Effect of Tacrolimus vs Intravenous Cyclophosphamide on Complete or Partial Response in Patients With Lupus Nephritis: A Randomized Clinical Trial

Abstract

Importance: Lupus nephritis (LN) is typically treated with intravenous cyclophosphamide (IVCY), which is associated with serious adverse effects. Tacrolimus may be an alternative for initial treatment of LN; however, large-scale, randomized clinical studies of tacrolimus are lacking.

Objective: To assess efficacy and safety of tacrolimus vs IVCY as an initial therapy for LN in China.

Design, setting, and participants: This randomized (1:1), open-label, parallel-controlled, phase 3, noninferiority clinical trial recruited patients aged 18 to 60 years with systemic lupus erythematosus and LN class III, IV, V, III+V, or IV+V primarily from outpatient settings at 35 centers in China. Inclusion criteria included body mass index of 18.5 or greater to less than 27, 24-hour urine protein of 1.5 g or greater, and serum creatinine of less than 260 μmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons). Overall, 314 were randomized. The first patient was enrolled March 10, 2015, and the study finished September 13, 2018. The follow-up period was 24 weeks. Data were analyzed from December 2019 to March 2020.

Interventions: Oral tacrolimus (target trough level, 4-10 ng/mL) or IVCY for 24 weeks plus prednisone.

Main outcomes and measures: Complete or partial response rate at week 24 (prespecified).

Results: A total of 314 patients were randomized (158 [50.3%] to tacrolimus and 156 [49.7%] to IVCY). Overall, 299 patients (95.2%) were treated (tacrolimus group, 157 [52.5%]; IVCY group, 142 [47.5%]). Baseline demographic and clinical characteristics were generally similar between groups (mean [SD] age, 34.2 [9.5] years; 262 [87.6%] female). Tacrolimus was found to be noninferior to IVCY for LN response at week 24. There was a complete or partial response rate of 83.0% (117 of 141 patients) in the tacrolimus group and 75.0% (93 of 124 patients) in the IVCY group (difference, 7.1%; 2-sided 95% CI, -2.7% to 16.9%; lower limit of 95% CI greater than -15%). At week 24, least-square mean change in Systemic Lupus Erythematosus Disease Activity Index score was -8.6 with tacrolimus and -6.4 with IVCY (difference, -2.2; 95% CI, -3.1 to -1.3). Changes in other immune parameters and kidney function were generally similar between groups. Serious treatment-emergent adverse events (TEAEs) were reported in 29 patients in the tacrolimus group (18.5%) and 35 patients in the IVCY group (24.6%). Most common serious study drug-related TEAEs were infections (14 [8.9%] and 23 [16.2%], respectively). Seven patients in each group withdrew due to AEs.

Conclusions and relevance: In this study, oral tacrolimus appeared noninferior to IVCY for initial therapy of active LN, with a more favorable safety profile than IVCY. Tacrolimus may be an alternative to IVCY as initial therapy for LN.

Trial registration: ClinicalTrials.gov Identifier: NCT02457221.

Conflict of interest statement

Conflict of Interest Disclosures: Dr L. Liu and Mr Kadeerbai reported being employees of Astellas Pharma China. All authors report nonfinancial support from Astellas Pharma, Inc. during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Study Flowchart

IVCY indicates intravenous cyclophosphamide; FAS, full analysis set; PPS, per-protocol set; SAF, safety set. aPPS comprised patients from the FAS with at least 12 weeks (85 ± 5 days) of follow-up (including early withdrawals due to lack of efficacy) who were compliant with medication (taking 80%-120% of required number of tablets) and had no major protocol deviations.

Figure 2.. Mean Change From Baseline to Week 24 for 24-Hour Urine Protein, Serum Albumin Level, and Serum Creatinine Level in the Per-Protocol Set

IVCY indicates intravenous cyclophosphamide. Whiskers indicate SEs. To convert serum albumin to grams per liter, multiply by 10; serum creatinine to milligrams per deciliter, divide by 88.4.