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

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ClinicalTrials.gov Identifier: NCT01752790
Recruitment Status : Withdrawn (The study will be part of a European multicenter trial (Infliximab Top-down Study in Kids with Crohn's disease))
First Posted : December 19, 2012
Last Update Posted : March 6, 2013
Sponsor:
Information provided by (Responsible Party):
Marina Aloi, University of Roma La Sapienza

Brief Summary:
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 or disease Intervention/treatment Phase
Pediatric Crohn's Disease Drug: Top-down Drug: Step-up Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : December 2012
Estimated Primary Completion Date : January 2014
Estimated Study Completion Date : December 2015


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. Clinical response or clinical remission as determined by PCDAI in top-down vs. step-up group [ Time Frame: 6, 12, 18, 24, 36 months ]
    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.

  2. Rate of mucosal healing in top-down vs. step-up group [ Time Frame: 6, 12, 24, 36 months ]
    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 :
  1. Rate of adverse events in top-down vs. step-up group [ Time Frame: 6,12,18,24,36 months ]
    The proportion of patients with adverse drug reaction and side effects attributable to therapy

  2. Hospitalization and surgery [ Time Frame: 6,12,24, 36 months ]
    The number of hospitalizations and surgical procedures in Top-down and step-up group

  3. Growth [ Time Frame: 6,12,24,36 months ]
    The pattern of growth in terms of Z-scores in top-down and step-up group



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Ages Eligible for Study:   6 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01752790


Locations
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Italy
Pediatric Gastroenterology and Liver Unit
Rome, Italy, 00161
Sponsors and Collaborators
University of Roma La Sapienza
Investigators
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Principal Investigator: Marina Aloi, Investigator Sapienza University of Rome
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Responsible Party: Marina Aloi, Research assistant, University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT01752790    
Other Study ID Numbers: 2473
First Posted: December 19, 2012    Key Record Dates
Last Update Posted: March 6, 2013
Last Verified: March 2013
Keywords provided by Marina Aloi, University of Roma La Sapienza:
Pediatric Crohn's disease
Biologics
Immunomodulators
Top-down
step-up
Additional relevant MeSH terms:
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Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Azathioprine
Antirheumatic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs