Dataset Information

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and serum creatinine of less than 260 μmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons).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

SUBMITTER: Zheng Z

PROVIDER: S-EPMC8969066 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Zheng Zhaohui Z Zhang Haitao H Peng Xiaomei X Zhang Chun C Xing Changying C Xu Gang G Fu Ping P Ni Zhaohui Z Chen Jianghua J Xu Zhonggao Z Zhao Ming-Hui MH Li Shaomei S Huang Xiangyang X Miao Lining L Chen Xiaonong X Liu Bicheng B He Yongcheng Y Li Jing J Liu Lijun L Kadeerbai Haishan H Liu Zhangsuo Z Liu Zhihong Z

JAMA network open 20220301 3

<h4>Importance</h4>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.<h4>Objective</h4>To assess efficacy and safety of tacrolimus vs IVCY as an initial therapy for LN in China.<h4>Design, setting, and participants</h4>This randomized (1:1), open-label, parallel-controlled, pha ...[more]

PMID: 35353167

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Project description:ImportanceLupus nephritis is typically treated with intravenous cyclophosphamide, which is associated with serious adverse effects. Oral mizoribine may be an alternative for induction therapy of lupus nephritis. However, large-scale, long-term, randomized clinical studies of mizoribine are lacking.ObjectiveTo assess the efficacy and safety of oral mizoribine vs intravenous cyclophosphamide as induction therapy for Chinese patients with lupus nephritis.Design, setting, and participantsThis prospective, multicenter, parallel-group, open-label, phase 3 randomized clinical trial recruited patients with class III, III+V, IV, IV+V, or V lupus nephritis aged 18 to 70 years from 40 centers in China. Inclusion criteria included 24-hour urinary protein level of 1.0 g or higher and systemic lupus erythematosus disease activity index of 8 or higher. The first patient was enrolled on November 29, 2014, and the study finished March 14, 2019. The follow-up period was 52 weeks. Data were analyzed from September 4, 2019, to January 21, 2020.InterventionsOral mizoribine (50 mg, 3 times a day) or cyclophosphamide (6 intravenous doses at 0.5-1.0 g/m2 body surface area, with a maximum dose of 1.0 g/d) for 52 weeks plus oral glucocorticoid.Main outcomes and measuresTotal remission rate (complete remission rate plus partial remission rate) after 52 weeks (prespecified).ResultsA total of 250 patients were randomized, and 243 patients (mean [SD] age, 34.6 [10.7] years, 213 women [87.7%]) were treated (123 patients [50.6%] in the mizoribine group and 120 patients [49.4%] in the cyclophosphamide group). The total remission rate at 52 weeks was 66.1% (76 of 115 patients) in the mizoribine group and 76.8% (86 of 112 patients) in the cyclophosphamide group, and the relative risk ratio (mizoribine vs cyclophosphamide) was 0.861 (95% CI, 0.729-1.016). The lower limit of this 2-sided 95% CI was greater than the noninferiority margin of 0.726, indicating that mizoribine was noninferior to cyclophosphamide. Changes in other immune parameters and kidney function were generally similar between the groups. The incidence of any treatment-related treatment-emergent adverse events was 80.5% (99 of 123 patients) in the mizoribine group and 78.7% (96 of 122 patients) in the cyclophosphamide group, and the most frequent adverse event in both groups was upper respiratory tract infection (41 patients [33.3%] and 37 patients [30.3%], respectively).Conclusions and relevanceThis randomized clinical trial shows that compared with intravenous cyclophosphamide, oral mizoribine was noninferior and well tolerated when used with glucocorticoid for induction therapy of active lupus nephritis. Mizoribine can be used as an alternative to intravenous cyclophosphamide as induction therapy for lupus nephritis.Trial registrationClinicalTrials.gov Identifier: NCT02256150.

Project description:ObjectiveMonthly intravenous (IV) cyclophosphamide for 6 months has been the standard induction regimen for lupus nephritis, followed by a maintenance regimen of quarterly infusions for 2 years. We undertook this study to compare the efficacy and safety of the standard regimen versus a high-dose IV cyclophosphamide regimen.MethodsWe performed a prospective randomized trial comparing monthly IV cyclophosphamide at 750 mg/m(2) body surface area for 6 months followed by quarterly IV cyclophosphamide for 2 years (traditional treatment) against high-dose IV cyclophosphamide (50 mg/kg daily for 4 days) (high-dose treatment). Entry criteria included renal lupus, neurologic lupus, or other organ system involvement with moderate-to-severe activity.ResultsFifty-one patients were randomized; 3 withdrew before treatment and 1 committed suicide after 2 months of high-dose treatment. Twenty-two had renal lupus, 14 had neurologic lupus, and 11 had other organ involvement. The outcome measure was the Responder Index for Lupus Erythematosus (complete response, partial response, no change, or worsening). At 6 months (the end of induction), 11 of 21 patients (52%) in the high-dose treatment group had a complete response compared with 9 of 26 patients (35%) in the traditional treatment group (P = 0.13). At the final visit (30 months), 10 of 21 patients (48%) in the high-dose treatment group had a complete response compared with 13 of 20 patients (65%) who continued with traditional treatment (P = 0.13). Six patients crossed over from traditional treatment to high-dose treatment because of lack of response, and 3 of those patients became complete responders.ConclusionThere was not strong evidence that monthly IV cyclophosphamide and high-dose IV cyclophosphamide differed in complete or in any (complete or partial) response to induction or maintenance therapy. However, nonresponders to monthly IV cyclophosphamide can sometimes be rescued with high-dose IV cyclophosphamide.

Project description:ObjectiveTo assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN).MethodsIn a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry.ResultsTreatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/μl in the RCB group versus 11 cells/μl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells.ConclusionThe addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.

Project description:BackgroundThe management of proliferative lupus nephritis (LN) comprises timely and coordinated immunosuppressive therapy. This study aimed to evaluate and compare the effectiveness and safety profile of low dose mycophenolate mofetil (MMF) and cyclophosphamide (CYC) in induction therapy of LN in Nepalese population.MethodsWe conducted a prospective, open-label, randomized trial over a period of one and half years. Forty-nine patients with class III to V lupus nephritis were enrolled, out of which 42 patients (21 in each group) could complete the study. CYC was given intravenously as a monthly pulse and MMF was administered orally in the tablet form in the maximum daily dose of 1.5 g in two divided doses.ResultsThe mean age of the patients was 25.43 ± 10.17 years with female to male ratio of 7.3:1. Mean baseline serum creatinine was 1.58 ± 1.38 mg/dL and eGFR was 62.38 ± 26.76 ml/min/1.73m2. Mean 24-h urinary protein was 4.35 ± 3.71 g per 1.73 m2 body surface area. At 6 months, serum creatinine (mg/dL) decreased from 1.73 to 0.96 in CYC and from 1.24 to 0.91 in the MMF group with improvement in eGFR (ml/min/1.73 m2) from 60.33 to 88.52 in CYC and from 64.42 to 89.09 in MMF group. Twenty-four-hour urinary protein (gm/1.73m2) reduced from 4.47 to 0.94 in CYC and from 4.5 to 0.62 in the MMF group. Primary end point was achieved in higher percentage of patients with MMF than CYC (28.6% vs. 19%) while equal proportion of patients (67% in each group) achieved secondary end point in both groups. Number of non-responders was higher in CYC group than in the MMF group (14.3% vs. 4.8%). There was no difference in the rate of achievement of secondary end point in both CYC and MMF groups (3.16 vs. 3.05 months). The occurrence of adverse events was higher in the CYC than in MMF group (56 vs. 15 events).ConclusionPresent study has concluded that MMF, used in relatively lower dose, is equally effective in inducing remission with reduction of proteinuria and improvement of kidney function with lesser adverse events than CYC in the induction therapy of proliferative lupus nephritis.Trial registrationRetrospectively registered to ClinicalTrials.gov PRS. NCT03200002 (Registered date: June 28, 2017).

Dataset Information

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

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

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

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