Administration of Allogenic UC-MSCs as Adjuvant Therapy for Critically-Ill COVID-19 Patients

NCT ID: NCT04457609

Last Updated: 2020-07-07

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-31
• Study Completion Date: 2020-09-30

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.

Conditions

COVID; Pulmonary Infection; Sars-CoV2

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Control Group

Patients receive standardized treatment, consisting of Oseltamivir and Azithromycin

Group Type: PLACEBO_COMPARATOR

Oseltamivir

Intervention Type: DRUG

Current standardized treatment for Covid-19

Azithromycin

Intervention Type: DRUG

Current standardized treatment for Covid-19

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

Group Type: EXPERIMENTAL

Oseltamivir

Intervention Type: DRUG

Current standardized treatment for Covid-19

Azithromycin

Intervention Type: DRUG

Current standardized treatment for Covid-19

Umbilical Cord Mesenchymal Stem Cells

Intervention Type: BIOLOGICAL

Adjuvant therapy on top of current standardized treatment (Oseltamivir + Azithromycin)

Interventions

Oseltamivir

Current standardized treatment for Covid-19

Intervention Type: DRUG

Azithromycin

Current standardized treatment for Covid-19

Intervention Type: DRUG

Umbilical Cord Mesenchymal Stem Cells

Adjuvant therapy on top of current standardized treatment (Oseltamivir + Azithromycin)

Intervention Type: BIOLOGICAL

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 95 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Indonesia University

OTHER

Sponsor Role: lead

Responsible Party

Ismail Hadisoebroto Dilogo

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ismail H Dilogo, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Indonesia University

Locations

Persahabatan General Hospital

Jakarta, DKI Jakarta, Indonesia

Site Status: RECRUITING

Sulianti Saroso Center for Infectious Disease

Jakarta, DKI Jakarta, Indonesia

Site Status: RECRUITING

Cipto Mangunkusumo General Hospital

Jakarta Pusat, DKI Jakarta, Indonesia

Site Status: RECRUITING

Universitas Indonesia Hospital

Depok, West Java, Indonesia

Site Status: RECRUITING

Countries

Indonesia

Central Contacts

Ismail H Dilogo, MD, PhD

Role: CONTACT

ismailortho@gmail.com

+621500135

Tri Kurniawati, BSc

Role: CONTACT

selpuncarscm@yahoo.co.id

+621500135

Facility Contacts

Erlina Burhan, MD, PhD

Role: primary

erlina_burhan@yahoo.com

+62214891708

Triya Damayanti, MD, PhD

Role: backup

+62214891708

Pompini A Sitompul, MD

Role: primary

+62216506559

Ismail H Dilogo, MD, PhD

Role: primary

+62211500135

Dita Aditianingsih, MD, PhD

Role: primary

+622150829292

Other Identifiers

ISMMSCCOVID19

Identifier Type: -

Identifier Source: org_study_id