The CLEAR study: a 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation

Abstract

Background and objectives: Adequate early mycophenolic acid (MPA) exposure is associated with lower rates of acute rejection in renal transplantation. The aim of this randomized controlled trial was to determine if higher initial mycophenolate mofetil (MMF) doses increased the proportion of patients reaching therapeutic MPA levels (30 to 60 mg.h/L) by day 5.

Design, setting, participants, & measurements: De novo renal transplant patients were randomized to receive intensified dosing of MMF (1.5 g twice daily on days 1 to 5, then 1.0 g twice daily) or standard dosing (1.0 g twice daily). All recipients received tacrolimus and prednisone. Full MPA areas under the curve (AUCs) were completed on days 3 and 5, whereas a limited sampling strategy was utilized at four subsequent time points.

Results: At day 5, 47.5% of the MMF 3-g arm achieved the MPA therapeutic window versus 54.4% of the MMF 2-g arm. However, MPA AUC levels were significantly higher in the 3-g arm at day 3 and 5. This resulted in a trend for fewer treated acute rejections at 6 months. Significantly more acute rejections (treated, biopsy-proven including and excluding borderline) occurred in patients with MPA AUC levels<30 mg.h/L compared with those >or=30 mg.h/L at day 5. No significant differences were seen in common adverse events.

Conclusions: A limited intensified dose of MMF increased early MPA exposure and was well tolerated. Further studies are required to determine whether limited intensified MMF dosing can reduce acute rejection.

Trial registration: ClinicalTrials.gov NCT00788567.

Figure 1.

Flowchart of patient disposition. The modified ITT group included 65 and 61 patients in the 3- and 2-g arms, respectively. All randomized patients were included if they had received at least one dose of MMF and had MPA AUC data at any time point on day 3.

Figure 2.

Mean MPA AUC levels for intensified (3-g) versus standard (2-g) arms. Complete MPA AUC levels were calculated using the trapezoidal rule for days 3 and 5. The limited sample formula was used to calculate abbreviated MPA AUC levels at day of discharge and months 1 and 3 (11). The day of discharge was on average 10.4 ± 5.8 days posttransplant.

Figure 3.

Time to (A) first suspected and treated acute rejection (B) first biopsy-proven acute rejection (including borderline patients), and (C) first biopsy-proven acute rejection (excluding borderline patients) by day 5 MPA AUC levels. (B and C) Biopsy results were obtained from the initial report of the acute rejection episode. One patient in the 2-g group had missing biopsy data. One patient did not have biopsy results reported in their initial report of the acute rejection episode. Therefore, biopsy results were obtained from a later time period.