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Status: OngoingResearch Proposal
Project Title: Predicting treatment response to adalimumab and ustekinumab using the MM-SES-CD in Crohn's disease
Scientific Abstract:
Background: Adalimumab and ustekinumab are two approved biologics for the treatment of Crohn?s disease (CD). In SEAVUE, adalimumab and ustekinumab were compared in a head-to-head trial. Biologic nave patients who had moderate to severely active CD received either adalimumab or ustekinumab throughout the entire duration of the study (from week 0 to 52). The primary outcome of the study was clinical remission (CR), defined as Crohn's Disease Activity Index (CDAI) < 150, at week 52. Endoscopic remission (ER) is an important treatment target in Crohn?s disease (CD). The SES-CD is a validated tool used to quantify mucosal inflammation and was used in the SEAVUE study. At the time of SES-CD development, each of the four parameters per segment was assigned a uniform score of 0-3, with a higher score indicating greater disease burden. This assumes a linear assignment of prognostic significance for achieving ER across all five ileocolonic segments. However, recent studies have suggested otherwise (1). The Modified Multiplier Simple Endoscopic Score for Crohn?s disease (MM-SES-CD) was developed using post-hoc clinical trial data and demonstrated significantly better accuracy than the SES-CD for predicting ER at week 52 (2). As its name suggests, the MM-SES-CD differentially weights various components of the SES-CD to account for the relative importance of each parameter on disease prognosis (2). Use of the MM-SES-CD in clinical trials may help establish more adequate balance between trial arms and could offer a more focused strategy to re-randomize patients after the induction phase. However, treatment response as a function of baseline MM-SES-CD has not yet been investigated.
Objective: The proposed study aims to evaluate whether baseline MM-SES-CD can be predictive of treatment response (defined as SES-CD < 3) to adalimumab and ustekinumab. Sensitivity analyses using more stringent criteria of SES-CD of 0 at week 52 will also be conducted. Exploratory analyses may include primary and secondary outcomes in the SEAVUE study as defined above.
Study Design:The SEAVUE trial compared adalimumab versus ustekinumab in 386 patients with moderate to severe CD who were nave to biologics (3). Ileocolonoscopies occurred at screening and 52 weeks after randomization and assessed using the SES-CD. In the proposed study, ileocolonoscopies at baseline and week 52 from the SEAVUE trial will be converted to MM-SES-CD scores, which is detailed in Appendix 1. This proposed analysis will only include patients with complete and evaluable SES-CD data at baseline. Analyses will be conducted on an intention to treat basis.
Participants: Participants with SES-CD ? 3 and confirmed mucosal ulceration at baseline will be included.
Primary/Secondary Outcomes: The primary outcome will be ER at week 52, defined as SES-CD < 3. SES-CD scores from week 52 ileocolonoscopies will be converted into MM-SES-CD scores. Details of score conversion can be found in Appendix 1 and is available at https://www.mcmasteribd.com/mm-ses-cd. Sensitivity analyses will be conducted on subpopulations (e.g. ileal/ileocolonic vs. colonic, stricturing vs. non-stricturing disease). Other outcomes will be evaluated in exploratory analyses, as defined above in SEAVUE.
Statistical Analysis: MM-SES-CD scores will be evaluated as continuous scores as well as in categories of severity. Multivariate regression analyses will evaluate the relationship between baseline MM-SES-CD scores and outcomes.
Brief Project Background and Statement of Project Significance:
Adalimumab and ustekinumab are two approved biologics for the treatment of Crohn?s disease (CD). In SEAVUE, adalimumab and ustekinumab were compared in a head-to-head trial. Biologic nave patients who had moderate to severely active CD received either adalimumab or ustekinumab throughout the entire duration of the study (from week 0 to 52). The primary outcome of the study was clinical remission (CR), defined as Crohn's Disease Activity Index (CDAI) < 150, at week 52. Secondary outcome measures included corticosteroid-free remission, clinical response (defined as CDAI decrease of at least 100 points from baseline), patient-reported outcome (PRO)-2 remission (defined as abdominal pain score ? 1 and stool frequency score ? 3), endoscopic remission (ER) (defined as SES-CD score ? 3 or SES-CD of 0 among patients with a baseline SES-CD of 3) at week 52.
Endoscopic remission (ER) is an important treatment target in Crohn?s disease (CD). The SES-CD is a validated tool used to quantify mucosal inflammation and was used in the SEAVUE study. At the time of SES-CD development, each of the four parameters per segment was assigned a uniform score of 0-3, with a higher score indicating greater disease burden. This assumes a linear assignment of prognostic significance for achieving ER across all five ileocolonic segments. However, recent studies have suggested otherwise. For example, in a post-hoc analysis of the SONIC trial, participants with deep and large ileal and rectal ulcers at baseline were 69% and 74% less likely to achieve ER compared to those with smaller ulcers, respectively. Further, the overall healing rate in the ileum was significantly lower than in the colon (1). These findings may suggest that individual parameters of the SES-CD have varying degrees of prognostic value for predicting ER.
The lack of prognostic heterogeneity offered by the SES-CD led to the development and internal validation of the Modified Multiplier Simple Endoscopic Score for Crohn?s disease (MM-SES-CD). The MM-SES-CD was developed using post-hoc clinical trial data and demonstrated significantly better accuracy than the SES-CD for predicting ER at week 52 (2). As its name suggests, the MM-SES-CD differentially weights various components of the SES-CD to account for the relative importance of each parameter on disease prognosis (2). For example, the presence of an ileal stricture as scored by the SES-CD (0=none, 1=single passable, 2=multiple passable, 3=non-passable) would be multiplied by 4 to obtain the corresponding score using the MM-SES-CD.
Use of the MM-SES-CD in clinical trials may help establish more adequate balance between trial arms and could offer a more focused strategy to re-randomize patients after the induction phase. However, treatment response as a function of baseline MM-SES-CD has not yet been investigated.
Specific Aims of the Project: The proposed study aims to evaluate whether baseline MM-SES-CD can be predictive of treatment response (defined as SES-CD < 3) to adalimumab and ustekinumab. Sensitivity analyses using more stringent criteria of SES-CD of 0 at week 52 will also be conducted. Exploratory analyses may include primary and secondary outcomes in the SEAVUE study as defined above.
Study Design: Individual trial analysis
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: For this analysis, participants with SES-CD ? 3 and confirmed mucosal ulceration at baseline will be included. Otherwise, no further exclusion criteria will be applied.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: The primary outcome will be ER at week 52, defined as SES-CD < 3. SES-CD scores from week 52 ileocolonoscopies will be converted into MM-SES-CD scores. Details regarding score conversion can be found in Appendix 1 and is available at https://www.mcmasteribd.com/mm-ses-cd. Sensitivity analyses will be conducted on subpopulations (e.g. ileal/ileocolonic vs. colonic, stricturing vs. non-stricturing disease). Other outcomes will be evaluated in exploratory analyses, as defined above in SEAVUE.
Main Predictor/Independent Variable and how it will be categorized/defined for your study: The main predictor of this study is baseline MM-SES-CD scores, which will be evaluated as continuous scores as well as in categories of severity (data not yet published): very mild or in remission (score
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Potential confounding variables that may be included in multivariable regression models include study region, age, sex, disease duration, baseline C-reactive protein level, baseline fecal calprotectin level, disease location, smoking, prior surgery, and history of stricturing disease
Statistical Analysis Plan:
Descriptive statistics will be used to summarize baseline characteristics of the study population (e.g. disease activity and patient demographics) as well as outcomes among the included patients. Dichotomous variables will be presented as proportions or percentages. Continuous variables will be reported as means with standard deviations or medians with interquartile ranges.
For this analysis, participants with SES-CD ? 3 and confirmed mucosal ulceration at baseline will be included. The primary outcome will be ER at week 52, defined as SES-CD < 3. SES-CD scores from week 52 ileocolonoscopies will be converted into MM-SES-CD scores. Details regarding score conversion can be found in Appendix 1 and is available at https://www.mcmasteribd.com/mm-ses-cd. Sensitivity analyses will be conducted on subpopulations (e.g. ileal/ileocolonic vs. colonic, stricturing vs. non-stricturing disease). Other outcomes will be evaluated in exploratory analyses, as defined above in SEAVUE.
The MM-SES-CD scores will be evaluated as continuous scores as well as in categories of severity (data not yet published): very mild or in remission (score
Narrative Summary: Adalimumab and ustekinumab are two approved biologics for the treatment of Crohn?s disease (CD). In SEAVUE, adalimumab and ustekinumab were compared in a head-to-head trial. Biologic nave patients who had moderate to severely active CD received either adalimumab or ustekinumab. The SES-CD is a quantifies mucosal inflammation, but lacks prognostic heterogeneity. In response to this disparity, the Modified Multiplier Simple Endoscopic Score for Crohn?s disease was developed and differentially weights various components of the SES-CD. The proposed study aims to evaluate whether baseline MM-SES-CD can be predictive of treatment response (defined as SES-CD < 3) to adalimumab and ustekinumab.
Project Timeline:
Start date: April 2023
Analysis completion: July 2023
Manuscript draft: September 2023
Dissemination Plan:
Anticipated products of this project include abstracts that will be submitted and potentially presented at conferences such as Canadian Digestive Diseases Week, Digestive Disease Week, and European Crohn?s and Colitis Organisation. A manuscript is expected to arise which will be submitted for publication to journals such as Clinical Gastroenterology and Hepatology, Journal of Crohn?s and Colitis, and Inflammatory Bowel Diseases. All results will be shared with the YODA Project at the time of submission.
Target audiences include clinicians and researchers who are interested in clinical trials of inflammatory bowel disease.
Bibliography:
1. Narula, N. et al. Ileal and Rectal Ulcer Size Affects the Ability to Achieve Endoscopic Remission. Am. J. Gastroenterol. (2020). doi:10.14309/ajg.0000000000000617
2. Narula N, Wong EC, Colombel JF, Sandborn WJ, Marshall JK, Daperno M, Reinisch W, Dulai PS. Predicting endoscopic remission in Crohn?s disease by the modified multiplier SES-CD (MM-SES-CD). Gut. 2021 Mar 24.
3. Janssen Scientific Affairs, L. Safety and Efficacy of Adalimumab Versus Ustekinumab for One Year (SEAVUE). 2018 July 7, 2021; Available from: https://clinicaltrials.gov/ct2/show/NCT03464136.