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Exploring the Efficacy and Safety of CS20AT04 (Allogenic Bone Marrow-Derived Stem Cell) in Systemic Lupus Erythematosus Patients

Primary Purpose

Systemic Lupus Erythematosus

Status

Recruiting

Phase

Phase 2

Locations

Korea, Republic of

Study Type

Interventional

Intervention

CS20AT04 (allogenic bone marrow derived mesenchymal stem cell)

About this trial

This is an interventional treatment trial for Systemic Lupus Erythematosus focused on measuring Systemic lupus erythematosus, Allogenic bone marrow-derived mesenchymal stem cell, Lupus Nephritis, Lupus Cytopenia, Cell Therapy, Phase IIa Clinical Trial

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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
5-1. 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))
5-2. 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)
Exclusion Criteria:

1. Patients unable or unwilling to provide written informed consent

2. Patients with any history of cancer, allergy, alcohol or substance abuse, active peptic ulcer disease, heart failure, liver disease, and coagulation disorder

3. Patients who have active severe central nervous system (CNS) lupus

4. Patients who have received biologic investigational agents in the past year

5. Patients undergoing intravenous immunoglobulin or plasma exchange therapy

6. Patients who are pregnant or are lactating

7. Patients with any evidence of a major infection

8. For the lupus nephritis sub-group only: Patients with serum creatinine > 250 μmol/L

Sites / Locations

Hanyang University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Assigned interventions

Arm Description

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.

Outcomes

Primary Outcome Measures

Reduction of corticosteroid dose to ≤ 7.5 mg/day of prednisone or equivalent

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

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

Renal response improvement

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

Secondary Outcome Measures

Proportion of subjects who achieve a prednisone dose of ≤ 7.5mg/day or equivalent

Proportion of subjects who achieve a prednisone dose of ≤ 7.5mg/day or equivalent by Week 12 and maintain this dose ≤ 7.5mg/day prednisone or equivalent from Week 12 to 24

Proportion of subjects achieving Low Level Disease Activity State

Proportion of subjects achieving Low Level Disease Activity State (LLDAS) at Week 24

Proportion of subjects with ≥ 4 point reduction from baseline in Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score

Proportion of subjects with ≥ 4 point reduction from baseline in SLEDAI-2K score at 24 weeks

Proportion of subjects with baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) ≥ 4 having SLE responder index 4 (SRI5)

Proportion of subjects with baseline SLEDAI-2K ≥ 4 having SLE responder index 5 (SRI5) response at 24 weeks, defined by (i) a ≥ 4 point reduction from baseline in SLEDAI-2K score, (ii) no worsening (increase of < 0.30 points from baseline) in Physician's Global Assessment (PGA), and (iii) no new British Isles Lupus Assessment Group of SLE Clinics (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with baseline at the time of assessment (i.e. at 24 weeks)

Proportion of subjects with baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) ≥ 5 having SLE responder index 5 (SRI5)

Proportion of subjects with baseline SLEDAI-2K ≥ 5 having SLE responder index 5 (SRI5) response at 24 weeks, defined by (i) a ≥ 5 point reduction from baseline in SLEDAI-2K score, (ii) no worsening (increase of < 0.30 points from baseline) in Physician's Global Assessment (PGA), and (iii) no new British Isles Lupus Assessment Group of SLE Clinics (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with baseline at the time of assessment (i.e. at 24 weeks)

Proportion of subjects with baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) ≥ 6 having SLE responder index 6 (SRI6)

Proportion of subjects with baseline SLEDAI-2K ≥ 6 having SRI6 response at 24 weeks, defined by (i) a ≥ 6 point reduction from baseline in SLEDAI-2K score, (ii) no worsening (increase of < 0.30 points from baseline) in Physician's Global Assessment (PGA), and (iii) no new British Isles Lupus Assessment Group of SLE Clinics (BILAG) A organ domain score or 2 new BILAG B organ domain scores compared with baseline at the time of assessment (i.e. at 24weeks)

Time to first severe modified SLE Flare Index (SFI) flare

Time to first severe modified SLE Flare Index (SFI) flare over 24 weeks

Change from baseline of hematologic parameters

For the lupus cytopenia sub-group only: Change from baseline of hematologic parameters (white blood cell counts, platelet counts, and hemoglobin) at 3 days, 1 week, 4 weeks, 12 weeks, and 24 weeks

Time to first hematologic flare

For the lupus cytopenia sub-group only: Time to first hematologic flare over 24 weeks

Change in baseline of renal function parameters

For the lupus nephritis sub-group only: Time to event for each of the individual components of treatment failure (death, ESRD, sustained doubling of serum creatinine, renal flare, extrarenal flare, or rescue therapy)

Time to event for each of the individual components of treatment failure

For the lupus nephritis sub-group only: Time to event for each of the individual components of treatment failure (death, End-Stage Renal Disease (ESRD), sustained doubling of serum creatinine, renal flare, extrarenal flare, or rescue therapy)

Time to complete remission

For the lupus nephritis sub-group only: Time to complete remission over 24 weeks, as defined by return to normal values of serum creatinine (< 106 μmol/L), proteinuria (< 0.3 g/24 h), and urine sediment.

Time to first renal flare

For the lupus nephritis sub-group only: Time to first renal flare over 24 weeks

Full Information

NCT ID

NCT04835883

First Posted

April 6, 2021

Last Updated

April 6, 2021

Sponsor

Hanyang University Seoul Hospital

Collaborators

Corestemchemon, Inc., Ministry of Health & Welfare, Korea

1. Study Identification

Unique Protocol Identification Number

NCT04835883

Brief Title

Exploring the Efficacy and Safety of CS20AT04 (Allogenic Bone Marrow-Derived Stem Cell) in Systemic Lupus Erythematosus Patients

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Recruiting

Study Start Date

September 26, 2019 (Actual)

Primary Completion Date

November 5, 2021 (Anticipated)

Study Completion Date

January 20, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Hanyang University Seoul Hospital

Collaborators

Corestemchemon, Inc., Ministry of Health & Welfare, Korea

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Systemic Lupus Erythematosus

Keywords

Systemic lupus erythematosus, Allogenic bone marrow-derived mesenchymal stem cell, Lupus Nephritis, Lupus Cytopenia, Cell Therapy, Phase IIa Clinical Trial

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Assigned interventions

Arm Type

Experimental

Arm Description

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.

Intervention Type

Biological

Intervention Name(s)

CS20AT04 (allogenic bone marrow derived mesenchymal stem cell)

Intervention Description

Two intravenous infusions of CS20AT04 (2.0×10^6cell/kg), on 0 day and on 12 weeks The target population of this study is subjects in South Korea with a diagnosis of either lupus nephritis or lupus cytopenia.

Primary Outcome Measure Information:

Title

Reduction of corticosteroid dose to ≤ 7.5 mg/day of prednisone or equivalent

Description

Time Frame

24 weeks

Title

Hematologic improvement without ongoing SLE treatment

Description

Time Frame

24 weeks

Title

Renal response improvement

Description

Time Frame

24 weeks

Secondary Outcome Measure Information:

Title

Proportion of subjects who achieve a prednisone dose of ≤ 7.5mg/day or equivalent

Description

Proportion of subjects who achieve a prednisone dose of ≤ 7.5mg/day or equivalent by Week 12 and maintain this dose ≤ 7.5mg/day prednisone or equivalent from Week 12 to 24

Time Frame

12 weeks, 24 weeks

Title

Proportion of subjects achieving Low Level Disease Activity State

Description

Proportion of subjects achieving Low Level Disease Activity State (LLDAS) at Week 24

Time Frame

24 weeks

Title

Proportion of subjects with ≥ 4 point reduction from baseline in Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score

Description

Proportion of subjects with ≥ 4 point reduction from baseline in SLEDAI-2K score at 24 weeks

Time Frame

24 weeks

Title

Proportion of subjects with baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) ≥ 4 having SLE responder index 4 (SRI5)

Description

Time Frame

24 weeks

Title

Proportion of subjects with baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) ≥ 5 having SLE responder index 5 (SRI5)

Description

Time Frame

24 weeks

Title

Proportion of subjects with baseline Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) ≥ 6 having SLE responder index 6 (SRI6)

Description

Time Frame

24 weeks

Title

Time to first severe modified SLE Flare Index (SFI) flare

Description

Time to first severe modified SLE Flare Index (SFI) flare over 24 weeks

Time Frame

24 weeks

Title

Change from baseline of hematologic parameters

Description

For the lupus cytopenia sub-group only: Change from baseline of hematologic parameters (white blood cell counts, platelet counts, and hemoglobin) at 3 days, 1 week, 4 weeks, 12 weeks, and 24 weeks

Time Frame

3 days, 1 week, 4 weeks, 12 weeks , and 24 weeks

Title

Time to first hematologic flare

Description

For the lupus cytopenia sub-group only: Time to first hematologic flare over 24 weeks

Time Frame

24 weeks

Title

Change in baseline of renal function parameters

Description

Time Frame

24 weeks

Title

Time to event for each of the individual components of treatment failure

Description

Time Frame

24 weeks

Title

Time to complete remission

Description

Time Frame

24 weeks

Title

Time to first renal flare

Description

For the lupus nephritis sub-group only: Time to first renal flare over 24 weeks

Time Frame

24 weeks

Other Pre-specified Outcome Measures:

Title

Change in SLE parameters compare to baseline

Description

Change in the following SLE parameters compared to baseline at 3 days, 1 week, 4 weeks, 12 weeks, and 24 weeks: Total Systemic Lupus Erythematosus Disease Activity Index- 2000 (SLEDAI-2K) score Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI) score British Isles Lupus Assessment Group (BILAG) scale (at 4 weeks, 12 weeks, and 24 weeks)

Time Frame

3 days, 1 week, 4 weeks, 12 weeks, and 24 weeks

Title

Change from baseline of Treg CD4+CD25+Foxp3+) and Th17 (CD3+CD8-IL-17A+) cell counts

Description

Change from baseline of Treg (CD4+CD25+Foxp3+) and Th17 (CD3+CD8-IL-17A+) cell counts at 3 days, 1 week, 4 weeks, 12 weeks, 24 weeks and 0.5 years, 1 year, 1.5 years, 2 years, 3 years after the first injection, as measured by flow cytometry (FACS) analysis * CD=Cluster of Differentiation, Foxp=forkhead box P, IL=Interleukin

Time Frame

3 days, 1 week, 4 weeks, 12 weeks, 24 weeks and 0.5 years, 1 year, 1.5 years, 2 years, 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 5-1. 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)) 5-2. 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) Exclusion Criteria: 1. Patients unable or unwilling to provide written informed consent 2. Patients with any history of cancer, allergy, alcohol or substance abuse, active peptic ulcer disease, heart failure, liver disease, and coagulation disorder 3. Patients who have active severe central nervous system (CNS) lupus 4. Patients who have received biologic investigational agents in the past year 5. Patients undergoing intravenous immunoglobulin or plasma exchange therapy 6. Patients who are pregnant or are lactating 7. Patients with any evidence of a major infection 8. For the lupus nephritis sub-group only: Patients with serum creatinine > 250 μmol/L

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Chan-Bum Choi, M.D.,Ph.D

Phone

+82222909208

cbchoi@hanyang.ac.kr

First Name & Middle Initial & Last Name or Official Title & Degree

Kwijoo Kim

Phone

+821027568321

kwjkim@corestem.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Chan-Bum Choi, M.D.,Ph.D.

Organizational Affiliation

Department of Rhumatology in Hanyang University Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Hanyang University Medical Center

City

Seoul

ZIP/Postal Code

KS013

Country

Korea, Republic of

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Chan-Bum Choi, M.D.,PhD.

Phone

+82222909208

cbchoi@hanyang.ac.kr

First Name & Middle Initial & Last Name & Degree

Kwijoo Kim

Phone

+821027568321

kwjkim@corestem.com

First Name & Middle Initial & Last Name & Degree

Chan-Bum Choi, MD, PhD

First Name & Middle Initial & Last Name & Degree

Sang-Cheol Bae, MD, PhD

12. IPD Sharing Statement

Learn more about this trial

Exploring the Efficacy and Safety of CS20AT04 (Allogenic Bone Marrow-Derived Stem Cell) in Systemic Lupus Erythematosus Patients

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