Lead Investigator: Vivek Rudrapatna, University of California San Francisco
Title of Proposed Research: Efficacy of Crohn’s Disease Treatment Stratified by Disease Phenotype
Vivli Data Request: 4949, 3190
Funding Source: Government Funding – NIH NIDDK T32 DK007007, NIH/NCATS UCSF-CTSI TL1 TR001871
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Crohn’s Disease is a heterogenous disorder encompassing distinct clinical phenotypes which arise from different biological pathways. Preclinical and clinical studies suggest that the efficacy of different agents does vary by disease phenotype, including anatomical location. Although these data are commonly collected in clinical trials, they have not been uniformly analyzed by strata nor meta-analyzed across studies by phenotype. As such, clinicians are left to recommend treatments based on best guess of efficacy rather than high-quality evidence. Therefore, we propose to meta-analyze this existing trial data as an important first step towards realizing precision medicine for Crohn’s Disease.
Statistical Analysis Plan:
Missing Values: For missing values corresponding to the primary endpoint we will perform non-responder imputation. For missing data corresponding to other variables we will perform group mean imputation. We will repeat the analysis using exclusion of missing data and perform sensitivity analysis to assess the robustness of our conclusions to these methods.
Statistical Procedure:
We will perform a mixed effects linear model meta-analysis and weight individual study effect sizes using the DerSimonian-Laird method. Treatment (active drug vs placebo), as well as aforementioned covariates (e.g. disease location, behavior, demographics (age, gender, race) and medication history including anti-tumor necrosis factor failure) will be treated as fixed effects. Individual studies will be treated as random effects.
We will also explore network meta-analysis methods if the size of the available data will permit this.
Measures to Adjust for Multiplicity, Confounders, Heterogeneity:
We will assess study heterogeneity using Q and I-squared statistics. We will adjust for multiple testing using the Benjamin-Hochberg method to maintain a false discovery rate at the 0.05 level.
Sensitivity Analysis: We will assess the sensitivity of our model to intention-to-treat vs per-protocol analysis, inclusion vs exclusion of patients receiving non-FDA approved dosing, as well as statistical significance with and without multiple hypothesis correction. We will also test the sensitivity of our model using leave-one-out tests, and interactively perform the meta-analysis with n-1 studies to test if the result are influenced by one particular study.
QC Plan: We anticipate that many of the requested patient-level datasets have already undergone data-cleaning activities as a part of the study database lock process in the course of carrying out the trial. Our data-cleaning activities will focus on harmonizing the data between data-sets to facilitate meaningful meta-analytic cross-comparison and usage of the statistical software.
Programming Plans: We will be performing all data visualization and statistical analysis in the R programming environment.
Requested Studies
A Multicenter, Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Adalimumab for the Induction and Maintenance of Clinical Remission in Chinese Patients With Moderately to Severely Active Crohn’s Disease and Elevated High-Sensitivity C-reactive Protein
Sponsor: AbbVie
Study ID: NCT02499783
Sponsor ID: M14-233
A Multi-Center, Randomized, Double-blind, Placebo-controlled Study of Adalimumab for the Maintenance of Clinical Remission in Japanese Subjects With Crohn’s Disease
Sponsor: Abbott
Study ID: NCT00445432
Sponsor ID: M06-837
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Maintenance of Clinical Remission in Subjects With Crohn’s Disease
Sponsor: Abbott
Study ID: NCT00055497
Sponsor ID: M02-433
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab Endoscopy Trial to Evaluate the Effects on Mucosal Healing in Subjects With Crohn’s Disease Involving the Colon
Sponsor: Abbott
Study ID: NCT00348283
Sponsor ID: M05-769
A Multi-Center, Randomized, Double-blind, Placebo-controlled Study of Adalimumab for the Induction of Clinical Remission in Japanese Subjects With Crohn’s Disease
Sponsor: Abbott
Study ID: NCT00445939
Sponsor ID: M04-729
A Multi-Center Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction and Maintenance of Clinical Remission in Subjects With Crohn’s Disease
Sponsor: Abbott
Study ID: NCT00077779
Sponsor ID: M02-404
A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction of Clinical Remission in Subjects With Moderate to Severe Crohn’s Disease Who Have Lost Response or Are Intolerant to Infliximab
Sponsor: Abbott
Study ID: NCT00105300
Sponsor ID: M04-691
A Phase II Study of the Human Anti-TNF Antibody Adalimumab for the Induction of Clinical Remission in Subjects With Crohn’s Disease
Sponsor: Abbott
Study ID: NCT00055523
IRP/Approver: AbbVie
Sponsor ID: M02-403
A Phase III, Multicenter, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Intravenous Antegren(TM) (Natalizumab) in Subjects With Moderately to Severely Active Crohn’s Disease With Elevated C-Reactive Protein
Sponsor: Biogen
Study ID: NCT00078611
Sponsor ID: ELN100226-CD307
A Phase 3 International, Multicenter, Double-blind, Placebo-controlled Study of the Safety, Efficacy, and Tolerability of Intravenous Antegren (Natalizumab) in Subjects With Moderate to Severely Active Crohn’s Disease
Sponsor: Biogen
Study ID: NCT00032799
Sponsor ID: CD301
A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction of Clinical Response and Remission by Vedolizumab in Patients With Moderate to Severe Crohn’s Disease
Sponsor: Millennium Pharmaceuticals, Inc.
Study ID: NCT01224171
Sponsor ID: C13011
A Phase 3, International, Multicenter, Double-blind, Placebo-controlled Study of the Efficacy, Safety, and Tolerability of Intravenous Antegren (Natalizumab) in Maintaining Clinical Response and Remission in Subjects With Crohn’s Disease
Sponsor: Biogen
Study ID: NCT00032786
Sponsor ID: CD303
A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab (MLN0002) in Patients With Moderate to Severe Crohn’s Disease
Sponsor: Millennium Pharmaceuticals, Inc.
Study ID: NCT00783692
Sponsor ID: C13007
(Note: Additional studies added as part of Data Request 4949)
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
Sponsor: Centocor, Inc.
Study ID: NCT00207662
Sponsor ID: CR004771
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
Sponsor: Centocor Ortho Biotech Services, L.L.C.
Study ID: NCT00094458
Sponsor ID: CR004804
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Induction Therapy in Subjects With Moderately to Severely Active Crohn’s Disease (UNITI-2)
Sponsor: Janssen Research & Development, LLC
Study ID: NCT01369342
Sponsor ID: CR018418
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Induction Therapy in Subjects With Moderately to Severely Active Crohn’s Disease Who Have Failed or Are Intolerant to TNF Antagonist Therapy (UNITI-1)
Sponsor: Janssen Research & Development, LLC
Study ID: NCT01369329
Sponsor ID: CR018415
Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Comparing REMICADE (Infliximab) and Placebo in the Prevention of Recurrence in Crohn’s Disease Patients Undergoing Surgical Resection Who Are at Increased Risk of Recurrence
Sponsor: Janssen Biotech, Inc.
Study ID: NCT01190839
Sponsor ID: CR017080
A Phase 2b, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Ustekinumab Therapy in Subjects With Moderately to Severely Active Crohn’s Disease Previously Treated With TNF Antagonist Therapy
Sponsor: Centocor, Inc.
Study ID: NCT00771667
Sponsor ID: CR015238
A Placebo-Controlled, Dose-Ranging Study Followed by a Placebo-Controlled, Repeated-Dose Extension of Anti-TNF Chimeric Monoclonal Antibody (cA2) in the Treatment of Patients With Active Crohn’s Disease
Sponsor: Centocor, Inc.
Study ID: NCT00269854
Sponsor ID: CR006256
ACCENT II – A Randomized, Double-blind, Placebo-controlled Trial of Anti-TNF Chimeric Monoclonal Antibody (Infliximab, Remicade) in the Long Term Treatment of Patients With Fistulizing CROHN’S Disease
Sponsor: Centocor, Inc.
Study ID: NCT00207766
Sponsor ID: CR005413
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Maintenance Therapy in Subjects With Moderately to Severely Active Crohn’s Disease
Sponsor: Janssen Research & Development, LLC
Study ID: NCT01369355
Sponsor ID: CR018421
A Multicenter, Randomized, Phase 2a Study of Human Monoclonal Antibody to IL-12p40 (CNTO 1275) in Subjects With Moderately to Severely Active Crohn’s Disease
Sponsor: Centocor, Inc.
Study ID: NCT00265122
Sponsor ID: CR005287
A Phase III Multi-national, Multi-centre, Double-blind Placebo-controlled Parallel Group, 26 Week Study to Assess the Safety and Efficacy of the Humanised Anti-TNF PEG Conjugate, CDP870 400 mg sc, (Dosed at Weeks 0, 2, 4 Then 4-weekly to Week 24), in the Treatment of Patients With Active Crohn’s Disease
Sponsor: UCB
Study ID: NCT00152490
Sponsor ID: C87031
A Phase III Multi-national, Multi-centre, Double-blind Placebo-controlled Parallel Group, 26 Week Study to Assess the Maintenance of Clinical Response to Humanised Anti-TNF PEG Conjugate, CDP870 400 mg sc, (Dosed 4-weekly From Weeks 8 to 24), in the Treatment of Patients With Active Crohn’s Disease Who Have Responded to Open Induction Therapy (Dosed at Weeks 0, 2 and 4) With CDP870
Sponsor: UCB
Study ID: NCT00152425
Sponsor ID: C87032
Phase IIIb, Multinational, Randomized, Double-blind, Placebo-controlled Trial to Assess the Efficacy and Safety of Certolizumab Pegol, a Pegylated Fab’ Fragment of a Humanized Anti-Tumor Necrosis Factor(TNF)-Alpha Monoclonal Antibody, Administered in Subjects With Moderately to Severely Active Crohn’s Disease.
Sponsor: UCB
Study ID: NCT00552058
Sponsor ID: C87085
A Phase II, Multi-center, Double-blind, Placebo-controlled, Parallel-group, Dose-response Study to Assess the Safety and Efficacy of CDP870/Certolizumab Pegol, Dosed Subcutaneously in Patients With Active Crohn’s Disease
Sponsor: UCB
Study ID: NCT00291668
Sponsor ID: C87037
Phase IIIb Open-label Induction and Double-blind Comparison of 2 Maintenance Schedules Evaluating Clinical Benefit and Tolerability of Certolizumab Pegol in Crohn’s Disease Patients With Prior Loss of Response or Intolerance to Infliximab
Sponsor: UCB
Study ID: NCT00308581
Sponsor ID: C87042
Public Disclosures:
- Rudrapatna, V.A., Ravindranath, V.G., Arneson, D.V., Mosenia, A., Butte, A.J. and Wang, S., 2023. Sequential regression and simulation: a method for estimating causal effects from heterogeneous clinical trials without a common control group. BMC Medical Research Methodology, 23(1), pp.1-12. doi: 10.1186/s12874-023-02020-5
- Rudrapatna, V.A., Ravindranath, V., Arneson, D.V., Mosenia, A., Butte, A.J. and Wang, S., 2023. Personalizing treatment selection in Crohn’s disease: a meta-analysis of individual participant data from fifteen randomized controlled trials. medRxiv, pp.2023-11. doi: 10.1101/2023.11.10.23291837
- Rudrapatna, V., Ravindranath, V., Arneson, D., Mosenia, A., Butte, A. and Wang, S., 2023. S936 Optimizing Treatment Selection in Crohn’s Disease Using Patient-Specific Features: An Individual Participant Data Meta-Analysis of Fifteen Randomized Controlled Trials. Official journal of the American College of Gastroenterology| ACG, 118(10S), pp.S701-S702. Doi: 10.14309/01.ajg.0000953384.20574.a3