Effect of Tacrolimus vs Intravenous Cyclophosphamide on Complete or Partial Response in Patients With Lupus Nephritis
Authors: Zhaohui Zheng, Haitao Zhang, Xiaomei Peng, Chun Zhang, Changying Xing, Gang Xu, Ping Fu, Zhaohui Ni, Jianghua Chen, Zhonggao Xu, Ming-hui Zhao, Shaomei Li, Xiangyang Huang, Lining Miao, Xiaonong Chen, Bicheng Liu, Yongcheng He, Jing Li, Lijun Liu, Haishan Kadeerbai, Zhangsuo Liu, Zhihong Liu
Journal: JAMA Network Open (2022)

<h3>Importance</h3> 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. <h3>Objective</h3> To assess efficacy and safety of tacrolimus vs IVCY as an initial therapy for LN in China. <h3>Design, Setting, and Participants</h3> 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and serum creatinine of less than 260 μmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons).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. <h3>Interventions</h3> Oral tacrolimus (target trough level, 4-10 ng/mL) or IVCY for 24 weeks plus prednisone. <h3>Main Outcomes and Measures</h3> Complete or partial response rate at week 24 (prespecified). <h3>Results</h3> 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. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02457221