Infusion of Allogeneic Stromal Mesenchymal Stem Cells From Wharton´s Jelly in Patients With Diffuse Cutaneous Systemic Sclerosis With Refractory Pulmonary Involvement to Treatment
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- lung capacity for gas transfer
研究概览
简要总结
Progressive SSc is an entity with limited therapeutic alternatives and a survival rate of less than 45% within the first 3 to 5 years. The disease causes severe limitations in quality of life, ranging from functional impairment to depression. Up to 20% of patients become refractory to conventional treatment with disease-modifying anti-rheumatic drugs (DMARDs) and cyclophosphamide therapy. This condition favors progression to visceral involvement, including gastrointestinal, pulmonary, and pulmonary hypertension manifestations. The latter, considered a poor prognostic factor, increases mortality in this patient population and drastically affects quality of life. For this reason, different therapeutic options have been considered, including cell transplantation and stem cell use.
Among the options studied to date are stromal mesenchymal cells derived from Wharton's jelly. These cells have been administered via intravenous infusion or direct application in various disease scenarios, ranging from vascular involvement to interstitial lung disease and pulmonary hypertension, with promising results in terms of clinical progression, quality of life improvement, and prognostic indices. This therapy has demonstrated a favorable safety profile at the time of administration and a low rate of adverse events, with self-limiting fever being the most frequent event.
Based on the above and considering the possibility of offering patients without therapeutic alternatives for the disease, in addition to palliative options, an intravenous infusion of stromal mesenchymal stem cells derived from Wharton's jelly is proposed for three patients with progressive SSc refractory to conventional therapy, with pulmonary involvement due to pulmonary hypertension.
Under this premise, the research question posed in this study is: What are the effects of the infusion of allogeneic mesenchymal stromal cells derived from Wharton's jelly in patients with systemic sclerosis refractory to conventional treatment with methotrexate or cyclophosphamide, in a population of three patients with severe pulmonary involvement due to pulmonary hypertension?
详细描述
This study aims to evaluate the therapeutic effects of allogeneic mesenchymal stromal cell infusion as a treatment in patients with systemic sclerosis refractory to conventional therapy. The study population will be selected from the database of families affiliated with Stem Regenerative Medicine according to the inclusion and exclusion criteria and verified by the academic committee.
Administration will be performed intravenously, at a concentration of 2 × 10⁶ mesenchymal cells per kilogram of patient body weight. Infusions will be scheduled in conjunction with cyclophosphamide treatment cycles, ten days after each administration within the cyclophosphamide regimen for each patient.
To assess safety and therapeutic effects, the occurrence of any adverse event will be documented from the start of infusion until completion of the trial at six months. To evaluate treatment response, assessments will be conducted pre-infusion and at six months post-infusion, including clinical variables, paraclinical parameters, and hemodynamic tests. Skin involvement will be evaluated using the modified Rodnan score, along with assessment of nailfold capillaroscopy, pulmonary function, and structural involvement by high-resolution chest tomography (HRCT), diffusion capacity for carbon monoxide (DLCO), and the 6-minute walk test.
As part of cardiovascular assessment, brain natriuretic peptide (BNP) levels and transthoracic echocardiography will be performed. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) and SYSQ will be used as assessment tools for pulmonary hypertension. A comparison of these parameters before initiation of therapy and after completion of 24 weeks of the infusion protocol will be conducted.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
this study is an open-label
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age> 18 years and <65 years.
- •Established diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology
- •SSc of poor prognosis, involving life-threatening severe visceral involvement (cardiac or pulmonary hypertension ), lack of response to conventional immunosuppressive therapy used in severe forms of the disease according to the European recommendations of EUSTAR and EBMT, relying on high doses of IV cyclophosphamide (either in monthly bolus for at least six months); or SSc with life-threatening pulmonary hypertension. Patients may or may not have pulmonary fibrosis.
- •Signed informed consent.
- •Presence of a consenting MSC donor
- •Affiliation to social security.
排除标准
- •Pregnancy or absence of appropriate contraception throughout the study.
- •Pulmonary artery systolic pressure (PASP) >75mmHg (on echocardiography or after right heart catheterization);
- •- Theorical DLCO <30%
- •Calculated creatinine clearance <30 ml/mn/m2
- •Clinical sign of a congestive heart failure refractory ;
- •Left ventricular ejection fraction <35% at myocardial scintigraphy or echocardiography;
- •Chronic atrial fibrillation requiring oral anticoagulant therapy;
- •Uncontrolled ventricular arrhythmia;
- •Pericardial effusion with hemodynamic compromise assessed by echocardiography.
- •Hepatic impairment defined as a persistent increase in transaminases or bilirubin to 3 times normal.
- •Psychiatric disorders, including drug taking and alcohol abuse.
- •Active neoplasia or concomitant myelodysplasia, antecedent of neoplasia.
- •Bone marrow failure defined by neutropenia <0.5 x 109 / L, thrombocytopenia <50 x 109 / L, anemia <8 g / dL, CD4 lymphopenia <200 x 106 / L.
- •Uncontrolled systemic hypertension.
- •Uncontrolled acute or chronic infection, HIV1, 2 or HTLV-1, 2seropositivity.
- •Chronic hepatitis B or C active.
- •Significant exposure to bleomycin, toxic oils, vinyl chloride, trichloroethylene or silica; eosinophilia-myalgia syndrome, eosinophilia fasciitis.
- •Risk of poor patient compliance
研究组 & 干预措施
Historical control
A historical control similar characteristics will be selected to compare to the treated patients.
干预措施: Mesenchymal Stem Cells from Wharton´s jelly (Biological)
结局指标
主要结局
lung capacity for gas transfer
时间窗: before and after 6 months treatment
DLCO: diffusing capacity for carbon monoxide
pulmonary function
时间窗: before and after 6 months treatment
forced vital capacity measured by forced spirometry.
submaximal excersice capacity
时间窗: before and after 6 months treatment
Submaximal exercise capacity will be assessed using the 6-minute walk test (6MWT), performed according to American Thoracic Society (ATS) guidelines. The test measures the total distance walked in six minutes on a flat surface and is expressed in meters. This assessment is used to quantify functional limitation and prognosis associated with pulmonary hypertension. The primary outcome will be the change in distance walked between baseline and 6 months. A clinically significant improvement is defined as an increase of more than 10% from the baseline distance.
cardiopulmonary hemodinamycs
时间窗: before and after 6 months treatment
Pulmonary vascular resistance (PVR) will be measured by right heart catheterization and expressed in Wood units. This parameter is used to assess pulmonary vascular involvement in pulmonary hypertension, previously confirmed by standard hemodynamic criteria. The outcome will be the change in PVR between baseline and 6 months after intervention.
cardiopulmonary hemodynamics
时间窗: before and after 6 months treatment
Systolic pulmonary artery pressure (sPAP) will be measured by right heart catheterization and expressed in mmHg. This parameter is used to assess the severity of pulmonary hypertension. Measurements will be obtained prior to mesenchymal stromal cell infusion and repeated at 6 months after intervention. The outcome will be the change in sPAP between baseline and 6 months.
quality of life and functional status
时间窗: before and after 6 months treatment
CAMPHOR score
parenchymatous pulmonary compromise
时间窗: before and after 6 months treatment
high resolution chest CT
次要结局
- cutaneous fibrosis(before and after 6 months treatment)
- adverse events and security profile(before and after 6 months treatment)