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

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ClinicalTrials.gov Identifier: NCT02457221
Recruitment Status : Completed
First Posted : May 29, 2015
Last Update Posted : October 10, 2018
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma China, Inc. )

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.

Condition or disease Intervention/treatment Phase
Lupus Nephritis Drug: Tacrolimus capsules Drug: Cyclophosphamide injections Drug: Prednisone Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 314 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 10, 2015
Actual Primary Completion Date : September 10, 2018
Actual Study Completion Date : September 10, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Tacrolimus group
Tacrolimus capsules + steroid
Drug: Tacrolimus capsules
oral
Other Name: Prograf

Drug: Prednisone
oral

Active Comparator: Cyclophosphamide group
Cyclophosphamide injections + steroid
Drug: Cyclophosphamide injections
intravenous injection

Drug: Prednisone
oral




Primary Outcome Measures :
  1. Remission rate (complete remission + partial remission) [ Time Frame: at 24 weeks ]
    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)


Secondary Outcome Measures :
  1. 24-hour urine protein [ Time Frame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24 ]
  2. Change of 24-hour urine protein from baseline [ Time Frame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24 ]
  3. Serum albumin [ Time Frame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24 ]
  4. Change of Serum albumin from baseline [ Time Frame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24 ]
  5. Serum creatinine [ Time Frame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24 ]
  6. Change of Serum creatinine from baseline [ Time Frame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24 ]
  7. eGFR comparing with baseline [ Time Frame: at Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, 24 ]
    eGFR: Estimated Glomerular Filtration Rate

  8. Percentage of patients converted to other immunosuppressive therapy [ Time Frame: during 24 weeks ]
  9. Percentage of patients with serum creatinine rising to two times of the baseline [ Time Frame: during 24 weeks ]
  10. Percentage of patients with dsDNA and ANA converting from positive to negative [ Time Frame: during 24 weeks ]
    ANA: Antinuclear Antibody

  11. SLE-DAI [ Time Frame: at Week 4, 12 and 24 ]
    SLE-DAI: Systemic Lupus Erythematosus - Disease Activity Index

  12. Immune parameters assessed by ESR, C3, C4 and dsDNA [ Time Frame: at Week 4, 12 and 24 ]
    ESR: Erythrocyte Sedimentation Rate, C3, C4: Complement C3, C4, dsDNA: Anti-Double-Stranded DNA Antibodies

  13. Change of SLE-DAI from baseline [ Time Frame: at Week 4, 12 and 24 ]
  14. Change of immune parameters from baseline [ Time Frame: at Week 4, 12 and 24 ]
  15. Renal biopsy AI (Active Index) [ Time Frame: at Week 24 ]
  16. CI (Chronic Index) [ Time Frame: at Week 24 ]
  17. Change of Renal biopsy AI (Active Index) from baseline [ Time Frame: at Week 24 ]
  18. Change of CI (Chronic Index) from baseline [ Time Frame: at Week 24 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02457221


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Sponsors and Collaborators
Astellas Pharma China, Inc.
Investigators
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Study Director: Medical Director Astellas Pharma China, Inc.

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Responsible Party: Astellas Pharma China, Inc.
ClinicalTrials.gov Identifier: NCT02457221     History of Changes
Other Study ID Numbers: F506-CL-0912
First Posted: May 29, 2015    Key Record Dates
Last Update Posted: October 10, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Access to anonymized individual participant level data collected during the trial, in addition to study-related supporting documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
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.
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.
URL: https://www.clinicalstudydatarequest.com/

Keywords provided by Astellas Pharma Inc ( Astellas Pharma China, Inc. ):
Tacrolimus
Cyclophosphamide
Prograf
lupus nephritis

Additional relevant MeSH terms:
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Lupus Nephritis
Lupus Erythematosus, Systemic
Nephritis
Kidney Diseases
Urologic Diseases
Glomerulonephritis
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Cyclophosphamide
Tacrolimus
Prednisone
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Calcineurin Inhibitors
Enzyme Inhibitors