OBJECTIVES AND METHODS

2OBJECTIVES AND METHODS

2.1. Objectives

To perform a systematic review of the beneficial and harmful effects of ustekinumab for the induction and maintenance treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response with, loss of response to, or intolerance to either conventional therapy (corticosteroids or immunomodulators) or one or more TNF alpha antagonist, or who were corticosteroid dependent.

2.2. Methods

All manufacturer-provided trials considered to be pivotal were included in the systematic review. Phase III studies were selected for inclusion based on the selection criteria presented in Table 5.

Table 5

Inclusion Criteria for the Systematic Review.

The literature search was performed by an information specialist using a peer-reviewed search strategy.

Published literature was identified by searching the following bibliographic databases: MEDLINE (1946–) with in-process records and daily updates via Ovid; Embase (1974–) via Ovid; and PubMed. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Stelara (ustekinumab) and Crohn’s disease.

No filters were applied to limit retrieval by study type. Retrieval was not limited by publication year or by language. Conference abstracts were excluded from the search results. See Appendix 2 for the detailed search strategies.

The initial search was completed on October 7, 2016. Regular alerts were established to update the search until the meeting of the CADTH Canadian Drug Expert Committee (CDEC) on February 15, 2017. Regular search updates were performed on databases that do not provide alert services.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the following sections of the Grey Matters checklist (https://www.cadth.ca/grey-matters): health technology assessment agencies, health economics, clinical practice guidelines, drug and device regulatory approvals, advisories and warnings, drug class reviews, databases (free) and Internet search. Google and other Internet search engines were used to search for additional Web-based materials. These searches were supplemented by reviewing the bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies.

Two CDR clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least one reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion. Included studies are presented in Table 6, Table 7, and Table 8; excluded studies (with reasons) are presented in 0.

Publication Details

Copyright

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

Publisher

Canadian Agency for Drugs and Technologies in Health, Ottawa (ON)

NLM Citation

Ustekinumab (Stelara) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 Apr. 2, OBJECTIVES AND METHODS.

Table 5Inclusion Criteria for the Systematic Review

Patient Population	Adult patients with moderately to severely active Crohn’s disease who have had an inadequate response with, loss of response to, or intolerance to either conventional therapy (corticosteroids or immunomodulators) or one or more TNF alpha antagonist, or who were corticosteroid dependent. Subgroups: Disease severity at baseline No prior experience with a TNF alpha antagonist or conventional therapy Previous therapy with a TNF alpha antagonist or conventional therapy: Failure or intolerance to a TNF alpha antagonist or conventional therapy No failure or intolerance to a TNF alpha antagonist or conventional therapy.
Intervention	Ustekinumab single IV induction infusion based on body weight at week 0; followed by 90 mg SC 8 weeks later, then every 8 or 12 weeks thereafter. Induction recommended IV dose (approximately 6 mg/kg): 260 mg if body weight is ≤ 55 kg 390 mg if body weight is > 55 kg to ≤ 85 kg 520 mg if body weight is > 85 kg.
Comparators	Adalimumab Infliximab Vedolizumab
Outcomes	Efficacy outcomes: Clinical remission (e.g., using the CDAI score)^a Clinical response (e.g., using the CDAI score) Health-related quality of life, functional and disability outcomes (e.g., IBDQ, SF-36) ^a Mucosal healing determined by histology or endoscopy Need for surgery for Crohn’s disease ^a Harms outcomes: Mortality SAEs WDAEs AEs, including but not limited to Infusion or injection-site reactions Hypersensitivity reactions Infections Malignancies Major cardiovascular events Neurological AEs (new onset or exacerbation of MS, PN, or GBS)
Study Design	Published and unpublished phase III RCT

: AE = adverse events; CDAI = Crohn’s Disease Activity Index; GBS = Guillain–Barré syndrome; IBDQ = Inflammatory Bowel Disease Questionnaire; IV = intravenous; MS = multiple sclerosis; PN = peripheral neuropathy; RCT = randomized controlled trial; SAE = serious adverse events; SC = subcutaneous injection; SF-36 = Short Form (36) Health Survey; TNF = tumour necrosis factor; WDAE = withdrawal due to adverse events.

a: These outcomes were identified as being of particular importance to patients in the input received by CADTH from patient groups.