Clinical trial NCT04356287: Treatment With Human Umbilical Cord-derived Mesenchymal Stromal Cells in Systemic Sclerosis
Official title: Phase I/II Randomized Controlled Trial of Umbilical Cord-derived mesenChymAl stRomal cElls in Systemic Sclerosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Sclerosis, Systemic
Mesenchymal Stem Cells
Keywords: Systemic Sclerosis
Umbilical cord-derived mesenchymal stromal cells
Scleroderma, Systemic
Lead sponsor: Sir Mortimer B. Davis - Jewish General Hospital
Sponsor class: OTHER
Collaborators: name: Medical University of South Carolina
name: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Université de Montréal
name: Assistance Publique - Hôpitaux de Paris
name: Centre hospitalier de l'Université de Montréal (CHUM)
name: University Paris 7 - Denis Diderot
First posted: 2020-04-22
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. SSc according to American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2103 classification criteria for systemic sclerosis
2. 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.
3. 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
4. Ineligibility or unwillingness to undergo autologous hematopoietic stem cell transplant

Exclusion Criteria:

1. Age \< 18 years
2. Pregnancy or unwillingness to use adequate contraception
3. 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)
4. Liver failure defined as an abnormal transaminase level (aspartate aminotransferase (ASAT), alanine aminotransaminase (ALAT) \> 3 normal) unless related to activity of the disease
5. Concurrent neoplasms or myelodysplasia
6. Uncontrolled hypertension
7. 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
8. Significant malnutrition with BMI \< 18 kg/m2
9. Severe concomitant psychiatric disorder
10. 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)
11. History of poor compliance
12. Concurrent enrolment in any other protocol using an investigational drug
13. Inability to provide informed consent

Primary outcomes:
measure: Measure of safety one month after first infusion
timeFrame: Month 1
Secondary outcomes:
measure: Change in modified Rodnan skin score (mRss) between Month 0 and Month 12
timeFrame: Month 0 and Month 12
Other outcomes:
measure: Safety at the time of infusion, 24 hours, 10 days +/- 24 hours, Month 6, Month 9 and Month 12 (adverse events)
timeFrame: 24 hours, 10 days +/- 24 hours, Month 6, Month 9 and Month 12
measure: Mortality occurring after randomization and up to study completion
timeFrame: 1 year
measure: Modified Rodnan skin score
timeFrame: Month 0, Month 3, Month 6 and Month 9
measure: World Health Organization (WHO) performance status
timeFrame: Month 0, Month 3, Month 6, Month 9 and Month 12
measure: Scleroderma-Health Assessment Questionnaire
timeFrame: Month 0, Month 3, Month 6, Month 9 and Month 12
measure: 36-Item Short Form Survey version 2 for health-related quality of life (SF-36v2)
timeFrame: Month 0, Month 3, Month 6, Month 9 and Month 12
measure: EuroQoL health status measure (EQ-5D-5L)
timeFrame: Month 0, Month 3, Month 6, Month 9 and Month 12
measure: Response to treatment
timeFrame: Month 0, Month 12
measure: Progression-free survival
timeFrame: Month 0, Month 12
measure: Global Rank Composite Score
timeFrame: Month 0, Month 12
measure: ACR Provisional Composite Response Index
timeFrame: Month 0, Month 12
Locations:
city: Montreal
country: Canada
facility: Sir Mortimer B. Davis Jewish General Hospital
state: Quebec
Study officials:
affiliation: Sir Mortimer B. Davis - Jewish General Hospital
name: Marie Hudson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang D, Zhang H, Liang J, Wang H, Hua B, Feng X, Gilkeson GS, Farge D, Shi S, Sun L. A Long-Term Follow-Up Study of Allogeneic Mesenchymal Stem/Stromal Cell Transplantation in Patients with Drug-Resistant Systemic Lupus Erythematosus. Stem Cell Reports. 2018 Mar 13;10(3):933-941. doi: 10.1016/j.stemcr.2018.01.029. Epub 2018 Mar 1.
citation: Liang J, Zhang H, Kong W, Deng W, Wang D, Feng X, Zhao C, Hua B, Wang H, Sun L. Safety analysis in patients with autoimmune disease receiving allogeneic mesenchymal stem cells infusion: a long-term retrospective study. Stem Cell Res Ther. 2018 Nov 14;9(1):312. doi: 10.1186/s13287-018-1053-4.