RAD IN DE NOVO RENAL TRANSPLANTATION: COMPARISON OF THREE DOSES ON THE INCIDENCE AND SEVERITY OF ACUTE REJECTION 1

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Abstract
The effects of three doses of RAD(40-O-[2-hydroxyethyl]-rapamycin), a novel macrolide with potentimmunosuppressive and antiproliferative properties, on the incidence andseverity of acute rejection episodes as well as its tolerability wereevaluated in a dose-ranging study in de novo renal transplantrecipients. In this double-blind, parallel group, multicenter study,recipients were randomized to receive 1 mg, 2 mg, or 4 mg/day of RAD incombination with Neoral® (cyclosporine, USP MODIFIED) and corticosteroids.The incidence and severity of biopsy-proven acute rejection episodes, graftsurvival, patient survival, infection rates, laboratory measurements, andadverse events were compared across groups after 6 months oftherapy. Among the 103 recipients, patients receiving 1, 2, or 4mg/day experienced a 32.4%, 14.7%, or 25.7% incidence of biopsy-proven acuterejection episodes within the first 6 months posttransplantation,respectively. Even though the study was not powered to demonstrate efficacy,the incidence of moderate and severe acute rejection episodes was found to besignificantly lower among patients in the 2 mg and 4 mg/day groups than in the1 mg/day group (P =0.002 and P =0.006, respectively). Overallgraft and patient survival rates were excellent. RAD was generally welltolerated. Although blood lipid levels increased in all groups, changes weremanageable with lipid-lowering agents and did not warrant discontinuation ofstudy medication. The incidence of viral and fungal infections was low;however, it was higher among recipients treated with 4mg/day. In combination with Neoral® and corticosteroids, RADdoses of 2 mg and 4 mg/day resulted in lower rates of acute rejection episodesand efficacy failure than the 1 mg/day dose and were significantly moreeffective in reducing the severity of rejection. Large-scale, controlled,follow-up studies are currently in progress to confirm these initialfindings.