More than 17 million people have been infected and more than 677K lives have been lost since the COVID-19 pandemic. Unfortunately, there is neither an effective treatment nor is there a vaccination for this deadly virus. The moderate to severe COVID-19 patients suffer acute lung injury and need oxygen therapy, and even ventilators, to help them breathe. When a person gets a viral infection, certain body cells (inflammatory/immune cells) get activated and release a wide range of small molecules, also known as cytokines, to help combat the virus. But it is possible for the body to overreact to the virus and release an overabundance of cytokines, forming what is known as a "cytokine storm". When a cytokine storm is formed, these cytokines cause more damage to their own cells than to the invading COVID-19 that they're trying to fight. Recently, doctors and research scientists are becoming increasingly convinced that, in some cases, this is likely what is happening in the moderate to severe COVID-19 patients. The cytokine storm may be contributing to respiratory failure, which is the leading cause of mortality for severe COVID-19 patients. Therefore, being able to control the formation of cytokine storms will also help alleviate the symptoms and aid in the recovery of severe COVID-19 patients.
The investigators reason that Regadenoson treatment will reduce COVID-19-induced lung injury
by inhibiting hyperinflammation. Our overarching goal is to demonstrate that Regadenoson
treatment increases survival by reducing hyperinflammation and pulmonary function. The
investigators will test the hypothesis that Regadenoson elicits clinical improvement and
enhances survival compared to placebo control patients with COVID-19. The investigators
hypothesize that the survival benefit of Regadenoson will be additive or synergistic with the
anti-viral drug, Remdesivir. Remdesivir and Dexamethasone are currently standard of care and
would remain so.
Specific Aim 1: will determine the initial high dose followed by low dose continuous infusion
that is safe and feasible in moderate to severe COVID-19 patients. Even if the dosages that
the investigators will use in moderate to severe COVID-19 patients has been proved to be safe
in myocardial perfusion imaging patients, sickle cells disease and lung transplantation
patients, it is still unclear whether it is safe in COVID-19 patients. Therefore, our primary
endpoint for this Aim will be safety. For the first 6 patients, the investigators will be
looking at any drug related side effects and toxicity of Regadenoson as the investigators did
in lung transplantation trial.
Specific Aim 2: will determine the potential efficacy of Regadenoson infusion in moderate to
severe COVID-19 patients. If Regadenoson infusion is safe and feasible in the moderate to
severe COVID-19 patients in Aim 1, the investigators will test its efficacy in 34 moderate to
severe COVID-19 patients in a randomized controlled trial of regadenoson versus placebo
control. The primary endpoints of this specific aim are: 1) Proportion of patients alive and
free of respiratory failure through the 30 day trial. Respiratory failure is defined based on
resource utilization requiring at least 1 of the following modalities, 2) Endotracheal
intubation and mechanical ventilation, 3) Oxygen delivered by high-flow nasal cannula
(heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20L/min
with fraction of delivered oxygen ≥0.5), 4) Noninvasive positive pressure ventilation or
CPAP, 5) ECMO.
Specific Aim 3: will explore the mechanisms of the effects of Regadenoson infusion in
moderate to severe COVID-19 patients. If Regadenoson is proved to be effective on treating
moderate to severe COVID-19 patients in Aim 2, the investigators will continue the study in
this Aim. The investigators will measure 1) the plasma levels of Regadenoson in the collected
blood samples (these will be done only on the first 6 patients as the investigators need
specific time points and want to limit non routine blood draws); 2) the levels of
pro-inflammatory cytokines (TNF-α, IL-1, IL-6, IL-12, IL-8, INF-γ, etc) and anti-inflammatory
cytokines ( IL-4 and IL-10), and 3) the levels of matrix metalloproteinase-9 (MM-9) and
tissue inhibitor of metalloproteinase-1 (TIMP-1) in blood samples which will be collected
from COVID-19 patients at prior baseline lab draws and also next day am routine labs. For the
first 6-patients the investigators will ask for 2- additional study lab draws, one at the
conclusion of the 30-min infusion and one at 4-hours into the 6-hours slow continuous
infusion. The investigators may limit this to 3 if there are no dose limiting toxicities. The
investigators are asking for up to 6 in the safety aim 1 in case one of the 3 has a dose
limiting toxicity the investigators would then provide to 6 total. 5 of 6 would need to be
without dose limiting toxicity to continue with the additional 34 patients.
Drug: Regadenoson
Regadenoson will be given intravenously as 5 ug/kg (up to 400 mg/patient) loading dose over 30 mins (to avoid unpleasant side effects sometimes associated with the rapid bolus injection of Regadenoson), followed by a continuous slow infusion (1.44micrograms/kg/hour) with the use of a pediatric infusion pump for 6 hours.
Other Name: LEXISCAN,
Other: Placebo Control
The same volume of saline will be given intravenously for 6 and half hours.
Other Name: Saline
Inclusion Criteria:
- Age: adults 18 years and older
- Laboratory-confirmed COVID-19+ by RT-PCR
- Moderate to Severe COVID-19 patients according to FDA's COVID-19 treatment guideline
on Management of Persons with COVID-19: Moderate illness is defined as individuals who
have evidence of lower respiratory disease by clinical assessment or imaging and a
saturation of oxygen (SpO2) >93% on room air at sea level. Severe Illness is defined
as individuals who have respiratory frequency >30 breaths per minute, SpO2 ≤ 93% on
room air at sea level, ratio of arterial partial pressure of oxygen to fraction of
inspired oxygen (PaO2/FiO2) <300, or lung infiltrates >50%
- Written informed consent must be obtained before any study procedure is performed.
Exclusion Criteria:
- Pregnant or breastfeeding women
- Symptoms or signs of acute myocardial ischemia
- Sinoatrial (SA) and Atrioventricular (AV) Nodal Block/dysfunction
- Symptoms or signs of Atrial Fibrillation/Atrial Flutter
- History of Hypotension
- History of severe hypertension not adequately controlled with anti-hypertensive
medications (Systolic blood pressure ≥ 200 mmHg and/or Diastolic blood pressure ≥ 110
mmHg)
- Severe renal impairment defined as glomerular filtration rate (GFR) < 30 ml/min
- History of clinically overt stroke within the past 3 years
- History of seizure disorder
- Pre-existing asthma or chronic obstructive pulmonary disease
- Chronic anti-coagulation or anti-platelet therapy that would preclude surgery
(prophylactic aspirin is acceptable)
- 12.Treatment within 30 days with Hydroxychloroquine (HCQ) or Azithromycin
- Treatment with Janus Kinase inhibitors
- Treatment with theophylline or aminophylline within 12 hours of study dosing
- Treatment with Persantine and/or Aggrenox within 5 days
- Other clinical conditions that in the opinion of the investigator would make the
subject unsuitable for the study
University of Maryland Medical Center
Baltimore, Maryland, United States
Investigator: Christine L Lau, MD, MBA
Contact: 410-328-8407
cllau@som.umaryland.edu
Melissa Culligan, RN
410-328-3995
mculligan@som.umaryland.edu
Manal Al-Suqi, MSTC
410-328-9409
MaAl-Suqi@som.umaryland.edu
Christine L Lau, MD, MBA, Principal Investigator
University of Maryland, Baltimore