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

NCT01752790 | Withdrawn Phase 4

• 1 other identifier: 2473
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Pediatric Crohn's Disease

Keywords

Pediatric Crohn's disease; Biologics; Immunomodulators; Top-down; step-up

Outcome Measures

Primary Outcomes (2)

• Clinical response or clinical remission as determined by PCDAI in top-down vs. step-up group

  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.

  6, 12, 18, 24, 36 months

• Rate of mucosal healing in top-down vs. step-up group

  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.

  6, 12, 24, 36 months

Secondary Outcomes (3)

• Rate of adverse events in top-down vs. step-up group

  6,12,18,24,36 months

• Hospitalization and surgery

  6,12,24, 36 months

• Growth

  6,12,24,36 months

Study Arms (2)

Top-down

EXPERIMENTAL

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

Step-up

ACTIVE COMPARATOR

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

Interventions

Top-down DRUG

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.

Also known as: Remicade, Imuran

Top-down

Step-up DRUG

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.

Also known as: Imuran, Medrol, Urbason

Step-up

Eligibility Criteria

• Age: 6 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

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

You may not qualify if:

• any prior treatment with immunosuppressive agents (AZA/6-MP, methotrexate, cyclosporine) or anti-TNFα,
• stenosing CD,
• pre-existing systemic disease,
• hepatic or renal dysfunction,
• systemic infection,
• suspected pregnancy,
• history of active or past tuberculosis,
• contraindication to steroid therapy

Sponsors & Collaborators

• University of Roma La Sapienza: lead

Study Sites (1)

Pediatric Gastroenterology and Liver Unit

Rome, 00161, Italy

Location

MeSH Terms

Conditions

Pediatric Crohn's disease

Interventions

Infliximab; Azathioprine; Methylprednisolone

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Thionucleosides; Sulfur Compounds; Organic Chemicals; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Marina Aloi, Investigator

  University of Roma La Sapienza

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research assistant

Study Record Dates

• First Submitted: December 12, 2012
• First Posted: December 19, 2012
• Study Start: December 1, 2012
• Primary Completion: January 1, 2014
• Study Completion: December 1, 2015
• Last Updated: March 6, 2013

Record last verified: 2013-03

Locations

IT (1)