Clinical trial NCT04457609: Administration of Allogenic UC-MSCs as Adjuvant Therapy for Critically-Ill COVID-19 Patients
Official title: Application of Umbilical Cord Mesenchymal Stem Cells as Adjuvant Therapy for Critically-Ill COVID-19 Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: COVID
Pulmonary Infection
Sars-CoV2
Keywords: Covid-19 Pneumonia
SARS-CoV-2
Mesenchymal Stem Cells
Umbilical Cord
Lead sponsor: Indonesia University
Sponsor class: OTHER
First posted: 2020-07-07
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Sterility tests are done three times to ensure cellular sterility. Subjects will receive MSCs through infusion through intravenous for 1 hour, following the administration of diphenhydramine and anticoagulant to prevent clotting.

Following the MSCs administration, monitoring at the patients is carried out every day, whereas laboratory testing for basic parameters (complete blood count, differential count, blood gas analysis, C-reactive protein, SGOT/SGPT (AST/ALT), Ureum/Creatinine, eGFR, electrolyte, procalcitonin, albumin, total bilirubin, D-Dimer, fibrinogen, troponin I and proBNP) are carried out every three days. Cytokine levels are measured before the administration and 7th day after the administration. Chest radiography is carried out every three days.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Clinical improvement: Presence of dyspnea
timeFrame: 15 days
measure: Clinical improvement: presence of sputum
timeFrame: 15 days
measure: Clinical improvement: fever
timeFrame: 15 days
measure: Clinical improvement: ventilation status
timeFrame: 15 days
measure: Clinical improvement: blood pressure
timeFrame: 15 days
measure: Clinical improvement: heart rate
timeFrame: 15 days
measure: Clinical improvement: respiratory rate
timeFrame: 15 days
measure: Clinical improvement: oxygen saturation
timeFrame: 15 days
Secondary outcomes:
measure: General laboratory outcome from leukocyte level
timeFrame: 15 days
measure: General laboratory outcome from lymphocytes level
timeFrame: 15 days
measure: General laboratory outcome from blood pH
timeFrame: 15 days
measure: General laboratory outcome from blood level of CO2
timeFrame: 15 days
measure: General laboratory outcome from blood base excess level
timeFrame: 15 days
measure: General laboratory outcome from blood oxygen partial pressure
timeFrame: 15 days
measure: General laboratory outcome from blood level of HCO3
timeFrame: 15 days
measure: General laboratory outcome from blood level of O2 saturation
timeFrame: 15 days
measure: General laboratory outcome from level of CRP
timeFrame: 15 days
measure: General laboratory outcome from level of SGOT/SGPT (AST/ALT)
timeFrame: 15 days
measure: General laboratory outcome from the level of ureum/creatinine level
timeFrame: 15 days
measure: General laboratory outcome from the level of eGFR
timeFrame: 15 days
measure: General laboratory outcome from the level of sodium
timeFrame: 15 days
measure: General laboratory outcome from the level of potassium
timeFrame: 15 days
measure: General laboratory outcome from the level of chloride
timeFrame: 15 days
measure: Changes in procalcitonin level
timeFrame: 15 days
measure: General laboratory outcome from albumin level
timeFrame: 15 days
measure: General laboratory outcome from total bilirubin level
timeFrame: 15 days
measure: Changes in D-Dimer level
timeFrame: 15 days
measure: Changes in fibrinogen level
timeFrame: 15 days
measure: Cardiac changes from troponin level
timeFrame: 15 days
measure: Cardiac changes from NT proBNP level
timeFrame: 15 days
measure: Changes in Leukemia Inhibiting Factor
timeFrame: 7 days
measure: Changes in level of IL-6
timeFrame: 7 days
measure: Changes in level of IL-10
timeFrame: 7 days
measure: Changes in level of vascular endothelial growth factor (VEGF)
timeFrame: 7 days
measure: Changes in level of ferritin
timeFrame: 7 days
measure: Changes in level of CXCR3
timeFrame: 7 days
measure: Changes in level of CD4
timeFrame: 7 days
measure: Changes in level of CD8
timeFrame: 7 days
measure: Changes in level of CD56
timeFrame: 7 days
measure: Radiologic Improvement from Chest X-Ray/CT Scan
timeFrame: 15 days
Other outcomes:
Locations:
city: Jakarta Pusat
country: Indonesia
facility: Cipto Mangunkusumo General Hospital
state: DKI Jakarta
city: Jakarta
country: Indonesia
facility: Persahabatan General Hospital
state: DKI Jakarta
city: Jakarta
country: Indonesia
facility: Sulianti Saroso Center for Infectious Disease
state: DKI Jakarta
city: Depok
country: Indonesia
facility: Universitas Indonesia Hospital
state: West Java
Study officials:
affiliation: Indonesia University
name: Ismail H Dilogo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: