Clinical trial NCT04365257: Prazosin to Prevent COVID-19 (PREVENT-COVID Trial)
Official title: Alpha-1 Adrenergic Receptor Antagonism to Prevent COVID-19 Cytokine Storm Syndrome and Acute Respiratory Distress Syndrome: A Randomized Study Comparing the Efficacy of Prazosin vs. Standard of Care for SARS-CoV-2 Infection
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: COVID-19
Keywords: SARS-CoV-2
Coronavirus disease 2019
COVID-19
Cytokine Storm Syndrome
Acute Respiratory Distress Syndrome
Prazosin
Alpha-1 receptor antagonist
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Fast Grants
First posted: 2020-04-28
Enrollment: 5
Sex: ALL
Minimum age (years): 45
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the efficacy and safety of prazosin to prevent cytokine storm syndrome and severe complications in hospitalized patients with Coronavirus disease 2019 (COVID-19).

Detailed description: In Coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an exuberant local or systemic immune response ('hyperinflammation') in the lung and other sites of viral replication, compromising organ function and leading to high morbidity and mortality. Emerging evidence suggests that a subset of patients with COVID-19 develops a cytokine storm syndrome that is associated with elevation of pro-inflammatory cytokines.

Catecholamines enhance inflammatory injury by augmenting the production of IL-6 and other cytokines through a self-amplifying feed-forward loop in immune cells that requires alpha-1 adrenergic receptor (⍺1-AR) signaling. The ⍺1-AR antagonist prazosin prevents cytokine storm and markedly increased survival following inflammatory stimuli in preclinical models. In a retrospective study of outcomes in acute respiratory distress syndrome or pneumonia, patients who were taking ⍺1-AR antagonists had significantly lower probability of needing invasive mechanical ventilation and dying in the hospital compared to non-users.

Prazosin may blunt surges in catecholamines and self-amplifying cytokine production (including interleukin 6) and, as an early preemptive therapy in patients prior to disease progression, may prevent cytokine storm syndrome and severe complications of COVID-19.

In this study, patients with positive SARS-CoV-2 testing who are hospitalized (but are not requiring more than 4 liters/minute of supplemental oxygen by nasal cannula) will be screened for eligibility. Patients who provide informed consent and meet eligibility requirements will be randomized in a 1:1 ratio to receive either prazosin or standard of care. Participants randomized to the study drug will receive prazosin for 28 days and all patients will be followed for a total of 60 days to capture outcomes.

Eligibility criteria: Inclusion Criteria:

* Subjects must be 45 years of age or older
* Provision of informed consent
* Subjects who tested positive for SARS-CoV-2 AND have clinical symptoms of COVID-19\* AND have been hospitalized, but are not requiring more than 4 liters/minute of supplemental oxygen by nasal cannula and are not requiring ICU/CCU-level care at time of enrollment

(\*)Acute respiratory tract infection (sudden onset of at least one of the following: fever, chills, sore throat, myalgia, diarrhea, cough, or shortness of breath) AND with no other etiology that fully explains the clinical presentation

Exclusion Criteria:

* Female subjects who identify as pregnant, self-reported positive pregnancy testing, or who are breastfeeding during the study period
* Age \>85 years
* Known history of known orthostatic hypotension, unexplained history of syncope, postural orthostatic tachycardia syndrome (POTS), neurally-mediated hypotension, heart failure, myocardial infarction, stable or unstable angina, history of coronary artery bypass surgery, stroke, carotid artery disease, or moderate to severe mitral or aortic stenosis
* Current use of tocilizumab, sarilumab, siltuximab, lopinavir/ritonavir, remdesivir, favipiravir, alpha-blockers, combined alpha/beta blockers (carvedilol, labetalol), sotalol, clonidine, phosphodiesterase type 5 inhibitors, asenapine, or alpha-methyldopa
* Need for vasopressors, inotropes, or intra-aortic balloon pump at time of enrollment
* Allergy or intolerance to quinazolines (including prazosin)
* Requires oxygen supplementation beyond 4 liters of oxygen/minute per nasal cannula at time of enrollment (i.e. not requiring oxygenation by non-rebreather, high-flow nasal cannula, CPAP/BiPAP, or invasive mechanical ventilation)
* Patients who are in the custody of state or federal entities (prisoners)

Primary outcomes:
measure: Death
timeFrame: up to day 60
measure: Hospitalized, Requiring Mechanical Ventilation and/or High Flow Nasal Cannula and/or ICU/CCU Admission (or Equivalent) and/or ECMO
timeFrame: up to day 60
measure: Hospitalized, Requiring Supplemental Oxygen, Not Requiring ICU/CCU Level Care (or Interventions Listed Under Outcome 2)
timeFrame: up to day 60
measure: Cumulative Incidence of Grade 3 and 4 Adverse Events
timeFrame: up to day 60
measure: Number of Participants With Serious Adverse Events
timeFrame: up to day 60
measure: Incidence of Symptomatic Hypotension or Hypotension Requiring Cessation of Prazosin
timeFrame: up to day 60
Secondary outcomes:
measure: Number of Participants With Laboratory Abnormalities in Peripheral Blood
timeFrame: up to day 60
measure: Duration of Laboratory Abnormalities in Peripheral Blood
timeFrame: up to day 60
measure: Number of Participants With Laboratory Abnormalities in Plasma
timeFrame: up to day 60
measure: Duration of Laboratory Abnormalities in Plasma
timeFrame: up to day 60
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Chetan Bettegowda, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References: