Efficacy and Safety of Top-down Therapy in Pediatric Crohn's Disease

This study has been withdrawn prior to enrollment.
(The study will be part of a European multicenter trial (Infliximab Top-down Study in Kids with Crohn's disease))
Sponsor:
Information provided by (Responsible Party):
Marina Aloi, University of Roma La Sapienza
ClinicalTrials.gov Identifier:
NCT01752790
First received: December 12, 2012
Last updated: March 5, 2013
Last verified: March 2013
  Purpose

Crohn's disease (CD) is an incurable debilitating disorder affecting an increasing number of children. The etiology remains elusive, but a genetically determined aberrant immune response against microbiota appears to be responsible. TNFα plays a pivotal role in the cytokine cascade of the inflammatory process and mediates multiple processes central to the pathogenesis of CD. The natural history of pediatric CD is characterized by recurrent flare-ups that severely impair patients growth, pubertal development and nutritional status. Epidemiological observations have shown that the course of CD, despite conventional treatment, inevitably progresses to the development of severe complications and surgery. Infliximab is the most widely used biological agent in moderate-to-severe pediatric CD. At present biologics are used after the failure of conventional drugs (step-up approach) and represent the peak of the CD therapeutic pyramid. The early use of biologics (top-down approach) has been demonstrated to be effective in adults with CD. The project aims at evaluating if a top-down approach may achieve mucosal healing before irreversible tissue damage present in late CD and thus alter the natural course of the disease, compared to the conventional approach. The study can also add information about the safety of infliximab used as first-line therapy and may add data on the benefit and costs of a reversal of the traditional therapeutic pyramid in pediatric CD, guiding the clinician in deciding in whom, when and how to introduce early aggressive treatment in daily practice.


Condition Intervention Phase
Pediatric Crohn's Disease
Drug: Top-down
Drug: Step-up
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Efficacy and Safety of Infliximab as First-line Therapy in Pediatric Crohn's Disease: a Randomized, Controlled, Open-label Trial

Resource links provided by NLM:


Further study details as provided by University of Roma La Sapienza:

Primary Outcome Measures:
  • Clinical response or clinical remission as determined by PCDAI in top-down vs. step-up group [ Time Frame: 6, 12, 18, 24, 36 months ] [ Designated as safety issue: No ]
    The proportion of patients with clinical remission or clinical response as determined by the Pediatric Crohn's Disease Activity Index (PCDAI)in the top-down compared to the step-up group. Clinical remission is defined as a PCDAI<10. Clinical response requires a 25-point decrease in PCDAI when compared to baseline.

  • Rate of mucosal healing in top-down vs. step-up group [ Time Frame: 6, 12, 24, 36 months ] [ Designated as safety issue: No ]
    The proportion of patients with intestinal mucosal healing as determined by the Crohn's Disease Endoscopic Index of Severity (CDEIS). Healing of intestinal inflammation is defined as a decrease in both endoscopic (CDEIS) and histological scores for >= 50 % when compared to baseline values.


Secondary Outcome Measures:
  • Rate of adverse events in top-down vs. step-up group [ Time Frame: 6,12,18,24,36 months ] [ Designated as safety issue: Yes ]
    The proportion of patients with adverse drug reaction and side effects attributable to therapy

  • Hospitalization and surgery [ Time Frame: 6,12,24, 36 months ] [ Designated as safety issue: No ]
    The number of hospitalizations and surgical procedures in Top-down and step-up group

  • Growth [ Time Frame: 6,12,24,36 months ] [ Designated as safety issue: No ]
    The pattern of growth in terms of Z-scores in top-down and step-up group


Enrollment: 0
Study Start Date: December 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Top-down
patients randomized on top-down arm will receive an induction regimen of three consecutive i.v. infusions of infliximab (Remicade, 5 mg/kg) at weeks 0, 2, and 6 plus azathioprine (2 mg/Kg per os/day). During maintaining phase, patients will receive subsequent infusions of infliximab (5 mg/kg every 8 weeks), starting 8 weeks after the end of the induction phase (week 14). At 12 motnhs patients will stop azathioprine and continue infliximab (5 mg/kg every 8 weeks)
Drug: Top-down
Patients randomized to top-down arm will receive an induction regimen of three consecutive i.v. infusions of infliximab (Remicade, 5 mg/kg) at weeks 0, 2, and 6 plus AZA (2 mg/Kg per os/day). Patients who will not respond to the induction regimen at week 8 will receive no further treatment with infliximab. Disease recurrences will be treated with infliximab (reduction of the interval between two doses). At 12 months pazients will discontinue azathioprine and continue infliximab (5mg/kg every 8 weeks). During the trial, other drugs will be not allowed, including immunosuppressive agents, other biological agents or steroids.
Other Names:
  • Remicade
  • Imuran
Active Comparator: Step-up
Patients randomized on Step-up arm will receive methylprednisolone (1-2 mg/Kg/day per os. for 2 weeks then tapering of 5 mg/week then stop) plus azathioprine (2 mg/Kg/die per os/day). Disease recurrences under azathioprine will be treated with steroid courses (methylprednisolone 1-2 mg/Kg/day per os. for 2 weeks then tapering of 5 mg/week then stop).
Drug: Step-up
Patients randomized on Step-up arm will receive methylprednisolone (1 mg/Kg/day per os. for 2 weeks then tapering of 5 mg/week then stop) plus azathioprine (2 mg/Kg/die per os/day).Disease recurrences under azathioprine will be treated with steroid courses (methylprednisolone 1-2 mg/Kg/day per os. for 2 weeks then tapering of 5 mg/week then stop). During the trial, other drugs will be not allowed, including immunosuppressive agents, other biological agents or steroids.
Other Names:
  • Imuran
  • Medrol
  • Urbason

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   6 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. diagnosis of CD,
  2. PCDAI>30,
  3. duration of disease less than 1 yr from the time of diagnosis (early CD).

Exclusion Criteria:

  1. any prior treatment with immunosuppressive agents (AZA/6-MP, methotrexate, cyclosporine) or anti-TNFα,
  2. stenosing CD,
  3. pre-existing systemic disease,
  4. hepatic or renal dysfunction,
  5. systemic infection,
  6. suspected pregnancy,
  7. history of active or past tuberculosis,
  8. contraindication to steroid therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01752790

Locations
Italy
Pediatric Gastroenterology and Liver Unit
Rome, Italy, 00161
Sponsors and Collaborators
University of Roma La Sapienza
Investigators
Principal Investigator: Marina Aloi, Investigator Sapienza University of Rome
  More Information

No publications provided

Responsible Party: Marina Aloi, Research assistant, University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT01752790     History of Changes
Other Study ID Numbers: 2473
Study First Received: December 12, 2012
Last Updated: March 5, 2013
Health Authority: Italy: The Italian Medicines Agency

Keywords provided by University of Roma La Sapienza:
Pediatric Crohn's disease
Biologics
Immunomodulators
Top-down
step-up

Additional relevant MeSH terms:
Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Azathioprine
Immunosuppressive Agents
Infliximab
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on July 23, 2014