Thalidomide Versus Infliximab in New Onset Crohn's Disease With Poor Prognostic Factors

Study Overview
=================
Brief Summary
-----------------
Crohn's disease (CD) is a life-long inflammatory bowel disease disease with an unknown pathogenesis. The ultimate goal of therapy is to modify the natural history of CD thus reducing complications. Thalidomide is a small molecule with immunomodulatory and anti-angiogenetic properties. It is currently approved for the treatment of erythema nodosum leprosum, an immunological complication of leprosy and multiple myeloma. It has also been used in several other inflammatory diseases of the skin and of the mucosal membranes, such as Behcet disease, oropharyngeal ulcers in AIDS, cutaneous lupus, and graft versus host disease. Many case series and one pediatric randomized controlled trial proved the efficacy of thalidomide in the treatment of children with CD refractory to standard treatments. In these patients, clinical remission was achieved in about 50% of the cases and was maintained for a mean time superior of 3 years. Mucosal healing after 52 weeks of treatment was observed in 40% of the patients in clinical remission. Moreover, thalidomide was found to have a steroid-sparing effect and to decrease the need for surgical interventions. The clinical and endoscopic efficacy of thalidomide was also observed in children with failure to respond or intolerance to anti-TNF biological drugs. The aim of this multicentric prospective randomized controlled is to evaluate the efficacy and safety of thalidomide vs infliximab in changing the natural history of CD in patients with poor prognostic outcome. Moreover, the study will evaluate the immunological and genetical mechanisms of CD, the mechanisms of action thalidomide in CD and will the pharmacokinetics, metabolomics and pharmacogenomics of thalidomide, and their impact on thalidomide safety and effectiveness.

Official Title
-----------------
Thalidomide, a Novel Immunological Treatment to Modify the Natural History of Paediatric Crohn's Disease: a New Proposal From a Well-established Paediatric Research Network

Conditions
-----------------
Crohn Disease

Intervention / Treatment
-----------------
* Drug: Thalidomide
* Drug: Infliximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age at diagnosis <18 years and >=6 years New diagnosis of CD based on Porto criteria CD with inflammatory phenotype (non-penetrating, non-fistulizing) and with no need for surgery except for perinal fistulas Presence of at least one of the following risk factors for poor prognosis: fistulizing perianal disease pan-enteric disease disease extension > 60 cm severe growth delay (height z-score < -2 DS) severe osteoporosis (z score < -2 DS) hypoalbuminemia (< 3g/dL) or high C-reactive protein (2 times higher the normal range) Acceptance of the Risk Evaluation and Mitigation Strategy (REMS) program for reducing the teratogenic risk. Exclusion Criteria: ongoing pregnancy presence of peripheral neuropathy HIV patients with transplanted organs ongoing major infections or other severe diseases participation to other experimental studies.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Thalidomide<br>Thalidomide is a immunomodulatory and antiangiogenetic drug with anti tumor necrosis factor (TNF) alpha properties | Drug: Thalidomide<br>* Thalidomide is a immunomodulatory and antiangiogenetic drug with anti TNF alpha properties<br>|
| Active Comparator: Infliximab<br>Infliximab is a chimeric monoclonal antibody against TNF alpha | Drug: Infliximab<br>* Infliximab is a chimeric monoclonal antibody against TNF alpha<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy in inducing mucosal healing | Proportion of patients that achieve mucosal healing, defined by a Simplified Endoscopic Activity Index for CD (SES-CD) ≤ 2. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy in inducing clinical response | Clinical response will be evaluated with the weighted Pediatric Crohn's Disease Activity Index (wPCDAI), defined by a reduction of wPCDAI > 50% from the basal values. | 12 weeks | 
| Efficacy in inducing clinical response | Clinical response will be evaluated with the weighted Pediatric Crohn's Disease Activity Index (wPCDAI), defined by a reduction of wPCDAI > 50% from the basal values. | 52 weeks | 
| Efficacy in inducing clinical remission | Clinical remission will be evaluated with the weighted Pediatric Crohn's Disease Activity Index (wPCDAI), defined by a wPCDAI <12.5. | 12 weeks | 
| Efficacy in inducing clinical remission | Clinical remission will be evaluated with the weighted Pediatric Crohn's Disease Activity Index (wPCDAI), defined by a wPCDAI <12.5. | 52 weeks | 
| Efficacy in reducing the need to change therapy | Evaluation of the proportion of patients that need a therapeutic change | 12 weeks | 
| Efficacy in reducing the need to change therapy | Evaluation of the proportion of patients that need a therapeutic change | 52 weeks | 
| Efficacy in reducing hospitalizations | Evaluation of the proportion of patients that need hospitalization. | 52 weeks | 
| Efficacy in reducing the need for surgery | Evaluation of the proportion of patients that need surgery | 52 weeks | 
| Efficacy in reducing erythrocyte sedimentation rate | Evaluation of the trend of erythrocyte sedimentation rate (ESR) | Each time point between enrolment and 52 weeks (0, 4, 8, 14, 26, 38, 52 weeks) | 
| Efficacy in reducing C-reactive protein | Evaluation of the trend of C-reactive protein (CRP) | Each time point between enrolment and 52 weeks (0, 4, 8, 14, 26, 38, 52 weeks) | 
| Efficacy in reducing faecal calprotectin | Evaluation of the trend of faecal calprotectin | Each time point between enrolment and 52 weeks (0, 4, 8, 14, 26, 38, 52 weeks) | 
| Efficacy in modifying body mass index | Evaluation of the trend of body mass index, defined as weight (kg)/height (m)^2 | Each time point between enrolment and 52 weeks (0, 4, 8, 14, 26, 38, 52 weeks) | 
| Efficacy in modifying height-for-age z score | Evaluation of the trend of height-for-age z score | Each time point between enrolment and 52 weeks (0, 4, 8, 14, 26, 38, 52 weeks) | 
| Efficacy in modifying weight-for-age z score | Evaluation of the trend of weight-for-age z score | Each time point between enrolment and 52 weeks (0, 4, 8, 14, 26, 38, 52 weeks) | 
| Evaluation of the Treatment-Emergent Adverse Events | Number and type | Between enrolment and 52 weeks | 
| Direct and indirect costs | Comparison of direct and indirect costs (i.e. drugs, medical supplies and equipment, laboratory and diagnostic tests, hospitalizations, visits, transportation to and from healthcare facilities, missing work and school days…) between the two groups | 52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Children, Crohn disease, Thalidomide, Mucosal healing