Phase I/II Randomized Clinical Trial of Allogeneic Adipose Tissue-derived Mesenchymal Stromal Cells Systemic Infusion in Severe Systemic Sclerosis

Overview

Systemic sclerosis (SSc) is a rare, severe and chronic systemic autoimmune disease (AD) characterized by vasculopathy, immune dysregulation and fibrosis leading to multi-organ dysfunction (primarily skin, lungs, heart gastrointestinal tract and kidneys), with high morbidity and mortality, altered health-related quality of life, all at high cost for patients and society. Treatment are mostly symptomatic and only autologous hematopoietic stem cell transplantation (AHSCT) has shown long term improvement in overall and event-free survival with disease-modifying properties. However, AHSCT is contra-indicated in case of advanced visceral involvement and in eligible patients, it is still associated with risk of toxicity. There is an urgent need to identify safe and effective treatments for severe SSc. Mesenchymal stromal cells (MSC) are multipotent cells which carry immunomodulatory, pro-angiogenic and anti-fibrotic properties, that can target SSc pathogenesis and its clinical manifestations. The increasing use of MSC, harvested from bone marrow (MSC(M)), adipose tissue (MSC(AT)), or umbilical cord (MSC(UC)) in a variety of indications, provides consistent evidence supporting their safety in humans. The efficacy of MSC(M) intravenous (IV) injection for treating acute graft versus host disease led to their marketing approval in 2012 and MSC(AT) (Alofisel) were approved for severe Crohn's fistula in 2018. MSC represent a promising therapeutic approach for SSc. We have previously a) shown disease-specific abnormalities in MSC(M) from SSc patients, providing strong rationale to use allogeneic MSC to treat SSc patients, b) published the first phase I/II dose escalation trial using allogenic MSC(M) infusion in 20 severe SSc patients (ClinicalTrials.gov: NCT02213705, PHRC AOM 11-250) with no safety issues, significant improvement in skin fibrosis at 3 to 6 months after infusion which appeared lower thereafter, thereby supporting the need for repeated infusions. In vitro, experimental and clinical studies suggest that MSC properties vary according to their tissue of origin/source. We demonstrated that compared to MSC(M), MSC(AT) are easier to harvest and display higher proliferative capability before entering senescence, higher genetic stability, and superior immunosuppressive properties. Considering the above rationale, we hypothesize that use of healthy donors allogeneic MSC(AT) produced by Etablissement Français du Sang (EFS) will demonstrate a) no safety issues, b) an efficacy profile that will increase with repeated infusion of allogeneic MSC(AT) to treat SSc.

Interventions

• Biological 2 infusions of MSC
  1 MSC(AT) (2x10\^6 cells/kg) injection at M0 and 1 MSC(AT) (2x10\^6 cells/kg) injection at M3
• Biological 1 infusion of MSC
  1 MSC(AT) (2x10\^6 cells/kg) injection at M0 and 1 placebo injection at M3
• Other Placebo
  Placebo at M0 and M3

Primary outcome measures

• Rate of treatment-related Serious Adverse Events [Time frame: After each infusion]

Secondary outcome measures (12)

• Rate of treatment-related Serious Adverse Events (SAE) [Time frame: At time of infusion]
• Rate of treatment-related Serious Adverse Events (SAE) [Time frame: Within 24 hours of infusion]
• Rate of treatment-related Serious Adverse Events (SAE) [Time frame: At 6 months]
• Rate of treatment-related Serious Adverse Events (SAE) [Time frame: At 9 months]
• Rate of treatment-related Serious Adverse Events (SAE) [Time frame: At 12 months]
• Mean modified Rodnan skin score (mRSS) difference [Time frame: Between Month 0 and month 12]
• Mean modified Rodnan skin score (mRSS) [Time frame: At 3 months]
• Mean modified Rodnan skin score (mRSS) [Time frame: At 6 months]
• WHO performance status [Time frame: At month 0]
• WHO performance status [Time frame: At month 3]
• WHO performance status [Time frame: At month 6]
• WHO performance status [Time frame: At month 12]

Eligibility criteria

Inclusion criteria

• Provide signed and dated informed consent;
• Willing to comply with all study procedures and be available for the duration of the study;
• Male or female, aged ≥ 18 and ≤ 70 years of age
• SSc patients according to American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2013 classification criteria for SSc
• Severe disease with either:

• disease duration of 2 years or less with a modified Rodnan skin score (mRss) ≥ 20 and (abnormal CRP > 5 mg/l and/or hemoglobin < 11 g/dL), or
• mRSS ≥ 15 without any restriction as to disease duration plus at least one major organ involvement as defined by:

• 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 : bronchiolar involvement, areas of ground-glass contusions or fibrosis (chest X-ray and/or high resolution computed tomography (HRCT) scan) and/or moderate Pulmonary hypertension with baseline resting systolic pulmonary arterial pressures > 35 mmHg and below 50 mmHg by cardiac echocardiography, or mean pulmonary artery pressure > 20 mmHg and < 40 mm Hg on right heart catheterization;
• renal involvement consisting of past renal crisis, microangiopathic hemolytic anemia, and/or renal insufficiency not explained by other causes than SSc;
• 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, 2nd or 3rd degree AV-block, mild to moderate pericardial effusion and/or presence of MRI involvement (Increased T1 or T2 mapping, late gadolinium enhancement, septal D sign). All causes of organ involvement should be attributed to SSc.
• Contraindication, inadequate response or unwillingness to undergo AHSCT(determined by patient and physician judgement)
• Contraindication, inadequate response or unwillingness or adverse events necessitating discontinuation of conventional immunosuppressive therapy (MMF, methotrexate);
• Women of reproductive potential must use highly effective contraception;
• Men of reproductive potential must use condoms;
• Health insurance.

Exclusion criteria

• Age < 18 years and > 70 years
• Pregnancy or unwillingness to use adequate contraception;
• Life-threatening end-organ damage defined as: 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 > 40 mmHg on right heart catheterization; glomerular filtration rate < 30mL/min
• Active Hepatitis (ASAT, ALAT > 3 normal)
• Neoplasms of less than 5 years, except for basal cell or in situ cervix carcinoma or concurrent myelodysplasia,
• Uncontrolled hypertension
• Uncontrolled acute or chronic infection
• HIV-1 or HIV-2 infection
• Body Mass Index < 16.5 kg/m2
• Severe psychiatric disorder
• Bone marrow insufficiency, defined as neutropenia < 1 x 109/L, thrombopenia < 50 x 109/L, anemia < 8 g/dL, lymphopenia < 0,5 x 109/L
• Inability to provide informed consent
• Patient included in another interventional clinical trial
• Patient under tutelle

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06722105 · APHP211026

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗