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

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ClinicalTrials.gov Identifier: NCT03580291
Recruitment Status : Not yet recruiting
First Posted : July 9, 2018
Last Update Posted : July 10, 2018
Sponsor:
Information provided by (Responsible Party):
Lingyun Sun, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Tracking Information
First Submitted Date  ICMJE January 12, 2018
First Posted Date  ICMJE July 9, 2018
Last Update Posted Date July 10, 2018
Estimated Study Start Date  ICMJE August 1, 2018
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 25, 2018)
Total remission rate [ Time Frame: weeks 24 ]
Complete remission rate (CR) and partial remission rate (PR)
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03580291 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2018)
  • The time for subjects of the two groups to achieve PR and CR [ Time Frame: Baseline to weeks 24 ]
  • Levels of 24-hour urinary protein [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Ratio of Urinary Protein / Creatinine [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Levels of serum albumin [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Levels of serum creatinine [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The estimated glomerular filtration rate ( eGFR ) [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Levels of Complement component 3 (C3) [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Levels of Complement component 4 (C4) [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The antinuclear antibody (ANA) levels [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The anti-double stranded DNA antibody (dsDNA) levels [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Patient Health Assessment Questionnaire (HAQ) score [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Physician Global Assessment (PhGA) score [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The (Systemic lupus Erythematosis Disease Activity index) SLEDAI score [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The (British Isles lupus assessment group ) BILAG score [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The SLE reaction index [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Total remission rate [ Time Frame: weeks 12 ]
    Complete remission rate (CR) and partial remission rate (PR)
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Baseline to weeks 24 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: June 25, 2018)
  • The time for subjects of the two groups to achieve PR and CR [ Time Frame: Baseline to weeks 24 ]
  • Levels of 24-hour urinary protein [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Ratio of Urinary Protein / Creatinine [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Levels of serum albumin [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Levels of serum creatinine [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The estimated glomerular filtration rate ( eGFR ) [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Complement3 (C3) [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Complement4 (C4) [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The antinuclear antibody (ANA) levels [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The anti-double stranded DNA antibody (dsDNA) levels [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Patient Health Assessment Questionnaire (HAQ) score [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Physician Global Assessment (PhGA) score [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The (Systemic lupus Erythematosis Disease Activity index) SLEDAI score [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The (British Isles lupus assessment group ) BILAG score [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • The SLE reaction index [ Time Frame: Baseline, weeks 4, 8, 12, 16, 20, 24 ]
  • Total remission rate [ Time Frame: weeks 12 ]
    Complete remission rate (CR) and partial remission rate (PR)
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Baseline to weeks 24 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Human Umbilical Cord Mesenchymal Stem Cells Treatment for Lupus Nephritis (LN)
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Lupus Nephritis
Intervention  ICMJE
  • Other: Mesenchymal stem cells
    The group receive pulse infusion of MSCs once of 2 x 10^6/kg body weight
  • Drug: Mycophenolate Mofetil
    This group receive oral MMF of 2.0 g / d.
  • Other: Placebo of Mesenchymal stem cells
    The group receive placebo of Mesenchymal stem cells.
  • Drug: Placebo of Mycophenolate Mofetil
    The group receive placebo of oral mycophenolate mofetil.
Study Arms  ICMJE
  • Experimental: Mesenchymal stem cells

    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.

    1. Dexamethasone of 10mg is intravenously injected before 30 minutes of cells infusion.
    2. 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.
    Interventions:
    • Other: Mesenchymal stem cells
    • Drug: Placebo of Mycophenolate Mofetil
  • Active Comparator: Mycophenolate Mofetil
    The group receive placebo of MSCs and oral Mycophenolate Mofetil of 2.0g/d. .
    Interventions:
    • Drug: Mycophenolate Mofetil
    • Other: Placebo of Mesenchymal stem cells
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 25, 2018)
230
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2021
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lingyun Sun, Ph.D M.D. +86(025)83106666 ext 61421 lingyunsun@nju.edu.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03580291
Other Study ID Numbers  ICMJE 2017001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Lingyun Sun, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Study Sponsor  ICMJE Lingyun Sun
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP