Clinical Trial: Efficacy and Safety of Top-down Therapy in Pediatric Crohn's Disease
Study Status: Withdrawn
Recruit Status: Withdrawn
Study Type: Interventional
Official Title: Efficacy and Safety of Infliximab as First-line Therapy in Pediatric Crohn's Disease: a Randomized, Controlled, Open-label Trial
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.
Detailed Summary: This is a single-center, open-label, randomized, prospective, controlled trial evaluating the efficacy and safety of infliximab (IFX) as first line therapy in children with moderate-to-severe CD. The estimated duration of the study is 36 months, including a recruitment phase of 12 months, a treatment phase of 12 months, composed by an induction phase of 8 weeks and a maintaining phase of 40 weeks, and a follow-up phase of 12 months. The study protocol is defined in accordance with Declaration of Helsinki and approved by the local ethical committee. Written informed consent will be obtained from all children's parents; children older than 12 years will sign a statement of assent. Children aged between 6 and 18 years with active CD confirmed by recognized clinical, radiological, endoscopic and histological criteria will be considered for the trial if they will satisfy the following criteria: 1. diagnosis of CD; 2. PCDAI>30; 3. duration of disease less than 1 year from the time of diagnosis (early CD). Exclusion criteria will be: any prior treatment with immunosuppressive agents (azathiorpine/6-mercaptopurine [AZA/6-MP], methotrexate, cyclosporine) or anti-TNFα, stenosing CD, pre-existing systemic disease, hepatic or renal dysfunction, systemic infection, suspected pregnancy, a history of active or past tuberculosis, or contraindication to corticosteroid (CS) therapy. Children who will have received any CS within 4 weeks before randomization will be also excluded. Patients who will have received 5-ASA will be eligible if the drug will be kept with a stable regimen for more than 4 weeks before the beginning of the study. Early CD will be arbitrarily defined as disease duration of <1 yr from the time of diagnosis. Eligible patients will be randomly allocated to receive a 8-week course of IFX plus AZA (top-down arm - TD) or CS plus AZA (step-up arm - SU). Randomization group assignments will be generated using a computer-generated randomization schedule by an i
Sponsor: University of Roma La Sapienza
Current Primary Outcome:
- 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.
- 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.
Original Primary Outcome:
- Clinical response [ 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.
- Mucosal healing [ 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.
Current Secondary Outcome:
- 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
- Hospitalization and surgery [ Time Frame: 6,12,24, 36 months ]The number of hospitalizations and surgical procedures in Top-down and step-up group
- Growth [ Time Frame: 6,12,24,36 months ]The pattern of growth in terms of Z-scores in top-down and step-up group
Original Secondary Outcome:
- Safety [ Time Frame: 6,12,18,24,36 months ]The proportion of patients with adverse drug reaction and side effects attributable to therapy
- Hospitalization and surgery [ Time Frame: 6,12,24, 36 months ]The number of hospitalizations and surgical procedures in Top-down and step-up group
- Growth [ Time Frame: 6,12,24,36 months ]The pattern of growth in terms of Z-scores in top-down and step-up group
Information By: University of Roma La Sapienza
Dates:
Date Received: December 12, 2012
Date Started: December 2012
Date Completion: December 2015
Last Updated: March 5, 2013
Last Verified: March 2013
