Induction and Maintenance Infliximab Therapy for the Treatment of Moderate-to-Severe Crohn’s Disease in Children

Background & Aims: The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn’s disease. Methods: Patients (n = 112) with a Pediatric Crohn’s Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46. A concurrent immunomodulator was required. Clinical response (decrease from baseline in the PCDAI score ≥15 points; total score ≤30) and clinical remission (PCDAI score ≤10 points) were evaluated at weeks 10, 30, and 54. Results: At week 10, 99 of 112 (88.4%) patients responded to infliximab (95% confidence interval: [82.5%, 94.3%]) and 66 of 112 (58.9%) patients achieved clinical remission (95% confidence interval: [49.8%, 68.0%]). At week 54, 33 of 52 (63.5%) and 29 of 52 (55.8%) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33.3%) and 12 of 51 (23.5%) patients receiving treatment every 12 weeks (P = .002 and P < .001, respectively). Conclusions: Pediatric patients responding to an induction regimen of infliximab were more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance therapy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates, but not response rates, at week 54 were superior with every 8-week dosing compared with every 12-week dosing. Background & Aims: The REACH study evaluated the safety and efficacy of infliximab in children with moderately to severely active Crohn’s disease. Methods: Patients (n = 112) with a Pediatric Crohn’s Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6. Patients responding to treatment at week 10 were randomized to infliximab 5 mg/kg every 8 or 12 weeks through week 46. A concurrent immunomodulator was required. Clinical response (decrease from baseline in the PCDAI score ≥15 points; total score ≤30) and clinical remission (PCDAI score ≤10 points) were evaluated at weeks 10, 30, and 54. Results: At week 10, 99 of 112 (88.4%) patients responded to infliximab (95% confidence interval: [82.5%, 94.3%]) and 66 of 112 (58.9%) patients achieved clinical remission (95% confidence interval: [49.8%, 68.0%]). At week 54, 33 of 52 (63.5%) and 29 of 52 (55.8%) patients receiving infliximab every 8 weeks did not require dose adjustment and were in clinical response and clinical remission, respectively, compared with 17 of 51 (33.3%) and 12 of 51 (23.5%) patients receiving treatment every 12 weeks (P = .002 and P < .001, respectively). Conclusions: Pediatric patients responding to an induction regimen of infliximab were more likely to be in clinical response and remission at week 54 without dose adjustment when their maintenance therapy was given every 8 weeks rather than every 12 weeks. Allowing for dose intensification in the case of relapse, remission rates, but not response rates, at week 54 were superior with every 8-week dosing compared with every 12-week dosing. See editorial on page 1167; CME quiz on page 1165. See editorial on page 1167; CME quiz on page 1165. The true incidence of Crohn’s disease (CD) in the pediatric population is unknown, but 25% of new diagnoses of inflammatory bowel disease occur in patients younger than 20 years of age.1Seidman E.G. Inflammatory bowel disease.in: Roy C.C. Silverman A. Alagille A. Clinical pediatric gastroenterology. 4th ed. Mosby, Philadelphia, PA1993: 471-493Google Scholar In children, both the disease and its treatment, which can include corticosteroids and immunomodulatory agents, can often result in significant long-term effects that include growth failure, osteopenia, and pathologic fractures.2Motil K.J. Grand R.J. Davis-Kraft L. Ferlic L.L. Smith E.O. Growth failure in children with inflammatory bowel disease: a prospective study.Gastroenterology. 1993; 105: 681-691PubMed Google Scholar, 3Semeao E.J. Jawad A.F. Zemel B.S. Neiswender K.M. Piccoli D.A. Stallings V.A. 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The efficacy and safety of infliximab, a monoclonal antibody that binds with high affinity and specificity to TNFα,5Knight D.M. Trinh H. Le J. Siegel S. Shealy D. McDonough M. Scallon B. Moore M.A. Vilcek J. Daddona P. Ghrayeb J. Construction and initial characterization of a mouse–human chimeric anti-TNF antibody.Mol Immunol. 1993; 30: 1443-1453Crossref PubMed Scopus (677) Google Scholar in the treatment of adult patients with moderately to severely active CD is well documented.6Cohen R. Tsang J. Hanauer S. Infliximab in Crohn’s disease: first anniversary clinical experience.Am J Gastroenterol. 2000; 95: 3469-3477Crossref PubMed Google Scholar, 7Hanauer S.B. Feagan B.G. Lichtenstein G.R. Mayer L.F. Schreiber S. Colombel J.F. Rachmilewitz D. Wolf D.C. Olson A. Bao W. Rutgeerts P. ACCENT I Study GroupMaintenance infliximab for Crohn’s disease: the ACCENT I randomized trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3550) Google Scholar, 8Ricart E. 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ACCENT I Study GroupMaintenance infliximab for Crohn’s disease: the ACCENT I randomized trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3550) Google Scholar Open-label studies and case reports suggest that a response to infliximab in CD is comparable in children and adults.10Hyams J.S. Markowitz J. Wyllie R. Use of infliximab in the treatment of Crohn’s disease in children and adolescents.J Pediatr. 2000; 137: 192-196Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 11Kugathasan S. Werlin S.L. Martinez A. Rivera M.T. Heikenen J.B. Binion D.G. Prolonged duration of response to infliximab in early but not late pediatric Crohn’s disease.Am J Gastroenterol. 2000; 95: 3189-3194Crossref PubMed Google Scholar, 12Serrano M.S. Schmidt-Sommerfeld E. Kilbaugh T.J. Brown R.F. Udall Jr, J.N. Mannick E.E. Use of infliximab in pediatric patients with inflammatory bowel disease.Ann Pharmacother. 2001; 35: 823-828Crossref PubMed Scopus (79) Google Scholar, 13Baldassano R. Braegger C.P. Escher J.C. DeWoody K. Hendricks D.F. Keenan G.F. Winter H.S. Infliximab (REMICADE) therapy in the treatment of pediatric Crohn’s disease.Am J Gastroenterol. 2003; 98: 833-838Crossref PubMed Scopus (165) Google Scholar We conducted a multicenter, randomized, open-label study of infliximab in pediatric patients with moderately to severely active CD. The study was entitled “A randomized, multicenter, open-label study to evaluate the safety and efficacy of anti-TNFα chimeric monoclonal antibody (infliximab, REMICADE, Malvern, PA) in pediatric subjects with moderate-to-severe Crohn’s disease” or the “REACH” study. In the REACH study, the efficacy of a 3-dose induction regimen of infliximab in reducing signs and symptoms of CD in children was evaluated. We also compared the efficacy and safety through 54 weeks of maintenance therapy given every 8 weeks with that given every 12 weeks. This multicenter, randomized, open-label study was conducted at 34 sites in North America (73.2% of patients), Western Europe (22.3% of patients), and Israel (4.5% of patients). Patients were enrolled from February 24, 2003, to March 31, 2004. The institutional review boards at participating sites approved the protocol. Written informed consent was obtained from all parents/legal guardians, and assent was obtained from children based on individual Institutional Review Board guidelines. Eligible patients were 6 to 17 years of age, inclusive, and had a Pediatric Crohn’s Disease Activity Index (PCDAI)14Hyams J.S. Ferry G.D. Mandel F.S. Gryboski J.D. Kibort P.M. Kirschner B.S. Griffiths A.M. Katz A.J. Grand R.J. Boyle J.T. Michener W.M. Levy J.S. Lesser M.L. Development and validation of a pediatric Crohn’s disease activity index.J Pediatr Gastroenterol Nutr. 1991; 12: 439-447Crossref PubMed Scopus (62) Google Scholar, 15Hyams J.S. Mandel F. Ferry G.D. Gryboski J.D. Kibort P.M. Kirschner B.S. Griffiths A.M. Katz A.J. Boyle J.T. Relationship of common laboratory parameters to the activity of Crohn’s disease in children.J Pediatr Gastroenterol Nutr. 1992; 14: 216-222Crossref PubMed Scopus (66) Google Scholar >30 at baseline. The diagnosis of CD, which was confirmed by endoscopy and biopsy, was made at least 3 months before screening. Patients also were required to have initiated treatment with an immunomodulator (ie, azathioprine, 6-mercaptopurine, or methotrexate) at least 8 weeks before screening, and were to have been receiving a stable dose for at least the previous 2 weeks. Patients receiving the following concomitant treatments were eligible to participate: aminosalicylates (if the dose was stable at least 2 weeks before screening), oral corticosteroids at the equivalent of 60 mg/day of prednisone or less (stable dose for 1 week), enteral nutrition (stable regimen for 2 weeks), or antibiotics (stable dose for at least 1 week before week 0). Rectal or parenteral corticosteroids were not permitted and had to be discontinued at least 2 weeks prior to screening. Patients were excluded from the study if they had received previous treatment with infliximab or any other agent targeted at reducing TNF. Eligible patients received an induction regimen of infliximab 5 mg/kg at weeks 0, 2, and 6. Four weeks later (at week 10), patients were evaluated for a clinical response to treatment as defined as a decrease from baseline in the PCDAI score of at least 15 points, with a total score of 30 or less. Patients who met these criteria, as assessed by the principal investigators, were randomized in a 1:1 ratio to receive subsequent infusions of infliximab 5 mg/kg every 8 weeks at weeks 14, 22, 30, 38, and 46, or every 12 weeks at weeks 18, 30, and 42. Patients who did not respond to the induction regimen at week 10 received no further treatment with infliximab and were discontinued from the study. The objectives of the REACH study were to assess the efficacy of a 3-dose induction regimen of infliximab in reducing signs and symptoms of pediatric CD, and to examine clinical response and clinical remission at week 54, and changes from baseline to week 54 in corticosteroid use and patient height. Patient allocation to treatment group was performed using an adaptive, stratified design with investigational site as the strata. The pharmacist prepared the infusion (infliximab, REMICADE®, Centocor, Inc., Malvern, PA), which was administered in an open-label manner. Patients were assessed at weeks 0, 2, 6, and 10. Patients who received infliximab every 8 weeks had additional visits at weeks 14, 22, 30, 38, 46, and 54, while those who received infliximab every 12 weeks had additional visits at weeks 18, 30, 42, and 54. At each visit, the components of the PCDAI score were measured. The PCDAI is a validated multi-item measure of severity of illness that, in contrast to the adult-derived Crohn’s Disease Activity Index (CDAI), includes linear growth and places less emphasis on subjectively reported symptoms and more on laboratory parameters of intestinal inflammation.14Hyams J.S. Ferry G.D. Mandel F.S. Gryboski J.D. Kibort P.M. Kirschner B.S. Griffiths A.M. Katz A.J. Grand R.J. Boyle J.T. Michener W.M. Levy J.S. Lesser M.L. Development and validation of a pediatric Crohn’s disease activity index.J Pediatr Gastroenterol Nutr. 1991; 12: 439-447Crossref PubMed Scopus (62) Google Scholar, 16Otley A. Loonen H. Parekh N. Corey M. Sherman P.M. Griffiths A.M. Assessing activity of pediatric Crohn’s disease: which index to use?.Gastroenterology. 1999; 116: 527-531Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar For a subset of patients, health-related quality of life was assessed by the IMPACT III Questionnaire, which was administered at weeks 0, 10, 30, and 54. The IMPACT III Questionnaire was specifically developed to assess quality of life in pediatric patients with inflammatory bowel disease. The questionnaire is validated only in patients ranging in age from 10 to 17 years in North America.17Griffiths A.M. Nicholas D. Smith C. Munk M. Stephens D. Durno C. Sherman P.M. Development of a quality-of-life index for pediatric inflammatory bowel disease: dealing with differences related to age and IBD type.J Pediatr Gastroenterol Nutr. 1999; 28: S46-S52Crossref PubMed Scopus (101) Google Scholar, 18Otley A. Smith C. Nicholas D. Munk M. Avolio J. Sherman P.M. Griffiths A.M. The IMPACT questionnaire: a valid measure of health-related quality of life in pediatric inflammatory bowel disease.J Pediatr Gastroenterol Nutr. 2002; 35: 557-563Crossref PubMed Scopus (180) Google Scholar However, 5 of the 76 patients who completed an IMPACT III questionnaire were 9 years old or younger; these patients were included in the analysis. The IMPACT III scores range from 35 to 175, with higher scores indicating better quality of life. Patients who lost clinical response were eligible to cross over one time during the study to receive treatment more frequently and/or at a higher dose. The treatment regimen to which patients crossed over was based on the length of time between the previous infusion and loss of clinical response. If clinical response was lost prior to 8 weeks from the previous infliximab infusion, for both the every-8-weeks and every-12-weeks groups, patients were eligible to cross over to infliximab 10 mg/kg every 8 weeks. Patients receiving infliximab every 12 weeks who lost clinical response within the period from week 8 to week 12 following the previous infusion were eligible to cross over to infliximab 5 mg/kg every 8 weeks. Loss of clinical response was defined by: (1) an increase in the PCDAI of at least 15 points from the reference PCDAI score at week 10 at 2 consecutive visits at least 7 days apart, or (2) the overall PCDAI score was higher than 30 points at any scheduled or unscheduled visit. Patients who lost response and crossed over were considered nonresponders in the analyses (treatment failures) for the remainder of the study. Blood samples for measurement of infliximab concentrations were collected at several time points during the study, including immediately before each infusion and at 60 minutes following infusion at weeks 0, 2, 6, and 42 (for patients receiving infliximab every 12 weeks) or 46 (for patients receiving infliximab every 8 weeks). Patients receiving corticosteroids were to maintain a stable dose until week 2, after which a defined tapering schedule was initiated if the patient’s condition had improved. A patient entering the study, who was receiving corticosteroid doses of at least 20 mg/day prednisone equivalent, tapered at a maximum rate of 10 mg/day per week. Patients entering the study receiving at least 10 but <20 mg/day tapered at a maximum rate of 5 mg/day per week; the maximum rate for patients receiving <10 mg/day prednisone equivalent was 2.5 mg/day per week. Aminosalicylates and immunomodulators were to be maintained at a constant dose for the duration of the study. Data for all of the 112 study participants are included in the safety analyses. At each visit, adverse events were documented, and blood samples for clinical laboratory evaluations were obtained. Blood samples were also collected to determine the presence of antinuclear antibodies at weeks 0, 30, and 54. Samples positive for antinuclear antibodies were tested for antidouble-stranded DNA antibodies. The criterion for a positive antidouble-stranded DNA antibodies result was the presence of an antinuclear antibodies ≥1:40 and a positive Crithidia assay test. Blood samples for measurement of antibodies to infliximab were collected at weeks 0, 30, and 54. The proportion of patients in clinical response at week 10 was assessed, and corresponding 95% confidence intervals were determined. Patients who met any of the following criteria for treatment failure between week 0 and week 10 were considered nonresponders in the analysis of clinical response at week 10: (1) had protocol-prohibited concomitant medication changes, (2) had CD-related surgery (drainage of abscess or seton placement acceptable), or (3) discontinued study participation. Patients who had insufficient data to assess their clinical response status at week 10 were also considered nonresponders. The proportion of patients in clinical remission (PCDAI score ≤10 points) at week 10 was also assessed. The proportions of patients in clinical response and in clinical remission at week 54, as well as the changes from baseline to week 54 in daily corticosteroid use, were compared between the maintenance regimens, that is, every 8 weeks versus every 12 weeks. Patients who lost clinical response and subsequently crossed over were considered nonresponders in the analyses for the remainder of the study. The same treatment failure and missing data rules as described above for the week-10 analyses were applied to the week-54 analyses. To assess patient clinical status at week 54 independent of whether patients required dose modification or changes in concomitant medications, clinical response and remission were evaluated, ignoring whether or not patients crossed over and suspending the treatment failure rules. Change from baseline in patient height status was assessed using the height z-score, which is a measure of the deviation of the patient’s height from the expected height of an age- and sex-matched population, in this case the 2000 Centers for Disease Control Growth Charts for the United States (http://www.cdc.gov/nchs/about/major/nhanes/growthcharts/zscore/zscore.htm). The z-score was calculated as the (observed height – reference population mean) divided by the standard deviation of the reference population. Patients with a 1-year delay in bone age, as assessed by radiograph of the wrist, had z-scores calculated at baseline and weeks 30 and 54. All analyses were based on an intent-to-treat principle. Analyses comparing the 2 maintenance regimens were performed using the χ2 test for dichotomous variables and using analysis of variance on the van der Waerden normal scores for continuous variables. To test for an overall effect of infliximab on a variable, regardless of dose or dosing interval, paired t-tests were used to compare baseline and postbaseline measurements. All statistical testing was 2 sided and utilized a 0.05 level of significance. The power to detect a significant treatment effect between the every-8-week and every-12-week treatment regimens, using a 2-sided χ2 test at the 0.05 level of significance and assuming that approximately 67% of the 110 patients were randomized at week 10 (or approximately 36 patients per group), was 65% (assuming 60% and 30% responses in the patients receiving infliximab every 8 weeks and every 12 weeks, respectively) and 31% (assuming 60% and 40% responses in the patients receiving infliximab every 8 weeks and every 12 weeks, respectively). A committee comprising the REACH Steering Committee members and Centocor, Inc. staff members designed this study; all Steering Committee members are authors of this manuscript. Centocor, Inc. collected data from all clinical sites to create the clinical database. Centocor, Inc. staff members and members of the REACH Steering Committee analyzed and interpreted the data, wrote this manuscript, and agreed to submit this manuscript for publication. The principal investigators approved the content of the manuscript before submission.