CHICAGO – Adalimumab induced and maintained clinical remission in children with moderate to severe Crohn’s disease and the treatment was not associated with any new safety signals in a double-blind, phase III, randomized trial.
The effect was most apparent in patients who were infliximab naive, Dr. Jeffrey S. Hyams said at the annual Digestive Disease Week.
Dr. Jeffrey S. Hyams
Adalimumab (Humira), a human monoclonal antibody to tumor necrosis factor (TNF)–alfa, is indicated for the treatment of a variety of conditions including Crohn’s disease in adults and juvenile idiopathic arthritis, but it is not approved for juvenile Crohn’s disease.
The study involved 188 patients, aged 6-17 years, with moderate to severe Crohn’s disease that had lasted for at least 12 weeks, despite concurrent treatment with oral corticosteroids for at least 2 weeks and/or immunomodulators for at least 8 weeks. Roughly 45% of patients had used the chimeric monoclonal antibody to TNF, infliximab (Remicade).
All study patients received 4 weeks of open-label adalimumab induction therapy and were stratified based on response at week 4 and prior infliximab use to high- or low-dose maintenance adalimumab. High-dose adalimumab was 40 mg every other week for patients weighing 40 kg or more and 20 mg every other week if less than 40 kg. Low-dose adalimumab was 20 mg every other week for patients weighing 40 kg or more and 10 mg every other week if less than 40 kg. Dose escalation was allowed for flare or non-response beginning at week 12.
At week 26, 39% of the high-dose patients and 28% of low-dose patients met the study’s primary end point of clinical remission, defined as a Pediatric Crohn’s Disease Activity Index of 10 or less, said Dr. Hyams, director of the gastroenterology department at Connecticut Children’s Medical Center in Hartford. In addition, more high-dose patients than low-dose patients achieved clinical remission at week 52 (33% vs. 23%). The difference between groups was not statistically significant at week 26 or week 52.
A clinical response, defined as a decrease in Pediatric Crohn’s Disease Activity Index of at least 15 points from baseline, was observed in more high-dose than low-dose patients at week 26 (59% vs. 48%) and week 52, with the difference reaching statistical significance only at week 52 (42% vs. 28%; P = .03), he said.
When the data were broken down according to prior infliximab use, remission rates among infliximab-experienced patients were similar between the high- and low-dose adalimumab arms at week 26 (17% vs. 20%) and week 52 (19% vs. 17%).
Among infliximab-naive patients, however, clinical remission rates were significantly greater at week 26 in the high-dose vs. low-dose group (57% vs. 35%, P = .026), especially among week-4 responders (63% for high-dose group vs. 38% for low-dose group, P = .016). In all, 82% of the 188 patients responded to induction at week 4. Remission rates among infliximab-naive patients were statistically similar at week 52 (45% vs. 28%, P = .065).
Dr. Hyams said there were no "obvious safety signals" among patients who received at least one maintenance dose of adalimumab. Serious adverse events were reported in 19 (20%) of the 95 low-dose patients and 22 (24%) of the 93 high-dose patients. Notably, serious infections were reported in only 3 low-dose (3.2%) and 5 high-dose (5.4%) patients. No malignancies were observed.
Adalimumab carries a boxed warning for an increased risk of serious infections leading to hospitalization or death, particularly tuberculosis. In August 2009, the Food and Drug Administration also required that boxed warnings be added to the TNF-blocker class of drugs because of an increased risk of lymphoma and other malignancies in children and adolescents.
When asked during a discussion of the study about the effect of adalimumab on fistulas, Dr. Hyams said that 15%-20% of patients had active fistulas,and a beneficial response to therapy occurred in about 50% of the low-dose patients and about 80% of the high-dose patients.
Another attendee asked if prior treatment with immunomodulators affected response, and Dr. Hyams said it did not. If the patient experienced a clinical response, corticosteroid therapy was tapered after week 4 and could be increased to the baseline dose for flare or nonresponse. Immunomodulator therapy could be discontinued at or after week 26 and could not be reinstated.
The study was sponsored by Abbott Laboratories and an Abbott employee prepared the first draft and assisted in the production of the slides. Dr. Hyams disclosed consulting and advisory committee/review panel participation and grant/research support from Abbott. Five of the 13 coauthors are Abbott employees and five others have financial relationships with Abbott.