title: Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial.
abstract: OBJECTIVE
  Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children.
  
  
  OBJECTIVE
  To determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease.
  
  
  METHODS
  Multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment, conducted August 2008-September 2012 in 6 pediatric tertiary care centers in Italy.
  
  
  METHODS
  Thalidomide, 1.5 to 2.5 mg/kg per day, or placebo once daily for 8 weeks. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks.
  
  
  METHODS
  Primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by ≥25% or ≥75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response.
  
  
  RESULTS
  Twenty-eight children were randomized to thalidomide and 26 to placebo. Clinical remission was achieved by significantly more children treated with thalidomide (13/28 [46.4%] vs 3/26 [11.5%]; risk ratio [RR], 4.0 [95% CI, 1.2-12.5]; P = .01; number needed to treat [NNT], 2.86). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group (75% response, 13/28 [46.4%] vs 3/26 [11.5%]; RR, 4.0 [95% CI, 1.2-12.5]; NNT = 2.86; P = .01; and 25% response, 18/28 [64.2%] vs 8/26 [30.8%]; RR, 2.1 [95% CI, 1.1-3.9]; NNT = 2.99; P = .01). Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (RR, 4.5 [95% CI, 1.4-14.1]; NNT = 2.45; P = .01). Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission, and 32 of 49 (65.3%) achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks (95% CI, 144.53-217.76) vs 6.3 weeks (95% CI, 3.51-9.15) in the placebo group (P < .001). Cumulative incidence of severe adverse events was 2.1 per 1000 patient-weeks, with peripheral neuropathy the most frequent severe adverse event.
  
  
  CONCLUSIONS
  In children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up. These findings require replication to definitively determine clinical utility of this treatment.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00720538.
authors.affiliation: Institute for Maternal and Child Health IRCCS "Burlo Garofolo," Trieste, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Lazzerini
authors.forename: Stefano
authors.initials: S
authors.lastname: Martelossi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Magazzù
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pellegrino
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Lucanto
authors.forename: Arrigo
authors.initials: A
authors.lastname: Barabino
authors.forename: Angela
authors.initials: A
authors.lastname: Calvi
authors.forename: Serena
authors.initials: S
authors.lastname: Arrigo
authors.forename: Paolo
authors.initials: P
authors.lastname: Lionetti
authors.forename: Monica
authors.initials: M
authors.lastname: Lorusso
authors.forename: Francesca
authors.initials: F
authors.lastname: Mangiantini
authors.forename: Massimo
authors.initials: M
authors.lastname: Fontana
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zuin
authors.forename: Gabriella
authors.initials: G
authors.lastname: Palla
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maggiore
authors.forename: Matteo
authors.initials: M
authors.lastname: Bramuzzo
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Pellegrin
authors.forename: Massimo
authors.initials: M
authors.lastname: Maschio
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Villanacci
authors.forename: Stefania
authors.initials: S
authors.lastname: Manenti
authors.forename: Giuliana
authors.initials: G
authors.lastname: Decorti
authors.forename: Sara
authors.initials: S
authors.lastname: De Iudicibus
authors.forename: Rossella
authors.initials: R
authors.lastname: Paparazzo
authors.forename: Marcella
authors.initials: M
authors.lastname: Montico
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ventura
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002648:Child; D003424:Crohn Disease / Q000188:drug therapy* / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D012074:Remission Induction; D012720:Severity of Illness Index; D013792:Thalidomide / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D013792:Thalidomide