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

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

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.

Study Overview

• Status: Terminated
• Conditions: Crohn Disease
• Intervention / Treatment: Drug: Thalidomide; Drug: Infliximab

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Dipartimento di Pediatria dell'Università di Napoli "Federico II"
  • Friuli Venezia Giulia
    • Trieste, Friuli Venezia Giulia, Italy, 34137
      • IRCCS Burlo Garofolo
  • Liguria
    • Genoa, Liguria, Italy, 16147
      • Pediatria III Gastroenterologia ed Endoscopia Digestiva, Istituto Giannina Gaslini
  • Lombardia
    • Monza, Lombardia, Italy, 20052
      • Fondazione MBBM , Azienda Ospedaliera San Gerardo - Università Milano Bicocca
  • Sicilia
    • Messina, Sicilia, Italy, 98124
      • Unità di Gastroenterologia Pediatrica e Fibrosi Cistica, Dipartimento di Scienze Pediatriche Mediche e Chirurgiche, Policlinico Universitario
  • Toscana
    • Firenze, Toscana, Italy, 50139
      • Gastroenterologia e Nutrizione Pediatrica, Azienda Ospedaliero Universitaria Meyer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Thalidomide; Thalidomide is a immunomodulatory and antiangiogenetic drug with anti tumor necrosis factor (TNF) alpha properties	Drug: Thalidomide; Thalidomide is a immunomodulatory and antiangiogenetic drug with anti TNF alpha properties
ACTIVE_COMPARATOR: Infliximab; Infliximab is a chimeric monoclonal antibody against TNF alpha	Drug: Infliximab; Infliximab is a chimeric monoclonal antibody against TNF alpha

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

Collaborators and Investigators

• Sponsor: IRCCS Burlo Garofolo
• Collaborators: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia; Centro di Riferimento Oncologico - Aviano
• Investigators: Study Chair: Alessandro Ventura, MD PhD, IRCCS Burlo Garofolo

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 27, 2018
• Primary Completion (ACTUAL): July 31, 2020
• Study Completion (ACTUAL): July 31, 2020

Study Registration Dates

• First Submitted: July 5, 2017
• First Submitted That Met QC Criteria: July 14, 2017
• First Posted (ACTUAL): July 18, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 4, 2020
• Last Update Submitted That Met QC Criteria: September 2, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Thalidomide; Children; Crohn disease; Mucosal healing
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Anti-Infective Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dermatologic Agents; Anti-Bacterial Agents; Leprostatic Agents; Thalidomide; Infliximab
• Other Study ID Numbers: NET-2013-02355002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No