Prazosin to Prevent COVID-19 (PREVENT-COVID Trial) (PREVENT)

• ClinicalTrials.gov Identifier: NCT04365257
• Recruitment Status: Terminated
• First Posted: April 28, 2020
• Results First Posted: January 31, 2023
• Last Update Posted: January 31, 2023
• Sponsor: Johns Hopkins University
• Collaborator: Fast Grants
• Information provided by (Responsible Party): Johns Hopkins University

Tracking Information

• First Submitted Date: April 24, 2020
• First Posted Date: April 28, 2020
• Results First Submitted Date: November 30, 2022
• Results First Posted Date: January 31, 2023
• Last Update Posted Date: January 31, 2023
• Actual Study Start Date: May 13, 2020
• Actual Primary Completion Date: March 31, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 30, 2022)

• Death [ Time Frame: up to day 60 ]
  Number of participants in each arm who expire.
• Hospitalized, 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 ]
  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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: up to day 60 ]
  Number of participants in each arm who develop serious adverse events during the study period.
• Incidence of Symptomatic Hypotension or Hypotension Requiring Cessation of Prazosin [ Time Frame: 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.

Original Primary Outcome Measures (submitted: April 24, 2020)

• Death [ Time Frame: up to day 60 ]
  Number of participants in each arm who expire.
• Hospitalized, 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 ]
  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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: up to day 60 ]
  Number of participants in each arm who develop serious adverse events during the study period.
• Incidence of symptomatic hypotension or hypotension requiring cessation of prazosin [ Time Frame: 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.

Current Secondary Outcome Measures (submitted: November 30, 2022)

• Number of Participants With Laboratory Abnormalities in Peripheral Blood [ Time Frame: 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.
• Duration of Laboratory Abnormalities in Peripheral Blood [ Time Frame: 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 [ Time Frame: up to day 60 ]
  Number of participants with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines.
• Duration of Laboratory Abnormalities in Plasma [ Time Frame: up to day 60 ]
  Number of days with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines.

Original Secondary Outcome Measures (submitted: April 24, 2020)

• Number of participants with laboratory abnormalities in peripheral blood [ Time Frame: 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.
• Duration of laboratory abnormalities in peripheral blood [ Time Frame: 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 [ Time Frame: up to day 60 ]
  Number of participants with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines.
• Duration of laboratory abnormalities in plasma [ Time Frame: up to day 60 ]
  Number of days with laboratory abnormalities in fractionated plasma catecholamines and plasma metanephrines.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: COVID-19

Intervention

• Drug: Prazosin
  Participants in this arm will receive the study drug as outlined in the arm description.
  Other Names:

  • Minipress
  • alpha-1 adrenergic receptor antagonist
  • alpha blocker
• Other: Standard of care
  Participants in this arm will receive standard of care.

Study Arms

• Experimental: 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.

  Intervention: Drug: Prazosin
• Active Comparator: Standard of care
  Subjects randomized to this arm will receive standard of care.
  Intervention: Other: Standard of care

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: November 30, 2022): 5
• Original Estimated Enrollment (submitted: April 24, 2020): 220
• Actual Study Completion Date: March 31, 2022
• Actual Primary Completion Date: March 31, 2022 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 45 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04365257
• Other Study ID Numbers: IRB00246659; COV2001 ( Other Identifier: Johns Hopkins University )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Johns Hopkins University
• Original Responsible Party: Same as current
• Current Study Sponsor: Johns Hopkins University
• Original Study Sponsor: Same as current
• Collaborators: Fast Grants

Investigators

• Principal Investigator: Chetan Bettegowda, MD/PhD; Johns Hopkins University

• PRS Account: Johns Hopkins University
• Verification Date: January 2023