Assess the Efficacy and Safety of Multi-target Therapy in Lupus Nephritis

An Multi-site, Open, Prospective Study to Assess the Efficacy and Safety of Multi-target Therapy in the Treatment of Class Ⅲ,Ⅳ,Ⅴ,Ⅲ+Ⅴand Ⅳ+Ⅴ Lupus Nephritis

The purpose of this study is to assess the efficacy and safety of multi-target therapy in the treatment of class Ⅲ,Ⅳ,Ⅴ,Ⅲ+Ⅴand Ⅳ+Ⅴ lupus nephritis.

Study Overview

• Status: Completed
• Conditions: Lupus Nephritis
• Intervention / Treatment: Drug: Tacrolimus+Mycophenolate mofetil; Drug: Cyclophosphamide

Detailed Description

1. To assess the efficacy of FK506 combined with MMF vs intravenous cyclophosphamide (CTX) pulses in treatment of class Ⅲ,Ⅳ,Ⅴ,Ⅲ+Ⅴand Ⅳ+Ⅴ Lupus Nephritis (LN).
2. To investigate the safety and tolerability of FK506 combined with MMF vs intravenous CTX pulses in the treatment of class Ⅲ,Ⅳ,Ⅴ,Ⅲ+Ⅴand Ⅳ+Ⅴ LN.

• Study Type: Interventional
• Enrollment (Actual): 362
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210002
      • Research Institute of Nephrology,Jinling Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent by subject or guardian
2. 18 to 65 years of age (inclusive 18 and 65), male or female
3. Diagnosis of SLE according to the American College of Rheumatology criteria (1997)
4. Diagnosis of Class Ⅲ,Ⅳ,Ⅴ,Ⅲ+Ⅴand Ⅳ+ⅤLN according to the ISN/RPS 2003 classification by light, immunofluorescence, and electron microscopy within 6 months before enrollment
5. Pathologic chronic index (CI) ≤3' without thrombotic microangiopathy (TMA)
6. SLE Disease Activity Index (DAI) >10'
7. Proteinuria ≥1.5g/d，with or without active urinary sediment
8. Serum creatinine (Scr)≤3.0mg/dl (265.2 mol/L)

Exclusion Criteria:

1. Previous treatment with MMF, CTX, tacrolimus, Cyclosporin A (CsA), large doses of immunoglobulin and methylprednisolone (MP), plasmapheresis or renal replacement therapy within the past 12 weeks. Oral glucocorticoids, azathioprine, intravenous MP (≤80mg/d)， short-time CsA (<2 weeks) or leflunomide (<4 weeks) are allowed
2. ALT or AST increase twice above the upper limit of the normal range
3. Hyperglycemia is defined as fasting blood glucose level ≥7.0 mmol/L and/or postprandial blood sugar level>11.1 mmol/L
4. Known hypersensitivity or contraindication to any components of MMF, tacrolimus, CTX or glucocorticoids

5. History of present illness:

   1. active HBV infection (HBsAg, HBeAg and anti-HBc positive or HBsAg, anti- HBe and anti-HBc positive), HCV infection, pulmonary tuberculosis, cytomegalovirus(CMV) infection (defined as CMV-IgM positive or CMV-DNA positive), fungal infection or HIV infection, within 3 months before the enrollment
   2. non-healed active peptic ulcer within 3 months before the enrollment
   3. drug or drinking abuse
   4. malnutrition (BMI <18.5kg/m2) or body weight <50Kg

6. Other active diseases, such as:

   1. severe cardiovascular diseases
   2. chronic obstructive pulmonary disease(COPD)or asthma requiring oral glucocorticoids
   3. marrow depression not due to SLE activation: white blood cell count <3000/mm3 or neutrophil count <1300/mm3 or platelet count <50000/mm3
7. Severe infection or need of antibiotic therapy
8. Female patients who are pregnant/breastfeeding or those patients (both gender) who refused contraception
9. Life-threatening complications such as large hydropericardium, pneumohemorrhagia, lupus encephalopathy and severe pulmonary hypertension or patients in need of MP pulse (>0.5g/d ) treatment because of aggravation of SLE
10. Known to be non-compliance or violation of the protocol base on investigator's judgement
11. Patient who participate of any other investigational drug study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Tacrolimus+Mycophenolate mofetil; FK506 4mg/d+MMF 1.0g/d	Drug: Tacrolimus+Mycophenolate mofetil; FK506 4mg/d,MMF 1.0g/d; Other Names: FK506+MMF
ACTIVE_COMPARATOR: Cyclophosphamide; CTX iv 0.75 g/m2 body surface area (BSA)	Drug: Cyclophosphamide; CTX 0.75g/m2 BSA; Other Names: CTX

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the efficacy of FK506 combined with MMF vs intravenous CTX pulses in treatment of class Ⅲ, Ⅳ,Ⅴ, Ⅲ+Ⅴand Ⅳ+Ⅴ LN.	The primary endpoint is the rate of complete remission at 24 weeks.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate the other efficacy indicators of FK506 combined with MMF vs intravenous CTX pulses in the treatment of class Ⅲ, Ⅳ,Ⅴ, Ⅲ+Ⅴand Ⅳ+Ⅴ LN.	The secondary endpoints include total remission, time to complete remission and remission, rate of complete remission and remission in patients with different types of LN, changes between baseline and after 24 week of induction treatment in proteinuria, albumin, SCr, eGFR, complement, autoantibodies, SLE-DAI and dosage and concentration of immunosuppressants between groups.	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the Safety of FK506 combined with MMF vs intravenous CTX pulses in treatment of class Ⅲ, Ⅳ,Ⅴ, Ⅲ+Ⅴand Ⅳ+Ⅴ LN.	Safety assessments include clinical manifestations, physical examination, laboratory tests laboratory tests (including hematology, serum chemistry, urinalysis), adverse events (including gastrointestinal toxicity and severe infections requiring antibiotics treatment) and concomitant medications.	24 weeks

Collaborators and Investigators

• Sponsor: Zhi-Hong Liu, M.D.
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; China Medical University, China; Beijing Friendship Hospital; RenJi Hospital; Huashan Hospital; West China Hospital; Ruijin Hospital; Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
• Investigators: Principal Investigator: Zhihong Liu, Master, Nanjing University School of Medicine

Publications and helpful links

General Publications

• Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z, Chen J, Lin H, Liu F, He Y, He Y, Miao L, Chen N, Li Y, Gu Y, Shi W, Hu W, Liu Z, Bao H, Zeng C, Zhou M. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med. 2015 Jan 6;162(1):18-26. doi: 10.7326/M14-1030.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (ACTUAL): May 1, 2011
• Study Completion (ACTUAL): February 1, 2012

Study Registration Dates

• First Submitted: April 6, 2009
• First Submitted That Met QC Criteria: April 6, 2009
• First Posted (ESTIMATE): April 7, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): August 29, 2013
• Last Update Submitted That Met QC Criteria: August 28, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: lupus nephritis;multi-target therapy; MMF; FK506
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Nephritis; Lupus Nephritis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: NJCT-0901