This is a pilot phase, open label, non-randomized study for the treatment of ARDS in patients infected with COVID-19. Subjects will be enrolled and treated with one dose of mesenchymal stem cells and follow-up will occur 90 days post-treatment.
A Study of Mesenchymal Stem Cells as a treatment in Patients with Acute Respiratory Distress
Syndrome caused by COVID-19 is a pilot phase, open label, non-randomized study, with a single
study center.
The current pandemic caused by the novel virus SARS-CoV-2 has lead to a health care crisis
affecting hospitals, hospital workers and health care structure globally. Many countries are
dealing with a disrupted infrastructure in health care and imminent economic downfall to an
extent that has not been seen in recent years. COVID-19 has lead to a large number of deaths
in several countries, and Mexico has not been an exception. Availability of supplies,
hospital space and equipment for mechanical ventilation are running critically low, and it
has been a challenge for hospitals coping with severe clinical symptoms in COVID-19. This
disease is characterized by pneumonia, fever, cough and occasional diarrhea, and the severity
has been largely attributed to the high affinity of the virus to Angiotensin-Converting
Enzyme 2 (ACE2) as the main receptor, and the Type II Transmembrane Serine Protease TMPRSS2
as the main host protease that mediates S protein activation on primary target cells in the
lung and small intestine.
Many agencies and professional societies are working worldwide in developing treatment
guidelines to care for patients with COVID-19, since the present treatments are supportive
but not yet curative, therefore these guidelines are based on scientific evidence and expert
opinion, the use of an array of drugs approved for other indications, as well as multiple
investigational agents that are being studied. Lately, Remdesivir, a novel small-molecule
adenine nucleotide analogue antiviral drug that has shown efficacy against Ebola virus in
rhesus monkeys has shown improvement in patients with oxygen support. The focus of the
research for a cure of COVID-19 has been centered on the individual's response in an
immunological context, where an over activation of the immune response can cause a production
of a large quantity of inflammatory molecules resulting in a cytokine storm with severe
physiological consequences. The cytokine storm induces an increase in inflammatory proteins
that results in edema, improper oxygen exchange, acute respiratory distress syndrome (ARDS),
other organ damage and secondary infection. In recent studies, mesenchymal stem cells (MSCs)
have proven to decrease the hyper inflammatory response in the lungs, leading to a steady
recovery in patients with ARDS. The use of umbilical cord mesenchymal stem cells (UC-MSCs)
may prove a potential effective measure for the treatment of the cytokine storm induced by
COVID-19.
A step forward in a treatment strategy for the novel virus infection in humans would be
critical for treating COVID-19 and especially ARDS-induced severe pneumonia, which is
currently depleting resources around the world. Because efforts to control lung injury via
pharmacological agents have been unsuccessful, mesenchymal stem cell (MSC)-based therapy is
being investigated, based on the characteristics of MSCs to self-renew in a limitless manner
and their multipotency.
Furthermore, MSC-based therapies have demonstrated in the past of having sufficient promising
effects in experimental treatment of ARDS via inhibition of alveolar collapse, collagen
accumulation, and cell apoptosis in lung tissue. Recent studies found that administrating
allogeneic MSCs in patients with ARDS resulted in no pre-specified adverse events, including
hypoxemia, cardiac arrhythmia, and ventricular tachycardia. MSCs are currently attracting
interest due to source potential, a high proliferation rate, and a painless procedure that is
free of ethical issues. Selection of a starting dose of approximately 100 million cells has
been chosen to approximate the standard dosage of cells employed in prior clinical studies.
This dosage may be adjusted depending on the data generated during the conduction of the
study.
MSCs play a positive role mainly in two ways, namely immunomodulatory effects and
differentiation abilities. MSCs can secrete many types of cytokines by paracrine secretion or
make direct interactions with immune cells, leading to immunomodulation. The immunomodulatory
effects of MSCs are triggered further by the activation of TLR receptor in MSCs, which is
stimulated by pathogen-associated molecules such as LPS or double-stranded RNA from virus,
like the HCoV-19.
There are many pilot studies conducted with MSC transplantation to explore their therapeutic
potential for HCoV-19 infected patients, in many of them the pulmonary function and symptoms
of patients were significantly improved days after MSC transplantation. Thus, in this study
we intend to prove the intravenous transplantation of MSCs as safe and effective for
treatment in patients with COVID-19 pneumonia, especially for patients in severe condition.
Primary Objective: To determine the feasibility and safety of intravenously administered MSCs
in patients with Acute Respiratory Distress Syndrome.
Secondary Objectives:
To assess preliminary response in respiratory performance in patients with ARDS.
To assess overall survival of patients. To determine mortality rate at 14 days post
treatment. To assess clinical and radiological improvements in patients.
Number of Subjects to be studied: 10
Endpoints
Primary Endpoint:
Evaluate Respiratory distress symptoms based on Berlin definition (RR; Oxygen saturation at
rest; Arterial partial pressure of oxygen (PaO2) / Fraction of inspiration O2 (FiO2)).
Determine the degree of ground-glass opacity and pneumonia infiltration in imaging studies
(X-ray or CT).
Evaluate clinical improvement based on APACHE II Score. Determine mortality rate at 2 weeks
post treatment.
Secondary Endpoints:
Adverse events related to MSC infusion (description, timing, grade, seriousness, and
relatedness) Hematological decompensation (based on CBC, SQ and metabolic panels) Objective
response rate Progression free survival, overall survival, and best overall response rate
Determine if any infusion reactions/toxicity occurs
Clinical and radiological parameters will be assessed at Baseline, 2, 4 and 14 day
post-treatment, and there will be a 3 month follow-up by telephone contact.
Biological: Mesenchymal Stem Cells derived from Wharton Jelly of Umbilical cords
Mesenchymal Stem Cells as a single-dose therapy via IV infusion at a dose of 1 X 10 8 cells.
Other Name: UCMSC
Inclusion Criteria:
- Ability to understand and the willingness to provide informed consent or a legally
authorized representative.
- Diagnosis of Acute Respiratory Distress Syndrome according to the Berlin Definition
following the failing of prior standard therapy, and other available therapies.
Mild: 200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg with PEEP or CPAP ≥ 5 cm H2Oc Moderate: 100 mm Hg <
PaO2/FIO2 ≤ 200 mm Hg with PEEP ≥ 5 cm H2O Severe: PaO2/FIO2 ≤ 100 mm Hg with PEEP ≥ 5 cm
H2O
- Diagnostic test positive for SARS-CoV-2
- Age ≥ 18 years
- Any man with a partner of child-bearing potential agrees to use adequate contraception
which will include two of the following: hormonal or barrier method of birth control,
or abstinence prior to study entry, for the duration of study participation, and for
30 days following completion of therapy.
Exclusion Criteria:
- Current or anticipated use of other investigational agents.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MSC infusion plus any patently atopic patients who have a history of
having experienced an episode of allergic anaphylaxis.
- Severe or uncontrolled medical disorder that would, in the investigator's opinion,
impair ability to receive study treatment (i.e., uncontrolled diabetes, chronic renal
disease).
- Known diagnosis of human immunodeficiency virus (HIV) infection.
Instituto de Medicina Regenerativa
Tijuana, Baja California, Mexico