Comparison of the Efficacy and Safety of Tacrolimus and Low-Dose Corticosteroid with High-Dose Corticosteroid for Minimal Change Nephrotic Syndrome in Adults

Abstract

Background: Tacrolimus is used as a steroid-sparing immunosuppressant in adults with minimal change nephrotic syndrome. However, combined treatment with tacrolimus and low-dose steroid has not been compared with high-dose steroid for induction of clinical remission in a large-scale randomized study.

Methods: In this 24-week open-label noninferiority study, we randomized 144 adults with minimal change nephrotic syndrome to receive 0.05 mg/kg twice-daily tacrolimus plus once-daily 0.5 mg/kg prednisolone, or once-daily 1 mg/kg prednisolone alone, for up to 8 weeks or until achieving complete remission. Two weeks after complete remission, we tapered the steroid to a maintenance dose of 5-7.5 mg/d in both groups until 24 weeks after study drug initiation. The primary end point was complete remission within 8 weeks (urine protein: creatinine ratio <0.2 g/g). Secondary end points included time until remission and relapse rates (proteinuria and urine protein: creatinine ratio >3.0 g/g) after complete remission to within 24 weeks of study drug initiation.

Results: Complete remission within 8 weeks occurred in 53 of 67 patients (79.1%) receiving tacrolimus and low-dose steroid and 53 of 69 patients (76.8%) receiving high-dose steroid; this difference demonstrated noninferiority, with an upper confidence limit below the predefined threshold (20%) in both intent-to-treat (11.6%) and per-protocol (17.0%) analyses. Groups did not significantly differ in time until remission. Significantly fewer patients relapsed on maintenance tacrolimus (3-8 ng/ml) plus tapered steroid versus tapered steroid alone (5.7% versus 22.6%, respectively; P=0.01). There were no clinically relevant safety differences.

Conclusions: Combined tacrolimus and low-dose steroid was noninferior to high-dose steroid for complete remission induction in adults with minimal change nephrotic syndrome. Relapse rates were significantly lower with maintenance tacrolimus and steroid compared with steroid alone. No clinically-relevant differences in safety findings were observed.

Keywords: corticosteroid; glomerulonephritis; immunosuppression; nephrotic syndrome; remission; tacrolimus.

Graphical abstract

Figure 1.

Schematic representation of the study design. This was a 24-week study comprising a remission phase and a maintenance phase. The remission phase comprised Week 0 to Day 14 postremission in patients who achieved remission within 8 weeks, and Weeks 0−8 in patients who did not achieve remission. Remission was defined as urine protein: creatinine ratio <0.2 g/g. Patients who did not achieve remission within 8 weeks were discontinued from the study. The remission phase continued for 2 weeks after remission was achieved, with the steroid dose maintained. Therefore, the end of the remission phase and the start of the maintenance phase varied from patient to patient. For example, a patient achieving remission at Week 2 would start the maintenance phase 2 weeks later at Week 4. By contrast, patients achieving remission at Week 8 would have their dose maintained for an additional 2 weeks before commencing the maintenance phase at Week 10 (these patients would still end the study at Week 24 after initiation of study medication). Blood tacrolimus trough concentration was maintained within the range of 5–10 ng/ml. The maintenance phase was the period from Day 15 after complete remission to within 24 weeks after initiation of study medication; the steroid dose was decreased by 5 mg/wk in both groups to a maintenance dose of 7.5 mg/d for patients weighing ≥80 kg, and 5 mg/d for patients weighing <80 kg. Blood tacrolimus trough concentration was maintained within the range of 3–8 ng/ml throughout the maintenance phase.

Figure 2.

Flow chart of study populations, including the number of patients who were assessed for eligibility, randomized, received at least one dose of treatment (modified ITT), and followed the study protocol (PPS). Tacrolimus and low-dose steroid: tacrolimus 0.05 mg/kg twice daily combined with prednisolone 0.5 mg/kg per day. High-dose steroid: 1 mg/kg per day prednisolone.

Figure 3.

Kaplan–Meier estimates of time to onset of remission for patients receiving combined tacrolimus and low-dose steroid compared with those receiving high-dose steroid (modified ITT and PPS). Patients were discontinued at Week 8 if they did not achieve remission; therefore, no remission events could occur after Week 8. However, one patient in the tacrolimus group was erroneously considered to have achieved remission by Week 8 and remained in the study. The patient achieved remission at Week 16. This patient was excluded from the PPS analysis. Tacrolimus and low-dose steroid: tacrolimus 0.05 mg/kg twice daily combined with prednisolone 0.5 mg/kg per day. High-dose steroid: 1 mg/kg per day prednisolone.

Figure 4.

Kaplan–Meier estimates of the time to relapse from complete remission to within 24 weeks after study drug initiation, by study group (modified ITT and PPS). Curves show the probability of remaining relapse-free at different time points for patients receiving combined tacrolimus and low-dose steroid compared with those receiving high-dose steroid. Data for patients without relapse up to the last visit day, who were lost to follow-up or were withdrawn from the study, were censored. Tacrolimus and low-dose steroid: tacrolimus 0.05 mg/kg twice daily combined with prednisolone 0.5 mg/kg per day. High-dose steroid: 1 mg/kg per day prednisolone.