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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314876

ABSTRACT

Background: Acute Respiratory Distress Syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal Stem Cells (MSC) are potent immunomodulatory cells. The aim of this study was to determine safety and explore efficacy of Umbilical Cord (UC)-MSC infusions in COVID-19 ARDS.Methods: A double-blind, phase 1/2a, randomized, controlled trial was performed in subjects with ARDS secondary to COVID-19, at a single institution in Miami, Florida, USA. Randomization and stratification by ARDS severity was used to foster balance among groups. Participants received two intravenous infusions of 100x106 UC-MSC, or vehicle, at day 0 and 3. The primary endpoint was safety, defined by occurrence of pre-specified infusion associated adverse events, along with adverse events during 28 day follow-up. All subjects were analyzed under an intention to treat design. Exploratory efficacy endpoints included survival at 28 days and time to recovery.Findings: 24 subjects (12 per group) were recruited between April 25 and July 21 2020. At 28 days post last infusion, patient survival was 91% and 42% in the UC-MSC and Control groups, respectively (p=0.015). No serious adverse events (SAEs) were observed related to UC-MSC infusions. There was no observed difference in number of subjects experiencing infusion-associated adverse events. Treatment unrelated SAEs were reported in 2 and 8 patients in the UC-MSC and Control groups, respectively (p=0.04). UC-MSC treatment was associated with increased SAE-free survival (p=0.008) and decreased time to recovery (p=0.03) compared to controls.Interpretation: UC-MSC infusions in COVID-19 subjects with ARDS were safe and associated with fewer SAEs, compared to control. Further, exploratory efficacy analyses provide preliminary evidence of reduction in mortality and time to recovery. Notwithstanding sample size limitations of this trial, the observed findings strongly support further investigation in a larger trial designed to estimate and test for efficacy.Trial Registration: (ClinicalTrials.gov NCT04355728).Funding Statement: The trial was funded by the Barilla Group and Family, The Cure Alliance, the Fondazione Silvio Tronchetti Provera, the Simkins Family Foundation, the North America’s Building Trades Unions, and the Diabetes Research Institute Foundation. This publication was supported by the Clinical Translational Research Site Grants Number UL1TR000460 and UL1TR002736 from the National Center for Advancing Translational Sciences (NCATS).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: Ethics Committee Approval by the regulatory and institutional review boards were obtained by the Western Institutional Review Board (WIRB) and UM Human Subject Research Office/Institutional Review Board, in accordance with local institutional requirements.

2.
Biomater Biosyst ; 4: 100031, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1540385

ABSTRACT

A pandemic brought on by COVID-19 has created a scalable health crisis. The search to help alleviate COVID-19-related complications through therapeutics has become a necessity. Zofin is an investigational, acellular biologic derived from full-term perinatal amniotic fluid that contains extracellular vesicles. Extracellular nanoparticles as such have been studied for their immunomodulatory benefits via cellular therapeutics and, if applied to COVID-19-related inflammation, could benefit patient outcome. Subjects (n = 8) experiencing mild-to-moderate COVID-19 symptoms were treated with the experimental intervention. Complete blood count, complete metabolic panel, inflammatory biomarkers, and absolute lymphocyte counts were recorded prior to and on days 4, 8, 14, 21, and 30 as markers of disease progression. Additionally, chest x-rays were taken of the patients prior to and on days 8 and 30. Patients experienced no serious adverse events. All COVID-19-associated symptoms resolved or became stable with no indication of disease worsening as found by patient and chest x-ray reports. Inflammatory biomarkers (CRP, IL-6, TNF- α ) and absolute lymphocyte counts improved throughout the study period. Findings from a proof-of-concept, expanded access trial for COVID-19 patients prove the acellular biologic is safe and potentially effective to prevent disease progression in a high-risk COVID-19 population with mild-to-moderate symptoms.

3.
Respir Med Case Rep ; 34: 101502, 2021.
Article in English | MEDLINE | ID: covidwho-1377826

ABSTRACT

Post-COVID-19 infection symptoms such as mental fog, tachycardia, and extreme fatigue are just a few of the symptoms wreaking havoc on patients' lives. Patients with long-term symptoms following COVID-19 are being called long haulers. To date, long haulers are receiving little to no guidance from physicians on their lingering COVID-19 symptoms with limited treatment options available. Zofin is an acellular biologic that contains the extracellular vesicle (EV) fraction of human amniotic fluid and is under investigation for use as a COVID-19 therapeutic. We obtained FDA and IRB approval to investigate the therapeutic use of Zofin in a single long hauler patient case experiencing prolonged shortness of breath and respiratory impairment. Administration of the EV product was shown to be safe. Furthermore, demonstrated respiratory improvements through chest X ray images and oxygen saturation measurement. The single patient IND studies were completed without any reported adverse events or safety concerns. Furthermore, these completed studies demonstrate the feasibility and a therapeutic potential of amniotic fluid-derived EVs for COVID-19 long hauler intervention.

4.
Stem Cells Transl Med ; 10(5): 660-673, 2021 05.
Article in English | MEDLINE | ID: covidwho-1008163

ABSTRACT

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE-free survival (P = .008), and time to recovery (P = .03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/therapy , Mesenchymal Stem Cell Transplantation/methods , Cytokines/blood , Double-Blind Method , Female , Humans , Male , Mesenchymal Stem Cell Transplantation/adverse effects , Mesenchymal Stem Cells , Middle Aged , SARS-CoV-2/drug effects , Severity of Illness Index , Treatment Outcome , Umbilical Cord/cytology
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