Mesenchymal Stromal Cells (MSC´s) in Renal Lupus

Study Overview
=================
Brief Summary
-----------------
Phase II Clinical Trial to Assess the dose-response and Efficacy of Umbilical Cord-derived Mesenchymal Stromal Cells (MSCs) in Severe Renal Systemic Lupus Erythematosus (SLE).

Detailed Description
-----------------
Phase IIa trial of escalating doses of intravenous (i.v.) MSCs in active SLE, followed by a Phase IIb, triple blind, controlled assessment of the selected MSC dosing versus Placebo, in SLE patients receiving Standard of Care Therapy for Severe Renal Disease,

Official Title
-----------------
Dose-response and Efficacy of Umbilical Cord-derived Mesenchymal Stromal Cells in Renal Systemic Lupus Erythematosus

Conditions
-----------------
Lupus Erythematosus, Systemic, Lupus Glomerulonephritis

Intervention / Treatment
-----------------
* Biological: MSC treatment
* Drug: Standard of Care
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Fulfilling 1997 updated American College of Rheumatology (ACR) Criteria or 2012 SLICC Classification Criteria for SLE Seropositive for antinuclear (≥1:80) and/or anti-DNA antibodies Fulfilling following criteria for active renal disease: Class III or IV proliferative disease (ISN/RPS) Renal Biopsy within 12 months plus... Active Urinary Sediment (> 5 red blood cells/high-power field and/or >8 white blood cells/high-power field and/or cylindruria during the current flare). UPC ratio ≥ 1 Exclusion Criteria: Estimated GFR < 40ml/min/m2 Addition during prior 3 months of randomization of: Bolus methylprednisolone or new immunosuppressive drug or intravenous immunoglobulin (IVIG) or Plasmapheresis. Addition during prior 6 months of randomization of Cyclophosphamide Addition during prior 12 months of randomization of Biological anti-B cell therapy Coexisting uncontrolled morbidity; Pregnancy or planned Pregnancy within next 12 months; uncontrolled infection or neoplastic disease. Pending unresolved surgical indication.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Superiority trial comparing MSCs versus Placebo in SLE patients with severe renal disease receiving Standard of Care treatment.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSC treatment<br>Intervention: a previously selected dose of MSCs (Phase IIa) will be administered by i.v. infusion at baseline and 6 months of follow-up (total 12 months), to patients with Severe Renal SLE subject also to Standard of Care treatment with Methylprednisolone and Cyclophosphamide followed by Mycophenolate. | Biological: MSC treatment<br>* Umbilical cord-derived Mesenchymal Stromal Cell<br>* Other names: Cellistem ® Lupus;Drug: Standard of Care<br>* Methylprednisolone; Cyclophosphamide; Prednisone; Mycophenolate<br>* Other names: Standard of Care for Lupus Nephritis;|
| Placebo Comparator: Placebo<br>Intervention: A Placebo (infusion vehicle) will be administered by i.v. infusion at baseline and 6 months of follow-up (total 12 months), to patients with Severe Renal SLE subject also to Standard of Care treatment with Methylprednisolone and Cyclophosphamide followed by Mycophenolate. | Drug: Standard of Care<br>* Methylprednisolone; Cyclophosphamide; Prednisone; Mycophenolate<br>* Other names: Standard of Care for Lupus Nephritis;Drug: Placebo<br>* MSC infusion vehicle<br>* Other names: Placebo (for MSC);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of Global Renal Response (GR) at Study Endpoint | Proportion of Patients that achieve Complete (CR) or Partial (PR) Renal Response at Endpoint | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of Complete Renal Response (CR) at Study Endpoint | Proportion of Patients that achieve CR criteria including: 1) Urinary Protein:Creatinine (UPC) ratio < 0.5; 2) estimated Glomerular Filtration Rate (GFR) ≥ 120 ml/min/m2, or at least 80% of baseline; 3) urinalysis < 10 red blood cells (RBC) and no RBC casts per high power field; 4) Prednisone dose ≤10 mg/day. | 12 months | 
| Achievement of Partial Renal Response (PR) at Study Endpoint | Proportion of Patients that achieve PR criteria including: 1) reduction of UPC ratio to at least 50% of baseline; 2) estimated GFR ≥120 ml/min/m2, or at least 80% of baseline; 3) Prednisone dose ≤10 mg/day. | 12 months | 
| Treatment Failure | Proportion of Patients that fulfill any of the following criteria for Treatment Failure including: 1) Daily Prednisone dose cannot be reduced ≤ 10 mg at week 24; 2) Daily Prednisone is increased above 10 mg after week 24; 3) Introduction of a new immunosuppressive regimen, not included in the trial; 4) Use of Rituximab prior to month 12. | 24 weeks and 12 months | 
| Response of SLE Responder Index (SRI). | Proportion of Patients that achieve SRI response, defined as a >4-point reduction in the SELENA-SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, with no worsening in physician's global assessment score versus baseline). The Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) is employed for this calculation.(SELENA-SLEDAI score). The SELENA-SLEDAI score addresses 24 descriptors in 9 organ-systems. Disease worsening increases the score that ranges from 0-105. The BILAG addresses 97 items in organ-system domains, in an ordinal (A-E) scale, converted to a numerical (0-96) scale for usual calculations. | 12 months | 
| Selena Sledai | Average change in Selena Sledai Score in patients and controls | 12 months | 
| BILAG score | Average hange in BILAG score in patients and controls | 12 months | 
| Disease Flares | Proportion of patients that experience flares as defined in the Selena Flare Index (SFI). Mild/Moderate Flares are defined by change of 3 or more points in the SELENA-SLEDAI score. Severe Flares are defined as an increase in the SELENA-SLEDAI score to more than 12 points | 12 months | 
| Biomarker Response | Changes in the levels of disease relevant biomarkers in peripheral blood/plasma, including 1) anti-dsDNA antibodies by ELISA; 2) complement proteins C3/C4 by nephelometry (mg/dL); 3) Percentage of CD4+ T helper cell subpopulations (Th1, Th17, Treg) and 4) B cell subpopulations (Naive, Memory, Transitional) by Flow cytometry; and 5) Cytokine Panel by Luminex, including Tumor Necrosis Factor (TNF) alpha, Transforming Growth Factor (TGF) Beta1, Interleukin (lL) 6, IL-17A, IL-10, B-cell activating factor/B Lymphocyte Stimulator (BAFF/BLys), Monocyte chemoattractant protein-1 (MCP-1/CCL2), C-X-C motif chemokine 10 (CXCL10), Interferon (IFN) gamma. | 24 weeks and 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Systemic Lupus Erythematosus, Mesenchymal Stromal Cells, Lupus nephritis