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Abstract
Introduction Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. Recently, data from phase 2 and 3 trials presented different results in patients with moderately to severely active ulcerative colitis. The aim of this study is to summarise the latest published trials to analysis the role of etrolizumab in treatment of moderately to severely active ulcerative colitis during induction and maintenance phases.
Methods Eligible randomised controlled trials (RCTs) will be retrieved from following databases: PubMed, Web of Science and the Cochrane Library. The last search time is May 2023. Two reviewers will independently identify RCTs according to inclusion and exclusion criteria. The primary outcome is clinical remission. The second outcomes are clinical response, endoscopic remission, endoscopic improvement, histological remission, any adverse event. The Grades of Recommendations, Assessment, Development and Evaluation tool will be established to estimate the evidence level of each outcome. All compute will be accomplished with Stata V.17.0 software.
Ethics and dissemination This systematic review and meta-analysis will be disseminated through peer-reviewed journals. No ethical approval requirements are required because the results presented in this study are conducted based on published data.
PROSPERO registration number CRD42023415369.
- systematic review
- gastroenterology
- inflammatory bowel disease
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This systematic review will be conducted with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols.
Induction and maintenance phases will be separately analysed.
Included studies will be strictly restricted as placebo-controlled, randomised clinical trials.
Grades of Recommendations, Assessment, Development and Evaluation is employed to assess evidence level of outcomes.
One potential limitation of this study is that substantial heterogeneity will exist among included studies.
Introduction
Description of the condition
Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is characterised by chronic, disabling, inflammatory disease of the colon that has a perennial detrimental influence on patient’s quality of life.1–4 Immunomodulators (such as azathioprine, mercaptopurine and tumour necrosis factor inhibitors), corticosteroids and targeted therapies are used for patients active UC; however, numerous patients do not retain an enduring response to these treatment, especially among patients with moderately to severely active UC.4–6 Hence, feasible, valuable and safe targeted therapy that possesses ability to implement clinical remission is warranted for these patients.
Etrolizumab is the first biologic, dual-action, anti-β7 monoclonal, IgG1-humanised antibody in the gut that specifically targets the β7 subunit of both the α4β7 and α4Eβ7 integrins, which regulate trafficking and retention of leucocyte/lymphocyte subsets, respectively, in the intestinal mucosa. Rutgeerts et al conducted the phase I, randomised trial in 2013 with 33 patients (26 in etrolizumab and 7 in placebo) and verified etrolizumab is well tolerated among patients with moderate-to-severe UC.7 In 2014, Vermeire et al published a first phase II, placebo-controlled, randomised clinical trial and demonstrated that etrolizumab is superior to placebo as regard achieving clinical remission in the induction therapy process.8 However, evidence-based data is still insufficient.9 The aim of this systematic review and meta-analysis of RCTs is to collect newest evidence on application of etrolizumab for patients with UC.
Methods
Literature search
This protocol was written following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines.10 Meanwhile, the systematic review will be conducted by following PRISMA guidelines.11 Here, we will perform literature search to collect relevant studies from PubMed, Embase and the Cochrane Library databases by using predefined key words (table 1) from inception until 1 July 2023. Furthermore, to broaden the search, previous published reviews and reference lists of relevant articles will be screened.
Search strategy
Eligibility criteria
Types of studies
Here, to generate high level evidence for this topic, we only included placebo-controlled RCTs. Also, to broaden the search, no restriction on geographical region or year of publication.
Types of participants
Patients, age>18, with moderately to severely active UC (Mayo Clinic total score of 6–12 with an endoscopic subscore of≥2, a rectal bleeding subscore of≥1, and a stool frequency subscore of ≥1), possess a definite diagnosis of UC for a duration of 3 months or more, as evidenced by clinical and endoscopic findings, along with evidence of disease extending to 20 cm or beyond from the anal margin, will be enrolled in present analysis.12
Types of interventions
Patients in intervention group will receive etrolizumab for induction or maintenance therapy. Simultaneously, patients also receive matching placebo, such as subcutaneous dummy adalimumab saline placebo.
Types of control group
For this group, patients will only receive matching placebo.
Outcomes
The primary outcomes are clinical remission, clinical response, while second outcomes are endoscopic remission, endoscopic improvement, histological remission and any adverse event.
Exclusion criteria
An article will be excluded if meets the one of the following exclusion criteria:
Pharmacokinetics, pharmacodynamics analysis.
Other subtype IBD, such as Crohn’s disease.
Case reports, case series, letters to editor, reviews, comments, animal studies or cost-effective studies.
Incomplete research data.
Articles that were written in non-English languages.
Study selection and data extraction
After downloading all identified records from PubMed, Embase and the Cochrane Library databases, according to pre-established eligibility and exclusion criteria, two trained investigators (XQ, MW) will independently identify eligible RCTs. During study selection, any divergences or other issues will be settled down by advisement with a third investigator (XX). The process of study selection is presented in figure 1.
Process of study selection.
For eligible RCTs, available information will be independently recorded by using a standardised Microsoft Excel file by two investigators (XQ, MW). Analogously, a third investigator (XX) will umpire in case of arising any divergences or other issues. The following items are regarded as valuable for readers to comprehend context of study: the name of RCT, year of publish, multicentre (yes or no), study period, therapy phase, sample size of each group, etrolizumab regime, the definitions of outcomes and follow-up. An email will be sent to author if valuable data missing. With respect to republished studies, we only collect the newest one.
Quality assessment
As the current systematic review merely including RCTs, the Cochrane Collaboration’s tool, Risk of Bias V.2.0 tool13 will be used to assess methodological quality of the included RCTs by two trained investigators (XQ, MW). Risk of Bias V.2.0 tool contains six sections: ‘randomization process’, ‘deviations from intended interventions’, ‘missing outcome data’, ‘measurement of the outcome’, ‘selection of the reported result’ and ‘overall’. In this process, intraclass correlation coefficient will be computed to detect consistency in the data obtained by the two investigators (XQ, MW) and a third investigator (XX) will redress evaluated results if necessary. The risk bias of included RCTs will be divided into the following three levels: ‘low risk’, ‘some concerns’ or ‘high risk’.
Measures of treatment effect
The Stata V.17.0 (Cambridge, UK) will be used to calculate statistics data. Here, for dichotomous data, risk ratio with its 95% CI will be estimated. For continuous data, weighted mean difference or standardised mean differences with its 95% CI will be estimated. Heterogeneity across RCTs is assessed by the Cochran Q statistic (χ2 test),14 and I2 are employed to depict the level of interstudy heterogeneity.15 In case of I2 more than 50%, or p value of χ2 test, data will be synthesised by using random-effect model with the Der Simonian-Laired method; otherwise, fix-effect model with the Mantel-Haenszel method will be used. A p value of less than 0.05 is considered as statistical significance, except for a p value of less than 0.10 for χ2 test.
Subgroup analysis and sensitivity analysis
For all outcomes, subgroup analyses are conducted according to therapy phase (induction therapy, maintenance therapy), publish year, sample size. Also, for all outcomes, sensitivity analyses are performed to check the stability and consistency of pooled results with leave one out method.
Assessment of publication bias
Publication bias will be visualised with funnel plot, and a p value of Egger’test will be calculated to estimate potential publication bias.16
Quality of evidence
For this systematic review and meta-analysis, the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) tool will be used to divide evidence level of each outcome into four grades: ‘high level’, ‘moderate level’, ‘low level’ and ‘critically low level’.17
Ethics statements
Patient consent for publication
Acknowledgments
Many thanks to RAJU DATHEPUTHE for check language issue.
References
Footnotes
Contributors XQ, HS and XX conceptualise this context. XQ, MW, WZ and WL will develop the study protocol and implement the systematic review under the supervision of HS and XX. All authors contributed to the drafting of the final protocol.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.