Safety and efficacy of autologous non-hematopoietic enriched stem cell nebulization in COVID-19 patients: a randomized clinical trial, Abu Dhabi 2020

Abstract

Background: The novel SARS-CoV-2 has caused the coronavirus disease 2019 (COVID-19) pandemic. Currently, with insufficient worldwide vaccination rates, identifying treatment solutions to reduce the impact of the virus is urgently needed.

Method: An adaptive, multicentric, open-label, and randomized controlled phase I/II clinical trial entitled the "SENTAD-COVID Study" was conducted by the Abu Dhabi Stem Cells Center under exceptional conditional approval by the Emirates Institutional Review Board (IRB) for COVID-19 Research Committee from April 4th to July 31st, 2020, using an autologous peripheral blood non-hematopoietic enriched stem cell cocktail (PB-NHESC-C) administered by compressor (jet) nebulization as a complement to standard care therapy. The primary endpoints include safety and efficacy assessments, adverse events, the mortality rate within 28 days, and the time to clinical improvement as measured by a 2-point reduction on a seven-category ordinal scale or discharge from the hospital whichever occurred first.

Results: The study included a total of 139 randomized COVID-19 patients, with 69 in the experimental group and 70 in the control group (standard care). Overall survival was 94.20% for the cocktail-treated group vs. 90.27% for the control group. Adverse events were reported in 50 (72.46%) patients receiving PB-NHESC-C and 51 (72.85%) in the control group (p = 0.9590), with signs and symptoms commonly found in COVID-19. After the first 9 days of the intervention, 67.3% of cocktail-treated patients recovered and were released from hospitals compared to 53.1% (RR = 0.84; 95% CI, 0.56-1.28) in the control group. Improvement, i.e., at least a 2-point reduction in the severity scale, was more frequently observed in cocktail-treated patients (42.0%) than in controls (17.0%) (RR = 0.69; 95% CI, 0.56-0.88).

Conclusions: Cocktail treatment improved clinical outcomes without increasing adverse events. Thus, the nebulization of PB-NHESC-C was safe and effective for treatment in most of these patients.

Trial registration: ClinicalTrials.gov. NCT04473170. It was retrospectively registered on July 16th, 2020.

Keywords: COVID-19; Immunomodulation; Nebulizers and vaporizers; Recovery of function; Stem cells.

Conflict of interest statement

Competing interestsThe procedure for obtaining the PB-NHESC-C mentioned in this report was advanced through research conducted and patented for ADSCC by YVC, AABH, and FMA. We declare that YMCA, CAVV, PS, YMA, AA, LAH, GMTZ, and RARJ are also staff members of ADSCC. For the rest thereof the co-authors, there are no competing interests. In May 2020, the patented procedure was approved by the Ministry of Economy of the United Arab Emirates, and also in May 2020, 5 of the authors (FMA, YVC, RARJ, AABH, and YMCA) received 3 Copyrights from the INTEROCO Copyright Office (EC-01-002809, EC-01-002810, and EC-01-002811), so this procedure including nebulization has been accredited to ADSCC. Nevertheless, YVC and the other patent authors resigned to be eligible to receive equity due to the licensing of this procedure.

© The Author(s) 2021.

Figures

Fig. 1

Patient allocation during the SENTAD-COVID Study. Legend: Four initially screened patients were excluded before randomization because 2 had been previously diagnosed with malignant diseases, and 2 were previously included in other clinical trials. After randomization, data from 4 additional patients were not analyzed. 2 patients in the control group had data error identifications. 2 patients were not followed in the PB-NHESC-C group: 1 was released from the hospital, and the other unfortunately died before the initial day of treatment

Fig. 2

Flow cytometry gating strategy. Legend: Immunophenotype characterization of peripheral blood non-hematopoietic enriched stem cell cocktail. 2A) Logic and manual gating strategy for cell characterization using five monoclonal antibody-conjugated CD markers simultaneously, including 7-Amino-Actinomycin D (7-AAD). 2B) Expression of angiotensin-converting enzyme 2 (ACE2)

Fig. 3

Representative immunofluorescence images of PB-NHESC-C. Legend: Sample of the PB-NHESC-C were stained with FITC-conjugated monoclonal surface antibody CD45 (1:100) and Hoechst nucleic acid dye 33,342 (10 μg/ml). Images were acquired using a Leica SP8 confocal microscope using a 63x objective. Two main subpopulations were identified: the Non-hematopoietic (*) and the Hematopoietic Stem Cells (arrow)

Fig. 4

Clinical improvement. Different trend line slopes during the clinical trial follow-up. Legend: Group A/S: Peripheral Blood Non-Hematopoietic Enriched Stem Cell Cocktail (PB- NHESC-C) Treated classified as severe; Group B/S: Controls classified as severe; Group A/M: PB-NHESC-C Treated classified as moderate; Group B/M: Controls classified as moderate

Fig. 5

Clinical impact on the assessed outcomes. Legend: NLR: Neutrophil to Lymphocyte Ratio; CRP: C-Reactive Protein; EI0: Exposure Incidence in controls; EI: Exposure Incidence in peripheral blood non-hematopoietic enriched stem cell cocktail treated-patients; RR: relative risk; 95% CI: confidence interval; RRR: relative risk reduction; NNT: number needed to treat to produce the effect; a: Z-test. *: significant; **: highly significant

Fig. 6

High-Resolution Computer Tomography Scans Images of a Patient’s Chest. Legend: Patient No. 4. Group A (peripheral blood non-hematopoietic enriched stem cell cocktail + standard care): Images a) Day of recruitment (April 1st). Images b) Four days after the first dose of stem cell treatment (April 13th, nebulization was initiated on April 9th, and the second dose was commenced on April 10th)