title: Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab.
abstract: BACKGROUND
  Natalizumab, a humanized monoclonal IgG(4) antibody to alpha4 integrin, was investigated as a treatment of active Crohn's disease (CD). The safety of natalizumab given in combination with infliximab has not previously been studied.
  
  
  METHODS
  Seventy-nine adult patients with active CD (Crohn's Disease Activity Index [CDAI] score > or = 150) despite ongoing infliximab treatment were randomized 2:1 to receive 3 intravenous infusions of natalizumab (300 mg; n = 52) or placebo (n = 27) every 4 weeks. Patients received infliximab (5 mg/kg) every 8 weeks for at least 10 weeks before randomization and throughout the study. The primary objective was to assess the short-term safety and tolerability of natalizumab in patients concurrently receiving infliximab. Secondary and tertiary objectives included measures of efficacy, health-related quality of life (HRQoL), and effects on inflammatory markers. A subset of patients also participated in a pharmacokinetic/pharmacodynamic (PK/PD) analysis of the effects of concurrent treatment.
  
  
  RESULTS
  Incidence of adverse events (AEs) was similar in the treatment groups. AEs frequently reported in both groups were headache, CD exacerbation, nausea, and nasopharyngitis. No patient had a hypersensitivity-like reaction to natalizumab, whereas 4 patients (5%) experienced reactions to infliximab. Two patients (4%) developed anti-natalizumab antibodies; 10 patients (14%) developed anti-infliximab antibodies. The mean CDAI score decreased with natalizumab plus infliximab but was unchanged with infliximab alone (-37.7 versus +3.5; P = 0.084). Patients in both groups showed small increases in HRQoL (P = 0.811). No drug-drug interactions were noted.
  
  
  CONCLUSIONS
  The combination of natalizumab plus infliximab was well tolerated. Several positive trends suggested that treating patients not in remission with infliximab plus natalizumab had greater efficacy than treatment with infliximab alone.
authors.affiliation: Gastrointestinal Unit, MGH Crohn's and Colitis Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. bsands@partners.org
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Sands
authors.forename: Richard
authors.initials: R
authors.lastname: Kozarek
authors.forename: Jack
authors.initials: J
authors.lastname: Spainhour
authors.forename: Charles F
authors.initials: CF
authors.lastname: Barish
authors.forename: Scott
authors.initials: S
authors.lastname: Becker
authors.forename: Lawrence
authors.initials: L
authors.lastname: Goldberg
authors.forename: Seymour
authors.initials: S
authors.lastname: Katz
authors.forename: Ronald
authors.initials: R
authors.lastname: Goldblum
authors.forename: Rena
authors.initials: R
authors.lastname: Harrigan
authors.forename: Deborah
authors.initials: D
authors.lastname: Hilton
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Hanauer
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D002097:C-Reactive Protein / Q000032:analysis; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D000069285:Infliximab; D039441:Integrin alpha4 / Q000276:immunology; D008297:Male; D000069442:Natalizumab; D011788:Quality of Life; D012709:Serum Albumin / Q000032:analysis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; D000069442:Natalizumab; D012709:Serum Albumin; D039441:Integrin alpha4; D002097:C-Reactive Protein; D000069285:Infliximab