Clinical trial NCT02457221: A Study to Compare the Efficacy and Safety of Tacrolimus Capsules and Cyclophosphamide Injection in Treatment of Lupus Nephritis
Official title: A Phase III, Randomized, Open, Parallel-controlled, Multi-center Study to Compare the Efficacy and Safety of Tacrolimus Capsules and Cyclophosphamide Injection in Treatment of Lupus Nephritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lupus Nephritis
Keywords: Tacrolimus
Cyclophosphamide
Prograf
lupus nephritis
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2015-05-29
Enrollment: 314
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this study is to evaluate the efficacy and safety of Tacrolimus capsules for induction remission in patients with lupus nephritis, and compare the efficacy and safety with Cyclophosphamide injections.

Detailed description: This is a randomized, open, 1:1 parallel controlled, multi-center, non-inferiority clinical study.

Eligibility criteria: Inclusion Criteria:

* 18.5≤Body Mass Index (BMI) \<27;
* Diagnosed as systemic lupus erythematosus (based on American Rheumatism Association Diagnostic Criteria 1997)
* Diagnosed as III, IV, V, III + V, IV + V lupus nephritis (according to the LN classification in International Society of Nephrology and Renal Pathology Society (ISN/RPS) 2003) within 24 weeks before enrollment with renal biopsy;
* 24-hour urine protein ≥ 1.5g, Scr\<260umol/L (or 3mg/dL)

Exclusion Criteria:

* Class II or VI lupus nephritis or renal biopsy chronic index (CI) \> 3 or with TMA;
* Received immunosuppressants (mycophenolate mofetil (MMF), cyclosporine, methotrexate, mechlorethamine, chlorambucil, tripterygium preparations, leflunomide etc.) treatment with a duration of more than one week within 30 days prior to enrollment;
* Received tacrolimus (except for topical use) or cyclophosphamide treatment within 30 days prior to enrollment;
* Received a course of methylprednisolone (MP) pulse therapy or gamma globulin treatment or plasma exchange within 30 days prior to enrollment;
* Patients with history of allergies to tacrolimus, cyclophosphamide or methylprednisolone;
* Pregnancy, lactation or patient unwilling to take contraceptive measures;
* Patients with estimated maintenance dialysis for more than eight weeks; or dialysis for more than two weeks prior to entering observation;
* Patients received kidney transplantation or plan to have kidney transplantation recently;
* Serum creatinine (Scr) ≥260umol/L (or 3mg/dL) or creatinine clearance rate (Ccr) \< 30ml/(min.1.73m2); according to Cockcroft-Gault formula: Ccr (ml/sec) = \[(140- age)× Weight (kg)\] × K / \[72×Scr (umol/L) ×0.6786\], Female K = 0.85, Male K = 1.0;
* Patients suffering from liver dysfunction (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 3 times the upper limit of normal lab value) or bilirubin more than 3 times the upper limit of normal lab value;
* Patients diagnosed with diabetes;
* History of gastrointestinal bleeding or pancreatitis within 3 months;
* Uncontrollable hyperkalemia after dietary therapy or reduction of potassium treatment (exceed the upper limit of normal lab value);
* Patients suffering from lupus pneumonia or lung injury;
* Patients with anemia (hemoglobin \<7g/dl) or bone marrow suppression (WBC \<3.0×109/L, and/or neutrophils \<1.5×109/L, and/or platelets \<50×109/L) not secondary to systemic lupus erythematosus;
* With congenital heart disease, arrhythmia, heart failure or other severe cardiovascular diseases;
* With refractory hypertension (defined as blood pressure still exceeds 180/110 mmHg despite taking three different types of antihypertensive drugs \[one of them is diuretic\] simultaneously);
* Patients with recurrent tumors within 5 years;
* Severe infection that requires intravenous antibiotics within 2 weeks prior to enrollment;
* Patients with infection of hepatitis B virus or hepatitis C virus; patients with active tuberculosis; patients with severe immunodeficiency diseases (including active cytomegalovirus infection (positive CMV IgM antibody), or human immunodeficiency virus (HIV) infection, etc.);
* Patients with lupus encephalopathy or other life-threatening complication of systemic lupus erythematosus;
* Patients participated in other clinical trials within three months before enrollment

Primary outcomes:
measure: Remission rate (complete remission + partial remission)
timeFrame: at 24 weeks
Secondary outcomes:
measure: 24-hour urine protein
timeFrame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
measure: Change of 24-hour urine protein from baseline
timeFrame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
measure: Serum albumin
timeFrame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
measure: Change of Serum albumin from baseline
timeFrame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
measure: Serum creatinine
timeFrame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
measure: Change of Serum creatinine from baseline
timeFrame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
measure: eGFR comparing with baseline
timeFrame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
measure: Percentage of patients converted to other immunosuppressive therapy
timeFrame: during 24 weeks
measure: Percentage of patients with serum creatinine rising to two times of the baseline
timeFrame: during 24 weeks
measure: Percentage of patients with dsDNA and ANA converting from positive to negative
timeFrame: during 24 weeks
measure: SLE-DAI
timeFrame: at Week 4, 12 and 24
measure: Immune parameters assessed by ESR, C3, C4 and dsDNA
timeFrame: at Week 4, 12 and 24
measure: Change of SLE-DAI from baseline
timeFrame: at Week 4, 12 and 24
measure: Change of immune parameters from baseline
timeFrame: at Week 4, 12 and 24
measure: Renal biopsy AI (Active Index)
timeFrame: at Week 24
measure: CI (Chronic Index)
timeFrame: at Week 24
measure: Change of Renal biopsy AI (Active Index) from baseline
timeFrame: at Week 24
measure: Change of CI (Chronic Index) from baseline
timeFrame: at Week 24
Other outcomes:
Locations:
city: Hefei
country: China
facility: Site CN00043
state: Anhui
city: Beijing
country: China
facility: Site CN00030
state: Beijing
city: Beijing
country: China
facility: Site CN00034
state: Beijing
city: Xiamen
country: China
facility: Site CN00041
state: Fujian
city: Guangzhou
country: China
facility: Site CN00056
state: Guangdong
city: Shenzhen
country: China
facility: Site CN00017
state: Guangdong
city: Liuzhou
country: China
facility: Site CN00045
state: Guangxi
city: Nanning
country: China
facility: Site CN00037
state: Guangxi
city: Nanning
country: China
facility: Site CN00038
state: Guangxi
city: Shijiazhuang
country: China
facility: Site CN00020
state: Hebei
city: Shijiazhuang
country: China
facility: Site CN00047
state: Hebei
city: Zhengzhou
country: China
facility: Site CN00028
state: Henan
city: Wuhan
country: China
facility: Site CN00023
state: Hubei
city: Wuhan
country: China
facility: Site CN00024
state: Hubei
city: Changsha
country: China
facility: Site CN00027
state: Hunan
city: Changsha
country: China
facility: Site CN00050
state: Hunan
city: Nanjing
country: China
facility: Site CN00012
state: Jiangsu
city: Nanjing
country: China
facility: Site CN00013
state: Jiangsu
city: Nanjing
country: China
facility: Site CN00025
state: Jiangsu
city: Wuxi
country: China
facility: Site CN00049
state: Jiangsu
city: Changchun
country: China
facility: Site CN00026
state: Jilin
city: Changchun
country: China
facility: Site CN00042
state: Jilin
city: Dalian
country: China
facility: Site CN00005
state: Liaoning
city: Shenyang
country: China
facility: Site CN00018
state: Liaoning
city: Shenyang
country: China
facility: Site CN00019
state: Liaoning
city: Qingdao
country: China
facility: Site CN00032
state: Shandong
city: Shanghai
country: China
facility: Site CN00001
state: Shanghai
city: Shanghai
country: China
facility: Site CN00014
state: Shanghai
city: Shanghai
country: China
facility: Site CN00015
state: Shanghai
city: Taiyuan
country: China
facility: Site CN00052
state: Shanxi
city: Chengdu
country: China
facility: Site CN00002
state: Sichuan
city: Chengdu
country: China
facility: Site CN00003
state: Sichuan
city: Tianjin
country: China
facility: Site CN00021
state: Tianjin
city: Wulumuqi
country: China
facility: Site CN00044
state: Xinjiang
city: Hangzhou
country: China
facility: Site CN00010
state: Zhejiang
Study officials:
affiliation: Astellas Pharma China, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Zheng Z, Zhang H, Peng X, Zhang C, Xing C, Xu G, Fu P, Ni Z, Chen J, Xu Z, Zhao MH, Li S, Huang X, Miao L, Chen X, Liu B, He Y, Li J, Liu L, Kadeerbai H, Liu Z, Liu Z. Effect of Tacrolimus vs Intravenous Cyclophosphamide on Complete or Partial Response in Patients With Lupus Nephritis: A Randomized Clinical Trial. JAMA Netw Open. 2022 Mar 1;5(3):e224492. doi: 10.1001/jamanetworkopen.2022.4492.