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and serum creatinine of less than 260 μmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons).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.

• 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 (JAMA Netw Open) Vol. 5 Issue 3 Pg. e224492 (03 01 2022) ISSN: 2574-3805 [Electronic] United States
• PMID: 35353167 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial)

Chemical References

• Immunosuppressive Agents
• Cyclophosphamide
• Tacrolimus

Topics

• Adult
• Cyclophosphamide (adverse effects, therapeutic use)
• Drug Therapy, Combination
• Female
• Humans
• Immunosuppressive Agents (adverse effects, therapeutic use)
• Lupus Nephritis (drug therapy)
• Male
• Tacrolimus (adverse effects, therapeutic use)
• Treatment Outcome
• Young Adult