Infliximab for maintenance of remission in Crohn's disease

Abstract

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

The primary aim of this systematic review is to determine the efficacy and safety of infliximab for maintaining remission in patients with CD.

Background

Description of the condition

Crohn’s disease (CD) is an inflammatory bowel disease affecting the gastrointestinal tract (Baumgart 2012). Clinical manifestations vary greatly based on disease phenotype. Clinical manifestations include inflammatory disease (characterized by abdominal pain and diarrhea), stricturing disease (typified by abdominal pain, cramping and bloating) and fistulizing disease. Furthermore, musculoskeletal, dermatological, hepatobiliary and ocular extra‐intestinal manifestations are relatively common (Baumgart 2012). Ongoing transmural inflammation can cause structural complications, such as strictures and fistulae (Cosnes 2002). Approximately 80% of CD patients eventually require surgery during the course of their disease (Munkholm 1995).

The incidence of CD ranges from 0 to 20.2 per 100,000 person‐years in North America and 0.3 to 12.7 per 100,000 person‐years in Europe (Ananthakrishnan 2015). The prevalence of CD has been reported to be 319 per 100,000 persons and 322 per 100,000 persons in North America and Europe, respectively (Ananthakrishnan 2015; Molodecky 2012). The incidence of CD peaks in the second to fourth decade of life, with a potential second peak in the sixth to seventh decades of life (Ananthakrishnan 2015).

Description of the intervention

Infiximab, a chimeric anti‐tumour necrosis factor‐alpha (TNF‐α) monoclonal antibody (Sandborn 1999), is an approved treatment for moderate to severe and fistulizing CD (FDA 2011). TNF‐α, a proinflammatory cytokine, plays a significant role in CD pathogenesis (Hanauer 2002). Macrophages and T lymphocytes produce TNF‐α, which subsequently induces proinflammatory cytokines interleukin‐1 (IL‐1) and IL‐6. These in turn enhance migration of leukocytes via endothelial cell and leukocyte adhesion molecule expression (Poggioli 2007), which subsequently activate leukocytes and induce metalloproteinases and acute‐phase reactants. TNF‐α serum, mucosal and fecal concentrations are elevated in patients with CD (Knight 1993; Poggioli 2007). Infliximab binds to and neutralizes TNF‐α and its activity (Hanauer 2002; Knight 1993; Poggioli 2007).

How the intervention might work

CD patients have significantly greater numbers of TNF‐α producing cells in the lamina propria of the bowel (Poggioli 2007), resulting in greater chronic active inflammation. The mechanism of action of infliximab consists of neutralization of both the soluble and transmembrane TNF‐α components (Mitoma 2005;Poggioli 2007) with subsequent reduction of TNF‐α expressing cells (Baert 1999). Infliximab reduces adhesion molecule expression (ICAM‐1 and LFA‐1) (Baert 1999). Infliximab use in patients with CD has been demonstrated to induce and maintain endoscopic and histological healing (D'Haens 1999). These outcomes are consistently demonstrated to be the most reliable factor associated with improved outcomes, including hospitalization and surgery (Khanna 2015;Shah 2016).

Why it is important to do this review

Prior to biologic medications, treatment options for CD patients were limited to enteric topical or systemic corticosteroids (e.g. budesonide, hydrocortisone or prednisone), aminosalicylates, and immunosuppressive medications (e.g. azathioprine, 6‐mercaptopurine, methotrexate). However, systemic corticosteroids and oral 5‐aminosalicylic acid as maintenance medication for CD do not reduce the risk of relapse (Akobeng 2016;Steinhart 2003). Furthermore, only low quality evidence demonstrated that azathioprine is superior to placebo for maintenance of remission in CD and its use is limited by adverse effects (Chande 2015). The ACCENT‐I and ACCENT‐II trials demonstrated that infliximab is effective for induction and maintenance of clinical remission in CD (Hanauer 2002; Sands 2004). Scheduled infliximab was more effective than sporadic treatment, it increased the proportion of patients with mucosal healing and decreased hospital admissions (Baert 2010;Rutgeerts 2006). In a 2008 Cochrane systematic review of four different anti‐TNF‐α agents, evidence from three randomized controlled trials demonstrated that maintenance of clinical remission (RR 2.50; 95% CI 1.64 to 3.80), clinical response (RR 1.66; 95% CI 1.00 to 2.76), corticosteroid‐sparing (RR 3.13; 95% CI 1.25 to 7.81), and fistula healing (RR 1.87; 95% CI 1.15 to 3.04) is achieved with administration of infliximab in CD patients who had previously responded to infliximab induction therapy (Behm 2008). However, a dedicated systematic review of infliximab for the maintenance of remission in CD does not exist. Furthermore, the advent of combination therapy with immunosuppressant agents and therapeutic drug monitoring has dramatically changed the use of infliximab for maintenance of remission in CD (Colombel 2010, Colombel 2012). Lastly, more studies have analyzed this subject in the time that has elapsed since the aforementioned review (Behm 2008).

Objectives

The primary aim of this systematic review is to determine the efficacy and safety of infliximab for maintaining remission in patients with CD.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) will be considered for inclusion.

Types of participants

Adult participants (> 18 years) with CD in remission (as per conventional clinical, radiological or endoscopic criteria) will be considered for inclusion. Patients with all disease locations and behaviours per the Montreal classification will be included (Satsangi 2006). No restrictions will be applied for sex, disease duration or previous medication exposure. Those with a clinical response to induction therapy will be eligible for inclusion. Patients with surgically‐induced remission will be included and analyzed separately if maintained on infliximab therapy. Remission disease will be defined using conventional criteria (i.e. CDAI < 150).

Types of interventions

Studies analyzing infliximab, alone or in combination with another agent, compared to placebo or active medical therapies for maintenance of remission in CD will be considered for inclusion.

Types of outcome measures

Primary outcomes

The primary outcome measure will be the proportion of patients who failed to maintain clinical remission (as defined by the included studies).

Secondary outcomes

Secondary outcome measures will include:

1) The proportion of patients who failed to maintain clinical response (as defined by the included studies);

2) The proportion of patients who failed to maintain endoscopic response (as defined by the included studies);

3) The proportion of patients who failed to maintain endoscopic remission (as defined by the included studies);

4) The proportion of patients who failed to maintain biomarker remission (as defined by the included studies);

5) Health‐related quality of life (as defined by the included studies);

6) Adverse events;

7) Serious adverse events; and

8) Adverse events resulting in study withdrawal.

Search methods for identification of studies

Electronic searches

Search strategies (Appendix 1) will be run in the following databases to identify potentially relevant studies:

1) MEDLINE (1946‐present);

2) EMBASE (1946‐present);

3) CENTRAL (Cochrane Library); and

4) Cochrane IBD Group Specialized register (inception‐present).

Searching other resources

In addition to electronic database searching, we will perform hand searches of conference proceedings over the past five years from Digestive Disease Week, the European Crohn's and Colitis Organization Congress, and the United European Gastroenterology Week. These searches may identify studies published in abstract form only. To identify ongoing studies, we will search the clinicaltrials.gov database. We will search reference sections of applicable systematic reviews and included studies to identify studies which may have been missed by the search strategies. We will also approach leading authors and experts to obtain relevant unpublished data.

Data collection and analysis

Selection of studies

Based on inclusion criteria above, eligibility of titles and abstracts identified by the literature search will be screened by two authors (RB and ND) independently. Disagreement will be resolved by discussion and consensus. A third author (VJ) will resolve cases in which consensus was not reached.

Data extraction and management

Information from selected studies will be collected using a standardized data collection form. Two authors (RB and CP) will independently extract data. Disagreement will be resolved by discussion and consensus. A third author (VJ) will be consulted when consensus was not reached.

The following data will be retrieved from the included studies:

1) General information (title, journal, year, publication type);

2) Study information (design, methods of randomization, concealment of allocation and blinding, power calculation, a priori and post hoc analyses);

3) Intervention and control (type and dose of medication; placebo or active comparator);

4) Eligibility (total number of patients screened and randomized);

5) Baseline characteristics for each arm (age, sex, ethnicity, disease severity, concurrent medications, prior medications);

6) Follow‐up (length of follow up, assessment of treatment compliance, withdrawals, number of patients lost to follow‐up); and

7) Outcomes (primary and secondary outcomes).

Assessment of risk of bias in included studies

From each included study, independent evaluation by two authors (RB and CP) will assess the quality of study methodology used with the Cochrane risk of bias tool (Higgins 2011). The following will be assessed:

1) Sequence generation (i.e. was the allocation sequence adequately generated?);

2) Allocation sequence concealment (i.e. was allocation adequately concealed?);

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

4) Incomplete outcome data (i.e. were incomplete outcome data adequately addressed?);

5) Selective outcome reporting (i.e. are reports of the study free of suggestion of selective outcome reporting?); and

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

Studies will be judged to be of high, low or unclear risk of bias. Disagreement will be resolved by consensus via discussion. A third author (VJ) will resolve cases where consensus was not reached. The overall quality of evidence supporting the primary and secondary outcomes will be assessed using the GRADE approach (Guyatt 2008; Schünemann 2011). Evidence retrieved from RCTs is usually regarded as high quality. However, the quality rating may be downgraded as a result of:

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 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).

Measures of treatment effect

Review Manager (RevMan 5.3.5) will be used to analyze data. All data will be analyzed on an intention‐to‐treat (ITT) basis. The risk ratio (RR) and corresponding 95% confidence interval (CI) will be calculated for dichotomous outcomes. For continuous outcomes, the mean difference (MD) and corresponding 95% CI will be calculated.

Unit of analysis issues

Combined outcomes at fixed follow‐up intervals will be implemented (i.e. clinical remission at fifty‐two weeks) for studies reporting multiple observations or follow‐up periods for same outcomes. Crossover trials will be included if data are available prior to the first crossover. Separate analyses will be conducted for infliximab versus placebo and infliximab versus active comparator. For studies allocating patients to multiple treatment arms, a pooled primary analysis will be performed for the treatment arms.

Dealing with missing data

In the cases of ambiguous or missing data, an attempt to contact the original study authors will be made. For dichotomous outcomes, patients with missing data will be assumed to be treatment failures. Sensitivity analyses will be conducted to assess the impact of this assumption on the effect estimate. We will conduct an available case analysis for continuous outcomes with missing data.

Assessment of heterogeneity

Heterogeneity will be assessed 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). Sensitivity analyses will be used to seek explanations for heterogeneity.

Assessment of reporting biases

We will evaluate potential reporting bias by comparing outcomes prespecified in protocols to those reported in published manuscripts. In cases where protocols are unavailable, we will compare outcomes listed in the methods section of published manuscripts to outcomes 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 (as determined by consensus). The pooled RR and 95% CI will be calculated for dichotomous outcomes. For continuous outcomes, the pooled mean difference (MD) and corresponding 95% CI will be calculated. We will calculate the standardized mean difference (SMD) and 95% CI when different scales are 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.

Subgroup analysis and investigation of heterogeneity

Planned subgroup analyses include:

1) Different drug doses and dosing frequencies;

2) Concomitant immunosuppressant medication use; and

3) Different disease behaviours.

Sensitivity analysis

Sensitivity analyses will examine the impact of the following variables on the pooled effect:

1) Random‐effects versus fixed‐effect modelling;

2) Low risk of bias versus unclear or high risk of bias; and

3) Relevant loss to follow up (> 10%): best‐case versus worst‐case scenario;

4) Full text manuscript versus abstract or unpublished studies.

Appendices

Appendix 1. Search strategy

EMBASE (1946 ‐ present)

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/ 22. Crohn*.mp. 23. inflammatory bowel disease*.mp. 24. IBD.mp. 25. 21 or 22 or 23 or 24 26. Infliximab.mp. 27. IFX.mp. 28. Remicade.mp. 29. 26 or 27 or 28 30. 20 and 25 and 29

MEDLINE (1946 ‐ present)

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/ 22. Crohn*.mp. 23. inflammatory bowel disease*.mp. 24. IBD.mp. 25. 21 or 22 or 23 or 24 26. Infliximab.mp. 27. IFX.mp. 28. Remicade.mp. 29. 26 or 27 or 28 30. 20 and 25 and 29

Conchrane CENTRAL

#1 MeSH descriptor: [Crohn Disease] explode all trees #2 Crohn #3 Inflammatory Bowel Disease #4 IBD #5 #1 or #2 or #3 or #4 #6 Infliximab #7 IFX #8 Remicade #9 #6 or #7 or #8 #10 #5 and #9

Contributions of authors

All authors were involved in the development of this protocol.

Declarations of interest

Robert Battat, Navjot Deol, Tran M Nguyen and Claire E Parker have no known conflicts.

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

Brian G 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.

Vipul Jairath has received scientific advisory board fees from Abbvie, Sandoz, Ferring and Janssen; speaker's fees from Takeda and Ferring; and travel support for conference attendance from Vifor pharmaceuticals.

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