Vedolizumab for induction and maintenance of remission in Crohn’s disease

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

The primary objective of this systematic review of the literature is to assess the efficacy and safety of vedolizumab in the induction and maintenance of remission in Crohn's disease.

Background

Description of the condition

Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD), characterised by transmural inflammation of the gastrointestinal tract. Its pathophysiology is thought to involve a complex interplay between genetic susceptibility, immune and environmental factors (Boyapati 2015). Worldwide, the incidence of CD is increasing, with the highest incidence in westernised nations (Molodecky 2012).

Symptoms depend on the area of bowel involved, but often include diarrhoea, abdominal pain, gastrointestinal bleeding and weight loss. Complications may further arise with the development of stricturing or fistulising disease. Conventional therapy is with corticosteroids followed by an immunomodulator (methorexate, azathioprine, 6‐mercaptopurine) or an anti‐TNF agent (infliximab, adalimumab, certolizumab). However this approach results in up to 55‐60% of patients failing to achieve remission at one year following diagnosis (D'Haens 2008). Despite the advent of anti‐TNF agents, many patients have either primary non‐response or secondary loss of response and as such, new therapies with different mechanisms of action are required.

Description of the intervention

Vedolizumab is a humanised monoclonal antibody which inhibits the α4β7 integrin. Integrins are adhesion molecules which allow for lymphocyte trafficking, an important process in T‐cell mediated inflammation. The value of inhibiting α4 integrins was recognised in the form of natalizumab, for both the treatment of multiple sclerosis and CD (von Andrian 2003). However, the contemporary use of natalizumab for CD has been limited by the risk of progressive multifocal leukoencephalopathy (Bloomgren 2012). Vedolizumab specifically inhibits the α4β7 integrin from binding to MAdCAM‐1, a molecule selectively expressed in the gastrointestinal tract (Butcher 1996). This more selective mechanism of action should theoretically reduce the likelihood of progressive multifocal leukoencephalopathy.

How the intervention might work

The value of α4β7 as a target in the treatment of inflammatory bowel diseases was initially demonstrated in animal colitis models (Hesterberg 1996). Furthermore, vedolizumab has been shown to be effective in inducing and maintaining remission in moderate to severe ulcerative colitis (UC) (Bickston 2014).

Why it is important to do this review

This review will aim to highlight the efficacy and risks of vedolizumab in CD, compared to other medical therapies and placebo. A prior systematic review in 2014 concluded that vedolizumab was more effective than placebo as induction and maintenance therapy for IBD, which includes CD and UC (Wang 2014). Similarly, another systematic review and meta‐analysis in 2014 concluded that vedolizumab was superior to placebo for inducing remission and response in UC (Bickston 2014). To our knowledge, there is no published systematic review and meta‐analysis which reviews the same question specifically in CD. This review would also aim to systematically review any updated literature since the aforementioned reviews.

Objectives

The primary objective of this systematic review of the literature is to assess the efficacy and safety of vedolizumab in the induction and maintenance of remission in Crohn's disease.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) will be considered for inclusion. This may include published conference abstracts.

Types of participants

Participants (adults or children) with CD (defined by clinical, histologic or endoscopic criteria), will be included in this review.

To avoid overlap with an existing Cochrane review (Iheozor‐Ejiofor 2019) we will only include participants who have achieved a medically induced remission. Participants who have had Crohn's‐related surgery in the preceding 6 months will be excluded.

Types of interventions

Studies comparing vedolizumab with a control arm consisting of placebo or other medical therapy for CD will be considered for inclusion.

Types of outcome measures

Primary outcomes

• Failure to achieve clinical remission (as defined by the primary studies)

• Clinical relapse (as defined by the primary studies)

Secondary outcomes

• Failure to achieve clinical response

• Failure to achieve endoscopic remission

• Failure to achieve endoscopic response

• Adverse event

• Serious adverse events

• Surgery

Timing of outcome measurement

Primary and secondary outcomes will each be assessed at 6 weeks, 12 weeks and 52 weeks where available.

Search methods for identification of studies

Electronic searches

The following electronic databases will be searched: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane IBD Review Group Specialised Trials Registrar, World Health Organisation trials registry (WHO ICTRP; https://www.who.int/ictrp/en/), and ClinicalTrials.gov (Appendix 1)

Searching other resources

We will conduct further searches based on reference lists of identified studies. We will also hand search conference abstracts (Digestive Diseases Week, United European Gastroenterology Week, European Crohn's and Colitis Organisation Congress) from 2008 onwards to identify studies published as abstracts at conferences. Experts in the field will also be consulted for additional published and unpublished studies.

Data collection and analysis

Selection of studies

Review authors (SH and AK) will independently screen titles and abstracts from our literature search for relevance based on our inclusion criteria. These studies will be retrieved and reviewed in full. Any disagreements between authors regarding inclusion criteria will be resolved through discussion with a third author (RB).

Data extraction and management

We will extract the following data:

• General information: title, author, year of publication, journal

• Study information: study design, setting, inclusion/exclusion criteria, type of disease activity scoring instrument used

• Population characteristics: baseline characteristics (age, sex, disease distribution, disease duration, concomitant medications, prior exposure to anti‐TNF agents), number of participants recruited, total number of patients screened and randomised to each group

• Intervention characteristics: dose and schedule of vedolizumab, use of adjunct therapies (corticosteroids, other immunomodulators), duration of treatment

• Follow‐up: length of follow‐up, withdrawals, number of patients lost to follow up

• Outcomes: primary and secondary as described above

If the above is not determined on review of the paper, we will email the authors to clarify the above. Data will be extracted and managed with a data collection form.

Assessment of risk of bias in included studies

The methodological quality of each study will be assessed independently by two review authors (SH and AK). For RCTs, we will use the revised Cochrane risk of bias tool, as based in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). Factors to be assessed are:

• Sequence generation (i.e., was the allocation sequence adequately generated?)

• Allocation sequence concealment (i.e., was allocation adequately concealed?)

• Blinding (i.e., was knowledge of the allocated intervention adequately prevented during the study?)

• Incomplete outcome data (i.e., were incomplete outcome data adequately addressed?)

• Selective outcome reporting (i.e., are reports of the study free of suggestion of selective outcome reporting?)

• Other potential sources of bias (i.e., was the study apparently free of other problems that could put it at high risk of bias?)

The studies will be judged to be of high, low or unclear risk of bias based on these factors.

Measures of treatment effect

Data will be analysed using Review Manager (RevMan). All data will be analysed on an intention‐to‐treat basis. Results will be expressed as the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, the mean difference (MD) and corresponding 95% CI will be calculated. For studies that report the log hazard ratio and standard error for time‐to‐event outcomes, we will calculate the hazard ratio (HR) and corresponding 95% CI using the generic inverse‐variance method. Definitions for clinical and endoscopic remission will be set by the investigators of included studies.

Unit of analysis issues

When studies report multiple observations for the same outcome, the outcomes will be combined for fixed intervals of follow‐up (e.g., clinical remission at eight weeks). Cross‐over trials will be included if data are available from the first phase of the study (i.e., before any cross‐over). Where studies allocated participants to more than one treatment arm, then these arms will be pooled for the primary analysis. Although some studies may report more than one efficacy or safety event per patient, the primary analysis will consider the proportion of patients who experienced at least one event.

Dealing with missing data

For studies with missing or unclear data, the original authors will be contacted by e‐mail. For dichotomous data which remains missing or unclear, it will be counted as a treatment failure, in line with Intention to Treat principle. For missing continuous data, we will conduct an available case analysis. Where appropriate, sensitivity analyses will be conducted to assess the impact of including unclear data on the effect estimate.

We will attempt to retrieve other missing information, such as study design and standard deviations, through e‐mail contact with the original authors.

Assessment of heterogeneity

We will assess for heterogeneity firstly by visual inspection of forest plots. We will observe for presence of statistical heterogeneity based on the Chi² test (with a P value of 0.10 considered significant). We will then aim to quantify statistical heterogeneity using the I² statistic, in line with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We will base our I² interpretation on:

• 0‐40%: might not be important

• 30‐60%: may represent moderate heterogeneity

• 50‐90%: may represent substantial heterogeneity

• 75‐100%: considerable heterogeneity

In situations of moderate to considerable heterogeneity, we will aim to exclude visually obvious outliers to determine if this explains the heterogeneity.

Assessment of reporting biases

Potential reporting bias will be evaluated by comparing outcomes listed in protocols to published manuscripts. If the protocols are not available, we will compare outcomes listed in the methods section of published manuscripts to those described in the results section. If a sufficient number of studies are included (i.e. > 10) in the pooled analyses, we plan to investigate potential publication bias using funnel plots.

Data synthesis

Data will be combined for meta‐analysis when we determine, by consensus, that patient groups, interventions and outcomes are sufficiently similar. For binary outcomes, we will calculate the pooled RR and 95% confidence interval. For continuous outcomes (if present), we will calculate the pooled mean difference and 95% confidence interval. The standardized mean difference (SMD) and 95% CI will be calculated when difference scales are used to measure the same outcome.

A fixed‐effect model will be used to pool data unless heterogeneity exists between the studies. If I² ≥ 50% we will employ the random‐effects model. Otherwise the fixed‐effects model will be used to pool data. We will not pool data for meta‐analysis if a high degree of heterogeneity (I² ≥ 75%) is detected.

Subgroup analysis and investigation of heterogeneity

If there is sufficient data, we will perform the following subgroup analyses:

• Participants on concomitant medications, compared with those who are not on concomitant medications.

• Paritcipants previously exposed to anti‐TNF inhibitors, compared with those not previously exposed.

Sensitivity analysis

Sensitivity analyses will examine the impact of the following variables on the pooled effect: random‐effects versus fixed‐effect modelling; low risk of bias only versus unclear or high risk of bias; and relevant loss to follow‐up (> 10% versus < 10%).

Summary of findings and assessment of the certainty of the evidence

The quality of the total body of evidence for the primary outcomes of interest will be assessed using the GRADE criteria (Schünemann 2011). Evidence from randomised trials is considered high quality and will be downgraded due to:

• study limitations (risk of bias)

• indirectness

• inconsistency (unexplained heterogeneity)

• imprecision

• publication bias

The overall quality of evidence for each outcome will be classified as high quality (i.e. further research is very unlikely to change our confidence in the estimate of effect); moderate quality (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); or very low quality (i.e. we are very uncertain about the estimate).

We will use GRADEpro GDT to produce summary of findings tables. The following seven key outcomes will be reported in our summary of findings table.

1. Failure to induce clinical remission at 6 weeks

2. Clinical relapse at 52 weeks

3. Failure to induce clinical response at 6 weeks

4. Failure to induce endoscopic remission at 6 weeks

5. Failure to induce endoscopic response at 6 weeks

6. Adverse events at 52 weeks

7. Need for surgery at 52 weeks

History

Protocol first published: Issue 5, 2020

Appendices

Appendix 1. Electronic search strategy

MEDLINE

1. random$.tw.

2. placebo$.tw.

3. single blind.mp.

4. double blind.mp.

5. triple blind.mp.

6. Single‐Blind Method/

7. Double‐Blind Method/

8. Randomized Controlled Trial/

9. or/1‐8

10. Exp Crohn Disease

11. Crohn*.mp.

12. 10 or 11

13. Vedolizumab.mp.

14. anti‐alpha4*.mp.

15. anti alpha 4*.mp.

16. anti‐alpha4beta7*.mp.

17. alpha4beta7 antibod*.mp.

18. alpha4beta7 inhibit*.mp.

19. MLN‐02.mp.

20. MLN 02.mp.

21. MLN‐0002.mp.

22. MLN 0002.mp.

23. MLN0002.mp.

24. Entyvio.mp.

25. or/13‐24

26. 9 AND 12 AND 25

Embase

1. random$.tw.

2. placebo$.tw.

3. single blind.mp.

4. double blind.mp.

5. triple blind.mp.

6. Single‐Blind Method/

7. Double‐Blind Method/

8. Randomized Controlled Trial/

9. or/1‐8

10. Exp Crohn Disease

11. Crohn*.mp.

12. 10 or 11

13. Vedolizumab.mp.

14. anti‐alpha4*.mp.

15. anti alpha 4*.mp.

16. anti‐alpha4beta7*.mp.

17. alpha4beta7 antibod*.mp.

18. alpha4beta7 inhibit*.mp.

19. MLN‐02.mp.

20. MLN 02.mp.

21. MLN‐0002.mp.

22. MLN 0002.mp.

23. MLN0002.mp.

24. Entyvio.mp.

25. or/13‐24

26. 9 AND 12 AND 25

CENTRAL

1. MeSH descriptor: [Crohn Disease]

2. Crohn*

3. Vedolizumab

4. anti‐alpha4*

5. anti alpha 4*

6. anti‐alpha4beta7*

7. alpha4beta 7 antibod*

8. alpha4beta7 inhibit*

9. MLN‐2

10. MLN 02

11. MLN‐0002

12. MLN 0002

13. MLN0002

14. Entyvio

15. #1 or #2

16. #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14

17. 15 AND 16

SR‐IBD

"MLN*" or "vedo*" or "anti‐alpha*"

Clinicaltrials.gov

Vedolizumab and Crohn Disease

Declarations of interest

Samuel Hui: none known.

Anuj Krishna: none known.

Nik Sheng Ding has received a research grant from Takeda and GESA; speaking fees from Abbvie, Ferring, Shire and Pfizer; and is on an advisory board for Abbvie.

Ray K Boyapati: none known.

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