Recombinant human interleukin 10 for induction of remission in Crohn's disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the efficacy and tolerability of recombinant human interleukin 10 (IL‐10) for induction of remission in Crohn's disease.
Background
Crohn's disease is a chronic inflammatory disorder that may involve any part of the gastrointestinal tract but most commonly the distal small bowel and/or colon. Although the exact cause of Crohn's disease remains unknown, it is now apparent that inflammation is associated with an imbalance between proinflammatory and anti‐inflammatory cytokines produced within the intestinal mucosa. Interleukin 10 (IL‐10) is an anti‐inflammatory, immunomodulatory cytokine that regulates mucosal inflammation by inhibiting T‐cell/macrophage activation and proinflammatory cytokine synthesis. IL‐10 acts to suppress inflammation resulting from both antigen‐specific and innate immune responses by reducing: monocyte HLA class‐II expression, T‐cell secretion of IL‐2 and interferon γ, activated monocyte production of IL‐1α, IL‐1β, IL‐6, IL‐8, TNF‐α, and granulocyte‐macrophage colony‐stimulating factor. IL‐10 also upregulates the production of IL‐1 receptor antagonist by monocytes (van Deventer 1997). Recombinant human interleukin 10 is identical to endogenous human interleukin 10 with the exception of a methionine residue at the amino terminus (Fedorak 2000). Recombinant human interleukin 10 (Tenovil; Schering‐Plough Research Institute, Kenilworth, NJ) comes in a sterilized, lyophilized white powder form containing sodium citrate, sucrose and glycerine. Prior to use the drug is reconstituted with sterile water to a clear colorless solution. Recent trials of cytokine and anticytokine therapies have demonstrated clearly that manipulations of T‐cell and macrophage‐derived cytokines may provide effective treatment for Crohn's disease.
Objectives
To determine the efficacy and tolerability of recombinant human interleukin 10 (IL‐10) for induction of remission in Crohn's disease.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials comparing recombinant human interleukin 10 to a placebo or control therapy will be considered for inclusion.
Types of participants
Participants include patients of any age with Crohn's disease defined by conventional clinical, radiological and endoscopic criteria, which is categorized as being active (Crohn's disease activity index 'CDAI' >150).
Types of interventions
Interventions that involve recombinant human interleukin 10 versus placebo or a control therapy will be considered for inclusion.
Types of outcome measures
The primary outcome measure will be the number of patients achieving remission as defined by the primary studies, and expressed as a percentage of the patients randomized (intention to treat analysis). Secondary outcome measures include: mean CDAI, clinical response, adverse events and withdrawal because of adverse events.
Search methods for identification of studies
A computer assisted search of the Cochrane Central Register of Controlled Trials and the Cochrane IBD Review Group Specialized Trials Register and the on‐line databases MEDLINE and EMBASE will be performed to identify relevant publications between 1966 and July 2004. The medical subject heading (MeSH) terms "Crohn disease" or "inflammatory bowel disease" and "interleukin" will be used to perform key word searches of each database. Manual searches of reference lists from potentially relevant papers will be performed in order to identify additional studies that may have been missed using the computer‐assisted search strategy. Abstracts from major gastroenterological meetings will be searched to identify research submitted in abstract form only. Personal contacts and leaders in the field will be contacted to identify other studies which may not be published. The manufacturer of rhIL‐10 (SCH 52000 or Tenovil, Schering Plough, Kelinworth, NJ, USA) will be contacted for additional data.
Data collection and analysis
Study selection
All publications identified by the search strategy will be assessed independently by two reviewers (EJ and JKM), and relevant studies will be selected according to the inclusion criteria. Any disagreement among reviewers will be resolved by consensus.
Assessment of methodological quality
The methodological quality of each RCT will be assessed independently by two reviewers (EJ and JKM) using the criteria described in the Cochrane Reviewer's Handbook (Alderson 2004) and the Jadad Scale (Jadad 1996). Any disagreement between reviewers will be resolved by consensus with a third reviewer (JWDM).
Research has shown that lack of adequate allocation concealment is associated with bias (Chalmers 1983; Schultz 1995; Moher 1998). Allocation concealment will be rated as: adequate (e.g. centralized or pharmacy controlled randomization, pre‐numbered or coded identical containers which are administered serially to participants, on‐site computer system combined with allocations kept in a locked unreadable computer file that can be accessed only after the characteristics of an enrolled participant have been entered, or sequentially numbered, sealed, opaque envelopes), unclear (i.e. not described in the trial report), or inadequate (e.g. alternation, the use of case record numbers, dates of birth, etc.).
The Jadad 1996 scale is a validated five‐point scale used to assess the likelihood of bias in research reports. The scale is summarized below:
a. was the study described as randomized? (yes=1 point, No =0)
b. was the method of randomization well described and appropriate? (yes=1 point, No =0)
c. was the study described as double blind? (yes=1 point, No =0)
d. was the double blinding well described and appropriate? (yes=1 point, No =0)
e. were withdrawals and dropouts described? (yes=1 point, No =0)
When insufficient information is provided to determine methodological quality study authors will be contacted to confirm the method of randomization and allocation concealment.
Data extraction
Two reviewers (EJ and JKM) will independently extract data using a data extraction form. Any disagreement among reviewers will be resolved by consensus.
Data analysis
Data will be analyzed using Review Manager (RevMan 4.2.7). All data will be analyzed on an intention‐to‐treat basis. Data will be extracted from the original research articles and converted into 2x2 tables. The presence of significant heterogeneity among studies will be assessed using the chi‐square test. As the chi‐square test has low power in the situation of a meta‐analysis, when trials have small sample size or are few in number, a p value of 0.10 will be regarded as statistically significant. For pooled data, summary test statistics will be derived using the odds ratio and 95% confidence intervals. A fixed effects model will be used for pooling of data when statistical heterogeneity is not present. When statistical heterogeneity is present a random effects model will be used. For continuous data, summary test statistics will be derived using the weighted mean difference and 95% confidence intervals. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data will be combined for analysis only if these definitions were sufficiently similar (determined by consensus).
