The goal of this large controlled trial was to test if MMF was superior to monthly cyclophosphamide in controlling lupus nephritis. Three hundred seventy patients with active lupus nephritis (class III, class IV, or class V) were randomized to treatment with either MMF at a target dose of three grams daily or cyclophosphamide at a dose of 0.5 to 1.0 gram per square meter of body surface area intravenously monthly. Randomization was stratified by patient race and renal biopsy class to ensure that treatment assignments were balanced among these groups. Both treatment groups also received oral prednisone, with a prescribed taper from a maximum dose of 60 milligrams daily. The primary study endpoint was renal response at 24 weeks of treatment, defined as a decrease in urine protein/creatinine ratio by at least 50% from baseline (or to < 3 if the baseline urine protein/creatinine ratio was ≥ 3) and stabilization or improvement in serum creatinine levels from baseline. Patients and investigators were not blinded, but study endpoints were determined by a central committee that was blinded to treatment assignment. Endpoints were analyzed on an intention-to-treat basis. The study was planned to have sufficient statistical power (90%) to detect a 15% difference between groups in the proportion of patients achieving a renal response, assuming that 70% of patients would respond to MMF. The study was conducted at 88 centers in 20 countries.
Most subjects were young women who were within one year of their diagnosis of lupus nephritis. Approximately 40% were white, 33% were Asian, and 27% were of other races. Sixteen percent had class V lupus nephritis only. One hundred eighty-five patients were randomized to each treatment. The groups were well balanced in clinical and laboratory characteristics. Among those assigned to the MMF arm, the median daily dose of MMF was 2.6 grams. Among those assigned to the cyclophosphamide arm, the median dose of cyclophosphamide was 0.75 grams per square meter, and the median number of infusions was six. Eighty-one percent of patients in the MMF group completed the trial through 24 weeks, as did 84% of those in the cyclophosphamide group.
Renal response was achieved by 56% of those in the MMF group and 53% in the cyclophosphamide group. Reponses in the secondary endpoints, including complete renal remission (8.6% versus 8.1%) also did not differ between groups. In the MMF group, 35 patients withdrew from the study (21 due to adverse events), while in the cyclophosphamide group, 29 patients withdrew (12 due to adverse events). Serious adverse events occurred in 27.7% and 22.8% of patients in the MMF and cyclophosphamide groups, respectively, including nine deaths in the MMF group and five deaths in the cyclophosphamide group. Serious infections occurred in 12% and 10% of patients, respectively.
