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Umbilical Cord Mesenchymal Stem Cells for COVID-19 ARDS: A Double Blind, Phase 1/2a, Randomized Controlled Trial

24 Pages Posted: 26 Oct 2020

See all articles by Giacomo Lanzoni

Giacomo Lanzoni

University of Miami - Diabetes Research Institute

Elina Linetsky

University of Miami - Diabetes Research Institute

Diego Correa

University of Miami - Diabetes Research Institute

Shari Messinger Cayetano

University of Miami - Division of Biostatistics

Antonio C. Marttos

University of Miami - Department of Medicine

Roger A. Alvarez

University of Miami - Department of Medicine

Antonio C. Marttos

University of Miami - Department of Medicine

Ana Alvarez Gil

University of Miami - Diabetes Research Institute

Raffaella Poggioli

University of Miami - Diabetes Research Institute

Phillip Ruiz

University of Miami - Department of Surgery

Khemraj Hirani

University of Miami - Diabetes Research Institute

Crystal A. Bell

University of Miami - Department of Medicine

Halina Kusack

University of Miami - Department of Medicine

Lisa Rafkin

University of Miami - Diabetes Research Institute

David Baidal

University of Miami - Diabetes Research Institute

Andrew Pastewski

University of Miami - Diabetes Research Institute

Kunal Gawri

University of Miami - Department of Medicine

Dimitrios Kouroupis

University of Miami - Diabetes Research Institute

Clarissa Leñero

University of Miami - Diabetes Research Institute

Alejandro MA Mantero

University of Miami - Division of Biostatistics

Sarah W. Metalonis

University of Miami - Division of Biostatistics

Xiaojing Wang

University of Miami - Diabetes Research Institute

Luis Roque

University of Miami - Diabetes Research Institute

Burlett Masters

University of Miami - Diabetes Research Institute

Norma S. Kenyon

University of Miami - Diabetes Research Institute

Enrique Ginzburg

University of Miami - Department of Surgery

Xiumin Xu

University of Miami - Diabetes Research Institute

Jianming Tan

Hainan Medical University - The Second Affiliated Hospital

Arnold I. Caplan

Case Western Reserve University - Skeletal Research Center

Marilyn K. Glassberg

University of Arizona - College of Medicine

Rodolfo Alejandro

University of Miami - Diabetes Research Institute

Camillo Ricordi

University of Miami - Diabetes Research Institute

More...

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.

Keywords: Mesenchymal Stem Cells, Mesenchymal Stromal Cells, MSC, Umbilical Cord, Subepitelial Lining, UC-MSC, COVID-19, Coronavirus, SARS-CoV-2, ARDS, acute respiratory distress syndrome, RCT, Randomised, Randomized, Controlled Trial, clinical trial, Trial, Phase 1/2a, Double Blind

Suggested Citation

Lanzoni, Giacomo and Linetsky, Elina and Correa, Diego and Cayetano, Shari Messinger and Marttos, Antonio C. and Alvarez, Roger A. and Marttos, Antonio C. and Gil, Ana Alvarez and Poggioli, Raffaella and Ruiz, Phillip and Hirani, Khemraj and Bell, Crystal A. and Kusack, Halina and Rafkin, Lisa and Baidal, David and Pastewski, Andrew and Gawri, Kunal and Kouroupis, Dimitrios and Leñero, Clarissa and Mantero, Alejandro MA and Metalonis, Sarah W. and Wang, Xiaojing and Roque, Luis and Masters, Burlett and Kenyon, Norma S. and Ginzburg, Enrique and Xu, Xiumin and Tan, Jianming and Caplan, Arnold I. and Glassberg, Marilyn K. and Alejandro, Rodolfo and Ricordi, Camillo, Umbilical Cord Mesenchymal Stem Cells for COVID-19 ARDS: A Double Blind, Phase 1/2a, Randomized Controlled Trial. Available at SSRN: https://ssrn.com/abstract=3696875 or http://dx.doi.org/10.2139/ssrn.3696875

Giacomo Lanzoni

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Elina Linetsky

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Diego Correa

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Shari Messinger Cayetano

University of Miami - Division of Biostatistics ( email )

Coral Gables, FL 33124
United States

Antonio C. Marttos

University of Miami - Department of Medicine ( email )

Coral Gables, FL 33124
United States

Roger A. Alvarez

University of Miami - Department of Medicine

Coral Gables, FL 33124
United States

Antonio C. Marttos

University of Miami - Department of Medicine

Coral Gables, FL 33124
United States

Ana Alvarez Gil

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Raffaella Poggioli

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Phillip Ruiz

University of Miami - Department of Surgery ( email )

Coral Gables, FL 33124
United States

Khemraj Hirani

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Crystal A. Bell

University of Miami - Department of Medicine ( email )

Coral Gables, FL 33124
United States

Halina Kusack

University of Miami - Department of Medicine ( email )

Coral Gables, FL 33124
United States

Lisa Rafkin

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

David Baidal

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Andrew Pastewski

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Kunal Gawri

University of Miami - Department of Medicine ( email )

Coral Gables, FL 33124
United States

Dimitrios Kouroupis

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Clarissa Leñero

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Alejandro MA Mantero

University of Miami - Division of Biostatistics ( email )

Coral Gables, FL 33124
United States

Sarah W. Metalonis

University of Miami - Division of Biostatistics ( email )

Coral Gables, FL 33124
United States

Xiaojing Wang

University of Miami - Diabetes Research Institute

1450 NW 10th Ave
Miami, FL 33136
United States

Luis Roque

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Burlett Masters

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Norma S. Kenyon

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Enrique Ginzburg

University of Miami - Department of Surgery ( email )

Coral Gables, FL 33124
United States

Xiumin Xu

University of Miami - Diabetes Research Institute

1450 NW 10th Ave
Miami, FL 33136
United States

Jianming Tan

Hainan Medical University - The Second Affiliated Hospital

Haikou, Hainan
China

Arnold I. Caplan

Case Western Reserve University - Skeletal Research Center ( email )

10900 Euclid Ave.
Cleveland, OH 44106
United States

Marilyn K. Glassberg

University of Arizona - College of Medicine ( email )

Department of History
Tucson, AZ 85721
United States

Rodolfo Alejandro

University of Miami - Diabetes Research Institute ( email )

1450 NW 10th Ave
Miami, FL 33136
United States

Camillo Ricordi (Contact Author)

University of Miami - Diabetes Research Institute

1450 NW 10th Ave
Miami, FL 33136
United States

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