COVID-19
Conditions
Keywords
SARS-CoV-2, Coronavirus disease 2019, COVID-19, Cytokine Storm Syndrome, Acute Respiratory Distress Syndrome, Prazosin, Alpha-1 receptor antagonist
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.
Interventions
DRUGPrazosin
Participants in this arm will receive the study drug as outlined in the arm description.
OTHERStandard of care
Participants in this arm will receive standard of care.
Sponsors
Fast Grants
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
45 Years to 85 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Symptomatic Hypotension or Hypotension Requiring Cessation of Prazosin | up to day 60 | Number of participants in each arm who develop symptomatic hypotension (systolic blood pressure \<90 mmHg) or hypotension requiring cessation of prazosin. |
| Hospitalized, Requiring Mechanical Ventilation and/or High Flow Nasal Cannula and/or ICU/CCU Admission (or Equivalent) and/or ECMO | up to day 60 | Number of participants in each arm who are hospitalized and requiring mechanical ventilation and/or high flow nasal cannula and/or ICU/CCU admission (or equivalent) and/or ECMO. |
| Hospitalized, Requiring Supplemental Oxygen, Not Requiring ICU/CCU Level Care (or Interventions Listed Under Outcome 2) | up to day 60 | Number of participants in each arm who are hospitalized and requiring supplemental oxygen, not requiring ICU/CCU level care (or interventions listed under Outcome 2). |
| Cumulative Incidence of Grade 3 and 4 Adverse Events | up to day 60 | Number of participants in each arm who develop grade 3 and 4 adverse events during the study period. |
| Number of Participants With Serious Adverse Events | up to day 60 | Number of participants in each arm who develop serious adverse events during the study period. |
| Death | up to day 60 | Number of participants in each arm who expire. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Laboratory Abnormalities in Peripheral Blood | up to day 60 | Number of days with laboratory abnormalities in peripheral blood (Lymphopenia, leukocytosis, anemia, thrombocytopenia, creatinine, AST/ALT, troponin I, pro-BNP, D-dimer, ferritin, interleukin (IL-6), soluble IL-2 receptor. |
| Number of Participants With Laboratory Abnormalities in Plasma | up to day 60 | Number of participants with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines. |
| Duration of Laboratory Abnormalities in Plasma | up to day 60 | Number of days with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines. |
| Number of Participants With Laboratory Abnormalities in Peripheral Blood | up to day 60 | Number of participants with laboratory abnormalities in peripheral blood (Lymphopenia, leukocytosis, anemia, thrombocytopenia, creatinine, AST/ALT, troponin I, pro-BNP, D-dimer, ferritin, interleukin (IL-6), soluble IL-2 receptor. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prazosin 1. Prazosin 1mg given to observe if medication is tolerated or if signs or symptoms of hypotension develop (e.g. dizziness, lightheadedness).
2. If the patient remains asymptomatic and BP \>110/60 mmHg, prazosin is continued at 1mg every 8 hours (q8h).
3. Day 3: If the patient remains asymptomatic and BP \>110/60 mmHg, increase dose to 2mg q8h.
4. Day 6: If the patient remains asymptomatic and BP \>110/60 mmHg, increase dose to 5mg q8h.
5. If the BP is \<100/60 mmHg at any time, the next dose should be held, and patient continues with the highest previously tolerated dose 8 hours later.
6. If the patient did not tolerate dose escalation to 5mg q8h, one attempt is made to increase dose to 3mg q8h. If this is not tolerated, the patient continues with the highest previously tolerated dose 8 hours later.
If BP monitoring is not available, repeated occurrences of postural dizziness should trigger drug dose reduction or BP monitoring.
Prazosin: Participants in this arm will receive the study drug as outlined in the arm description. | 3 |
| Standard of Care Subjects randomized to this arm will receive standard of care.
Standard of care: Participants in this arm will receive standard of care. | 2 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Patient Noncompliance | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Prazosin | Standard of Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 0 Participants | 3 Participants |
| Age, Continuous | 53.3 years | 71 years | 60.4 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 1 / 3 | 1 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 2 |
Outcome results
Primary
Cumulative Incidence of Grade 3 and 4 Adverse Events
Number of participants in each arm who develop grade 3 and 4 adverse events during the study period.
Time frame: up to day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prazosin | Cumulative Incidence of Grade 3 and 4 Adverse Events | 0 Participants |
| Standard of Care | Cumulative Incidence of Grade 3 and 4 Adverse Events | 0 Participants |
Primary
Death
Number of participants in each arm who expire.
Time frame: up to day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prazosin | Death | 0 Participants |
| Standard of Care | Death | 0 Participants |
Primary
Hospitalized, Requiring Mechanical Ventilation and/or High Flow Nasal Cannula and/or ICU/CCU Admission (or Equivalent) and/or ECMO
Number of participants in each arm who are hospitalized and requiring mechanical ventilation and/or high flow nasal cannula and/or ICU/CCU admission (or equivalent) and/or ECMO.
Time frame: up to day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prazosin | Hospitalized, Requiring Mechanical Ventilation and/or High Flow Nasal Cannula and/or ICU/CCU Admission (or Equivalent) and/or ECMO | 0 Participants |
| Standard of Care | Hospitalized, Requiring Mechanical Ventilation and/or High Flow Nasal Cannula and/or ICU/CCU Admission (or Equivalent) and/or ECMO | 1 Participants |
Primary
Hospitalized, Requiring Supplemental Oxygen, Not Requiring ICU/CCU Level Care (or Interventions Listed Under Outcome 2)
Number of participants in each arm who are hospitalized and requiring supplemental oxygen, not requiring ICU/CCU level care (or interventions listed under Outcome 2).
Time frame: up to day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prazosin | Hospitalized, Requiring Supplemental Oxygen, Not Requiring ICU/CCU Level Care (or Interventions Listed Under Outcome 2) | 2 Participants |
| Standard of Care | Hospitalized, Requiring Supplemental Oxygen, Not Requiring ICU/CCU Level Care (or Interventions Listed Under Outcome 2) | 1 Participants |
Primary
Incidence of Symptomatic Hypotension or Hypotension Requiring Cessation of Prazosin
Number of participants in each arm who develop symptomatic hypotension (systolic blood pressure \<90 mmHg) or hypotension requiring cessation of prazosin.
Time frame: up to day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prazosin | Incidence of Symptomatic Hypotension or Hypotension Requiring Cessation of Prazosin | 0 Participants |
| Standard of Care | Incidence of Symptomatic Hypotension or Hypotension Requiring Cessation of Prazosin | 0 Participants |
Primary
Number of Participants With Serious Adverse Events
Number of participants in each arm who develop serious adverse events during the study period.
Time frame: up to day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prazosin | Number of Participants With Serious Adverse Events | 0 Participants |
| Standard of Care | Number of Participants With Serious Adverse Events | 0 Participants |
Secondary
Duration of Laboratory Abnormalities in Peripheral Blood
Number of days with laboratory abnormalities in peripheral blood (Lymphopenia, leukocytosis, anemia, thrombocytopenia, creatinine, AST/ALT, troponin I, pro-BNP, D-dimer, ferritin, interleukin (IL-6), soluble IL-2 receptor.
Time frame: up to day 60
Population: Data was not collected because no participant had laboratory abnormalities in peripheral blood.
Secondary
Duration of Laboratory Abnormalities in Plasma
Number of days with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines.
Time frame: up to day 60
Population: Data was not collected because no participant had laboratory abnormalities in plasma.
Secondary
Number of Participants With Laboratory Abnormalities in Peripheral Blood
Number of participants with laboratory abnormalities in peripheral blood (Lymphopenia, leukocytosis, anemia, thrombocytopenia, creatinine, AST/ALT, troponin I, pro-BNP, D-dimer, ferritin, interleukin (IL-6), soluble IL-2 receptor.
Time frame: up to day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prazosin | Number of Participants With Laboratory Abnormalities in Peripheral Blood | 0 Participants |
| Standard of Care | Number of Participants With Laboratory Abnormalities in Peripheral Blood | 0 Participants |
Secondary
Number of Participants With Laboratory Abnormalities in Plasma
Number of participants with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines.
Time frame: up to day 60
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prazosin | Number of Participants With Laboratory Abnormalities in Plasma | 0 Participants |
| Standard of Care | Number of Participants With Laboratory Abnormalities in Plasma | 0 Participants |