7. Induction and maintenance adalimumab therapy for the treatment of moderate to severe Crohn's disease in children
J. Hyams1, A.M. Griffiths2, J. Markowitz3, R. Baldassano4, W. Faubion5, R. Colletti6, M. Dubinsky7, J. Kierkus8, Y. Wang9, B. Huang9, B. Bittle9, M. Marshall9, A. Lazar10
1Connecticut Children's Medical Center, Hartford, CT, United States; 2Hospital for SickKids, Toronto, ON, Canada; 3Cohen Children's Medical Center of New York, New Hyde Park, NY, United States; 4Children's Hospital of Philadelphia, Philadelphia, PA, United States; 5Mayo Clinic, Rochester, MN, United States; 6University of Vermont, Burlington, VT, United States; 7Cedars Sinai Medical Center, Los Angeles, CA, United States; 8Children's Memorial Health Institute, Warsaw, Poland; 9Abbott, Abbott Park, IL, United States; 10Abbott, Ludwigshafen, Germany
Aim: A multi-center, randomized, double-blind study to compare efficacy and safety of two adalimumab dosage regimens for induction and maintenance of clinical remission in pediatric patients with moderate to severe Crohn's disease (CD).
Methods: Patients aged 6 to 17 years with CD (Pediatric Crohn's Disease Activity Index [PCDAI] >30 at baseline, with endoscopic or radiologic confirmation) for ≥12 weeks (Wks), despite concurrent (or failure/intolerance of) treatment with oral corticosteroid and/or immunosuppressants. Prior infliximab (IFX) exposure, discontinued for loss of response or intolerance, was allowed. Patients received open-label adalimumab induction per baseline body weight (BW; 160 mg at Wk0, 80 mg at Wk2 for BW ≥ 40 kg, 80 mg at Wk0, 40 mg at Wk2 for BW < 40 kg). At Wk4, patients were stratified per Wk4 clinical response (PCDAI decrease ≥15 points from baseline) and prior IFX exposure, and randomized 1:1 to double-blind adalimumab maintenance therapy for 48 Wks at high-dose (40 mg every other Wk (eow) if Wk4 BW ≥ 40 kg, 20 mg eow if Wk4 BW < 40 kg) or low-dose (20 mg eow if Wk4 BW ≥ 40 kg; 10 mg eow if Wk4 BW < 40 kg). Patients could increase to blinded weekly dose for flare/non-response after Wk12. Primary endpoint was Wk26 clinical remission (PCDAI ≤ 10), secondary endpoints included Wk26 clinical response (overall, and by Wk4 response and prior IFX exposure). Percentages of patients achieving endpoints in high-dose versus low-dose maintenance groups were compared. Treatment-emergent adverse events were monitored to evaluate safety.
Results: 192 patients received adalimumab induction (56% male, 89% white, 64% ≥13 years old, 64% ≥40 kg, 44% prior IFX use, median PCDAI = 40.0 at baseline). 87% and 80% of randomized patients with 80 mg/40 mg and 160 mg/80 mg induction doses, respectively, achieved clinical response at Wk4. 188 patients were randomized (low-dose: 95; high-dose: 93); 124 completed the study (low-dose: 58; high-dose: 66). A higher proportion of high-dose patients achieved clinical remission or response at Wk26 compared with low-dose patients. Remission and response rates at Wk26 were greatest for IFX-naïve patients, especially those who were Wk4 responders (Table). No new safety signals were detected.
Conclusion:In this pediatric trial, adalimumab was efficacious for inducing and maintaining remission of CD, with a safety profile comparable to that observed in adult patients with CD. Greatest efficacy was observed for IFX-naïve patients receiving high-dose adalimumab, especially those who responded to adalimumab induction, but adalimumab treatment also benefitted IFX-experienced patients.
|Prior IFX||Wk4 Response||ADA Low-dose, % (n/N)||ADA High-dose, % (n/N)||P valuea,b,c|
|Clinical Remission Overall||28 (27/95)||39 (36/93)||0.075|
|Yes||20 (8/41)||17 (7/42)||0.736|
|Yes||22 (7/32)||19 (6/32)||0.756|
|No||11 (1/9)||10 (1/10)||–|
|No||35 (19/54)||57 (29/51)||0.026*|
|Yes||38 (18/48)||63 (27/43)||0.016*|
|No||17 (1/6)||25 (2/8)||–|
|Clinical Response Overall||48 (46/95)||59 (55/93)||0.073|
|Yes||29 (12/41)||48 (20/42)||0.086|
|Yes||31 (10/32)||56 (18/32)||0.044*|
|No||22 (2/9)||20 (2/10)||–|
|No||63 (34/54)||69 (35/51)||0.541|
|Yes||67 (32/48)||74 (32/43)||0.419|
|No||33 (2/6)||38 (3/8)||–|
|aCochran-Mantel-Haenszel test adjusted for prior IFX use and Wk4 response status for overall. bChi-square test (or Fisher's exact test for small cell counts) within each category of prior IFX use or Wk4 response. cIf blank, test not performed due to small sample size.
*Statistically significant at an α = 5% level.