PICKET
Thalidomide improves clinical remission in children with Crohn’s disease METHODS Study design: Double-blinded, placebo controlled, randomised control trial. Setting: Six paediatric tertiary care centres in Italy between August 2008 and September 2012. Patients: 56 children with Crohn’s disease which was active despite immunosuppressive treatment. Intervention: Thalidomide (1.5–2.5 mg/kg/day) or placebo once daily for 8 weeks. Open-label extension meant children who received the placebo and did not respond were given thalidomide for 8 weeks. All responders were given an additional course of at least 52 weeks. Primary outcome: Clinical remission at 8 weeks, measured using the Paediatric Crohn’s Disease Activity Index and PCDAI score at 4 weeks and 8 weeks. Follow-up period: Four weeks and 8 weeks. Outcomes at 8 weeks
Thalidomide
Main results: More children (13/28 (46.4%)) who received thalidomide achieved clinical remission than those who received the placebo (3/26 (11.5%)), (RR 4.0 (95% CI 1.2 to 12.5, NNT 2.9) and improvement in PCDAI score. In an open-label extension of the study to placebo non-responders after 8 weeks, 11/21 (52.4%) achieved remission after 8 weeks of thalidomide treatment. The most frequently reported serious adverse event was peripheral neuropathy but only in high doses of long duration. The cumulative incidence of all serious adverse events was 2.1 per 1000 patient-weeks. Conclusion: Thalidomide compared with placebo in treating unresponsive Crohn’s disease resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an openlabel follow-up. Abstracted from Lazzerini M, Martelossi S, Magazzù G, et al. Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn’s disease: a randomized clinical trial. JAMA 2013;310:2164–73.
Placebo
Risk ratio (95% CI)
lose column
Clinical remission
13 (46.4%)
3 (11.5%)
4 (1.2 to 12.5)
0.01
≥75% improvement in PCDAI
13 (46.4%)
3 (11.5%)
4 (1.2 to 12.5)
0.01
≥50% improvement in PCDAI
18 (64.2%)
7 (26.9%)
2.3 (1.22 to 4.81)
0.01
≥25% improvement in PCDAI
18 (64.2%)
8 (30.8%)
2.11 (−1.11 to 3.90)
0.01
However, the findings have yet to lead to wider usage perhaps as a result of the potential toxicity and the development and adoption of monoclonal antibody treatment. This is a thought-provoking trial though the design is complex and does not perhaps answer all the questions it intended to. More than 60% of the children randomised had not received monoclonal antibody treatment. The reasons for this are not clear but this form of therapy is now standard in many countries in addition to purine analogues and methotrexate in severe disease. The generalisability of the findings is therefore debateable. Although the study showed a significant benefit of thalidomide treatment over placebo it would have been more informative had it tested thalidomide as a further add-on in children on monoclonal antibody therapy. With this in mind and with the baggage that thalidomide carries, it is clear that trials testing its efficacy as an add-on after monoclonal antibody treatment are required before making any recommendations. Sophie Harbour,1 Nick Brown2 1
Neonatal Department, Princess Anne Hospital, Southampton, UK 2 Paediatric Department, Salisbury District Hospital, Salisbury, UK Correspondence to Dr Sophie Harbour, Neonatal Department, Princess Anne Hospital, Southampton SO16 5YA, UK; [email protected]
To cite Harbour S, Brown N. Arch Dis Child Educ Pract Ed 2015;100:111. Published Online First 26 February 2015
REFERENCES 1 Henderson P, Hansen R, Cameron FL, et al. Rise in incidence of pediatric inflammatory bowel disease in Scotland. Inflamm Bowel Dis 2012;18:999–1005. 2 Rägo L, Santoso B. Drug regulation: history, present and future. In: Drug benefits and risks. 65–77. 3 Walker SL, Waters MF, Lockwood DN. The role of thalidomide in the management of erythema nodosum leprosum. Lepr Rev 2007;78:197–215. 4 Palumbo A, Bringhen S, Kumar SK, et al. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. Lancet Oncol 2014;15:333–42. 5 Ehrenpreis ED, Kane SV, Cohen LB, et al. Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial. Gastroenterology 1999;117:1271–7.
Harbour S, et al. Arch Dis Child Educ Pract Ed 2015;100:111. doi:10.1136/archdischild-2014-307581
111
COMMENTARY
T
he incidence of paediatric Crohn’s Disease is increasing, and the median age of diagnosis decreasing.1 Onset in childhood is frequently linked to more severe disease and a number of children develop disease that is refractory to immunosuppressive drugs. The option of an alternative to the high risk surgery inherent to the disease is an attractive one. Thalidomide is an immunomodulatory drug which was first marketed in 1957. Its exact mechanism of action is unknown. It has a well-known tragic history. In the early 1960s when marketed as a cure for morning sickness it resulted in about 10 000 cases worldwide of phocomelia. As a result, much stricter drug regulations were developed.2 In recent years, thalidomide has had an unexpected resurgence in new roles including multiple myeloma and leprosy associated erythema nodosum leprosum.3 In the UK, thalidomide is currently recommended by NICE as first-line treatment for multiple myeloma with the caveat that “patient, prescriber and supplying pharmacy must comply with a pregnancy prevention programme. Every prescription must be accompanied by a complete Prescription Authorisation Form.” The FDA has also raised a concern about secondary malignancies in the thalidomide analogue, lanalidomide.4 It has also been used in adult inflammatory bowel disease. A previous small trial in the use of thalidomide to treat refractory adult Crohn’s disease in 1999 showed a modest benefit.5
Copyright of Archives of Disease in Childhood -- Education & Practice Edition is the property of BMJ Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Thalidomide improves clinical remission in children with Crohn’s disease METHODS Study design: Double-blinded, placebo controlled, randomised control trial. Setting: Six paediatric tertiary care centres in Italy between August 2008 and September 2012. Patients: 56 children with Crohn’s disease which was active despite immunosuppressive treatment. Intervention: Thalidomide (1.5–2.5 mg/kg/day) or placebo once daily for 8 weeks. Open-label extension meant children who received the placebo and did not respond were given thalidomide for 8 weeks. All responders were given an additional course of at least 52 weeks. Primary outcome: Clinical remission at 8 weeks, measured using the Paediatric Crohn’s Disease Activity Index and PCDAI score at 4 weeks and 8 weeks. Follow-up period: Four weeks and 8 weeks. Outcomes at 8 weeks
Thalidomide
Main results: More children (13/28 (46.4%)) who received thalidomide achieved clinical remission than those who received the placebo (3/26 (11.5%)), (RR 4.0 (95% CI 1.2 to 12.5, NNT 2.9) and improvement in PCDAI score. In an open-label extension of the study to placebo non-responders after 8 weeks, 11/21 (52.4%) achieved remission after 8 weeks of thalidomide treatment. The most frequently reported serious adverse event was peripheral neuropathy but only in high doses of long duration. The cumulative incidence of all serious adverse events was 2.1 per 1000 patient-weeks. Conclusion: Thalidomide compared with placebo in treating unresponsive Crohn’s disease resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an openlabel follow-up. Abstracted from Lazzerini M, Martelossi S, Magazzù G, et al. Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn’s disease: a randomized clinical trial. JAMA 2013;310:2164–73.
Placebo
Risk ratio (95% CI)
lose column
Clinical remission
13 (46.4%)
3 (11.5%)
4 (1.2 to 12.5)
0.01
≥75% improvement in PCDAI
13 (46.4%)
3 (11.5%)
4 (1.2 to 12.5)
0.01
≥50% improvement in PCDAI
18 (64.2%)
7 (26.9%)
2.3 (1.22 to 4.81)
0.01
≥25% improvement in PCDAI
18 (64.2%)
8 (30.8%)
2.11 (−1.11 to 3.90)
0.01
However, the findings have yet to lead to wider usage perhaps as a result of the potential toxicity and the development and adoption of monoclonal antibody treatment. This is a thought-provoking trial though the design is complex and does not perhaps answer all the questions it intended to. More than 60% of the children randomised had not received monoclonal antibody treatment. The reasons for this are not clear but this form of therapy is now standard in many countries in addition to purine analogues and methotrexate in severe disease. The generalisability of the findings is therefore debateable. Although the study showed a significant benefit of thalidomide treatment over placebo it would have been more informative had it tested thalidomide as a further add-on in children on monoclonal antibody therapy. With this in mind and with the baggage that thalidomide carries, it is clear that trials testing its efficacy as an add-on after monoclonal antibody treatment are required before making any recommendations. Sophie Harbour,1 Nick Brown2 1
Neonatal Department, Princess Anne Hospital, Southampton, UK 2 Paediatric Department, Salisbury District Hospital, Salisbury, UK Correspondence to Dr Sophie Harbour, Neonatal Department, Princess Anne Hospital, Southampton SO16 5YA, UK; [email protected]
To cite Harbour S, Brown N. Arch Dis Child Educ Pract Ed 2015;100:111. Published Online First 26 February 2015
REFERENCES 1 Henderson P, Hansen R, Cameron FL, et al. Rise in incidence of pediatric inflammatory bowel disease in Scotland. Inflamm Bowel Dis 2012;18:999–1005. 2 Rägo L, Santoso B. Drug regulation: history, present and future. In: Drug benefits and risks. 65–77. 3 Walker SL, Waters MF, Lockwood DN. The role of thalidomide in the management of erythema nodosum leprosum. Lepr Rev 2007;78:197–215. 4 Palumbo A, Bringhen S, Kumar SK, et al. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. Lancet Oncol 2014;15:333–42. 5 Ehrenpreis ED, Kane SV, Cohen LB, et al. Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial. Gastroenterology 1999;117:1271–7.
Harbour S, et al. Arch Dis Child Educ Pract Ed 2015;100:111. doi:10.1136/archdischild-2014-307581
111
COMMENTARY
T
he incidence of paediatric Crohn’s Disease is increasing, and the median age of diagnosis decreasing.1 Onset in childhood is frequently linked to more severe disease and a number of children develop disease that is refractory to immunosuppressive drugs. The option of an alternative to the high risk surgery inherent to the disease is an attractive one. Thalidomide is an immunomodulatory drug which was first marketed in 1957. Its exact mechanism of action is unknown. It has a well-known tragic history. In the early 1960s when marketed as a cure for morning sickness it resulted in about 10 000 cases worldwide of phocomelia. As a result, much stricter drug regulations were developed.2 In recent years, thalidomide has had an unexpected resurgence in new roles including multiple myeloma and leprosy associated erythema nodosum leprosum.3 In the UK, thalidomide is currently recommended by NICE as first-line treatment for multiple myeloma with the caveat that “patient, prescriber and supplying pharmacy must comply with a pregnancy prevention programme. Every prescription must be accompanied by a complete Prescription Authorisation Form.” The FDA has also raised a concern about secondary malignancies in the thalidomide analogue, lanalidomide.4 It has also been used in adult inflammatory bowel disease. A previous small trial in the use of thalidomide to treat refractory adult Crohn’s disease in 1999 showed a modest benefit.5
Copyright of Archives of Disease in Childhood -- Education & Practice Edition is the property of BMJ Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
