Adalimumab for maintenance of remission in Crohn's disease

Abstract

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

The objective of this review is to assess the efficacy and safety of adalimumab for maintenance of remission in patients with quiescent CD.

Background

Description of the condition

Crohn's disease (CD) is a chronic, episodic, inflammatory condition of the gastrointestinal system, with affected regions consisting of transmural ulceration separated by normal mucosa. The small intestine is most commonly affected, although the large intestine may also be involved. Common symptoms include abdominal pain, diarrhea, weight loss, bleeding, nausea and vomiting. Enteric complications may include bowel obstruction, perforation, abscesses, fistulas, and peri‐anal disease. Approximately 20% of CD patients experience extra‐intestinal complications that may include musculoskeletal, ocular, dermatologic, hepatobiliary, renal and hematological conditions (Doherty 2015).

The pathophysiology of Crohn’s disease is complex and not completely understood. However, it is known that there is a genetic component, as evidenced by concordance between monozygotic twins, familial and ethnic aggregation, and genetic anticipation (Khor 2011; Loddo 2015). Evidence also exists for strong epigenetic and environment factors, with tobacco use being the most studied environmental factor, showing that early tobacco use increases the risk of developing CD (Cosnes 1996; Khor 2011). The disease is known to occur after an episode of infectious gastroenteritis, suggesting that an altered gut microbiota may be a factor in the pathogenesis of CD (Chassaing 2011; Matsuoka 2015). It is believed that an altered relationship between the gut microflora and the host immune system plays a major role in CD. One key potential mechanism by which this altered relationship is thought to mediate the development of CD is through increased permeability between epithelial cells lining the intestinal barrier. The increased permeability permits an increased flux of intestinal antigens to the lamina propria, causing an enhanced immune reaction. In‐vitro and animal studies have linked the increase in permeability to T cells, TNF‐α, and interferon‐γ (Baumgart 2012).

Conventional medications for CD include anti‐inflammatory drugs, immunosuppressants and corticosteroids. However, if the patient does not respond, or loses response to these first line treatments, then biologic therapies such as TNF‐α agents including infliximab, certolizumab pegol and adalimumab are then considered for the treatment of CD.

Description of the intervention

Adalimumab is a monoclonal antibody that binds to and inactivates tumor necrosis factor‐alpha (TNF‐α), thereby limiting the inflammatory response that occurs in CD. Since its initial approval by the FDA for treatment of rheumatoid arthritis, adalimumab has been approved for several other diseases including hidradenitis suppurativa, iritis, ankylosing, psoriatic, and juvenile idiopathic arthritis; plaque psoriasis; ulcerative colitis; and CD (FDA 2011). Adalimumab is indicated for cases of moderate to severe CD for symptomatic control and induction and maintenance of clinical remission (Cassinotti 2008).

How the intervention might work

It has been demonstrated that patients with CD have higher concentrations of TNF‐α and decreased immune cell apoptosis in their intestinal mucosa (Sabatino 2004). Inhibition of TNF‐α by adalimumab reduces activity of neutrophils, proliferation of T‐cells, activation of macrophages, and survival of immune cells, thereby limiting the immune response (Tracey 2008). In addition, TNF‐α inhibition has been shown to increase intestinal T‐cell and monocyte apoptosis in patients with CD (Asgharpour 2013).

Why it is important to do this review

Maintenance of remission of Crohn's disease is a clinically important goal, as relapses of the disease can have a profound impact on the quality of life of patients (Ghosh 2007). Commonly employed treatment options for active CD include corticosteroids, which are effective for short‐term disease control, but associated with several adverse events. Furthermore, corticosteroid resistance occurs in as many as 20% of cases, therefore rendering this option unfavourable and ineffective for maintenance of remission (Munkholm 1994; Steinhart 2003). As well, many patients do not respond to treatment with aminosalicylates and immunosuppressives (Hanauer 2002).

Adalimumab is a promising option for the treatment of moderate to severe CD. The CHARM trial showed that adalimumab is more effective than placebo in maintaining remission in moderate to severe CD after 56 weeks from initiation of therapy (Colombel 2007). Unfortunately, the human immune system may reduce the effectiveness of interventions over time, and the effectiveness of a monoclonal antibody for initial remission of CD may not predict its ability to maintain remission. For example, it has been shown that repeated infusions of Infliximab, a chimeric monoclonal antibody to TNF‐α used to treat CD, may lead to the production of antibodies to the drug itself, thereby reducing its ability to maintain remission (Baert 2003). It is therefore necessary to conduct a review to determine the efficacy and safety of adalimumab for maintenance of remission in CD.

Objectives

The objective of this review is to assess the efficacy and safety of adalimumab for maintenance of remission in patients with quiescent CD.

Methods

Criteria for considering studies for this review

Types of studies

We will consider randomized controlled trials (RCTs) that have assessed the efficacy and safety of adalimumab for maintenance of remission in CD for inclusion in this systematic review.

Types of participants

This systematic review will include patients of any age who have been diagnosed with CD using clinical, radiological, endoscopic or histological criteria. Patients must be in remission at study entry to be included.

Types of interventions

This systematic review will include trials that compared adalimumab to either a placebo or an active comparator.

Types of outcome measures

Primary outcomes

The primary outcome will be the proportion of patients with CD who failed to maintain clinical remission, as defined by the original trials. Analyses will be performed according to the intention‐to‐treat (ITT) principle.

Secondary outcomes

Secondary outcome measures will include the proportion of patients :

1) Who fail to maintain clinical response;

2) Who fail to maintain endoscopic remission;

3) Who fail to maintain endoscopic response;

4) Who fail to maintain histologic remission;

5) Who fail to maintain histologic response;

6) Who fail to maintain steroid withdrawal;

7) Who develop adverse events;

8) Who develop serious adverse events;

9) Who withdrew due to adverse events; and

10) Quality of life.

Search methods for identification of studies

Electronic searches

The following databases will be searched for relevant studies: MEDLINE (Ovid, 1946 to present); EMBASE (Ovid, 1984 to present); CENTRAL; and The Cochrane IBD Group Specialized Register. The search strategies are listed in Appendix 1.

Searching other resources

In addition to searching the electronic databases, we will identify additional studies by manually searching the reference lists of relevant papers. We will conduct hand searches of conference proceedings from Digestive Disease Week, United European Gastroenterology Week and the European Crohn's and Colitis Organisation Congress for the last five years. We will identify ongoing trials by approaching leading experts in the field, and by searching the clinicaltrials.gov database and controlled‐trials.com databases.

Data collection and analysis

Selection of studies

Two authors (JC and MA) will independently assess the titles and abstracts of studies identified by our search criteria to determine eligibility according to our inclusion criteria.Disagreements will be discussed until a consensus among the authors is reached. In the event that a consensus cannot be reached, we will consult with a third author (TN).

Data extraction and management

Data will be independently extracted by two authors (JC and MA) using a standardized extraction form. Any disagreements over extracted data will first be discussed then brought to a third author (TN) for resolution as required. The following information will be extracted:

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

2. Study design features (method of randomization, concealment of allocation and blinding, power calculation, a priori and post‐hoc analyses, dates of enrolment and follow‐up, study duration, number of centers and location, and study withdrawals);

3. Intervention (dose and type of medication, and whether it was compared to placebo or active comparator);

4. Eligibility (number of participants screened and their randomization);

5. Patient characteristics (age, sex, race, severity of disease, current and prior medications);

6. Follow‐up (dates of follow‐up along with withdrawals and number of patients lost to follow‐up); and

7. Primary and secondary outcomes.

Assessment of risk of bias in included studies

Two authors (JC and MA) will independently assess risk of bias using the Cochrane risk of bias tool (Higgins 2011). We will assess several study characteristics to assess the risk of bias including random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other potential sources of bias. Based on these criteria, the studies will be characterized as having a low, high or unclear risk of bias for each category. Any disagreements regarding risk of bias will be first discussed and then brought to the third author (TN) as necessary. We will use GRADE to assess the overall quality of the evidence supporting the primary and secondary outcomes (Schünemann 2011). For the 'Summary of findings' table, we plan to include the following outcomes: failure to maintain clinical remission (at study endpoint), failure to maintain clinical response, failure to maintain endoscopic response, quality of life, adverse events, serious adverse events and study withdrawal due to adverse events.

RCTs begin as high quality evidence, and can be downgraded according to:

1. Risk of bias;

2. Indirect evidence;

3. Inconsistency (unexplained heterogeneity);

4. Imprecision (sparse data); and

5. Reporting bias (publication bias).

After considering each of these elements, the overall quality of the evidence supporting each outcome will be classified as high quality (further research is very unlikely to change our confidence in the estimate of effect); moderate quality (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (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 (we are very uncertain about the estimate) (Guyatt 2008).

Measures of treatment effect

We will use Review Manager 5 (RevMan5) to analyze the data. For dichotomous outcomes, we will calculate the risk ratio (RR) with a 95% confidence interval (CI). For continuous outcomes, we will calculate the mean difference (MD) with a 95% CI.

Unit of analysis issues

To ensure independent comparisons between each treatment group (e.g. dose groups) and placebo, we plan to divide the placebo group across the number of treatment groups to deal with trials with multiple arms. For trials with an odd number of participants in the placebo group, we will split the placebo group so that the placebo group for the lower dose arm has a larger number of participants. This will help avoid overestimating treatment effects for the higher dose arm. Crossover trials will be included if the data prior to the first crossover are available. We will report on the proportion of subjects who experience at least one event, for studies where events may reoccur (e.g. adverse events).

Dealing with missing data

We will contact study authors to obtain missing data. According to the ITT analysis, patients with missing dichotomous outcome data will be assumed to be treatment failures. We will perform a sensitivity analysis to determine the impact of the assumption of treatment failure for missing data on the effect estimate. We will conduct an available case analysis in the event of missing continuous outcome data.

Assessment of heterogeneity

Heterogeneity will be assessed using Chi² test and the I² statistic (Higgins 2003). An I² value of less than 25% will be considered indicative of low heterogeneity, greater than 50% indicative of moderate heterogeneity and greater than 75% high heterogeneity. For the Chi² test, we will consider a P‐value of 0.10 to be statistically significant. If the I² statistic and Chi² test suggest heterogeneity, we will visually inspect the forest plot for outliers. We will use sensitivity analysis (e.g. excluding outliers) to explore potential explanations for heterogeneity.

Assessment of reporting biases

We will evaluate reporting bias by comparing outcomes listed in protocols (or in the methods section of the published manuscript if no protocol is available) to those reported in the final manuscripts. If a sufficient number of studies are included (>10) in the pooled analysis, a funnel plot will be used to assess publication bias (Egger 1997).

Data synthesis

Data from individual trials will be combined for meta‐analysis when interventions, patient groups and outcomes are sufficiently similar. This will be determined by discussion and consensus among the author team. We will calculate the pooled RR with 95% CI for dichotomous outcomes, and the pooled MD with 95% CI for continuous outcomes that are measured with the same scale. When different scales are used to measure the same underlying construct (e.g. quality of life), we will calculate the standardized mean difference (SMD) with 95% CI. If no heterogeneity is present, we will use a fixed‐effect model to pool the data. However, if there is heterogeneity (I² = 50 to 75%), we will use a random‐effects model to pool data . If there is a high degree of heterogeneity (I² > 75%) detected, we will not pool data for meta‐analysis.

Subgroup analysis and investigation of heterogeneity

We plan for the following subgroup analyses:

1. Patient characteristics (disease duration, disease severity, disease extent, concomitant medication, previous exposure to anti‐TNF‐α therapy); and

2. Drug doses and routes of administration.

Sensitivity analysis

Sensitivity analysis will be used to examine the impact of the following variables on the pooled effect estimate:

1. Random‐effects versus fixed‐effects modelling;

2. Low risk of bias versus unclear or high risk of bias;

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

4. Full‐text manuscripts versus abstract or unpublished studies.

Appendices

Appendix 1. Search Strategies

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. Adalimumab.mp. 27. Humira.mp. 28. Exemptia.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. randomized controlled trial/ 14. or/1‐13 15. (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) 16. 14 not 15 17. Exp Crohn disease/ 18. Crohn*.mp. 19. inflammatory bowel disease*.mp. 20. IBD.mp. 21. 17 or 18 or 19 or 20 22. Adalimumab.mp. 23. Humira.mp. 24. Exemptia.mp. 25. 22 or 23 or 24 26. 16 and 21 and 25

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 Adalimumab #7 Humira #8 Exemptia #9 #6 or #7 or #8 #10 #5 and #9

SR‐IBD

Title: Adalimumab and Crohn

Humira and Crohn

What's new

Date	Event	Description
15 November 2018	Amended	Pre‐specified outcomes for 'Summary of findings' table added to protocol

Contributions of authors

All authors were involved in the development of this protocol.

Declarations of interest

Jeremy Cepek: None known

Mohamad Abbass: None known

Tran M Nguyen: None known

Claire E Parker: None known

John K MacDonald: None known

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: Dr Jairath has received consulting fees from Abbvie, Sandoz, Takeda, Pfizer, and Janssen; and Lecture fees from Takeda, Ferring, Janssen, and Shire. All of these activities are outside the submitted work.

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

Edited (no change to conclusions)