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Center for Global Research Data

Efficacy of biologic drugs in short-duration versus long-duration inflammatory bowel disease

Lead Investigator: Shomron Ben-Horin, Sun Yatsen 1st affiliated Hospital
Title of Proposal Research: Efficacy of biologic drugs in short-duration versus long-duration inflammatory bowel disease
Vivli Data Request: 4048, 4329
Funding Source: The research project is supported in part by the ‘Talpiot’ medical leadership grant from the Sheba Medical Center (to SBH).
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Crohn’s disease (CD) and ulcerative colitis (UC) are remitting-relapsing 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 (‘Top-down’ strategy) as opposed to later in the course of disease (‘Step-up’ approach).

Electronic databases (MEDLINE, EMBASE/EMBASE classic Cochrane CENTRAL register of controlled trials, the Cochrane Inflammatory Bowel Disease (IBD) Group Specialized Trials Register, and Clinicaltrials.gov registry) will be searched to identify all randomized placebo-controlled clinical trials of Food and Drug Administration (FDA)-approved biologics for CD and UC (by March 2016). Two independent reviewers will screen identified papers, extract data, and assess the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. Individual-patient-level data (IPD) will be extracted from the identified trials through data-sharing platforms for pharmaceutical companies’ sponsored trials and by contacting principal investigators of independent investigator-initiated trials. We will analyze induction of remission in patients with early-disease (<18months since disease onset) versus patients with longer disease duration, using a generalized linear mixed effect model as well as by a two-stage approach using coefficient for the treatment-by-subgroup interaction within each trial. We will perform receiver operator curve analysis of optimal disease-duration for response to biologics. All analyses will be separate for CD and UC. 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.

Ethics and dissemination: This meta-analysis has been approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University. Findings will be published in peer-reviewed journal and disseminated via presentations at scientific meetings and links with patients groups and organizations.

Study Registration number: PROSPERO: CRD42018041961

Benefits to science and public health:

• The meta-analysis, whose protocol is described, will be the first to evaluate by individual-patient level data the association between duration of inflammatory bowel disease (IBD) and response to biologic drugs, thereby accounting for multiple confounders that may impact the outcome of biologics treatment.
• The meta-analysis will only analyze data from randomized placebo controlled clinical trials thereby ensuring high-quality source data with standardized outcomes measures

Statistical Analysis Plan

General approach in meta-analysis

In the current analysis we will employ individual participant data (IPD) meta-analysis, considered the “gold-standard”, provided that the raw data from the trials are available. Two main techniques will be used in the analysis of IPD, known as one-stage and two-stage approaches. Briefly, the one-stage approach employs the methodology of mixed models applied to the full set of IPD, and two-stage approach is based on synthesizing the estimates of an effect calculated within each study separately. The one-stage approach is believed to be preferable for estimating patient-level interactions, essential for testing hypotheses in the current project, as it allows for the direct estimation of interactions. The choice of two-stage vs. one stage modeling for the primary analysis depends on the level of heterogeneity of the duration of disease (short term vs. long term) – the main covariate in the study – measured by Q estimate as suggested by Simmonds and Higgins, whereas the two-stage approach is preferred over one-stage approach if Q/t<<1, where t is the number of studies and Q is a measure of heterogeneity of covariates in each study calculated as; Q=∑▒(m_i^2)/(σ_zi^2 ), where m is the difference of the mean covariate value in each study from the overall covariate value and σ is the standard deviation of the covariate (z) in each study. For the purpose of completeness of analysis, both two-stage and one-stage approaches will be performed. We will use variance of the random treatment effect as a measure of heterogeneity, along with Q statistic and I2 estimates, being more intuitive for interpretation, even though the later measures originate from the two-stage meta-analysis approach. To assess whether the variation across trials was due to true heterogeneity or chance, heterogeneity among studies will be evaluated using the Chi-square test (a p- value≤0.10 considered statistically significant) and the I2 statistic. I2 values range from 0% to 100%, with 0% representing no observed heterogeneity. An I2 value>50% is considered substantial.

All analyses in the study will be performed on all available cases from the trials. The missing pattern of the main covariates will be inspected and missing values of outcomes and main covariates will be imputed in cases where these covariates are known risk factors for the outcomes, e.g. gender, age or clinical history, and are not missing in more than 50% of observations in a trial. We will impute median values separately within each trial. Multiple imputation techniques will be used to complete the data required for the primary outcome analysis, and present the data along with the main analysis, as a part of sensitivity analysis. This analysis assumes that missing covariates and endpoints were missing (completely) at random (M(C)AR).

Specific analyses performed

The primary analysis of the primary outcome will be performed using two approaches:

a mixed effects logistic regression separately within UC or CD strata. An interaction term of the treatment and sub-group of disease duration is included in the model, following the recommendations on performing meta-analyses of sub-group treatment effects and reducing across-trial confounding. Specifically, in the one-stage approach: we will use a generalized linear mixed model (GLMM), accounting for the clustering among patients from the same study by including random study intercept to provide a more conservative estimate of the likelihood of benefit of biologics. The model includes the treatment-by-duration of disease interaction and a random effect for the interaction term if duration of disease varies substantially between the studies (Q/t>1). The link function of the model (logistic, log-binomial, poisson, negative binomial) is chosen based on the outcome distribution and the model fit.

The two-staged approach will also be performed, in which the coefficient for the treatment-by-subgroup interaction within each trial was computed as log odds/relative ratio for the outcome for biologics versus placebo in patients with short disease duration compared to those with long duration of disease. Thereafter, treatment effect measures for the dichotomous outcome of induction of remission in short versus long duration of disease are determined. as pooled ratio with 95% confidence interval of these individual trial coefficient.
As a secondary analysis of the primary outcome, the treatment effect will be adjusted in the model by including the following covariates: 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). Covariates are handled by the below mentioned sub-analyses, and by meta-regression (if more than 10 studies were available). The procedure PROC NLMIXED will be undertaken to perform the analysis described above.
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 (CDAI<150 or Mayo≤2 with no individual subscore>1 for CD and UC, respectively);
3) Using a fixed-effect model to pool data if heterogeneity assessment reveals I2 <50%;
4) including only trials in which all patients were anti-TNF naïve;
5) including only patients who rolled over to the maintenance phase after responding to induction (only for the outcome of maintenance of remission, in applicable trials)
6) analyzing the primary outcomes using techniques of Bayesian analysis with vague priors for the treatment effect estimates.
7) analyzing the primary outcomes separately for industry and academic sources.

To assess the optimal threshold for duration of disease that best “predicts” the likelihood of patients’ response to treatment, a summary Receiver Operator Characteristics (ROC) curve will be constructed based on the random effects generalized linear model adjusting for clustered structure of the pooled database, with the study outcomes as outlined above and continuous disease duration as independent covariate in the model.

SAS 9.4 and R version 3.2.5 software will be used for the main statistical analysis. We will generate Forest plots of pooled effect estimates (RR or OR) with 95% CIs, as well as funnel plots. The latter are assessed for evidence of asymmetry and therefore possible publication bias or other small study effects, using the Egger test, if there are sufficient (n=10) eligible studies included in the meta-analysis, in line with published recommendations.

Requested Studies:

A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by MLN0002 in Patients With Moderate to Severe Ulcerative Colitis
Sponsor: Takeda
Study ID: NCT00783718
Sponsor ID: C13006

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: Takeda
Study ID: NCT00783692
Sponsor ID: C13007

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: Takeda
Study ID: NCT01224171
Sponsor ID: C13011

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, 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 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 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: AbbVie
Study ID: NCT00077779
Sponsor ID: M02-404

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: AbbVie
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: AbbVie
Study ID: NCT00445939
Sponsor ID: M04-729

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: AbbVie
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: AbbVie
Study ID: NCT00055497
Sponsor ID: M02-433

A Phase II Study of the Human Anti-TNF Antibody Adalimumab for the Induction of Clinical Remission in Subjects With Crohn’s Disease
Sponsor: AbbVie
Study ID: NCT00055523
Sponsor ID: M02-403

A Multi-Center, Randomized, Double-Blind, Placebo-controlled Study of Adalimumab in Japanese Subjects With Moderately to Severely Active Ulcerative Colitis.
Sponsor: AbbVie
Study ID: NCT00853099
Sponsor ID: M10-447

A Multicenter, Randomized, Double-blind Placebo-controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction of Clinical Remission in Subjects With Moderately to Severely Active Ulcerative Colitis
Sponsor: AbbVie
Study ID: NCT00385736
Sponsor ID: M06-826

A Multicenter, 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 Moderately to Severely Active Ulcerative Colitis
Sponsor: AbbVie
Study ID: NCT00408629
Sponsor ID: M06-827

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: AbbVie
Study ID: NCT00105300
Sponsor ID: M04-691

(Note: Additional studies added as part of Data Request 4329)

The study performed by Chinese PLA hospital, Shandong University. Study title: Low-dose Infliximab for Induction and Maintenance Treatment in Chinese Patients with Moderate to Severe Active Ulcerative Colitis
Data Contributor: I WILL BRING MY OWN
Study ID: PMID 25844841, Study PI: Jiang XL

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, 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 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

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 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
Sponsor: Janssen Research & Development, LLC
Study ID: NCT00487539
Sponsor ID: CR014176

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
Sponsor: Janssen Research & Development, LLC
Study ID: NCT00488631
Sponsor ID: CR014179

A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
Sponsor: Centocor, Inc.
Study ID: NCT00036439
Sponsor ID: CR004777

A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
Sponsor: Centocor, Inc.
Study ID: NCT00096655
Sponsor ID: CR004783

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

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

Comparison of the Efficacy and Safety of Infliximab, as Monotherapy or in Combination With Azathioprine, Versus Azathioprine Monotherapy in Moderate to Severe Active Ulcerative Colitis (Part 1) Comparison of Maintenance Versus Intermittent Infliximab Treatment in Maintaining Remission: A Follow-Up of Efficacy and Safety (Part 2)
Sponsor: Merck Sharp & Dohme Corp.
Study ID: NCT00537316
Sponsor ID: P04807

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Infliximab in Chinese Subjects With Active Ulcerative Colitis
Sponsor: Xian-Janssen Pharmaceutical Ltd.
Study ID: NCT01551290
Sponsor ID: CR018769

Public disclosure:

Shomron Ben-Horin, Lena Novack, Ren Mao, Jing Guo, Yue Zhao, Ruslan Sergienko, Jian Zhang, Taku Kobayashi, Toshifumi Hibi, Yehuda Chowers, Laurent Peyrin-Biroulet, Jean Frederic Colombel, Gilaad G. Kaplan, Min-hu Chen. Efficacy of biologic drugs in short-duration versus long-duration inflammatory bowel disease: A systematic review and an individual-patient data meta-analysis of randomized controlled trials. Gastroenterology, 2021, ISSN 0016-5085.
doi.org/10.1053/j.gastro.2021.10.037