Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: A randomized clinical trial

Marzia Lazzerini, Stefano Martelossi, Giuseppe Magazzù, Salvatore Pellegrino, Maria Cristina Lucanto, Arrigo Barabino, Angela Calvi, Serena Arrigo, Paolo Lionetti, Monica Lorusso, Francesca Mangiantini, Massimo Fontana, Giovanna Zuin, Gabriella Palla, Giuseppe Maggiore, Matteo Bramuzzo, Maria Chiara Pellegrin, Massimo Maschio, Vincenzo Villanacci, Stefania ManentiGiuliana Decorti, Sara De Iudicibus, Rossella Paparazzo, Marcella Montico, Alessandro Ventura

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2164-2173
Number of pages10
JournalJournal of the American Medical Association
Volume310
Issue number20
DOIs
Publication statusPublished - 2013

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Thalidomide
Crohn Disease
Randomized Controlled Trials
Placebos
Numbers Needed To Treat
Odds Ratio
Peripheral Nervous System Diseases
Immunosuppressive Agents
Tertiary Care Centers
Pharmaceutical Preparations
Italy
Therapeutics
Pediatrics

ASJC Scopus subject areas

  • Medicine(all)

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Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease : A randomized clinical trial. / Lazzerini, Marzia; Martelossi, Stefano; Magazzù, Giuseppe; Pellegrino, Salvatore; Lucanto, Maria Cristina; Barabino, Arrigo; Calvi, Angela; Arrigo, Serena; Lionetti, Paolo; Lorusso, Monica; Mangiantini, Francesca; Fontana, Massimo; Zuin, Giovanna; Palla, Gabriella; Maggiore, Giuseppe; Bramuzzo, Matteo; Pellegrin, Maria Chiara; Maschio, Massimo; Villanacci, Vincenzo; Manenti, Stefania; Decorti, Giuliana; De Iudicibus, Sara; Paparazzo, Rossella; Montico, Marcella; Ventura, Alessandro.

In: Journal of the American Medical Association, Vol. 310, No. 20, 2013, p. 2164-2173.

Research output: Contribution to journalArticle

Lazzerini, M, Martelossi, S, Magazzù, G, Pellegrino, S, Lucanto, MC, Barabino, A, Calvi, A, Arrigo, S, Lionetti, P, Lorusso, M, Mangiantini, F, Fontana, M, Zuin, G, Palla, G, Maggiore, G, Bramuzzo, M, Pellegrin, MC, Maschio, M, Villanacci, V, Manenti, S, Decorti, G, De Iudicibus, S, Paparazzo, R, Montico, M & Ventura, A 2013, 'Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: A randomized clinical trial', Journal of the American Medical Association, vol. 310, no. 20, pp. 2164-2173. https://doi.org/10.1001/jama.2013.280777
Lazzerini, Marzia ; Martelossi, Stefano ; Magazzù, Giuseppe ; Pellegrino, Salvatore ; Lucanto, Maria Cristina ; Barabino, Arrigo ; Calvi, Angela ; Arrigo, Serena ; Lionetti, Paolo ; Lorusso, Monica ; Mangiantini, Francesca ; Fontana, Massimo ; Zuin, Giovanna ; Palla, Gabriella ; Maggiore, Giuseppe ; Bramuzzo, Matteo ; Pellegrin, Maria Chiara ; Maschio, Massimo ; Villanacci, Vincenzo ; Manenti, Stefania ; Decorti, Giuliana ; De Iudicibus, Sara ; Paparazzo, Rossella ; Montico, Marcella ; Ventura, Alessandro. / Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease : A randomized clinical trial. In: Journal of the American Medical Association. 2013 ; Vol. 310, No. 20. pp. 2164-2173.
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abstract = "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.",
author = "Marzia Lazzerini and Stefano Martelossi and Giuseppe Magazz{\`u} and Salvatore Pellegrino and Lucanto, {Maria Cristina} and Arrigo Barabino and Angela Calvi and Serena Arrigo and Paolo Lionetti and Monica Lorusso and Francesca Mangiantini and Massimo Fontana and Giovanna Zuin and Gabriella Palla and Giuseppe Maggiore and Matteo Bramuzzo and Pellegrin, {Maria Chiara} and Massimo Maschio and Vincenzo Villanacci and Stefania Manenti and Giuliana Decorti and {De Iudicibus}, Sara and Rossella Paparazzo and Marcella Montico and Alessandro Ventura",
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TY - JOUR

T1 - Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease

T2 - A randomized clinical trial

AU - Lazzerini, Marzia

AU - Martelossi, Stefano

AU - Magazzù, Giuseppe

AU - Pellegrino, Salvatore

AU - Lucanto, Maria Cristina

AU - Barabino, Arrigo

AU - Calvi, Angela

AU - Arrigo, Serena

AU - Lionetti, Paolo

AU - Lorusso, Monica

AU - Mangiantini, Francesca

AU - Fontana, Massimo

AU - Zuin, Giovanna

AU - Palla, Gabriella

AU - Maggiore, Giuseppe

AU - Bramuzzo, Matteo

AU - Pellegrin, Maria Chiara

AU - Maschio, Massimo

AU - Villanacci, Vincenzo

AU - Manenti, Stefania

AU - Decorti, Giuliana

AU - De Iudicibus, Sara

AU - Paparazzo, Rossella

AU - Montico, Marcella

AU - Ventura, Alessandro

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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