Treatment sequence network meta-analysis in Crohn’s disease: a methodological case study

Abstract

Objective: Several biologic therapies are available for the treatment of mild-to-moderate Crohn’s disease (CD). This network meta-analysis (NMA) aimed to assess the comparative efficacy of ustekinumab, adalimumab, vedolizumab and infliximab in the maintenance of clinical response and remission after 1 year of treatment.

Methods: A systematic literature search was performed to identify relevant randomized controlled trials (RCTs). Key outcomes of interest were clinical response (CD activity index [CDAI] reduction of 100 points; CDAI-100) and remission (CDAI score under 150 points; CDAI < 150). A treatment sequence Bayesian NMA was conducted to account for the re-randomization of patients based on different clinical definitions, the lack of similarity of the common comparator for each trial and the full treatment pathway from the induction phase onwards.

Results: Thirteen RCTs were identified. Ustekinumab 90 mg q8w was associated with statistically significant improvement in clinical response relative to placebo and vedolizumab 300 mg. For clinical remission, ustekinumab 90 mg q8w was associated with statistically significant improvement relative to placebo and vedolizumab 300 mg q8w. Findings from sub-population analyses had similar results but were not statistically significant.

Conclusions: The NMA suggest that ustekinumab is associated with the highest likelihood of reaching response or remission at 1 year compared with placebo, adalimumab and vedolizumab. Results should be interpreted with caution because this is a novel methodology; however, the treatment sequence analysis may be the most methodologically sound analysis to derive estimates of comparative efficacy in CD in the absence of head-to-head evidence.

Keywords:

• Network meta-analysis
• Crohn’s disease
• biologics
• adaptive trial design
• study design
• indirect treatment comparisons
• ustekinumab

Transparency

Declaration of funding

This study was funded by Janssen Inc. Cornerstone received financial support from Janssen Inc. for the conduct of this study.

Author contributions: A.V. was involved with analysis of the data, drafting the manuscript and approving the final version to be published. F.R.W., P.D., M.H., B.H. and C.C. assisted with interpretation of data, critically reviewed for important intellectual content for the work and approved the final version to be published.

Declaration of financial/other relationships

P.D. and M.H. have disclosed that they are employees of Janssen Inc. B.H. has disclosed that he is an employee of the Ottawa Hospital Research Institute and provides methodological advice for Cornerstone Research Group Inc. C.C. has disclosed that she/he is an employee and shareholder of Cornerstone Research Group Inc. A.V. and F.R.W. have disclosed that they are employees of Cornerstone Research Group Inc. Cornerstone consults for various pharmaceutical, medical device and biotech companies.

CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work but have no relevant financial or other relationships to disclose.

Previous presentation

The work from this study has been previously presented as an abstract at the 2017 Canadian Digestive Diseases Week. Our work builds off initial concepts presented by Pacou and colleagues at ISPOR in 2016.

Acknowledgments

The authors would like to acknowledge Meaghan Bartlett for writing support, and the peer reviewers for their helpful comments.