Clinical trial NCT03580291: 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
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Lupus Nephritis
Keywords: Lupus Nephritis
Mesenchymal stem cell
Lead sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Sponsor class: OTHER
First posted: 2018-07-09
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Total remission rate
timeFrame: weeks 24
Secondary outcomes:
measure: The time for subjects of the two groups to achieve PR and CR
timeFrame: Baseline to weeks 24
measure: Levels of 24-hour urinary protein
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: Ratio of Urinary Protein / Creatinine
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: Levels of serum albumin
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: Levels of serum creatinine
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: The estimated glomerular filtration rate ( eGFR )
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: Levels of Complement component 3 (C3)
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: Levels of Complement component 4 (C4)
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: The antinuclear antibody (ANA) levels
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: The anti-double stranded DNA antibody (dsDNA) levels
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: Patient Health Assessment Questionnaire (HAQ) score
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: Physician Global Assessment (PhGA) score
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: The (Systemic lupus Erythematosis Disease Activity index) SLEDAI score
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: The (British Isles lupus assessment group ) BILAG score
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: The SLE reaction index
timeFrame: Baseline, weeks 4, 8, 12, 16, 20, 24
measure: Total remission rate
timeFrame: weeks 12
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: Baseline to weeks 24
Other outcomes:
Locations:
city: Nanjing
country: China
facility: The Affiliated Drum Tower Hospital of Nanjing University Medical School
state: Jiangsu
Study officials:
References: