title: Phase I and phase II safety and efficacy trial of intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302) for the prevention of acute allograft rejection.
abstract: BACKGROUND
  ISIS 2302, an antisense oligonucleotide that inhibits the expression of human intercellular adhesion molecule (ICAM)-1, was evaluated in combination with a cyclosporine (CsA)-prednisone (Pred) regimen first in a phase I safety and pharmacokinetic study and then in a phase II assessment of prophylaxis of acute rejection episodes in deceased donor renal allografts.
  
  
  METHODS
  Both phase I and phase II trials were double-blinded and placebo-controlled, including 17 stable and 39 de novo patients, respectively, in time-lagged, ascending-dose regimens. Each study compared the outcomes of 8 alternate-day intravenous infusions of four ISIS 2302 dose levels (0.05, 0.5, 1.0, or 2.0 mg/kg) versus placebo (3:1 ratio). Patients were followed for 34 days (phase I) or 6 months (phase II). All transplant patients were followed for 3 years.
  
  
  RESULTS
  ISIS 2302 produced no evident toxicity; a significant, dose-related increase in activated partial thromboplastin time was accompanied by a trend toward a decreased platelet count. ISIS 2302 did not alter the pharmacokinetic behavior of CsA. At 6 months, the rates of acute rejection episodes were 38.1% in the ISIS 2302 group versus 20.0% in the placebo group. Three-year graft survivals were similar. The mean creatinine values at 1, 2, and 3 years for all ISIS dose groups combined versus placebo over 3 years showed no significant differences.
  
  
  CONCLUSIONS
  ISIS 2302 did not evoke side-effects and produced slightly improved renal function. However, in this pilot study, it did not further reduce the rate of acute rejection episodes or increase graft survival compared to a concentration-controlled CsA-Pred regimen.
authors.affiliation: Division of Immunology and Organ Transplantation, Department of Surgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA. Barry.D.Kahan@uth.tmc.edu
authors.forename: Barry D
authors.initials: BD
authors.lastname: Kahan
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Stepkowski
authors.forename: Murat
authors.initials: M
authors.lastname: Kilic
authors.forename: Steven M
authors.initials: SM
authors.lastname: Katz
authors.forename: Charles T
authors.initials: CT
authors.lastname: Van Buren
authors.forename: Maria S
authors.initials: MS
authors.lastname: Welsh
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Tami
authors.forename: William R
authors.initials: WR
authors.lastname: Shanahan
mesh_terms: D003404:Creatinine / Q000097:blood; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D054735:Phosphorothioate Oligonucleotides; D010919:Placebos; D013873:Thionucleotides / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*
chemical_list: D007166:Immunosuppressive Agents; D020319:Oligodeoxyribonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D010919:Placebos; D013873:Thionucleotides; D003404:Creatinine; C089753:alicaforsen