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

Abstract

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

The primary objective will be to determine the efficacy and safety of vedolizumab used for induction and maintenance of remission in CD.

Background

Crohn's disease (CD) is a chronic idiopathic inflammatory disease that can affect any part of the gastrointestinal tract from mouth to anus. CD patients typically present with symptoms of recurrent abdominal pain, non‐bloody diarrhea and weight loss. Conventional therapies for patients with active CD include corticosteroids, methotrexate, azathioprine and 6‐mercaptopurine. While these medications are effective, it is estimated that 16 to 20% of patients with active disease fail to respond to corticosteroids (Faubion 2001; Munkholm 1994). Furthermore, results from a two year open‐label randomized trial found that 57.8% of patients who received conventional therapy (corticosteroids followed by antimetabolite treatment) failed to achieve remission (D'Haens 2008).

Infliximab, a neutralizing murine immunoglobulin (Ig)G₁chimeric anti‐tumour necrosis factor alpha (anti‐TNF‐α) monoclonal antibody, is effective for patients with moderate to severely active disease who fail to respond to conventional therapy and those with fistulizing disease (Akobeng 2006; Kornbluth 2010). Other anti‐TNF‐α antagonists proven to be effective for the treatment of CD include adalimumab and certolizumab pegol (Colombel 2007; Hanauer 2006; Rutgeerts 2012; Sandborn 2007; Sandborn 2011; Schreiber 2007). Despite currently available drug therapies, some patients will require surgery due to drug intolerance or lack of response. Furthermore, a large proportion of anti‐TNF‐α treated CD patients lose response to conventional drug therapy within one year of treatment (Billioud 2011). Identification of other treatment strategies for Crohn's disease is thus an important area of research.

Cellular adhesion molecules play an important role in the pathogenesis of intestinal inflammation, and have been studied as potential therapeutic targets in inflammatory bowel disease. One such target is the alpha4beta7 (α4β7) integrin, a molecule found on circulating T lymphocytes that is involved in recruitment of leukocytes to the gastrointestinal tract (Erle 1994). The major ligand of α4β7, mucosal adressin‐cell adhesion molecule‐1 (MAdCAM‐1), is selectively expressed on the endothelium of the intestinal vasculature and is present in increased concentrations in areas of intestinal inflammation. Studies evaluating natalizumab, a humanized IgG4 monoclonal antibody that leads to inhibition of the alpha4 (α4) integrin, found it to be effective for the induction and maintenance of remission of Crohn's disease (MacDonald 2007; Sandborn 2005; Targan 2007). However, reports of progressive multifocal leukoencephalopathy (PML) in patients taking natalizumab as part of multi‐drug therapy have raised concerns regarding the safety of broad inhibition of the α4 integrin (Bloomgren 2012; Yousry 2006). Therapies directed at the α4β7 integrin may be associated with a more selective inhibition of T cell homing, possibly resulting in less impairment of systemic immunity while reducing intestinal inflammation.

Vedolizumab is a humanized monoclonal IgG1 antibody specific for the α4β7 integrin that does not cross‐react with the alpha4 monomer. Treatment with vedolizumab results in reduced intestinal inflammation in a cotton‐top tamarin model of colitis (Hesterberg 1996). Further study in healthy cynomolgus monkeys showed that vedolizumab has selective activity in its effects on gastrointestinal tissue. In the gut vedolizumab reduced the frequency of leukocytes and β lymphocytes. This was not seen in other organs (Fedyk 2012). Moderate to high quality data from a recent Cochrane review shows that vedolizumab is superior to placebo for induction of clinical remission and response and endoscopic remission in patients with moderate to severely active ulcerative colitis (Bickston 2014). Moderate quality data suggests that vedolizumab is superior to placebo for prevention of relapse in patients with quiescent ulcerative colitis (Bickston 2014). This systematic review and meta‐analysis summarizes the current evidence regarding the use of vedolizumab for induction and maintenance of remission in CD.

Objectives

The primary objective will be to determine the efficacy and safety of vedolizumab used for induction and maintenance of remission in CD.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials will be considered for inclusion.

Types of participants

Adult patients (>18 years of age) with active or quiescent CD as defined by conventional clinical, histological or endoscopic criteria will be considered for inclusion.

Types of interventions

Trials where vedolizumab was compared to placebo or a control medication will be considered for inclusion.

Types of outcome measures

The primary outcome measures will be the proportion of patients who failed to achieve clinical remission and the proportion of patients who relapsed as defined by the included studies. Secondary outcomes will include the proportion of patients who failed to have a clinical response, failure to enter endoscopic remission, failure to have an endoscopic response, endoscopic relapse, disease‐specific quality of life, adverse events, withdrawal due to adverse events, serious adverse events, C‐reactive protein and fecal calprotectin.

Search methods for identification of studies

We will search PubMed (1966 to date), MEDLINE (1966 to date), EMBASE (1980 to date), and CENTRAL (Cochrane Library) to identify applicable studies. The search strategies are reported in Appendix 1.

We will hand search conference abstracts from 1999 onwards to identify studies published as abstracts (e.g. Digestive Disease Week and United European Gastroenterology Week). References from published articles will be searched to identify additional citations. Unpublished data from on‐going trials will be identified by correspondence with authors and experts in the field.

Data collection and analysis

Selection of studies

Publications identified by the search strategy will be independently assessed by two authors (RK and MHM). Relevant studies will be selected according to the inclusion criteria.

Data extraction and management

Two authors (MHM and JKM) will independently extract data from the included studies. The extracted data will include patient demographics (e.g. age, disease distribution, disease duration), concomitant medications, prior exposure to anti‐TNF‐α antagonists, the type of disease activity scoring instrument used, treatment and control modalities, the number of subjects randomized to each treatment group, the duration of treatment and follow‐up, and the number of subjects lost to follow‐up and outcome data. The corresponding author will be contacted in cases where data are not available from the published reports. Disagreement regarding data extraction will be resolved by discussion and consensus.

Assessment of risk of bias in included studies

Two authors (MHM and JKM) will independently assess the methodological quality of the included studies using the Cochrane risk of bias tool (Higgins 2011). We will assess the following items:

1. Sequence generation (i.e. method of randomisation);

2. Allocation sequence concealment;

3. Blinding;

4. Incomplete outcome reporting (i.e. the investigators had determined methods of dealing with attrition);

5. Selective outcome reporting (i.e. the investigators reported all a priori outcomes); and

6. Other sources of bias (i.e. anything else in the study that could have increased the risk of bias).

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

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria will be applied to assess the overall quality of evidence supporting the primary and selected secondary outcomes. Evidence from randomized controlled trials begin as high quality evidence. They can then be downgraded due to: (1) risk of bias , (2) indirect evidence, (3) inconsistency (unexplained heterogeneity), (4) imprecision, and (5) publication bias. The overall quality of evidence for each outcome will be determined and 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); and very low quality (i.e. we are very uncertain about the estimate) (Guyatt 2008; Schünemann 2011). Disagreement among authors regarding risk of bias will be resolved by discussion and consensus.

Measures of treatment effect

Data will be analyzed using Review Manager (RevMan 5.3.5). All data will be analyzed on an intention‐to‐treat (ITT) basis. For dichotomous outcomes we will calculate the risk ratio (RR) and corresponding 95% confidence interval (CI). For continuous outcomes we will calculate the mean difference (MD) and corresponding 95% CI.

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 8 weeks). Cross‐over trials will be included if data are available from the first phase of the study (i.e., before any cross‐over). Separate analyses will be conducted for comparisons between vedolizumab versus placebo as well as vedolizumab versus active comparator. Where studies allocated subjects to more than one vedolizumab treatment arm, then these will be pooled for the primary analysis. When possible, additional subgroup analyses will be performed to compare efficacy and safety among different doses of vedolizumab. 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

Where possible, study authors will be contacted to request missing data. Patients with missing outcomes will be assumed to be treatment failures. Where appropriate, we will perform a sensitivity analysis to assess the impact of this assumption on the effect estimate.

Assessment of heterogeneity

We will assess heterogeneity among studies using the Chi² test (a P value of 0.10 will be considered statistically significant) and the I² statistic. An I² value of 25% indicates low heterogeneity, 50% indicates moderate heterogeneity and 75% indicates high heterogeneity (Higgins 2003). We will use sensitivity analyses to explore potential explanations for heterogeneity.

Assessment of reporting biases

We will assess potential reporting bias by comparing outcomes listed in protocols to published manuscripts. If protocols are not available we will compare outcomes listed in the methods section of published manuscripts to those reported in the results section. If a sufficient number of studies are included (i.e. > 10) in the pooled analyses, we will investigate potential publication bias using funnel plots (Egger 1997).

Data synthesis

Data from individual trials will be combined for meta‐analysis when the interventions, patient groups and outcomes are sufficiently similar (to be determined by consensus). The pooled RR and 95% CI will be calculated for dichotomous outcomes. For continuous outcomes the pooled MD and corresponding 95% CI will be calculated. We will calculate the standardized mean difference (SMD) and 95% CI when different scales have been used to measure the same underlying construct. A fixed‐effect model will be used to pool data unless heterogeneity exists between the studies. A random‐effects model will be employed if heterogeneity exits (I² 50 to 75%). We will not pool data for meta‐analysis if a high degree of heterogeneity (I² ≥ 75%) is detected.

Appendices

Appendix 1. Search strategies

PubMed (1966 to date)

1. (singl* OR doubl* OR tripl* OR trebl* OR blind* OR mask* OR placebo* OR single‐blind* OR double‐blind* OR triple‐blind* OR random* OR (controlled clinical)) 2. crohn* OR IBD OR "inflammatory bowel disease*" 3. (MLN‐02 OR MLN02 OR (MLN 02) OR LDP‐02 OR LDP02 OR (LDP 02) OR MLN0002 OR MLN‐0002 OR (MLN 0002) OR LDP0002 OR LDP‐0002 OR (LDP 0002) OR vedolizumab) 4. (anti‐alpha4* OR (anti alpha4*) OR antialpha4* OR (alpha4beta7 antibod*)) 5. (#1 AND #2) 6. (#3 OR #4) 7. (#5 AND #6)

EMBASE + EMBASE Classic (1947 to date)

1. random$.tw. 2. factorial$.tw. 3. (crossover$ or cross over$ or cross‐over$).tw. 4. placebo$.tw. 5. single blind.mp. 6. double blind.mp. 7. triple blind.mp. 8. (singl$ adj blind$).tw. 9. (double$ adj blind$).tw. 10. (tripl$ adj blind$).tw. 11 assign$.tw.. 12. allocat$.tw. 13. crossover procedure/ 14. double blind procedure/ 15. single blind procedure/ 16. triple blind procedure/ 17. randomized controlled trial/ 18. or/1‐17 19. (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) 20. 18 not 19 21. exp Crohn disease/ or crohn*.mp. or exp colon Crohn disease/ 22. (inflammatory bowel disease* or IBD).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 23. 21 or 22 24. 20 and 23 25. vedolizumab.mp. or exp vedolizumab/ 26. (MLN‐02 or MLN02 or "MLN 02" or LDP‐02 or LDP02 or "LDP 02" or MLN0002 or MLN‐0002 or "MLN 0002" or LDP0002 or LDP‐0002 or "LDP 0002").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 27. (anti‐alpha4* or "anti alpha4*" or antialpha4* or "alpha4beta7 antibod*").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 28. 25 or 26 or 27 29. 24 and 28

MEDLINE (1946 to date)

1. random$.tw. 2. factorial$.tw. 3. (crossover$ or cross over$ or cross‐over$).tw. 4. placebo$.tw. 5. single blind.mp. 6. double blind.mp. 7. triple blind.mp. 8. (singl$ adj blind$).tw. 9. (double$ adj blind$).tw. 10. (tripl$ adj blind$).tw. 11 assign$.tw. 12. allocat$.tw. 13. crossover procedure/ 14. double blind procedure/ 15. single blind procedure/ 16. triple blind procedure/ 17. randomized controlled trial/ 18. or/1‐17 19. (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) 20. 18 not 19 21. exp Crohn disease/ or crohn*.mp. 22. (inflammatory bowel disease* or IBD).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 23. 21 or 22 24. 20 and 23 25. vedolizumab.mp. 26. (MLN‐02 or MLN02 or "MLN 02" or LDP‐02 or LDP02 or "LDP 02" or MLN0002 or MLN‐0002 or "MLN 0002" or LDP0002 or LDP‐0002 or "LDP 0002").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 27. (anti‐alpha4* or "anti alpha4*" or antialpha4* or "alpha4beta7 antibod*").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 28. 25 or 26 or 27 29. 24 and 28

COCHRANE CENTRAL

#1. crohn* OR IBD OR "inflammatory bowel disease*" #2. MLN‐02 or MLN02 or (MLN 02) or LDP‐02 or LDP02 or (LDP 02) or MLN0002 or MLN‐0002 or (MLN 0002) or LDP0002 or LDP‐0002 or (LDP 0002) or vedolizumab #3. anti‐alpha4* or (anti alpha4*) or antialpha4* or (alpha4beta7 antibod*) #4. #2 or #3 #5. #1 and #4

SR‐IBD

“MLN*” “OR LDP*” OR “vedo*” OR “alpha4* OR “anti‐alpha*” OR antialpha*

What's new

Date	Event	Description
1 November 2017	Amended	This protocol is being withdrawn.

Declarations of interest

Dr. Khanna has received honoraria from AbbVie, Jansen, and Takeda for consultancy. All of these activities are outside the submitted work.

Brian Feagan has received fee(s) from Abbott/AbbVie, Amgen, Astra Zeneca, Avaxia Biologics Inc., Bristol‐Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, Tillotts Pharma AG, UCB Pharma for Board membership; fee(s) from Abbott/AbbVie, Actogenix, Albireo Pharma, Amgen, Astra Zeneca, Avaxia Biologics Inc., Axcan, Baxter Healthcare Corp., Boehringer‐Ingelheim, Bristol‐Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Merck, Millennium, Nektar, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, Tillotts, UCB Pharma, Vertex Pharma, Warner‐Chilcott, Wyeth, Zealand, and Zyngenia for consultancy; and lecture fee(s) from: Abbott/AbbVie, JnJ/Janssen, Takeda, Warner‐Chilcott, and UCB Pharma. All of these activities are outside the submitted work.

Brian Bressler has received fee(s) from Janssen, Abbvie, Celltrion, and Takeda for consultancy; has grants/grants pending from Janssen; payment for lectures from Takeda, Ferring, Actavis, Janssen, Abbvie, and Shire; stock/stock options with Qu Biologics and travel expenses from Janssen, and Abbvie. All of these activities are outside the submitted work.

Greg Rosenfeld has received fees from Abbvie, Janssen and Shire for lectures; and fees from Abbvie for development of educational presentations. All of the fees received are outside the scope of the submitted work.

Barrett Levesque has received fee(s) from Santarus, Prometheus Labs, Takeda, Abbvie, and Nestle Health Sciences for consultancy. All of these activities are outside the submitted work.

Mahmoud Mosli, Mindy Lam, Nancy Fu and John MacDonald have no known conflicts of interest.

Notes

This protocol is being withdrawn because the composition of the author team does not adhere to Cochrane COI policy.

Withdrawn from publication for reasons stated in the review