An 8-week course of daily oral thalidomide induced clinical remission in 13 of 28 children and adolescents with refractory Crohn’s disease who participated in the first multicenter, double-blind, placebo-controlled clinical trial for this indication, which was reported online Nov. 26 in JAMA.
Thalidomide also consistently reduced scores on the Pediatric Crohn Disease Activity Index (PCDAI), decreased erythrocyte sedimentation rate, improved weight-for-age measures, and increased physicians’ global assessment scores, said Marzia Lazzerini, Ph.D., of the Institute for Maternal and Child Health, Trieste (Italy), and her associates.
The drug also induced longer maintenance of remission than did placebo in an extended follow-up phase of the trial, they noted.
"These findings require replication to definitively determine the utility of this treatment," the investigators said.
Previous observational studies have reported that thalidomide yielded "encouraging results" in patients with Crohn’s disease, with remission rates of 40%-70%. The drug also has proved effective against inflammatory diseases of the skin and mucous membranes.
Dr. Lazzerini and her colleagues performed their clinical trial in 54 patients aged 2-18 years, who were treated at six pediatric tertiary care centers in Italy over a 4-year period.
All the study participants had active Crohn’s disease despite receiving immunosuppressant therapy, or had been forced to discontinue such therapy because of adverse events or increasing resistance to its beneficial effects. Previous treatments included prednisone, azathioprine, mercaptopurine, methotrexate, infliximab, and oral or intravenous cyclosporine.
A total of 28 patients were randomly assigned to receive thalidomide at a dose appropriate for their weight, and 26 were randomized to receive a matching placebo for 8 weeks. Patients, parents, and health caregivers were blinded to treatment assignment. In an open-label extension phase of the study, patients in the placebo group who were not in clinical remission were given thalidomide and followed for an additional 8 weeks.
All patients who responded to thalidomide were then followed for a minimum of 1 year to monitor long-term efficacy and adverse events.
The primary efficacy endpoints were clinical remission at week 8, a 25% reduction in PCDAI score at week 4, or a 75% or greater reduction in PCDAI score at week 4 or week 8.
Thirteen of the 28 patients receiving thalidomide (46.4%) achieved clinical remission at week 8, compared with 3 of 26 patients receiving placebo (11.5%), for a risk ratio of 4. The number of patients who needed to be treated to achieve one clinical remission was 2.86.
The other efficacy endpoints also strongly favored thalidomide: 64.2% of the thalidomide group had a 25% response at week 8, compared with only 30.8% of the placebo group, and 46.4% of the thalidomide group had a 75% response at week 8, compared with only 11.5% of the placebo group.
A total of 21 patients who failed to respond to placebo received thalidomide in the extended phase of the study. Eleven (52.4%) of them achieved clinical remission at week 8, for a risk ratio of 4.5. The number needed to treat was 2.45.
The overall remission rate for both phases of the trial was 63.3%, and the mean time to reach remission was 10 weeks, the investigators reported (JAMA 2013 Nov. 26 [doi: 10.1001/jama.2013.280777]).
The mean duration of clinical remission was 181.1 weeks among the patients who received thalidomide, compared with 6.3 weeks among those who received placebo.
There were nine severe adverse events requiring the suspension of treatment, with peripheral neuropathy, a known adverse effect of thalidomide, being the most frequent. Other severe adverse events included amenorrhea and bradycardia, which also were reported previously in association with thalidomide. "Patients treated with thalidomide should be monitored for bradycardia, and dose reduction or discontinuation may be required," Dr. Lazzerini and her associates said.
One patient developed an acute neurologic event while taking thalidomide, which was thought to be possibly a migraine or transient ischemic attack. Another child had a seizure and was diagnosed as having idiopathic epilepsy unrelated to treatment. Thalidomide was discontinued in both patients.
"All immunosuppressants used for treating Crohn’s disease present a risk of severe adverse events," the researchers noted. "Overall, this study suggests that safety of thalidomide in children with Crohn disease may be acceptable compared with that of other drugs. However, the study was clearly underpowered to detect rare adverse events."
This study was supported by the Italian Medicines Agency. Pharmion/Celgene, the manufacturer of thalidomide, provided the study drug and matching placebo. Dr. Lazzerini and her associates reported no financial conflicts of interest.
