Treatment With Human Umbilical Cord-derived Mesenchymal Stromal Cells in Systemic Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to test the safety and efficacy of Umbilical Cord-derived Mesenchymal Stromal Cells (UCMSC) for the treatment of Systemic Sclerosis (SSc).

Detailed Description
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A single-center, three-arm, randomized, double-blind, placebo-controlled trial is proposed. A total of 18 SSc patients will be enrolled in 3 successive blocks of 6 patients each. After being informed about the study and potential risks, all patients giving written informed consent will be randomized to one of two treatment arms or a placebo arm (total of 6 patients per arm). Within each block, the 6 patients will be randomized in a 2:2:2 ratio in one of the following arms: placebo, 1 infusion of UCMSC (M0), or 2 infusions of UCMSC (M0, M3). Second infusions of UCMSC will be performed only in the absence of Treatment Related Severe Adverse Events (TRSAE). Randomization into blocks 2 and 3 will be staggered, to allow the detection of TRSAE prior to inclusion of patients in a subsequent block, i.e. the second block will be randomized only in the absence of TRSAE one month after the first infusion of all 6 patients in block one, and similarly for the third block.

Official Title
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Phase I/II Randomized Controlled Trial of Umbilical Cord-derived mesenChymAl stRomal cElls in Systemic Sclerosis

Conditions
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Sclerosis, Systemic, Mesenchymal Stem Cells

Intervention / Treatment
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* Biological: UCMSC
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SSc according to American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2103 classification criteria for systemic sclerosis Severe disease defined as: i) disease duration of 2 years or less with an mRss of > 20 and (ESR > 25 mm and/or hemoglobin < 11 g/dL, not explained by other causes than SSc), or ii) mRss >15 without any restriction as to disease duration plus at least one major organ involvement as defined by: a) respiratory involvement consisting of lung diffusion capacity for carbon monoxide (DLCO) and/or forced vital capacity (FVC) < 80% predicted and evidence of interstitial lung disease (chest X-ray and/or high resolution computed tomography (HRCT) scan); b) renal involvement consisting of past renal crisis and/or stage 2 or 3 chronic kidney disease (glomerular filtration rate between 30-89 mL/min) not explained by other causes than SSc; c) cardiac involvement consisting of reversible congestive heart failure, atrial or ventricular rhythm disturbances such as recurrent episodes of atrial fibrillation or flutter, recurrent atrial paroxysmal tachycardia, conduction abnormalities (2nd or 3rd degree atrioventricular block), and/or mild to moderate pericardial effusion. All causes of organ involvement should be attributed to SSc. Inadequate response (determined by patient and physician judgement) or adverse events necessitating discontinuation of standard therapy (usually consisting of methotrexate 25 mg subcutaneous (or as tolerated) per week and/or mycophenolate mofetil 2-3 gm/d (or as tolerated) for at least 3 months Ineligibility or unwillingness to undergo autologous hematopoietic stem cell transplant Exclusion Criteria: Age < 18 years Pregnancy or unwillingness to use adequate contraception Life-threatening end-organ damage defined as: FVC < 45% and/or DLCO (corrected for hemoglobin) < 30% predicted; Left ventricular ejection fraction < 40% by cardiac echocardiography; Pulmonary hypertension with baseline resting systolic pulmonary arterial pressures > 50 mmHg by cardiac echocardiography, or mean pulmonary artery pressure > 25 mmHg (and pulmonary wedge pressure < 15 mmHg) on right heart catheterization; stage 4 or more chronic kidney disease (glomerular filtration rate < 30 ml/min) Liver failure defined as an abnormal transaminase level (aspartate aminotransferase (ASAT), alanine aminotransaminase (ALAT) > 3 normal) unless related to activity of the disease Concurrent neoplasms or myelodysplasia Uncontrolled hypertension Uncontrolled acute or chronic infection (HIV, HTLV-1/2 (Human T-lymphotropic virus), hepatitis B surface Ag positive, hepatitis C positive) or high risk thereof Significant malnutrition with BMI < 18 kg/m2 Severe concomitant psychiatric disorder Bone marrow insufficiency defined as neutropenia < 0.5 x 109 cell/L, thrombocytopenia < 30 x 109 cell/L, anemia < 8g/dL, CD4+ T lymphopenia < 200 x 106 cell/L due to other diseases than SSc (CD4 - cluster of differentiation 4) History of poor compliance Concurrent enrolment in any other protocol using an investigational drug Inability to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: One infusion of UCMSC<br>Patients receive one intravenous infusion of UCMSC at month 0 and one intravenous infusion of placebo at month 3. Each experimental infusion will consist of 1 million UCMSC/kg suspended in 50 ml of PlasmaLyte A. Each placebo infusion will consist of a similar volume of PlasmaLyte A. | Biological: UCMSC<br>* Each infusion will consist of 1 million MSC/kg suspended in 50 mL of PlasmaLyte A.<br>* Other names: umbilical cord derived mesenchymal stromal cells;|
| Experimental: Two infusions of UCMSC<br>Patients receive one intravenous infusion of UCMSC at month 0 and one intravenous infusion of UCMSC at month 3. Each experimental infusion will consist of 1 million UCMSC/kg suspended in 50 ml of PlasmaLyte A. | Biological: UCMSC<br>* Each infusion will consist of 1 million MSC/kg suspended in 50 mL of PlasmaLyte A.<br>* Other names: umbilical cord derived mesenchymal stromal cells;|
| Placebo Comparator: Placebo infusions<br>Patients receive intravenous placebo infusions at months 0 and 3. Each placebo infusion will consist of 50 ml of PlasmaLyte A. | Other: Placebo<br>* Each infusion will consist of 50 mL of PlasmaLyte A.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of safety one month after first infusion | Treatment related severe adverse event using the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 classification [https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm] | Month 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in modified Rodnan skin score (mRss) between Month 0 and Month 12 | A measure of skin thickness; difference between Month 12 and Month 0 on the mRss [Khanna et al., 2017] | Month 0 and Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Sclerosis, Umbilical cord-derived mesenchymal stromal cells, Scleroderma, Systemic