A Study to Compare the Efficacy and Safety of Tacrolimus Capsules and Cyclophosphamide Injection in Treatment of Lupus Nephritis

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

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.

Study Overview

• Status: Completed
• Conditions: Lupus Nephritis
• Intervention / Treatment: Drug: Prednisone; Drug: Tacrolimus capsules; Drug: Cyclophosphamide injections

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 314
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • Site CN00043
  • Beijing
    • Beijing, Beijing, China
      • Site CN00030
    • Beijing, Beijing, China
      • Site CN00034
  • Fujian
    • Xiamen, Fujian, China
      • Site CN00041
  • Guangdong
    • Guangzhou, Guangdong, China
      • Site CN00056
    • Shenzhen, Guangdong, China
      • Site CN00017
  • Guangxi
    • Liuzhou, Guangxi, China
      • Site CN00045
    • Nanning, Guangxi, China
      • Site CN00037
    • Nanning, Guangxi, China
      • Site CN00038
  • Hebei
    • Shijiazhuang, Hebei, China
      • Site CN00020
    • Shijiazhuang, Hebei, China
      • Site CN00047
  • Henan
    • Zhengzhou, Henan, China
      • Site CN00028
  • Hubei
    • Wuhan, Hubei, China
      • Site CN00023
    • Wuhan, Hubei, China
      • Site CN00024
  • Hunan
    • Changsha, Hunan, China
      • Site CN00027
    • Changsha, Hunan, China
      • Site CN00050
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Site CN00012
    • Nanjing, Jiangsu, China
      • Site CN00013
    • Nanjing, Jiangsu, China
      • Site CN00025
    • Wuxi, Jiangsu, China
      • Site CN00049
  • Jilin
    • Changchun, Jilin, China
      • Site CN00026
    • Changchun, Jilin, China
      • Site CN00042
  • Liaoning
    • Dalian, Liaoning, China
      • Site CN00005
    • Shenyang, Liaoning, China
      • Site CN00018
    • Shenyang, Liaoning, China
      • Site CN00019
  • Shandong
    • Qingdao, Shandong, China
      • Site CN00032
  • Shanghai
    • Shanghai, Shanghai, China
      • Site CN00001
    • Shanghai, Shanghai, China
      • Site CN00014
    • Shanghai, Shanghai, China
      • Site CN00015
  • Shanxi
    • Taiyuan, Shanxi, China
      • Site CN00052
  • Sichuan
    • Chengdu, Sichuan, China
      • Site CN00002
    • Chengdu, Sichuan, China
      • Site CN00003
  • Tianjin
    • Tianjin, Tianjin, China
      • Site CN00021
  • Xinjiang
    • Wulumuqi, Xinjiang, China
      • Site CN00044
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Site CN00010

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tacrolimus group; Tacrolimus capsules + steroid	Drug: Prednisone; oral; Drug: Tacrolimus capsules; oral; Other Names: Prograf
Active Comparator: Cyclophosphamide group; Cyclophosphamide injections + steroid	Drug: Prednisone; oral; Drug: Cyclophosphamide injections; intravenous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission rate (complete remission + partial remission)	complete remission: urine protein < 0.5g/24hr, and serum albumin≥3.5g/dl, and stable renal function (Scr increase ≤ 15% baseline value) partial remission: urine protein 0.5-3.5g/24hr (≥ 0.5 g/24hr and < 3.5 g/24hr), and urine protein decreased by >50% comparing with the baseline, and serum albumin ≥ 3.0g/dl, and stable renal function (Scr increase ≤ 15% baseline value)	at 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-hour urine protein		at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
Change of 24-hour urine protein from baseline		at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
Serum albumin		at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
Change of Serum albumin from baseline		at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
Serum creatinine		at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
Change of Serum creatinine from baseline		at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
eGFR comparing with baseline	eGFR: Estimated Glomerular Filtration Rate	at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24
Percentage of patients converted to other immunosuppressive therapy		during 24 weeks
Percentage of patients with serum creatinine rising to two times of the baseline		during 24 weeks
Percentage of patients with dsDNA and ANA converting from positive to negative	ANA: Antinuclear Antibody	during 24 weeks
SLE-DAI	SLE-DAI: Systemic Lupus Erythematosus - Disease Activity Index	at Week 4, 12 and 24
Immune parameters assessed by ESR, C3, C4 and dsDNA	ESR: Erythrocyte Sedimentation Rate, C3, C4: Complement C3, C4, dsDNA: Anti-Double-Stranded DNA Antibodies	at Week 4, 12 and 24
Change of SLE-DAI from baseline		at Week 4, 12 and 24
Change of immune parameters from baseline		at Week 4, 12 and 24
Renal biopsy AI (Active Index)		at Week 24
CI (Chronic Index)		at Week 24
Change of Renal biopsy AI (Active Index) from baseline		at Week 24
Change of CI (Chronic Index) from baseline		at Week 24

Collaborators and Investigators

• Sponsor: Astellas Pharma China, Inc.
• Investigators: Study Director: Medical Director, Astellas Pharma China, Inc.

Publications and helpful links

General Publications

• 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.

Helpful Links

• Link to results on the Astellas Clinical Study Results website.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2015
• Primary Completion (Actual): September 10, 2018
• Study Completion (Actual): September 10, 2018

Study Registration Dates

• First Submitted: May 22, 2015
• First Submitted That Met QC Criteria: May 27, 2015
• First Posted (Estimated): May 29, 2015

Study Record Updates

• Last Update Posted (Actual): November 1, 2024
• Last Update Submitted That Met QC Criteria: October 30, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Cyclophosphamide; Tacrolimus; Prograf; lupus nephritis
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Nephritis; Lupus Nephritis; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Calcineurin Inhibitors; Prednisone; Cyclophosphamide; Tacrolimus
• Other Study ID Numbers: F506-CL-0912

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No