Application of Umbilical Cord Mesenchymal Stem Cells as Adjuvant Therapy for Critically-Ill COVID-19 Patients
试验速览
- 阶段
- 1 期
- 入组人数
- 40
- 试验地点
- 4
- 主要终点
- Clinical improvement: Presence of dyspnea
研究概览
简要总结
Novel Coronavirus (2019nCoV) or Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) that causes Coronavirus Disease 2019, or known as Covid-19 has recently become a global health emergency since it was first detected in Wuhan, the People Republic of China in December 2019. Since then, the prevalence has rapidly increased worldwide. In Indonesia, by the end of April 2020, around 10,000 patients have been tested positive for Covid-19 infection, with a case fatality rate of around 8%.
The pathogenesis of Covid-19 is still under investigation and to our understanding, ACE2 receptors in the alveoli serve as the binding site of the S-protein of envelope spike virus of SARS-CoV-2. TMPRSS2 enzyme aids the fusion between cell membrane and capsid of the virus, allowing penetration of virus into the cell. Vesicles containing virion fuse with cell membrane and released as new virions. Cytopathic effect of the virus and its ability to overcome immune response determines the degree of infection.
Differences in immunological profile among degrees of severity of Covid-19 may vary especially for the number of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-6, IL-8, leukemia-inhibiting factors (LIF), immunological markers such as CXCR3+CD4+, CXCR3+CD8+ T cell and CXCR3+ NK cells, implying the ongoing cytokine storm. The previous studies also found increasing number for infection markers such as procalcitonin, ferritin, and C-reactive protein. The decreasing number of anti-inflammatory cytokines in such as IL-10 also supports this finding.
Previous studies have shown immunomodulating and anti-inflammatory capacity of the mesenchymal stem cells (MSCs). MSCs contributed to the shifting of pro-inflammatory Th2 into anti-inflammatory Th2. One of the most recent study on the usage of MSCs on Covid-19 patients showed increased expression of leukemia inhibitory factor (LIF), which give rise to inhibitory effect of T lymphocyte and natural killer (NK) cell population. Vascular epithelial growth factor (VEGF) is found increasing following MSCs administration, which indicates the ability to improve the disrupted capillaries due to SARS-Cov-2 infection. The ability of MSCs in differentiating to alveolar cells is proven by the presence of SPM and SPC2, surfactant proteins produced by type II alveolar cells. MSCs are unable to be infected by SARS-CoV-2 since they don't have ACE2 receptors and TMPRSS2 enzyme.
详细描述
This study is a double blind, randomized control trial (RCT). This study will be concluded in 2 months, from May to July 2020, from subject selection to the end of follow up. Research subjects are obtained consecutively from Covid-19 patients who receive care in the intensive care unit (ICU) across four Covid-19 referral hospitals, including Persahabatan Hospital, Sulianti Saroso Center for Infectious Disease, Cipto Mangunkusumo General Hospital, and Universitas Indonesia Hospital, with 10 subjects obtained from each hospital and total 40 subjects for this RCT. Subjects from each hospitals are divided into control and experimental groups. Subject belongs to the control group will receive standardized therapy (consisting of oseltamivir and azithromycin), whereas subjects in the experimental group will receive MSCs infusion, in addition to standardized therapy.
Subject Criteria Inclusion Criteria for MSC Donor from Umbilical Cord:
Umbilical cord is collected from elective caesarean section from a fullterm pregnancies without any complication and free from HIV, Hepatitis B, C, D virus, Cytomegalovirus, Rubella Virus, and free from fungal and bacterial contamination.
Informed consent all of the subjects must be filled and signed up before ruled in this study.
As soon as after delivery, the umbilical cord is collected and processed in sterile specimen 0,9% NaCl at 4oC for 8 hours. The umbilical cord transported to the laboratory and cultured in GMP lab, at Stem Cells Medical Technology Integrated Service Unit Cipto Mangunkusumo Hospital. Cellular viability and proliferation are evaluated after cell characterization test by flow cytometer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 95 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients aged 18-95 years old
- •Confirmed for diagnosis of Covid-19 through RT-PCR from nasopharyngeal swab and/or bronchoalveolar lavage for patients under intubation
- •Laboratory results showed leukopenia and lymphopenic
- •Chest radiography shows pneumonia appearance and/or ground-glass opacity on chest CT-Scan
- •Patients/their families are willing to sign the informed consent
排除标准
- •History of malignancy
- •Pregnant, or show positive result on pregnancy test
- •Patients was/are currently participating in other clinical trials within the last 3 months
研究组 & 干预措施
Experiment Group
Patients receive intravenous infusion of 1x10^6 unit of umbilical-cord derived mesenchymal stem cells (UC-MSCs)/kgBW in 100 cc of 0.9% NaCl for 1 hour, in addition to standardized treatment
干预措施: Oseltamivir (Drug)
Control Group
Patients receive standardized treatment, consisting of Oseltamivir and Azithromycin
干预措施: Oseltamivir (Drug)
Control Group
Patients receive standardized treatment, consisting of Oseltamivir and Azithromycin
干预措施: Azithromycin (Drug)
Experiment Group
Patients receive intravenous infusion of 1x10^6 unit of umbilical-cord derived mesenchymal stem cells (UC-MSCs)/kgBW in 100 cc of 0.9% NaCl for 1 hour, in addition to standardized treatment
干预措施: Azithromycin (Drug)
Experiment Group
Patients receive intravenous infusion of 1x10^6 unit of umbilical-cord derived mesenchymal stem cells (UC-MSCs)/kgBW in 100 cc of 0.9% NaCl for 1 hour, in addition to standardized treatment
干预措施: Umbilical Cord Mesenchymal Stem Cells (Biological)
结局指标
主要结局
Clinical improvement: Presence of dyspnea
时间窗: 15 days
Assessing whether the patients still have dyspnea, one of cardinal symptoms of Covid-19, assessed from the respiratory rate
Clinical improvement: presence of sputum
时间窗: 15 days
Assessing whether the patients still have productive cough, one of cardinal symptoms of Covid-19, assessed from lung auscultation
Clinical improvement: fever
时间窗: 15 days
Assessing the presence of fever from measurement of body temperature checking, assessed on daily basis
Clinical improvement: heart rate
时间窗: 15 days
Assessing the patients' heart rate on daily basis
Clinical improvement: respiratory rate
时间窗: 15 days
Assessing the patients' respiratory rate on daily basis
Clinical improvement: oxygen saturation
时间窗: 15 days
Assessing the patients' oxygen saturation on daily basis
Clinical improvement: ventilation status
时间窗: 15 days
Assessing whether the patients still require ventilation, one of cardinal symptoms of ARDS in Covid-19, assessed from patients' ability during ventilation weaning phase
Clinical improvement: blood pressure
时间窗: 15 days
Assessing the patients' blood pressure on daily basis
次要结局
- General laboratory outcome from leukocyte level(15 days)
- General laboratory outcome from lymphocytes level(15 days)
- General laboratory outcome from blood oxygen partial pressure(15 days)
- General laboratory outcome from blood pH(15 days)
- General laboratory outcome from blood level of CO2(15 days)
- General laboratory outcome from blood base excess level(15 days)
- General laboratory outcome from blood level of HCO3(15 days)
- General laboratory outcome from blood level of O2 saturation(15 days)
- General laboratory outcome from level of CRP(15 days)
- Changes in D-Dimer level(15 days)
- Changes in fibrinogen level(15 days)
- Cardiac changes from troponin level(15 days)
- Cardiac changes from NT proBNP level(15 days)
- Changes in Leukemia Inhibiting Factor(7 days)
- Changes in level of IL-6(7 days)
- Changes in level of IL-10(7 days)
- Changes in level of vascular endothelial growth factor (VEGF)(7 days)
- Changes in level of ferritin(7 days)
- Changes in level of CXCR3(7 days)
- Changes in level of CD4(7 days)
- Changes in level of CD8(7 days)
- General laboratory outcome from level of SGOT/SGPT (AST/ALT)(15 days)
- General laboratory outcome from the level of sodium(15 days)
- General laboratory outcome from the level of potassium(15 days)
- General laboratory outcome from the level of ureum/creatinine level(15 days)
- General laboratory outcome from the level of chloride(15 days)
- Changes in procalcitonin level(15 days)
- General laboratory outcome from albumin level(15 days)
- General laboratory outcome from total bilirubin level(15 days)
- General laboratory outcome from the level of eGFR(15 days)
- Changes in level of CD56(7 days)
- Radiologic Improvement from Chest X-Ray/CT Scan(15 days)
研究者
Ismail Hadisoebroto Dilogo
Principal Investigator
Indonesia University