binion DG. Editorial: improved efficacy of biological maintenance therapy in “early” compared with “late” Crohn’s disease: strike while the iron is hot with anti-TNF agents? Am J Gastroenterol. 2010 Jul;105(7):1583-5
15. Schreiber S, Reinisch W, Colombel JF, Sandborn WJ, Hommes DW, Robinson AM, Huang B, Lomax KG, Pollack PF. Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn’s disease. J Crohns Colitis. 2013 Apr;7(3):213-21
16. Nuij V, Fuhler GM, Edel AJ, Ouwendijk RJ, Rijk MC, Beukers R, Quispel R, van Tilburg AJ, Tang TJ, Smalbraak H, Bruin KF, Lindenburg F, Peyrin-Biroulet L, van der Woude CJ; Dutch Delta IBD Group. Benefit of Earlier Anti-TNF Treatment on IBD Disease Complications? J Crohns Colitis. 2015 Nov;9(11):997-1003
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2019-4107

General Information

How did you learn about the YODA Project?: Other

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT00036439 - A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
  2. NCT00096655 - A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
  3. NCT00487539 - A Phase 2/3 Multicenter, Randomized, Placebo-controlled, Double blind Study to Evaluate the Safety and Efficacy of Golimumab Induction Therapy, Administered Subcutaneously, in Subjects with Moderately to Severely Active Ulcerative Colitis
  4. NCT00207662 - ACCENT I - A Randomized, Double-blind, Placebo-controlled Trial of Anti-TNFa Chimeric Monoclonal Antibody (Infliximab, Remicade) in the Long-term Treatment of Patients With Moderately to Severely Active Crohn's Disease
  5. NCT00537316 - Efficacy & Safety of Infliximab Monotherapy Vs Combination Therapy Vs AZA Monotherapy in Ulcerative Colitis (Part 1) Maintenance Vs Intermittent Therapy for Maintaining Remission (Part 2)
  6. NCT01551290 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Infliximab in Chinese Subjects With Active Ulcerative Colitis
  7. NCT00488631 - A Phase 3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Golimumab Maintenance Therapy, Administered Subcutaneously, in Subjects With Moderately to Severely Active Ulcerative Colitis
  8. 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: Published

Research Proposal

Project Title: Efficacy of biologic drugs in short-duration versus long-duration inflammatory bowel disease: individual-patient level meta-analysis

Scientific Abstract: Background: Biologic monoclonal antibody drugs (?Biologics?) are efficacious for Crohn?s disease (CD) and ulcerative colitis (UC), but there are no systematic assessments of their efficacy if administered early after disease onset as opposed to later in the course of disease. Objective: to compare clinical response to biologics between patients with early-disease (

Brief Project Background and Statement of Project Significance: Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-driven inflammatory diseases of the gut, collectively known as inflammatory bowel disease (IBD). Understanding of the progressive structural damage to the gut caused by incessant and/or recurrent bouts of inflammation in CD has led to the hypothesis that early initiation of biologic therapy (Top-down strategy) may better control underlying inflammation and prevent disease progression, compared with a later initiation of these drugs (Step-up approach) [1,2]. This contention has been supported by the SUTD trial which showed clinical benefit for top-down versus step-up treatment with infliximab in patients with CD [3]. REACT, a non-blinded controlled cluster randomized trial, did not show clinical benefit but did find lower rate of disease complications among CD patients treated by top-down compared to step-up approach [4]. However, no trial has directly compared efficacy of biologics in patients with early versus late disease. Such comparison is only available through some post-hoc sub-analyses of clinical trials and uncontrolled observations in retrospective cohorts. Some [5-7], albeit not all [8], of these studies seemed to indicate a better response rate to anti-TNF agents among CD patients with early as opposed to late-disease. Nonetheless, the impact of duration of CD on the response to biologic therapy has hitherto not been systematically investigated. Furthermore, whether such correlation exists in patients with UC has not been specifically explored.
Therefore, the primary objectives of the present study are to investigate the impact of disease duration on the rate of remission induction in CD and in UC, separately analyzed. To this end, we will compare the efficacy of FDA-approved biologics? in patients with early short-term disease versus those with a long-duration of disease. This first-of-its-kind meta-analysis at IPD level of interaction of disease duration with the response to biologics in UC and CD may elucidate the impact of early initiation of biologics, which is of paramount importance for clinical practice and management strategies of inflammatory bowel disease.

Specific Aims of the Project: We will analyze the following secondary endpoints in a comparative analysis of patients with short versus long-duration of disease:
- The proportion of induction of response. Clinical response is defined as CDAI reduction of 100 points from baseline for CD and as a total Mayo Drop ?30% AND ? 3 points with either bleeding score of 0 or 1 OR drop of bleeding score?1, for UC trials. When these are not available, the response is defined as per the clinical trial's designated response definition.
- The proportion of response and remission at the end of the maintenance phase of the trial (when applicable), at specific time-period between week 16-54 designated for assessment of the maintenance treatment by the trial.
- in UC patients: the proportion of colectomy for patients with short versus long-duration of disease at the end of the trial.
-- Rate of intestinal surgeries and rate of hospitalizations for patients with short versus long-duration of disease at the end of the trial.

Study Design:

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

Software Used: I am not analyzing participant-level data / plan to use another secure data sharing platform

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Electronic databases (MEDLINE, EMBASE/EMBASE classic Cochrane CENTRAL register of controlled trials, the Cochrane IBD Group Specialized Trials Register, and Clinicaltrials.gov registry) were searched to identify all randomized placebo-controlled clinical trials of FDA-approved biologics for CD and UC (by March 2016). Patients over 18 years old were included in the study. Inclusion and Exclusion criteria of these trials defined the study population. The following is the list of studies' ID in addition to those requested from YODA :
NCT00783718 (C13006)
NCT00783692 (C13007) GEMINI 2
NCT01224171 (C13011) GEMINI 3
JAPIC CTI-060298 Japan Kobayashi,
PMID 25844841 Jiang XL
NCT00032799 ENACT-1
NCT00032786 ENACT-2
NCT00078611 ENCORE
NCT00077779
NCT00445939 (M04-729)
NCT00445432 (M06-437)
NCT00055497 (M02-433)
NCT00853099 (M10-447)

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: The primary outcome in the study is induction of remission defined as remission at the end of induction as per the study-specific pre-defined timepoint and within 4-14 weeks following initiation of treatment by biologics approved by the FDA for IBD at the time of launching of this study (November 2015). A Crohn's Disease Activity Index (CDAI) 1 is the primary remission outcome for UC trials. If these scores were unavailable, the remission/response measures are based on the specific clinical score and outcome definition employed by the respective clinical trial.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Biologics treatment in interaction with duration of disease (before and after 18 months from the disease onset).

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Exposure to prior anti-TNF, use of concomitant immunomodulators, prior surgery, disease phenotype and extent for CD, disease extent for UC, age, gender, BMI, smoking status, CRP (elevated or not at baseline as per the laboratory normal range in the respective trial ), albumin (below normal or not), difference in clinical scores used to measure the efficacy outcomes, and the class of the biologic (anti-TNF vs. anti-integrins)

Statistical Analysis Plan: Secondary analyses include analyses of the response to induction, the maintenance of response, maintenance of remission, and the proportion of colectomy (for UC patients only), as well as the sub-group analysis of the primary outcome within the strata of patients treated with anti-TNF class of drugs and patients treated by anti-integrins.
Pre-planned sensitivity analyses will assess the primary outcome by:
1) including also trials with high risk of bias;
2) including only the studies employing the pre-defined clinical score criterion for remission induction (CDAI1 for CD and UC, respectively);
3) Using a fixed-effect model to pool data if heterogeneity assessment reveals I2

Narrative Summary: Crohn?s disease (CD) and ulcerative colitis (UC) are inflammatory diseases often culminating in disease complications and/or the need of surgery. Biologic monoclonal antibody drugs (?Biologics?) are efficacious for both diseases, but there are no systematic assessments of their efficacy if administered early after disease onset as opposed to later in the course of disease. We will analyze individual data from available clinical trials, by comparing health outcomes of patients receiving the Biologics before and after 18 months after the disease onset. The analysis will provide an important information for gastroenterologists in administering the Biologics.

Project Timeline: We will analyze the data within 6 months after data become available to the researchers. Most of the analysis has been performed in the YODA trails platform, separately from other companies' trials. The analysis included data cleaning, variables definitions and a meta-analysis based on the separate YODA trials.
The proposed analysis will be conducted within the Vivli platform. Full approval for #2019-4107 will be contingent upon closing out #2015-0677. We would like the datasets derived under #2015-0677 (or at least the sascodes used by us for creating those datasets) be made available to us under #2019-4107, to save months of work while cleaning and defining the working variables. Upon completion of analyses we will summarize the findings in a manuscript (additional 2-3 months) and submit for publication.

Dissemination Plan: Findings will be published in a peer-reviewed journal and disseminated via presentations at scientific meetings and links with patients groups and organizations. BMJ is one of the optional journals for publication.

Bibliography:

1. Peyrin-Biroulet L, Billioud V, D’Haens G, Panaccione R, Feagan B, Pans J, Danese S, Schreiber S, Ogata H, Hibi T, Higgins PD, Beaugerie L, Chowers Y, Louis E, Steinwurz F, Reinisch W, Rutgeerts P, Colombel JF, Travis S, Sandborn WJ. Development of the Paris definition of early Crohn’s disease for disease-modification trials: results of an international expert opinion process. Am J Gastroenterol 2012; 107:1770-6
2. D’Haens GR, Panaccione R, Higgins PD, Vermeire S, Gassull M, Chowers Y, Hanauer SB, Herfarth H, Hommes DW, Kamm M, Lfberg R, Quary A, Sands B, Sood A, Watermeyer G, Lashner B, Lmann M, Plevy S, Reinisch W, Schreiber S, Siegel C, Targan S, Watanabe M, Feagan B, Sandborn WJ, Colombel JF, Travis S. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol 2011; 106:199-212
3. D’Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, De Vos M, van Deventer S, Stitt L, Donner A, Vermeire S, Van de Mierop FJ, Coche JC, van der Woude J, Ochsenkhn T, van Bodegraven AA, Van Hootegem PP, Lambrecht GL, Mana F, Rutgeerts P, Feagan BG, Hommes D; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial Lancet. 2008 Feb 23;371(9613):660-7
4. Khanna R, Bressler B, Levesque BG, Zou G, Stitt LW, Greenberg GR, Panaccione R, Bitton A, Par P, Vermeire S, D’Haens G, MacIntosh D, Sandborn WJ, Donner A, Vandervoort MK, Morris JC, Feagan BG. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomised controlled trial. Lancet 2015 ;386:1825-34
5. Schreiber S, Colombel JF, Bloomfield R et al. Increased response and remission rates in short-duration Crohn’s disease with subcutaneous certolizumab pegol: an analysis of PRECiSE 2 randomized maintenance trial data. Am J Gastroenterol 2010; 105:1574-82
6. Schreiber S, Reinisch W, Colombel JF et al. Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn’s disease. J Crohns Colitis 2013;7:213-21
7. Ma C, Beilman CL, Huang VW et al. Anti-TNF Therapy Within 2 Years of Crohn’s Disease Diagnosis Improves Patient Outcomes: A Retrospective Cohort Study. Inflamm Bowel Dis 2016; 22:870-9
8. Kotze PG, Ludvig JC, Teixeira FV et al. Disease duration did not influence the rates of loss of efficacy of the anti-TNF therapy in Latin American Crohn?s disease patients. Digestion. 2015;91(2):158-63.
9. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. http://handbook.cochrane.org/. Accessed 17 Oct 2015
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