Clinical trial NCT06722105: Phase I/II Randomized Clinical Trial of Allogeneic Adipose Tissue-derived Mesenchymal Stromal Cells Systemic Infusion in Severe Systemic Sclerosis
Official title: Phase I/II Randomized Clinical Trial of Allogeneic Adipose Tissue-derived Mesenchymal Stromal Cells Systemic Infusion in Severe Systemic Sclerosis
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Severe Systemic Sclerosis
Keywords: Systemic autoimmune disease
Allogenic mesenchymal stromal cells infusion
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2024-12-09
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-center, three-arm, randomized, double-blind, placebo-controlled trial
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Provide signed and dated informed consent;
2. Willing to comply with all study procedures and be available for the duration of the study;
3. Male or female, aged ≥ 18 and ≤ 70 years of age
4. SSc patients according to American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2013 classification criteria for SSc
5. 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:

     1. 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;
     2. renal involvement consisting of past renal crisis, microangiopathic hemolytic anemia, and/or renal insufficiency not explained by other causes than SSc;
     3. 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.
6. Contraindication, inadequate response or unwillingness to undergo AHSCT(determined by patient and physician judgement)
7. Contraindication, inadequate response or unwillingness or adverse events necessitating discontinuation of conventional immunosuppressive therapy (MMF, methotrexate);
8. Women of reproductive potential must use highly effective contraception;
9. Men of reproductive potential must use condoms;
10. Health insurance.

Exclusion Criteria:

1. Age \< 18 years and \> 70 years
2. Pregnancy or unwillingness to use adequate contraception;
3. 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
4. Active Hepatitis (ASAT, ALAT \> 3 normal)
5. Neoplasms of less than 5 years, except for basal cell or in situ cervix carcinoma or concurrent myelodysplasia,
6. Uncontrolled hypertension
7. Uncontrolled acute or chronic infection
8. HIV-1 or HIV-2 infection
9. Body Mass Index \< 16.5 kg/m2
10. Severe psychiatric disorder
11. 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
12. Inability to provide informed consent
13. Patient included in another interventional clinical trial
14. Patient under tutelle

Primary outcomes:
measure: Rate of treatment-related Serious Adverse Events
timeFrame: After each infusion
Secondary outcomes:
measure: Rate of treatment-related Serious Adverse Events (SAE)
timeFrame: At time of infusion
measure: Rate of treatment-related Serious Adverse Events (SAE)
timeFrame: Within 24 hours of infusion
measure: Rate of treatment-related Serious Adverse Events (SAE)
timeFrame: At 6 months
measure: Rate of treatment-related Serious Adverse Events (SAE)
timeFrame: At 9 months
measure: Rate of treatment-related Serious Adverse Events (SAE)
timeFrame: At 12 months
measure: Mean modified Rodnan skin score (mRSS) difference
timeFrame: Between Month 0 and month 12
measure: Mean modified Rodnan skin score (mRSS)
timeFrame: At 3 months
measure: Mean modified Rodnan skin score (mRSS)
timeFrame: At 6 months
measure: WHO performance status
timeFrame: At month 0
measure: WHO performance status
timeFrame: At month 3
measure: WHO performance status
timeFrame: At month 6
measure: WHO performance status
timeFrame: At month 12
measure: Scleroderma-Health Assessment Quetionnaire
timeFrame: At month 0
measure: Scleroderma-Health Assessment Quetionnaire
timeFrame: At month 3
measure: Scleroderma-Health Assessment Quetionnaire
timeFrame: At month 6
measure: Scleroderma-Health Assessment Quetionnaire
timeFrame: At month 12
measure: Short Form (36) health survey (SF36v2)
timeFrame: At month 0
measure: Short Form (36) health survey (SF36v2)
timeFrame: At month 3
measure: Short Form (36) health survey (SF36v2)
timeFrame: At month 6
measure: Short Form (36) health survey (SF36v2)
timeFrame: At month 12
measure: EQ-5D-5L quality of life questionnaire
timeFrame: At month 0
measure: EQ-5D-5L quality of life questionnaire
timeFrame: At month 3
measure: EQ-5D-5L quality of life questionnaire
timeFrame: At month 6
measure: EQ-5D-5L quality of life questionnaire
timeFrame: At month 12
measure: Forced Vital Capacity (FVC)
timeFrame: At month 0
measure: Forced Vital Capacity (FVC)
timeFrame: At month 3
measure: Forced Vital Capacity (FVC)
timeFrame: At month 6
measure: Forced Vital Capacity (FVC)
timeFrame: At month 12
measure: Diffusing capacity of Lung for carbon monoxide (DLCO)
timeFrame: At month 0
measure: Diffusing capacity of Lung for carbon monoxide (DLCO)
timeFrame: At month 3
measure: Diffusing capacity of Lung for carbon monoxide (DLCO)
timeFrame: At month 6
measure: Diffusing capacity of Lung for carbon monoxide (DLCO)
timeFrame: At month 12
measure: Response to treatment
timeFrame: At month 3
measure: Response to treatment
timeFrame: At month 6
measure: Response to treatment
timeFrame: At month 12
measure: Progression Free Survival
timeFrame: At month 12
measure: Global Rank Composite Score (GRCS)
timeFrame: At month 3
measure: Global Rank Composite Score (GRCS)
timeFrame: At month 6
measure: Global Rank Composite Score (GRCS)
timeFrame: At month 12
measure: Composite response index in dcSSc (CRISS)
timeFrame: At month 3
measure: Composite response index in dcSSc (CRISS)
timeFrame: At month 6
measure: Composite response index in dcSSc (CRISS)
timeFrame: At month 12
measure: Overall survival
timeFrame: At month 12
measure: Impact of allogeneic MSC(AT) infusion on the immune response
timeFrame: Up to 6 months
measure: Cost effectiveness of the allogeneic MSC(AT) infusion
timeFrame: At month 12
Other outcomes:
measure: Exploring immune landscape in SSc skin biopsies and signatures predicting treatment response
timeFrame: Up to 12 months
measure: Evaluating new MSC potency assays interrogating MSC efferocytosis
timeFrame: Up to 12 months
Locations:
Study officials:
References: