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Human Umbilical Cord Mesenchymal Stem Cells Treatment for Lupus Nephritis (LN)

Primary Purpose

Lupus Nephritis

Status
Unknown status
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Mesenchymal stem cells
Mycophenolate Mofetil
Placebo of Mesenchymal stem cells
Placebo of Mycophenolate Mofetil
Sponsored by
Lingyun Sun
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lupus Nephritis focused on measuring Lupus Nephritis, Mesenchymal stem cell

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Subjects who met the American college of Rheumatology (ACR, 1997) classification criteria for SLE;
  2. Ages: 18-60 years old (including);
  3. Presence of class III, IV, V, III+V or IV+V LN as determined by renal biopsy within 12 weeks of randomization(2003 ISN/RPS LN classification criteria);
  4. Morning proteinuria /creatinine ratio >1.0 or 24 hours Proteinuria >1.0g, with or without microscopic hematuria(>5 red blood cells/high-power field);
  5. Women of childbearing age agreed to adopt effective contraception measures during the trial period;
  6. Urine pregnancy tests were negative in women of childbearing age;
  7. Subject signed the informed consent form voluntarily and complied with the requirements of the research program.

Exclusion Criteria:

  1. Received MMF, CTX, other potent immunosuppressive agents (including cyclosporine, tacrolimus, Tripterygium wilfordii and leflunomide) or biologics (Rituximab or others) within the past 12 weeks.
  2. Previous failure to respond to MMF.
  3. Known intolerance to MMF.
  4. Renal biopsy showing ≥50% glomerulus sclerosis.
  5. Renal biopsy showing capillary loops necrosis, microthrombus formation in capillary loops, or cellular crescent in ≥50% of glomeruli.
  6. Patients diagnosed with other autoimmune diseases apart from SLE: dermatomyositis/polymyositis, mixed connective tissue disease, scleroderma, rheumatoid arthritis, etc. However, participants with secondary Sjogren's syndrome are allowed to take part in the study.
  7. Patients suffering from severe liver or kidney dysfunction (total bilirubin more than 14mg/L, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal lab value; creatinine clearance rate (Ccr) < 30ml/min or serum creatinine (Scr) ≥265.2umol/L).
  8. Patients with hematological abnormalities (white blood cell <3000/uL, hemoglobin <8g/dL, and/or platelets <50000/uL).
  9. Patients diagnosed with severe or uncontrolled cardiovascular, neurological, pulmonary (including obstructive pulmonary disease and interstitial lung disease), hepatic, endocrine (including uncontrolled diabetes mellitus), and gastrointestinal disorders.
  10. Known active or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis, atypical mycobacterial infection, granulomatous disease showed by chest X-ray, hepatitis B, hepatitis C, HIV infection and herpes zoster, whereas not including onychomycosis). Any infection requiring hospitalization within 4 weeks prior to enrollment or intravenous antimicrobial treatment within 2 weeks prior to randomization.
  11. History of malignancy, including solid tumor and hematologic malignancies (except basal cell carcinoma which has been excised or successfully treated).
  12. Women who are pregnant or breastfeeding.

Sites / Locations

  • The Affiliated Drum Tower Hospital of Nanjing University Medical School

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Mesenchymal stem cells

Mycophenolate Mofetil

Arm Description

The group receive pulse infusion of MSCs and placebo of oral Mycophenolate Mofetil (MMF). The cells of 2 x 10^6/kg body weight are suspended in 100ml saline and infused intravenously. Dexamethasone of 10mg is intravenously injected before 30 minutes of cells infusion. A sterile blood transfusion device is used during the venous transfusion, and it is washed with saline before infusion. Take a slow infusion of about 20 drops per minute in the first 15 minutes. Increase to about 60 drops per minute if the patient had no complaints of discomfort.

The group receive placebo of MSCs and oral Mycophenolate Mofetil of 2.0g/d. .

Outcomes

Primary Outcome Measures

Total remission rate
Complete remission rate (CR) and partial remission rate (PR)

Secondary Outcome Measures

The time for subjects of the two groups to achieve PR and CR
Levels of 24-hour urinary protein
Ratio of Urinary Protein / Creatinine
Levels of serum albumin
Levels of serum creatinine
The estimated glomerular filtration rate ( eGFR )
Levels of Complement component 3 (C3)
Levels of Complement component 4 (C4)
The antinuclear antibody (ANA) levels
The anti-double stranded DNA antibody (dsDNA) levels
Patient Health Assessment Questionnaire (HAQ) score
Physician Global Assessment (PhGA) score
The (Systemic lupus Erythematosis Disease Activity index) SLEDAI score
The (British Isles lupus assessment group ) BILAG score
The SLE reaction index
Total remission rate
Complete remission rate (CR) and partial remission rate (PR)
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Full Information

First Posted
January 12, 2018
Last Updated
July 9, 2018
Sponsor
Lingyun Sun
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1. Study Identification

Unique Protocol Identification Number
NCT03580291
Brief Title
Human Umbilical Cord Mesenchymal Stem Cells Treatment for Lupus Nephritis (LN)
Official Title
A Randomized, Double-Blind, Parallel-Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of Human Umbilical Cord Mesenchymal Stem Cells in Patients With Lupus Nephritis
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Unknown status
Study Start Date
August 1, 2018 (Anticipated)
Primary Completion Date
June 1, 2021 (Anticipated)
Study Completion Date
June 1, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Lingyun Sun

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Lupus nephritis (LN) is one of the most serious complications and the main cause of death in patients with systemic lupus erythematosus (SLE).The investigators have investigated the usefulness, and confirmed the efficacy and safety of mesenchymal stem cells (MSC) treatment of LN in animal models, in vitro experiments and phase I clinical trial. In this study, a randomized, placebo-controlled, parallel group, non-inferiority, prospective, multicenter clinical trial is performed to investigate the efficacy and safety of MSC transplantation in the treatment of LN compared to mycophenolate mofetil (MMF).
Detailed Description
Lupus nephritis (LN) is one of the most serious complications and the main cause of death in patients with systemic lupus erythematosus (SLE). Type III, type IV and type V LN are severe clinical entities with poor prognosis, and its treatment remains challenging. Currently, type III, type IV, type V, type III plus V and type IV plus V LN are treated mainly according to the guidelines developed by KDIGO and the European Association for Anti-Rheumatism and European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association (EULAR/ERAEDTA). The main therapeutic regimens recommended by these guidelines include glucocorticoid combined with immunosuppressants such as cyclophosphamide (CTX), mycophenolate mofetil (MMF), etc. These medications can significantly induce disease remission and improve the long-term survival. However, some patients do not adequately response to the treatment of the combination of steroids and immunosuppressants, and the disease activity cannot be well-controlled. The high prevalence of steroids and immunosuppressants related adverse effects, such as steroid-related diabetes, bone necrosis, hypertension, peptic ulcer, CTX-related bone marrow and gonadal suppression, MMF-related infection risk and so on, have been found in long-term follow-up study. In addition, to date, there is insufficient data to support the use of new biologics, such as rituximab and abatacept in the induction therapy in patients with LN. Mesenchymal stem cells (MSCs) can be obtained from several tissues and possess multiple differentiation potencies and immunomodulatory effects. The investigators have investigated the usefulness, and confirmed the efficacy and safety of MSC treatment of LN in animal models, in vitro experiments and phase I clinical trial. The studies also for the first time found that the MSC abnormalities are involved in the onset and development of lupus both in the lupus mice model and in SLE patients. The investigators found that the efficacy of allogeneic (xenogeneic) MSC transplantation is superior to autologous MSC transplantation in LN mice model. Thus, in current opinion, SLE is not only a hematopoietic stem cell disease, but also a mesenchymal stem cell disease. The investigators treated the refractory LN patients with allogenic MSC treatment, the outcomes revealed that the total response rate was 60%, the mortality rate of 2 to 5 years decreased from 35% - 45% to 6%. These results strongly support the use of allogenic MSC transplantation in the refractory LN patients. The mechanisms of MSC treatment include correcting the immune unbalance, inducing immune tolerance, tissue repair and the improvement of organ function. Allogeneic MSC transplantation for the treatment of SLE and other refractory autoimmune diseases have shown significant efficacy and excellent safety. However, these studies have limitations due to the lack of large-scale, multi-center, randomized, controlled, prospective study to further confirm the efficacy of allogeneic MSC transplantation, as well as the guideline for MSC treatment in SLE needs to be developed. Therefore, a randomized, placebo-controlled, parallel group, non-inferiority, prospective, multicenter clinical trial is urgent needed to promote the application of MSC transplantation in SLE treatment, to bring the benefit of the patients with SLE.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lupus Nephritis
Keywords
Lupus Nephritis, Mesenchymal stem cell

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
230 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Mesenchymal stem cells
Arm Type
Experimental
Arm Description
The group receive pulse infusion of MSCs and placebo of oral Mycophenolate Mofetil (MMF). The cells of 2 x 10^6/kg body weight are suspended in 100ml saline and infused intravenously. Dexamethasone of 10mg is intravenously injected before 30 minutes of cells infusion. A sterile blood transfusion device is used during the venous transfusion, and it is washed with saline before infusion. Take a slow infusion of about 20 drops per minute in the first 15 minutes. Increase to about 60 drops per minute if the patient had no complaints of discomfort.
Arm Title
Mycophenolate Mofetil
Arm Type
Active Comparator
Arm Description
The group receive placebo of MSCs and oral Mycophenolate Mofetil of 2.0g/d. .
Intervention Type
Other
Intervention Name(s)
Mesenchymal stem cells
Intervention Description
The group receive pulse infusion of MSCs once of 2 x 10^6/kg body weight
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Intervention Description
This group receive oral MMF of 2.0 g / d.
Intervention Type
Other
Intervention Name(s)
Placebo of Mesenchymal stem cells
Intervention Description
The group receive placebo of Mesenchymal stem cells.
Intervention Type
Drug
Intervention Name(s)
Placebo of Mycophenolate Mofetil
Intervention Description
The group receive placebo of oral mycophenolate mofetil.
Primary Outcome Measure Information:
Title
Total remission rate
Description
Complete remission rate (CR) and partial remission rate (PR)
Time Frame
weeks 24
Secondary Outcome Measure Information:
Title
The time for subjects of the two groups to achieve PR and CR
Time Frame
Baseline to weeks 24
Title
Levels of 24-hour urinary protein
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
Ratio of Urinary Protein / Creatinine
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
Levels of serum albumin
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
Levels of serum creatinine
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
The estimated glomerular filtration rate ( eGFR )
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
Levels of Complement component 3 (C3)
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
Levels of Complement component 4 (C4)
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
The antinuclear antibody (ANA) levels
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
The anti-double stranded DNA antibody (dsDNA) levels
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
Patient Health Assessment Questionnaire (HAQ) score
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
Physician Global Assessment (PhGA) score
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
The (Systemic lupus Erythematosis Disease Activity index) SLEDAI score
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
The (British Isles lupus assessment group ) BILAG score
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
The SLE reaction index
Time Frame
Baseline, weeks 4, 8, 12, 16, 20, 24
Title
Total remission rate
Description
Complete remission rate (CR) and partial remission rate (PR)
Time Frame
weeks 12
Title
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame
Baseline to weeks 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects who met the American college of Rheumatology (ACR, 1997) classification criteria for SLE; Ages: 18-60 years old (including); Presence of class III, IV, V, III+V or IV+V LN as determined by renal biopsy within 12 weeks of randomization(2003 ISN/RPS LN classification criteria); Morning proteinuria /creatinine ratio >1.0 or 24 hours Proteinuria >1.0g, with or without microscopic hematuria(>5 red blood cells/high-power field); Women of childbearing age agreed to adopt effective contraception measures during the trial period; Urine pregnancy tests were negative in women of childbearing age; Subject signed the informed consent form voluntarily and complied with the requirements of the research program. Exclusion Criteria: Received MMF, CTX, other potent immunosuppressive agents (including cyclosporine, tacrolimus, Tripterygium wilfordii and leflunomide) or biologics (Rituximab or others) within the past 12 weeks. Previous failure to respond to MMF. Known intolerance to MMF. Renal biopsy showing ≥50% glomerulus sclerosis. Renal biopsy showing capillary loops necrosis, microthrombus formation in capillary loops, or cellular crescent in ≥50% of glomeruli. Patients diagnosed with other autoimmune diseases apart from SLE: dermatomyositis/polymyositis, mixed connective tissue disease, scleroderma, rheumatoid arthritis, etc. However, participants with secondary Sjogren's syndrome are allowed to take part in the study. Patients suffering from severe liver or kidney dysfunction (total bilirubin more than 14mg/L, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal lab value; creatinine clearance rate (Ccr) < 30ml/min or serum creatinine (Scr) ≥265.2umol/L). Patients with hematological abnormalities (white blood cell <3000/uL, hemoglobin <8g/dL, and/or platelets <50000/uL). Patients diagnosed with severe or uncontrolled cardiovascular, neurological, pulmonary (including obstructive pulmonary disease and interstitial lung disease), hepatic, endocrine (including uncontrolled diabetes mellitus), and gastrointestinal disorders. Known active or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis, atypical mycobacterial infection, granulomatous disease showed by chest X-ray, hepatitis B, hepatitis C, HIV infection and herpes zoster, whereas not including onychomycosis). Any infection requiring hospitalization within 4 weeks prior to enrollment or intravenous antimicrobial treatment within 2 weeks prior to randomization. History of malignancy, including solid tumor and hematologic malignancies (except basal cell carcinoma which has been excised or successfully treated). Women who are pregnant or breastfeeding.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lingyun Sun, Ph.D M.D.
Phone
+86(025)83106666
Ext
61421
Email
lingyunsun@nju.edu.cn
Facility Information:
Facility Name
The Affiliated Drum Tower Hospital of Nanjing University Medical School
City
Nanjing
State/Province
Jiangsu
ZIP/Postal Code
210008
Country
China
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lingyun Sun, M.D.
Phone
+86(25)83106666
Ext
61421

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Human Umbilical Cord Mesenchymal Stem Cells Treatment for Lupus Nephritis (LN)

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