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
| Autor: | Steven M. Katz, Stanislaw M. Stepkowski, Charles T. Van Buren, Murat Kilic, Barry D. Kahan, Joseph A. Tami, Maria Welsh, William R. Shanahan |
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| Rok vydání: | 2004 |
| Předmět: |
Graft Rejection
Male medicine.medical_specialty Urology Phosphorothioate Oligonucleotides Renal function Kidney Function Tests Placebo Oligodeoxyribonucleotides Antisense Placebos Electrocardiography chemistry.chemical_compound Double-Blind Method Pharmacokinetics medicine Humans Transplantation Creatinine medicine.diagnostic_test business.industry Middle Aged Thionucleotides Intercellular adhesion molecule Surgery Regimen chemistry Toxicity Female business Immunosuppressive Agents Partial thromboplastin time |
| Zdroj: | Transplantation. 78:858-863 |
| ISSN: | 0041-1337 |
| DOI: | 10.1097/01.tp.0000128857.77893.d2 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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