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Project Title: Treatment effects on longitudinal IBDQ-32 outcomes in Crohn's disease: a secondary analysis of the SONIC trial
Scientific Abstract: Background: Health-related quality of life is a patient-centered outcome in Crohn's disease. The SONIC trial collected the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ-32) repeatedly during randomized treatment. Objective: To compare longitudinal IBDQ-32 outcomes among infliximab, azathioprine, and combination therapy and examine their relationship with conventional disease-activity outcomes. Study Design: Secondary individual-participant-data analysis of the randomized, double-blind SONIC trial (NCT00094458). Participants: All randomized participants with a baseline IBDQ-32 assessment; available post-baseline observations will contribute to longitudinal analyses. Primary and Secondary Outcome Measure(s): Primary: change in IBDQ-32 total score from baseline across scheduled visits. Secondary: total score at each visit, four domain scores, and exploratory associations of IBDQ improvement with corticosteroid-free clinical remission, CDAI, CRP, and endoscopic outcomes where available. Statistical Analysis: Intention-to-treat linear mixed-effects models with treatment, visit, treatment-by-visit interaction, baseline score, and random participant effects; adjusted mean differences with 95% confidence intervals. Missing-data and multiplicity sensitivity analyses will be performed.
Brief Project Background and Statement of Project Significance: Crohn's disease affects symptoms, physical and social functioning, and emotional well-being. The IBDQ-32 is a disease-specific health-related quality-of-life instrument comprising 32 items and four domains; total scores range from 32 to 224, with higher scores indicating better quality of life. Although the SONIC randomized trial established the comparative efficacy of infliximab, azathioprine, and their combination using clinical remission and endoscopic outcomes, the repeated participant-level IBDQ data permit a more complete evaluation of patient-experienced benefit over time. This project is significant because it will quantify the magnitude, timing, and consistency of quality-of-life changes under the three randomized strategies and clarify their concordance with symptom-based and objective disease measures. The analysis will produce generalizable evidence for clinicians, patients, trialists, and guideline developers on interpreting patient-reported outcomes alongside conventional Crohn's disease endpoints. It will also assess whether conclusions are robust to missing questionnaire data and alternative clinically interpretable definitions of improvement. Results will be reported transparently with effect estimates and confidence intervals, without redistributing copyrighted questionnaire wording or participant-level data.
Specific Aims of the Project: Aim 1: Compare longitudinal change in IBDQ-32 total score among randomized infliximab, azathioprine, and combination-therapy groups. Hypothesis: combination therapy produces greater and/or earlier improvement than either monotherapy. Aim 2: Compare longitudinal changes in the bowel, systemic, emotional, and social domain scores, controlling multiplicity across domains. Hypothesis: treatment effects are directionally consistent but may differ in magnitude by domain. Aim 3: Examine whether IBDQ-32 improvement is associated with corticosteroid-free clinical remission, change in CDAI, CRP, and endoscopic outcomes at aligned visits. Hypothesis: IBDQ improvement is associated with clinical and objective improvement, but concordance is incomplete. Aim 4: Evaluate robustness to missing outcome data, alternative covariance structures, and prespecified subgroup interactions considered exploratory.
Study Design: Individual trial analysis
What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations
Software Used: R, RStudio
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Data source: de-identified participant-level data and supporting documentation from the SONIC trial (NCT00094458/C0168T67) supplied through the YODA secure platform. The analytic cohort will include all randomized participants in the three treatment groups who have a non-missing baseline IBDQ-32 total score. For the primary longitudinal model, all available scheduled post-baseline IBDQ observations will be used; participants need not have complete follow-up. Exclusion criteria: participants not randomized, lacking a baseline IBDQ-32 assessment, or lacking sufficient item-level data to derive a total score under the study's documented scoring rules. No additional demographic or clinical exclusions will be imposed. Analysis will follow randomized assignment (intention-to-treat). A per-protocol/as-treated analysis may be used only as a clearly labeled sensitivity analysis if treatment exposure and protocol-deviation data permit. No external participant-level dataset will be pooled with YODA data, and all participant-level analyses will occur within the YODA secure platform.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Primary outcome: change from baseline in IBDQ-32 total score across scheduled post-randomization assessments (weeks 2, 6, 10, 18, 26, 34, 42, and 50, subject to confirmation in the data documentation). The score will follow documented trial rules (range 32-224; higher is better). Primary estimands are adjusted between-group mean differences in change over time, with visit-specific contrasts. Secondary outcomes: total score at each visit; changes in bowel, systemic, emotional, and social domains; proportions achieving clinically important improvement using a literature-based threshold fixed before outcome inspection; and associations between IBDQ change and corticosteroid-free clinical remission, CDAI change/remission, CRP, and endoscopic healing/activity at aligned assessments. Domain, responder, concordance, and subgroup analyses are secondary or exploratory. Any change required by data availability will be documented before final modeling and disclosed.
Main Predictor/Independent Variable and how it will be categorized/defined for your study: Main independent variable: randomized treatment assignment--azathioprine monotherapy, infliximab monotherapy, or infliximab plus azathioprine--coded categorically with prespecified pairwise contrasts. Time will be scheduled visit as a categorical variable. The principal effect is the treatment-by-visit interaction, yielding adjusted differences in change and visit-specific contrasts. Primary analyses retain randomized assignment regardless of discontinuation or switching. Baseline IBDQ-32 is included for precision; as-treated definitions, if feasible, are sensitivity analyses only.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Variables used to describe the cohort and evaluate precision, heterogeneity, or concordance include age, sex, region/site where permissible, disease duration and location/behavior, prior therapies, baseline corticosteroid use, smoking if available, baseline CDAI and components, CRP and relevant laboratory measures, baseline endoscopic activity, treatment exposure, concomitant medications, discontinuation/rescue therapy, visit timing, and reasons for missing assessments. Exploratory effect modification will be limited to clinically plausible characteristics with adequate sample size: baseline CRP elevation, endoscopic activity, disease duration, baseline IBDQ-32, and corticosteroid use. Continuous covariates generally remain continuous; arbitrary dichotomization and stepwise selection will not be used.
Statistical Analysis Plan:
All analyses will use R/RStudio within the YODA secure platform. Baseline characteristics and outcome availability will be summarized by randomized group using mean/SD or median/IQR and count/percent; randomized-group baseline significance tests are not planned. IBDQ-32 item, domain, and total scores will follow trial documentation, with range, internal-coherence, floor/ceiling, and visit-window checks.
The primary likelihood-based linear mixed-effects model will include categorical randomized treatment, categorical scheduled visit, treatment-by-visit interaction, baseline IBDQ-32 total score, and an appropriate within-participant correlation/random-effects structure. All observed post-baseline outcomes from eligible randomized participants contribute under a missing-at-random assumption. Adjusted mean changes and pairwise group differences at each visit and across follow-up will be reported with 95% confidence intervals. Residuals, influential observations, covariance structure, and convergence will be assessed; robust standard errors or bootstrap intervals will be used if assumptions are materially violated.
Analogous models will analyze four domains. Clinically important improvement will use generalized mixed models or visit-specific risk differences/ratios after fixing the threshold from validation literature. Associations between IBDQ change and CDAI, CRP, endoscopy, remission, or healing will use correlation and suitable longitudinal generalized models and will be labeled associational, not causal.
Multiplicity-adjusted inference will address prespecified pairwise treatment contrasts for the primary total-score family. Domain and subgroup analyses will use false-discovery-rate control or be labeled exploratory; interactions will be tested directly. Missingness patterns/reasons will be summarized by treatment and visit. Sensitivity analyses will include multiple imputation with baseline and longitudinal predictors, complete cases, and if feasible delta-adjusted pattern-mixture analyses for departures from missing at random. Alternative covariance structures, permitted scoring rules, and definable per-protocol/as-treated populations will also be assessed. Effect estimates, 95% confidence intervals, exact denominators, and limitations will be emphasized; two-sided alpha=0.05 applies to the primary analysis.
Narrative Summary: This study will use de-identified participant-level data from the SONIC randomized trial to examine how health-related quality of life changed over time in adults with Crohn's disease treated with infliximab, azathioprine, or combination therapy. We will analyze the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ-32), including total and domain scores, and evaluate whether quality-of-life improvement is associated with clinical remission and objective disease measures. Repeated-measures methods will account for multiple assessments within each participant, and missing data will be examined through sensitivity analyses. The study may improve interpretation of patient-reported outcomes and clarify how patient-experienced treatment benefits relate to conventional measures of Crohn's disease activity.
Project Timeline: Start within 2 weeks after access. Months 1-2: documentation review, variable mapping, scoring reproduction, analysis-plan finalization, and data checks. Months 3-5: primary/secondary analyses and missing-data diagnostics. Months 6-7: sensitivity and exploratory analyses. Months 8-9: manuscript, tables, and figures. Month 10: coauthor review. Month 11: first journal submission. Month 12: report results to YODA and archive reproducible code and approved aggregate outputs under platform and agreement requirements.
Dissemination Plan: The principal product will be a peer-reviewed manuscript on longitudinal IBDQ-32 treatment effects and relationships with clinical and objective Crohn's disease outcomes. Audiences include patients, gastroenterologists, outcomes researchers, trialists, guideline developers, and policy stakeholders. A gastroenterology or IBD journal will be chosen after results are known and matched to scope. Results may also be presented at a scientific meeting. Findings will be reported regardless of direction or significance and under applicable guidance for secondary randomized-trial analyses. Aggregate tables, figures, and code will be shared only as permitted by the Data Use Agreement, instrument licensing, and disclosure review; participant-level data and IBDQ item wording will not be redistributed. A final summary and citation will be reported to YODA.
Bibliography:
1. Colombel JF, Sandborn WJ, Reinisch W, et al.; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395. doi:10.1056/NEJMoa0904492.
2. Irvine EJ, Zhou Q, Thompson AK. The Short Inflammatory Bowel Disease Questionnaire: a quality of life instrument for community physicians managing inflammatory bowel disease. CCRPT Investigators. Am J Gastroenterol. 1996;91(8):1571-1578.
3. Irvine EJ. Development and subsequent refinement of the Inflammatory Bowel Disease Questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1999;28(4):S23-S27. doi:10.1097/00005176-199904001-00003.