Open-label, Single-arm, 24-week Investigator Study to Evaluate the Efficacy and Safety of CS20AT04 (HLA-haplo Matched Allogenic Bone Marrow-Derived Stem Cells) Administered in Patients With Lupus Nephritis or Lupus Cytopenia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Renal response improvement
研究概览
简要总结
This is an open-label, one-arm single-center phase Ⅱa study exploring the efficacy and safety of CS20AT04 (HLA-haplo Matched Allogenic Bone Marrow-Derived Stem Cells) in two subpopulation group of systemic lupus erythematosus patients - lupus nephritis and lupus cytopenia.
详细描述
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown cause that can affect virtually every organ. A subset of SLE patients continues to suffer significant morbidity and mortality from active disease, with visceral organ involvement. Therefore, it is urgent to develop a more effective therapy for SLE disorder, especially for treatment-refractory patients.
Bone marrow-derived mesenchymal stem cells are known to be effective in modulating immune cells such as T lymphocytes, B lymphocytes, dendritic cells, and Neutral Killer (NK) cells and treating acute Graft-Versus-Host Disease (GVHD). Also, based on the anti-inflammatory and immunomodulatory properties, bone marrow-derived mesenchymal stem cells have been widely studied as a candidate for the treatment of refractory immune- and inflammation-mediated disease, and have extensive experience of use.
Half-matched allogeneic bone marrow-derived mesenchymal stem cells, the active ingredient of CS20AT04 Injection, not only have the potential to differentiate into various mesenchymal cells but also have various immunomodulatory and anti-inflammatory effects, and thus are expected to induce and maintain remission of lupus nephritis and lupus cytopenia.
This study is designed to investigate the following. Subjects enrolled into the CS20AT04 with corticosteroid taper regimen arm will receive two infusions of CS20AT04(2.0×10^6cell/kg), on 0 day and on 12 weeks post-enrollment. Subjects will return for efficacy and safety assessments on 3 days, 1 week, and every 4 weeks each post-infusion until Week 24. Safety monitoring will be continued at 1 year, 3 years, and 5 years post-infusion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with HLA-haplo-matched bone marrow donor less than 70 years old
- •Patients meeting:
- •at least 4 of the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria, including at least 1 clinical criterion and 1 immunology criterion; or
- •at least 4 of the 11 Revised American College of Rheumatology (ACR) Criteria for Classification of Systemic Lupus Erythematosus, according to the 1997 Update of the 1982 ACR
- •Patients having a positive test result for antinuclear antibody (ANA; titer at least 1:80) and/or anti-double stranded DNA antibody (anti-dsDNA Ab) at screening
- •Patients (non-responder or partial responder), defined as :
- •unresponsive to treatment with standard care(such as monthly i.v. pulse cyclophosphamide (CYC) 500-1000 mg/m2, mycophenolate (MMF) ≥ 2 gm/day, azathioprine (AZA) ≥ 200 mg/day, leflunomide (LEF) 20 mg/day, oral CYC, cyclosporine, mizoribine ≥ 150 mg/day, mycophenolic acid ≥ 1.44 g/day, tacrolimus (TAC) ≥ 1.5 mg twice a day alone or in combination for at least 6 months) or
- •with continued daily dosage of ≥15mg of prednisone or its equivalent for maintenance treatment
- •For the lupus cytopenia sub-group only:
- •Patients with refractory cytopenia (at least one of anemia, leukopenia, or thrombocytopenia) in absence of any other identifiable cause, defined as:
- •[Red blood cell associated] -Hemolytic anemia (Hgb ≤ 10g/dL) with reticulocytosis, or [White cell associated]
- •Neutrophil count < 1,000/mm3 (in the absence of other known cause such as corticosteroids, drugs, and infection), and/or
- •Lymphocyte count < 1,500/mm3 [Platelet associated]
- •Platelet count < 100,000/mm3 (in the absence of other known cause such as drugs, portal hypertension, and thrombotic thrombocytopenic purpura (TTP))
- •For the lupus nephritis sub-group only: •Patients with clinical disease activity of lupus nephritis, defined by:
- •laboratory tests documented active lupus nephritis three consecutive times: (i) decrease in renal function (serum creatinine > 106 μmol/L) (ii) increase in proteinuria (defined as urine protein/creatinine ratio (UPC) > 1), and (iii) deterioration in microscopic hematuria (defined as > 10 red cells per high power field) in the absence of menstrual hematuria or urinary tract infection at the time of screening or the presence of cellular casts
- •renal biopsy documenting lupus nephritis according to the International Society of Nephrology/Renal Pathology Society classification of active or active/chronic lupus nephritis in renal biopsy class III, class IV-S or IV-G, class V, class III + V, or class IV + V (within 1 year)
排除标准
- •Patients unable or unwilling to provide written informed consent
- •Patients with any history of cancer, allergy, alcohol or substance abuse, active peptic ulcer disease, heart failure, liver disease, and coagulation disorder
- •Patients who have active severe central nervous system (CNS) lupus
- •Patients who have received biologic investigational agents in the past year
- •Patients undergoing intravenous immunoglobulin or plasma exchange therapy
- •Patients who are pregnant or are lactating
- •Patients with any evidence of a major infection
- •For the lupus nephritis sub-group only: Patients with serum creatinine > 250 μmol/L
研究组 & 干预措施
Assigned interventions
Subjects enrolled into the CS20AT04 with corticosteroid taper regimen arm will receive two infusions of CS20AT04 (2.0×10^6cell/kg), on 0 day and on 12 weeks post-enrollment.
干预措施: CS20AT04 (allogenic bone marrow derived mesenchymal stem cell) (Biological)
结局指标
主要结局
Renal response improvement
时间窗: 24 weeks
As Lupus nephritis (LN) sub-group specific endpoint, a renal response at 24 weeks adjudicated based on the following parameters: Urine Protein to Creatinine Ratio (UPCR) of ≤0.5mg/mg, and Estimated Glomerular Filtration Rate (eGFR)≥60mL/min/1.73m2 or no confirmed decrease from baseline in eGFR of \> 20%, and Did not receive any rescue medication for LN, and Did not receive over than 7.5mg prednisone for ≥7 consecutive days in total during week 12 through 24, just prior to the renal response assessment
Reduction of corticosteroid dose to ≤ 7.5 mg/day of prednisone or equivalent
时间窗: 24 weeks
The primary efficacy objective of this study is to assess the efficacy of CS20AT04, in combination with a 24-week corticosteroid taper regimen, as measured by: Reduction of corticosteroid dose to ≤ 7.5 mg/day of prednisone or equivalent at Week 4 , and continued through Week 12
Hematologic improvement without ongoing SLE treatment
时间窗: 24 weeks
As Lupus cytopenia sub-group specific endpoint, Hgb increase of ≥ 1.5 g/dL, or Neutrophil count increase of ≥ 100% from pre-treatment level and an absolute increase of 500/mm3 x 10\^9/L, or For pre-treatment platelet count \> 20 X 10\^9/L, a platelet absolute increase of ≥ 30 X 10\^9/L For pre-treatment platelet count ≤ 20 X 10\^9/L, a platelet absolute increase ≥ 20 X 10\^9/L and ≥ 100% increase from pre-treatment level
次要结局
- Proportion of subjects with baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) ≥ 5 having SLE responder index 5 (SRI5)(24 weeks)
- Change from baseline of hematologic parameters(3 days, 1 week, 4 weeks, 12 weeks , and 24 weeks)
- Proportion of subjects with baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) ≥ 4 having SLE responder index 4 (SRI5)(24 weeks)
- Proportion of subjects with baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) ≥ 6 having SLE responder index 6 (SRI6)(24 weeks)
- Proportion of subjects with ≥ 4 point reduction from baseline in Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score(24 weeks)
- Proportion of subjects who achieve a prednisone dose of ≤ 7.5mg/day or equivalent(12 weeks, 24 weeks)
- Proportion of subjects achieving Low Level Disease Activity State(24 weeks)
- Time to first severe modified SLE Flare Index (SFI) flare(24 weeks)
- Time to first hematologic flare(24 weeks)
- Change in baseline of renal function parameters(24 weeks)
- Time to event for each of the individual components of treatment failure(24 weeks)
- Time to complete remission(24 weeks)
- Time to first renal flare(24 weeks)
研究者
Chan-Bum Choi
Principal Investigator
Hanyang University Seoul Hospital