Treat COVID-19 Patients With Regadenoson

• ClinicalTrials.gov Identifier: NCT04606069
• Recruitment Status: Not yet recruiting
• First Posted: October 28, 2020
• Last Update Posted: October 28, 2020
• Sponsor: University of Maryland, Baltimore
• Information provided by (Responsible Party): Christine Lau, University of Maryland, Baltimore

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
COVID-19; Lung Inflammation	Drug: Regadenoson; Other: Placebo Control	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Clinical Trial on the Safety and Efficacy of Regadenoson for Moderate to Severe COVID-19 Adult Patients
• Estimated Study Start Date: November 1, 2020
• Estimated Primary Completion Date: November 30, 2021
• Estimated Study Completion Date: January 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Active Arm; Regadenoson will be given intravenously as 5 ug/kg loading dose (up to 400 mg/patient) 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.	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,
Placebo Comparator: Control Arm; The same volume of saline will be given intravenously for 30 mins followed by a continuous infusion for 6 hours.	Other: Placebo Control; The same volume of saline will be given intravenously for 6 and half hours.; Other Name: Saline

Outcome Measures

Primary Outcome Measures :

1. Proportion of patients alive and free of respiratory failure through the 30-day trial. [ Time Frame: 30 Days ]

   Respiratory failure is defined based on resource utilization requiring at least 1 of the following modalities:

   1. Endotracheal intubation and mechanical ventilation
   2. 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)
   3. Noninvasive positive pressure ventilation or CPAP
   4. Whether patient is on ECMO

Secondary Outcome Measures :

1. Change of the levels of the inflammatory cytokines prior, during and post drug infusion. [ Time Frame: 30 days ]
   We will collect blood samples of the regadenoson and placebo treated patients at the baseline, 30mins, 4 hours during drug infusion and 12 hour post drug infusion. It may also including the daily blood collected on normal standard care base. The inflammatory cytokines, including IL-1 beta, IL-6, IL-4, IL-8, IL-10, IL-12, IL-17, TNF-α, and IFN-γ will be measured using the Luminex™ 100 Multi-analyte System at The UM SOM Cytokine Core Laboratory. The levels of of cytokines will be measure in picogram/milliliter (pg/ml).
2. Change of the levels of MMP-2 and MMP-9 prior, during and post drug infusion. [ Time Frame: 30 days ]
   The same blood samples used in outcomes 2 will be used to measure the levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 using gelatin zymography as described in our previous publications (Zhao et al, 2010 & 2011). The enzyme levels will be quantified using The Image Lab 5.1 software. The unit will be nanogram/ml (ng/ml).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Melissa Culligan, RN; 410-328-3995; mculligan@som.umaryland.edu

Contact: Manal Al-Suqi, MSTC; 410-328-9409; MaAl-Suqi@som.umaryland.edu

Locations

United States, Maryland

University of Maryland Medical Center

Baltimore, Maryland, United States, 21201

Contact: Christine L Lau, MD, MBA 410-328-8407 cllau@som.umaryland.edu

Contact: Manal Al-Suqi, MSTC 410-328-9409 MaAl-Suqi@som.umaryland.edu

Sponsors and Collaborators

University of Maryland, Baltimore

Investigators

• Principal Investigator: Christine L Lau, MD, MBA; University of Maryland, Baltimore

More Information

Publications:

Lau CL, Beller JP, Boys JA, Zhao Y, Phillips J, Cosner M, Conaway MR, Petroni G, Charles EJ, Mehaffey JH, Mannem HC, Kron IL, Krupnick AS, Linden J. Adenosine A2A receptor agonist (regadenoson) in human lung transplantation. J Heart Lung Transplant. 2020 Jun;39(6):563-570. doi: 10.1016/j.healun.2020.02.003. Epub 2020 Feb 13.

Field JJ, Majerus E, Gordeuk VR, Gowhari M, Hoppe C, Heeney MM, Achebe M, George A, Chu H, Sheehan B, Puligandla M, Neuberg D, Lin G, Linden J, Nathan DG. Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease. Blood Adv. 2017 Aug 28;1(20):1645-1649. doi: 10.1182/bloodadvances.2017009613. eCollection 2017 Sep 12. Erratum in: Blood Adv. 2017 Oct 19;1(23 ):2058.

Zhao Y, Xiao A, diPierro CG, Carpenter JE, Abdel-Fattah R, Redpath GT, Lopes MB, Hussaini IM. An extensive invasive intracranial human glioblastoma xenograft model: role of high level matrix metalloproteinase 9. Am J Pathol. 2010 Jun;176(6):3032-49. doi: 10.2353/ajpath.2010.090571. Epub 2010 Apr 22.

Zhao Y, Sharma AK, LaPar DJ, Kron IL, Ailawadi G, Liu Y, Jones DR, Laubach VE, Lau CL. Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation. Am J Physiol Lung Cell Mol Physiol. 2011 May;300(5):L718-29. doi: 10.1152/ajplung.00227.2010. Epub 2011 Mar 4.

• Responsible Party: Christine Lau, Dr. Robert W. Buxton Professor and Chair Department of Surgery, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT04606069
• Other Study ID Numbers: HP-00091372
• First Posted: October 28, 2020
• Last Update Posted: October 28, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Pneumonia; Inflammation; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Respiratory Tract Infections; Regadenoson; Adenosine A2 Receptor Agonists; Purinergic P1 Receptor Agonists; Purinergic Agonists; Purinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs