A randomized trial of OKT4A (anti-CD4) monoclonal antibody (mab) induction therapy versus conventional immunosuppression for cadaver donor (CD) renal allograft recipients is proposed. The design of this clinical protocol is based upon our efforts to provide increasingly selective immunosuppression, by utilizing heterologous antibodies to interrupt the recipient response to a donor allograft. OKT4A is a murine IgG2a mab, reactive with the CD4 subset of human T- lymphocytes. Anti-CD4 mAb delays the onset of allograft rejection and fosters the development of tolerance in small animals. The immunosuppressive efficacy of OKT4A has been confirmed by us, in Cynomolgus renal allograft recipients. Administration of OKT4A as the sole immunosuppressive therapy in this model, extended the mean allograft survival from 11 to 39 days. The objectives of this prospectively randomized trial are to determine the influence of OKT4A treatment upon three specific goals: 1) the recovery of allograft function; 2) the prevention of rejection; and 3) the development of donor specific tolerance in renal allograft recipients randomly assigned to receive OKT4A. Cyclosporine (CsA) will be withheld until satisfactory renal function is established (creatinine <3.5mg%). It is anticipated that OKT4A administration will compensate for the omission of CsA, while precluding the potential addition of CsA toxicity to renal allografts, already compromised by preservation injury. The daily dose of OKT4A will start at 0.3 mg/kg/day. Subsequent changes in OKT4A dosage will be determined by flow cytometric assessment of peripheral blood CD4+ T-cells. OKT4A therapy will be continued for 14 consecutive days. Patients assigned to the conventional group will receive CsA from the outset following transplantation. A protocol of rescue OKT3 therapy has been formulated for each treatment arm. Recipient anti-murine responses are anticipated in most OKT4A recipient by 14-17 days after the start of treatment. However, primary OKT4A treatment is not expected to interfere with OKT3 rescue, as OKT4a and OKT3 are mAbs with different idiotypes. The end points of evaluation for the first phase of this trial will include the comparative incidence of 1) primary graft non-function and 2) acute allograft rejection. Early acute rejection is anticipated in 60% of the conventionally treated group. A 20-25% reduction in the rate of rejection could be determined to be statistically significant, with a study group of 300 recipients. We anticipate that each of the 6 designated CCTT centers will enroll 50 CD recipients over a two year study period. This population is more feasible than the 1000 patients that would be necessary to confirm OKT4A efficacy, based upon a possible 5% improvement in one year allograft survival (from the current 85%, to 90%). Nevertheless, a reduction in primary graft non-function and acute rejection should prove to be clinically significant by shortening the initial hospital stay and reducing the number of readmissions. In a second phase of this initial, between 6 and 12 months after transplantation, an additional end point of our study will assess the development of recipient tolerance, by the withdrawal of steroids from OKT4A versus conventionally treated recipients.
| Colvin, R B; Cohen, A H; Saiontz, C et al. (1997) Evaluation of pathologic criteria for acute renal allograft rejection: reproducibility, sensitivity, and clinical correlation. J Am Soc Nephrol 8:1930-41 |
