Thalidomide for maintenance of remission in Crohn's disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
1. To evaluate the efficacy of thalidomide for maintenance of remission in Crohn's disease.
2. To evaluate adverse events associated with the use of thalidomide in Crohn's disease.
Background
There is no cure for Crohn's disease and treatment is mainly directed toward induction and maintenance of remission. Maintenance of remission is a major issue in the management of Crohn's disease. Corticosteroids, the mainstay of treatment of acute exacerbations are not effective for maintenance of remission and its chronic use is limited by numerous adverse events. Recent studies suggest that anti‐TNF‐α monoclonal antibodies such as infliximab (Hanauer 2002) and adalimumab (Colombel 2007) are effective for maintaining remission in Crohn's disease. Thalidomide, a TNF‐α production inhibitor may have a role in the management of Crohn's disease (Ehrenpreis 1999), but it is not clear whether it is an effective maintenance therapy.
Thalidomide is best known for its role in the history of drug development when it caused an epidemic of birth defects in the mid twentieth century (McBride 1961). At that time it was already known that thalidomide also displayed favorable effects on erythema nodosum leprosum. Consequently the drug has been used for various diseases including Behçet disease, graft‐versus‐host disease, rheumatoid arthritis and inflammatory bowel disease (Sands 1999).
The therapeutic effect of thalidomide is mediated via suppression of tumor necrosis factor‐alpha (TNF‐α) synthesis by means of an enhanced degradation of messenger RNA (Bauditz 2002; Meierhofer 2003). In this regard, thalidomide may be an alternative to the expensive anti‐TNF‐α agents currently used for the treatment of Crohn´s disease. As a small chemical compound it lacks the disadvantage of monoclonal antibodies that are immunogenic and have to be administered parenterally. Other effects of thalidomide such as decreasing levels of interleukin‐12 (2) and blockade of leukocyte transmigration (Meierhofer 1999) provide additional arguments for therapeutic use in Crohn´s disease.
In addition to case series (Bariol 2002; Kane 2002; Plamondon 2007), open label clinical trials in refractory Crohn´s disease have been published, suggesting a beneficial effect of thalidomide (Ehrenpreis 1999; Gupta 2003; Vasiliaukas 1999). In some of these studies, steroids could be tapered and symptoms of fistulae were reduced. These data were corroborated by a study including six pediatric patients that did not previously respond to infliximab therapy (Gupta 2003).
Teratogenicity, peripheral neuropathy, and drowsiness are well known adverse effects of thalidomide that may preclude its long term use. Patients receiving thalidomide are required to use two effective contraceptive methods due to the highly teratogenic nature of the drug. These aspects are of particular interest when the drug is used as maintenance therapy. The aim of this systematic review is to summarize the efficacy and safety of thalidomide maintenance therapy for Crohn's disease.
Objectives
1. To evaluate the efficacy of thalidomide for maintenance of remission in Crohn's disease.
2. To evaluate adverse events associated with the use of thalidomide in Crohn's disease.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials with treatment durations of at least 3 months.
Types of participants
Patients of any age with Crohn's disease whose disease was in remission at the time of entry into the study. Remission should have been defined with a recognised Crohn's disease activity index.
Types of interventions
Studies comparing thalidomide to placebo or active comparator will be considered for inclusion.
Types of outcome measures
The primary outcome measure will be the occurrence of clinical or endoscopic relapse as defined by the primary studies and expressed as a percentage of the number of patients randomized (intention to treat analysis). Secondary endpoints will include the occurrence of adverse events such as birth defects, peripheral neuropathy and drowsiness.
Search methods for identification of studies
A. Electronic search
The following electronic databases will be searched for relevant studies:
1. MEDLINE (1966‐to date);
2. EMBASE (1984‐to date);
3. Cochrane Central Register of Controlled Trials; and
4. Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders (IBD/FBD) Group Specialised Trial Register.
The search strategy will not be limited by language.
B. Reference searching
The references of all identified studies will be inspected for more trials.
C. Personal contacts
Leaders in the field will be contacted to try and identify other studies.
D. Drug companies
Manufacturers of thalidomide will be contacted for additional information.
MEDLINE on PUBMED will be searched using the following search strategy:
1. Crohn* disease
2. crohn disease (MESH)
3. regional enteritis
4. ileitis
5. ileitis (MESH)
6. inflammatory bowel disease
7. inflammatory bowel diseases (MESH)
8. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7
9. thalidomide
10. thalidomide (MESH)
11. thalidomid
12. lenalidomide
13. lenalidomide (MESH)
14. 9 OR 10 OR 11 or 12 OR 13
15. remission OR relapse
16. disease‐free survival (MESH)
17. 15 OR 16
18. 8 AND 14 AND 17
The above search strategy will be adapted and used to search the other electronic databases.
Data collection and analysis
Step 1. Potentially relevant papers will be identified by the two authors using the above search strategy.
Step 2. The authors, after reading the full texts, will independently assess the eligibility of all trials identified based on the inclusion criteria above. Disagreement among reviewers will be discussed and agreement reached by consensus.
Step 3. The methodological quality of selected trials will be assessed independently by the two reviewers using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005) and the Jadad scale (Jadad 1996). The former is based on the evidence of a strong relationship between allocation concealment and direction of effect. The categories are defined below:
A. adequate allocation concealment;
B. allocation concealment unclear; and
C. inadequate allocation concealment.
The Jadad scale is a validated five point scale which measures some important factors that impact on the quality of a trial. This is summarised below:
a. was the study described as randomised?
b. was the method of randomisation well described and appropriate?
c. was the study described as double blind?
d. was the double blinding well described and appropriate?
e. were withdrawals and dropouts described?
Each item will be given a score of 1 if the answer is 'yes' and 0 if the answer is 'no'. One point will be deducted if the described method of randomization or blinding was inappropriate.
DATA COLLECTION
A data extraction form will be developed and used to extract information on relevant features and results of included studies. The two reviewers will separately extract and record data on the predefined checklist. Extracted data will include the following items:
a. characteristics of patients: age, sex, disease distribution, disease duration, disease activity index;
b. total number of patients originally assigned to each intervention group;
c. intervention: type and amount of enteral nutrition; mode of administration;
d. control: no intervention, placebo or other interventions;
e. concurrent medications; and
f. outcomes: time of assessment, length of follow up, type of Crohn's disease activity index used, definitions of remission and relapse, relapse rates, time to relapse, quality of life assessment, adverse events.
STATISTICAL ANALYSIS
The Cochrane Collaboration review manager (RevMan 5.0.9) will be used for data analysis. Data will be analysed according to the intention to treat principle, using as the denominator, the total number of patients randomised. 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. The effect of heterogeneity will be quantified using the I2value. 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 would have been set by the authors of each paper, and the data will be combined for analysis only if these definitions are sufficiently similar (determined by consensus).
Subgroup analysis
When possible, subgroup analysis will be performed based on the following:
a. age of participants {adults (>16 years) versus children};
b. disease distribution;
c. dose of thalidomide;
d. duration of treatment;
e. concurrent medications (especially immunosuppressive agents such as azathioprine, 6‐mercaptopurine, methotrexate, cyclosporine and mycophenolate mofetil); and
f. length of follow up.
Sensitivity analyses
When necessary, sensitivity analyses will be conducted based on the following:
a. only including patients whose outcome is known (i.e. number of patients who completed the study used as denominator);
b. random effects versus fixed effects models; and
c. study quality.
