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Original Investigation
November 27, 2013

Effect of Thalidomide on Clinical Remission in Children and Adolescents With Refractory Crohn Disease: A Randomized Clinical Trial

Author Affiliations
  • 1Institute for Maternal and Child Health IRCCS “Burlo Garofolo,” Trieste, Italy
  • 2Paediatric Sciences, University of Messina, Messina, Italy
  • 3Paediatric Gastroenterology Unit, Institute Giannina Gaslini, Genoa, Italy
  • 4Department of Sciences for Woman and Child Health, University of Florence, Meyer Children Hospital, Florence, Italy
  • 5Paediatric Department, Children's Hospital “V. Buzzi,” Milan, Italy
  • 6Paediatric Gastroenterology, University of Pisa, Pisa, Italy
  • 7University of Trieste, Italy
  • 8Department of Pathology, Spedali Civili, Brescia, Italy
  • 9Department of Life Science, University of Trieste, Trieste, Italy
JAMA. 2013;310(20):2164-2173. doi:10.1001/jama.2013.280777

Importance  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.

Design, Setting, and Patients  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.

Interventions  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.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00720538