Timing of Dose Escalation
The proportion of patients who escalated to blinded weekly dosing at different times during the study was similar between the patients receiving LD and HD adalimumab (P = 0.74); 39.6% (19/48) and 34.3% (12/35) of patients escalated at week 12, 29.2% (14/48) and 37.1% (13/35) of patients escalated between weeks 12 and 26, and 31.3% (15/48) and 28.6% (10/35) of patients escalated between weeks 26 and 52 in the LD and HD groups, respectively.
Efficacy of Adalimumab in Patients Who Escalated to Blinded Weekly Dosing
Week 52 remission and response rates in patients who escalated to blinded weekly dosing are shown in Figure 2. Of the 83 patients who escalated to blinded weekly dosing, 24.1% achieved remission and 51.8% achieved response (Fig. 2A, B). No statistically significant differences between LD and HD adalimumab were observed in remission or response rates for patients who escalated to blinded weekly dosing (Fig. 2A, B). Rates of remission and response after escalation were similar to those reported for the intent-to-treat population of IMAgINE 1 (28.2% remission, 35.1% response; Fig. 2A, B). Of note, patients in the intent-to-treat population who escalated to weekly dosing were considered as nonremitters or nonresponders. An analysis of remission within the LD and HD groups revealed that the highest rate of remission occurred in those who escalated to 40 mg weekly (data not shown). In subgroup analyses by previous infliximab status, a significantly higher percentage of infliximab-naive patients in the HD group achieved remission at week 52 than infliximab-naive patients in the LD group (Fig. 2C). No significant difference was observed between the LD and HD groups in infliximab-experienced patients (Fig. 2C, D). Overall, in all patients who dose escalated, no significant difference in the rate of remission was observed between infliximab-naive and infliximab-experienced patients at week 52 (27.3% naive versus 20.5% experienced, P = 0.47; Fig. 2C). Additionally, response rates at week 52 (59.1% naive versus 43.6% experienced, P = 0.16) were similar between infliximab-naive and infliximab-experienced patients in each dose group (Fig. 2D). Additional subgroup analyses of patients who escalated to weekly dosing are shown in Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/IBD/B232. No significant differences in remission rates were observed between treatment groups or between the various subgroups at week 52. Patients who escalated to blinded weekly dosing and used immunomodulators at baseline had a statistically significantly higher response rate at week 52 (28/44, 63.6%) than patients who did not use immunomodulators at baseline and escalated to blinded weekly dosing (15/39, 33.5%, P = 0.022). No significant differences were observed in week 52 response rates in the other subgroups assessed (see Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/IBD/B232).
Predictors of Dose Escalation
When baseline characteristics were used to predict the likelihood of dose escalation, patients who used immunomodulators at baseline (Table 1) were significantly less likely to escalate to weekly dosing than patients who did not use immunomodulators at baseline (odds ratio 0.50; P = 0.042, 95% confidence interval = 0.25–0.97) (Table 2). None of the other baseline characteristics, including disease location, were found to be associated with dose escalation. Among week 4 demographic or clinical variables, treatment dose was a significant predictor, with patients receiving HD less likely to escalate to weekly dosing than patients receiving LD adalimumab (odds ratio 0.52; P = 0.048, 95% confidence interval = 0.28–0.99). No other week 4 variables, including CRP, PCDAI, and remission and response status at randomization, were significant predictors of escalating to weekly dosing (Table 2). Patients who remained on every other week dosing had similar response rates at week 4 compared with those who escalated to blinded weekly dosing after week 12, although the remission rate at week 4 in patients who never dose escalated was numerically higher (Fig. 3). Median serum adalimumab trough levels at week 4 were statistically significantly higher in patients who remained on every other week dosing compared with patients who later escalated to weekly dosing (16.4 and 14.0 μg/mL, respectively, P < 0.05) (Table 3); however, this was not significant in multivariate analyses.
Adalimumab Trough Serum Concentration in Patients Who Escalated to Weekly Dosing
The median adalimumab trough serum concentration before and after escalation to weekly dosing (although not necessarily determined close to the time of escalation) by observed remission and response status at week 52 is shown in Table 4. The median (range) time difference between serum concentrations before and after escalation was 85 (57–245) days. For patients receiving HD adalimumab, numerically higher median adalimumab trough serum concentration was observed after dose escalation in patients who achieved remission or response at week 52 relative to patients who did not achieve these efficacy endpoints at week 52. No such numerical difference was seen for the LD dose-escalated group. As previously reported,5,12 6 patients developed anti-adalimumab antibodies during the study, 4 of whom escalated to blinded weekly dosing.
Treatment-emergent adverse events experienced during the double-blind maintenance period for patients who remained on every other week dosing and those who escalated to blinded weekly dosing are summarized in Table 5. Overall, the exposure-adjusted rate of any adverse event was similar between patients who remained on every other week dosing and those who escalated to blinded weekly dosing. Serious adverse events were mostly worsening of CD for patients receiving every other week or weekly dosing. Escalating to weekly dosing was not associated with an increased risk of adverse events, and no new safety signals were identified. No cases of tuberculosis, malignancy, or deaths were reported in IMAgINE 1. The serious infections observed in patients who dose escalated were abdominal and anal abscesses and device-related sepsis. Additionally, the overall safety profile of patients who escalated to double-blind weekly dosing was similar to that observed when these patients were receiving treatment every other week, with the exceptions of the exposure-adjusted rates of serious adverse events and adverse events leading to discontinuation, which were numerically higher after dose escalation, and hepatic events, which were numerically higher before dose escalation (see Supplementary Table 2, Supplemental Digital Content 2, http://links.lww.com/IBD/B233).
The efficacy of adalimumab in inducing and maintaining remission with every other week dosing in children with CD was demonstrated in the IMAgINE 1 clinical trial.5 In this present analysis, we demonstrated that escalation to weekly dosing can be a beneficial treatment strategy for children with CD who lose response on every other week adalimumab maintenance dosing. At week 52, overall remission and response rates in patients who received weekly adalimumab dosing were 24.1% and 51.8%, respectively. These rates are similar to those observed for the intent-to-treat analysis in the IMAgINE 1 clinical trial.5 No significant differences in remission or response rates were observed between patients receiving LD or HD adalimumab; however, the proportions of patients achieving these endpoints were numerically higher in the HD-randomized treatment group. Furthermore, escalation to weekly dosing was not associated with increased safety risks.
The current European Crohn's and Colitis Organization/European Society for Paediatric Gastroenterology, Hepatology, and Nutrition consensus guidelines recommend dose optimization for patients losing response to therapy before switching biologic therapy.13 We demonstrated that patients losing response to treatment or not responding initially can achieve clinically meaningful remission rates at 1 year with weekly dosing, including patients with previous infliximab use. Although, numerically more infliximab-naive patients achieved remission and response than infliximab-experienced patients, no significant differences between the subgroups were observed. Furthermore, in our study, previous anti-TNF use was not associated with dose escalation, which has been shown to be a predictor in a pooled analysis of several pediatric and adult CD studies.14
Approximately half of the patients receiving LD adalimumab escalated to weekly dosing. Treatment dose at week 4 was the only statistically significant predictor of dose escalation; patients treated with HD adalimumab were less likely to escalate to weekly dosing than those treated with LD adalimumab. Additionally, in our study, the analysis of factors predicting dose escalation identified that patients using concomitant immunomodulators at baseline were less likely to require dose escalation. Although remission and response rates at week 4 were similar between patients regardless of baseline immunomodulator use, previously reported mean serum adalimumab levels were slightly higher in patients on concomitant immunomodulators (no immunomodulator use: 12.2 ± 6.32 μg/mL, immunomodulator use: 14.9 ± 6.98 μg/mL).12,15 The difference was not statistically significant, and the range of the concentrations in both groups largely overlapped. The role that baseline immunomodulator use plays in predicting dose escalation requires further study.
Results from the IMAgINE 1 study have shown that higher serum adalimumab concentrations were associated with greater levels of efficacy in pediatric CD.12 Similarly, in this analysis, we demonstrated that in patients who moved to weekly dosing and those who achieved remission or response at week 52 had higher serum adalimumab trough levels after dose escalation relative to patients who did not achieve these endpoints. Although treatment dose after week 4 was not a significant predictor of dose escalation, patients who moved to weekly dosing had significantly lower serum adalimumab trough levels at week 4 than patients who remained on every other week dosing, whereas the range of the values was similar between both groups. Additionally, the adalimumab trough level at week 4 was not an independent predictor of dose escalation later in the study, based on logistic regression analysis. Immunogenicity was low in the IMAgINE 1 study. As previously reported,5,12 only 6 patients developed anti-adalimumab antibodies during the study; these numbers are too small to make any conclusion regarding efficacy and anti-adalimumab antibodies.
This analysis has a few limitations. First, dose escalation was restricted to 1 year and to double-blind treatment. Second, the decision to move to weekly dosing was based on prespecified PCDAI criteria and not due to serum adalimumab trough levels or anti-drug antibodies. Furthermore, additional clinical investigations such as imaging or biomarkers of inflammation, including fecal markers, were not collected at the time of dose adjustment. Of note, the analyses were post hoc. The present data, however, demonstrate that weekly adalimumab dosing is safe and a beneficial treatment option for pediatric patients who lose clinical response or do not respond to every other week dosing.
AbbVie Inc. funded the study and the analysis, and reviewed and approved the publication for submission. Medical writing support was provided by Kristina Kligys, PhD, of AbbVie Inc., and Katie Groschwitz, PhD, of Complete Publication Solutions, LLC. AbbVie provided funding to Complete Publication Solutions for medical writing support.
M. C. Dubinsky reports having received consulting fees or honoraria and support for travel to meetings for study purposes from AbbVie. J. Rosh reports having received consulting fees from AbbVie, Janssen, Receptos, and Soligenix; speaker fees from AbbVie and Prometheus; and research support from AbbVie and Janssen (paid to his institution). W. A. Faubion reports having received consulting fees and fees for participation in review committees and advisory boards from AbbVie (paid to his institution) and support for travel to meetings for study purposes from AbbVie. J. Kierkus reports having received speaker fees from AbbVie and research support from AbbVie (paid to his institution). F. Ruemmele reports having received speaker fees from Schering-Plough, Nestlé, MeadJohnson, Ferring, MSD, Johnson & Johnson, and Centocor. J. S. Hyams reports having received consulting fees from Janssen Orthobiotech, AbbVie, TNI Biotech, EnteraHealth, Pfizer, Soligenix, Takeda, Avaxia, and Celgene; and speaker fees and payment for development of educational presentations from Janssen Orthobiotech. S. Eichner, Y. Li, B. Huang, N. M. Mostafa, A. Lazar, and R. B. Thakkar are AbbVie employees and may own AbbVie stock and/or options.
1. Pigneur B, Seksik P, Viola S, et al.. Natural history of Crohn's disease: comparison between childhood- and adult-onset disease. Inflamm Bowel Dis. 2010;16:953–961.
2. Hyams J, Crandall W, Kugathasan S, et al.. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology. 2007;132:863–873; quiz 1165–1166.
3. Humira (Adalimumab). Full Prescribing Information. North Chicago, IL: AbbVie Inc.; 2014.
5. Hyams JS, Griffiths A, Markowitz J, et al.. Safety and efficacy of adalimumab for moderate to severe Crohn's disease in children. Gastroenterology. 2012;143:365–374.e362.
6. Hyams JS, Lerer T, Griffiths A, et al.. Long-term outcome of maintenance infliximab therapy in children with Crohn's disease. Inflamm Bowel Dis. 2009;15:816–822.
7. Hyams JS, Lerer T, Griffiths A, et al.. Outcome following infliximab therapy in children with ulcerative colitis. Am J Gastroenterol. 2010;105:1430–1436.
8. Katz L, Gisbert JP, Manoogian B, et al.. Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response. Inflamm Bowel Dis. 2012;18:2026–2033.
9. Kopylov U, Mantzaris GJ, Katsanos KH, et al.. The efficacy of shortening the dosing interval to once every six weeks in Crohn's patients losing response to maintenance dose of infliximab. Aliment Pharmacol Ther. 2011;33:349–357.
10. Sandborn WJ, Colombel JF, Schreiber S, et al.. Dosage adjustment during long-term adalimumab treatment for Crohn's disease: clinical efficacy and pharmacoeconomics. Inflamm Bowel Dis. 2011;17:141–151.
11. Wolf D, D'Haens G, Sandborn WJ, et al.. Escalation to weekly dosing recaptures response in adalimumab-treated patients with moderately to severely active ulcerative colitis. Aliment Pharmacol Ther. 2014;40:486–497.
12. Sharma S, Eckert D, Hyams JS, et al.. Pharmacokinetics and exposure-efficacy relationship of adalimumab in pediatric patients with moderate to severe Crohn's disease: results from a randomized, multicenter, phase-3 study. Inflamm Bowel Dis. 2015;21:783–792.
13. Ruemmele FM, Veres G, Kolho KL, et al.. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis. 2014;8:1179–1207.
14. Billioud V, Sandborn WJ, Peyrin-Biroulet L. Loss of response and need for adalimumab dose intensification in Crohn's disease: a systematic review. Am J Gastroenterol. 2011;106:674–684.
15. Hyams J, Ruemmele F, Colletti RB, et al.. Impact of concomitant immunosuppressant use on adalimumab efficacy in children with moderately to severely active Crohn's disease: results from IMAgINE 1. Gastroenterology. 2014;146:S-214.
dose adjustment; dose escalation; disease flare; adalimumab; pediatric Crohn's disease
Supplemental Digital Content
© Crohn's & Colitis Foundation of America, Inc.