Clinical trial NCT04365257
Conditions: COVID-19
Keywords: SARS-CoV-2 Coronavirus disease 2019 COVID-19 Cytokine Storm Syndrome Acute Respiratory Distress Syndrome Prazosin Alpha-1 receptor antagonist
Sponsor: Johns Hopkins University
Start date: 2020-05-13; Completion date: 2022-03-31
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: Subjects randomized to this arm will receive standard of care.
Interventions: intervention 1: Prazosin intervention 2: Standard of care
Intervention descriptions: intervention 1: Participants in this arm will receive the study drug as outlined in the arm description. intervention 2: Participants in this arm will receive standard of care.

Protocol documents:
Prot_SAP_000.pdf: 
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 	 Alpha-1 Adrenergic eceptor Antagonism to Prevent COVD-1	 Cytokine Storm
Syndrome and Acute espiratory Distress Syndrome: A andomized Study Comparing the
Efficacy of Prazosin vs. Standard of Care for SAS-CoV- infection

hr 	 Prazosin to Prevent COVD-1	 (PEVENT-COVD Trial)
Jhs Hpks Prc  	 COV1
 	
Cca Phas	 
IND 
psr/Prcpa Ivsar	
Chetan ettegowda
 M.D.
 Ph.D.
Johns Hopkins University
 N. Wolfe Street
Phipps 118
altimore
 MD 187
1-	-8 (phone)
1-	-83 (fax)
cbetteg1@jhmi.edu
IND Numbr	 ND 1		73
Cducd by	 Johns Hopkins University

udy A	 Prazosin (Minipress®)
Vrs/Da f Issu	 Version .
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PROTOCO 
UMMARY

amp 
z	
As per recommendation of the COVD-1	 eview Committee at The Johns Hopkins University
School of Medicine
 an initial interim analysis will be performed after 3 patients have completed
8 days of follow-up (1 in each arm; 13  of recruitment) to analyze safety endpoints and early
signs of efficacy. f the intervention is deemed safe
 after discussion with the centralized Data and
Safety Monitoring oard (DSM)
 recruitment may continue to the next interim analysis (33  and
7  completion of 8 day follow-up) to reach a target enrollment of  patients (11 in each
arm) based on power analyses for the outlined patient population.

udy Ppua	
1.
Subjects must be  years of age or older
.
Provide consent to participate
3.
Subjects who tested positive for SAS-CoV- AND have clinical symptoms of COVD-1	
and have been hospitalized
 but are not requiring more than  liters/minute of
supplemental oxygen by nasal cannula and are not requiring CU/CCU-level care at time
of enrollment

udy Dura	
April 1
  to December 31
 . The total duration of treatment with prazosin will be 
weeks (8 days) from initial dose. Patients will be followed for  days.

udy Ds	
This randomized phase  trial will assess the efficacy of prazosin (Arm 1) vs. standard of care
(Arm ) in patients with positive SAS-CoV- testing who are symptomatic and hospitalized
 but
are not requiring more than  liters/minute of supplemental oxygen by nasal cannula. Adults 
years of age and older may participate. A total of  eligible subjects will be randomized in a 1:1
ratio to receive either prazosin 1 mg by mouth every 8 hours (with dose escalation as defined in

c 4.5) or standard of care. After 3 patients have completed 8 days of follow-up (1 in
each arm; 13  of recruitment)
 a first interim analysis will be performed to analyze safety
endpoints and early signs of efficacy. Enrollment will then depend on the recommendation of the
Data and Safety Monitoring oard. Additional interim analyses will occur after 33  and 7  of
the patients have completed 8 days of follow-up. Power calculation suggest a target enrollment
of  patients (11 in each arm).
Radmza	
andomization will be done by block randomization.
Assssms	
The following will be assessed in all subjects:
●
Safety and efficacy: Day  (baseline)
 1
 3
 7
 1
 1
 8
 and .


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The following laboratory values will be collected based on each participating center’s standard of
care practice
 while the subjects are admitted at inpatient wards:
●
Plasma fractionated catecholamines
 metanephrines
 and other circulating inflammatory
and organ damage marker levels: Day  (baseline)
 1
 3
 7
 1
 and 1.
●
lood antibody titer to SAS-CoV-: etween Day 1 to Day 

udy A	
●
Prazosin
Prmary Effcacy Objcv	
Evaluate the efficacy of treatment with prazosin (given for a total of 8 days) at day  to prevent
severe COVD-1	 (requiring mechanical ventilation  high flow nasal cannula  length
of CU/CCU admission  death) in treated versus untreated subjects who tested positive for
SAS-CoV- and have clinical symptoms of COVD-1	 including being hospitalized
 but are not
requiring more than supplemental oxygen by nasal cannula and are not requiring CU or CCU-
level care at time of admission.
Prmary Edp	
Clinical event scale of disease severity (evaluated up to Day ):
1.
Death
.
Hospitalized
 requiring mechanical ventilation  high flow nasal cannula 
CU/CCU admission (or equivalent setting)  ECMO
3.
Hospitalized
 requiring supplemental oxygen
 not requiring CU/CCU level care (or
interventions listed under )
Prmary 
afy Objcv	
Evaluate the safety of treatment with prazosin in subjects diagnosed with COVD-1	
Prmary 
afy Edps	
1.
Cumulative incidence of grade 3 and  adverse events during the study period
.
Cumulative incidence of serious adverse events during the study period
3. Cumulative incidence of symptomatic hypotension (SP <	 mmHg) or hypotension
requiring cessation of prazosin

cdary Objcvs	
1.
Compare rates and duration of laboratory abnormalities in peripheral blood including
lymphopenia
 leukocytosis
 anemia
 thrombocytopenia
 creatinine
 AST/ALT
 troponin 
pro-NP
 D-dimer
 ferritin
 interleukin (L-)
 soluble L- receptor
.
Compare rates and duration of laboratory abnormalities in peripheral blood including
fractionated plasma catecholamines and plasma metanephrines
3.
Analyze the interaction between prazosin and D-dimer


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TABE OF CONTENT
POTOCOL SUMMAY

TALE OF CONTENTS

LST OF AEVATONS

1. STUDY OJECTVES
7
1.1. Primary Efficacy Objective
7
1..
Primary Safety Objective
7
1.3. Secondary Objectives
7
. ACKGOUND AND SCENTFC ATONALE
7
.1.
Abstract
7
..
ackground
8
.3.
Known potential risks
1
..
Known potential benefits
11
..1. Potential benefits of treatment
11
... Potential benefits of clinical monitoring and virologic testing
1
3. PATENT POPULATON
1
3.1. nclusion Criteria for Enrollment
1
3.. Exclusion Criteria for Enrollment
13
.
NVESTGATONAL PLAN
13
.1. Definitions
13
.. andomization
1
.3. ntervention
1
.. ationale for medication dosing
1
.. Specific dosing and dose escalation considerations for prazosin
1
.. Definition of an Overdose for this Protocol
17
.7. Prohibited Medications:
17
.8. Subject Withdrawal
18
.
PHAMACEUTCAL NFOMATON
18
.1. Agent Accountability
18
..
Mode of Action
18
.3.
Description
18
..
Packaging
1	
..
Storage
1	
..
oute of Administration
1	
.7.
Subject Care mplications
1	
.8.
eturns and econciliations

.
STATSTCAL CONSDEATONS



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.1.
Sample Size and Power Considerations

..
Statistical Analysis
1
.3.
Endpoints
1
7.
STUDY POCEDUES

7.1.
Study Calendar

7..
Efficacy And Laboratory Measures

8.
ADVESE EVENTS
 SKS
 AND ENEFTS

8.1. Potential enefits of treatment

8.. Potential benefits of clinical monitoring

8.3. Potential risks

8.. Alternatives

8.. Definitions

8..1. Adverse Event (AE)

8... Serious Adverse Event (SAE)

8..
elationship

8.7.
Expectedness
7
8.8.
Handling of Expedited Safety eports
8
8.	.
eporting
8
8.	.1. outine Adverse Event eporting
8
8.	.. Laboratory Test Abnormalities
8
8.	.3. Serious Adverse Event eporting
	
	. SAFETY OVESGHT
3
	.1.
Monitoring Plan
3
	..
Halting Criteria for the Study
3
1.
ETHCS/POTECTON OF HUMAN SUJECTS
31
1.1.
Ethical Standard
31
1..
nstitutional eview oard
3
1.3.
nformed Consent Process
3
1..
Subject Confidentiality
3
1..
Future Use of Stored Specimens
3
1..
Data management and monitoring
33
1..1.
Source Documents
33
1...
Data Management Plan
33
1..3.
Data Capture Methods
33
1...
Study ecord etention
33
11. EFEENCES
3


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LST OF AEVATONS
AD: Adverse Drug eaction
AE: Adverse Event/Adverse Experience
ADS: Acute espiratory Distress Syndrome
CCU: Cardiac Care Unit
CDC: United States Centers for Disease Control and Prevention
CF: Code of Federal egulations
CLA: Clinical Laboratory mprovement Amendment of 1	88
CO: Conflict of nterest
COVD-1	: Coronavirus Disease
CF: Case eport Form
CSS: Cytokine Storm Syndrome
CS: Cytokine elease Syndrome
DMC: Data Management Center
DSM: Data and Safety Monitoring oard
ECMO: Extracorporeal Membrane Oxygenation
EUA: Emergency Use Authorization
FDA: Food and Drug Administration
GCP: Good Clinical Practice
CF: nformed Consent (nformed Consent Form)
CH: nternational Conference on Harmonization
CU: ntensive Care Unit
EC: ndependent ethics committee
: nstitutional review board
WS: nteractive web response system
MES: Middle East espiratory Syndrome
MES-CoV: Middle East espiratory Syndrome Coronavirus
T-PC: everse Transcriptase Polymerase chain reaction
PPE: Personal Protective Equipment
SAE: Serious adverse event
SAS: Severe Acute espiratory Syndrome
SAS-CoV-1: Severe Acute espiratory Syndrome Coronavirus 1
SAS-CoV-: Severe Acute espiratory Syndrome Coronavirus 
UP: Unanticipated Problem
UPnonAE: Unanticipated Problem that is not an Adverse Event


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1. 
TUDY OBJECTIVE
1.1. Prmary Effcacy Objcv
Evaluate the efficacy of treatment with prazosin (given for a total of 8 days) at day  to prevent
severe COVD-1	 (requiring mechanical ventilation  high flow nasal cannula  length
of CU/CCU admission  death) in treated versus untreated subjects who tested positive for
SAS-CoV-
 have clinical symptoms of COVD-1	
 and have been hospitalized
 but are not
requiring more than supplemental oxygen by nasal cannula and are not requiring CU or CCU-
level care (see inclusion criteria for details).
1.2.
Prmary 
afy Objcv
Evaluate the safety of treatment with prazosin in subjects exposed to COVD-1	.
1.3. 
cdary Objcvs
1.
Compare rates and duration of laboratory abnormalities in peripheral blood including
lymphopenia
 leukocytosis
 anemia
 thrombocytopenia
 creatinine
 AST/ALT
 troponin

 pro-NP
 D-dimer
 ferritin
 interleukin (L-)
 soluble L- receptor
.
Compare rates and duration of laboratory abnormalities in peripheral blood including
fractionated plasma catecholamines (adrenaline
 noradrenaline
 dopamine) and
fractionated plasma metanephrines (metanephrine
 normetanephrine)
3.
Analyze the interaction between prazosin and D-dimer
2. BACKGROUND AND 
CIENTIFIC RATIONAE
2.1.
Absrac
Severe acute respiratory syndrome coronavirus  (SAS-CoV-) is the cause of Coronavirus
disease 1	 (COVD-1	) and an ongoing pandemic
 with a currently estimated case fatality rate
of 3.  in China
 and . -8.8  worldwide1–7. ased on experiences in China
 about   of
patients presenting with COVD1	 infection will require critical (intensive care unit) level care
 with
about half surviving to hospital discharge. No proven therapy exists for the treatment or
prophylaxis of SAS-CoV- infection
 particularly those with critical symptoms.
The mortality of COVD-1	 appears to be driven by a dysregulated immune response to SAS-
CoV-
 resulting in acute respiratory distress syndrome (ADS)
 respiratory failure
 and multi-
organ failure8
	. Emerging evidence suggests that a subset of COVD-1	 is characterized by the
development of a cytokine storm syndrome (CSS) that resembles cytokine release syndrome
(CS)8
1
11.
COVD-1	-CSS
is
immunologically
characterized
by
the
elevation
of
pro-
inflammatory cytokines11
1. L- levels diverge profoundly between non-survivors and survivors
in the weeks after symptom onset
 making them predictors of COVD-1	 severity and in-hospital
mortality1
13
1. Tocilizumab
 a monoclonal antibody targeting the L- receptor
 is currently being
investigated for the treatment of patients with COVD-1	-CSS and ADS1–18. To date
 it has
shown efficacy in a small case series18
 but this strategy is limited to patients who already display
severe or critical COVD-1	 symptoms. As hospital and critical care capacity during this pandemic
is at risk of being exceeded in several nations around the world
 preventative approaches that
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We recently showed that CS observed with bacterial infections
 chimeric antigen receptor
(CA)-T cell therapy
 and other T cell-activating therapies is accompanied by a surge in
catecholamines1	. Catecholamines enhance inflammatory injury by augmenting the production of
L- and other cytokines through a self-amplifying feed-forward loop in immune cells that requires
alpha-1 adrenergic receptor signaling1	. nhibition of catecholamine signaling by treatment with
prazosin
 a pan-alpha-1 adrenergic receptor antagonist
 was effective at preventing cytokine
storm and resulted in markedly reduced mortality in multiple animal models. These findings offer
a rationale for studying alpha-1 receptor antagonists in the early stages of COVD-1	 to prevent
progression to severe disease
 ADS
 and cytokine storm
 thereby reducing necessity and the
length of time that critical care management is required.
n this trial
 we hypothesize that the treatment of individuals with prazosin who test positive for
SAS-CoV- AND are (i) asymptomatic or have symptoms that do not require hospitalization O
(ii) have symptoms and warrant inpatient hospital care not to exceed oxygen supplementation by
nasal cannula at time of admission could reduce catecholamine surges and secondary cytokine
dysregulation. This reduction in disease amplification would directly lead to less severe symptoms
and mortality. Preventative strategies to ameliorate COVD-1	 severity are critical during the
ongoing SAS-CoV- pandemic where scarcity of healthcare resources threatens to result in
excessive mortality.
2.2.
Backrud
Severe acute respiratory syndrome coronavirus  (SAS-CoV-) is the cause of Coronavirus
disease 1	 (COVD-1	) and an ongoing pandemic
 with a currently estimated case fatality rate
of 3.  in China
 and . -8.8  worldwide1–7. No proven therapy exists for the treatment or
prophylaxis of SAS-CoV- infection.
n early stages of infection with SAS-CoV-
 an appropriate immune response is initiated against
the virus
 as occurs against similar coronavirus infections SAS-CoV-1 and MES-CoV1
. n a
subset of patients
 the disease course can progress to a dysregulated immune state characterized
by systemic hyperinflammation and cytokine storm1
1
3. This state manifests as ADS
 shock
and multi-organ failure. esulting mortality equals or exceeds   in this population
.
nterventions that address this subset of patients are critically needed. Current approaches are
limited to supportive measures and experimental therapies. Disease-modifying therapies that
address the underlying pathophysiology and prevent progression to the hyperinflammatory state
will be essential for mitigating morbidity and mortality due to COVD-1	.
iomarkers of advanced stages and poor outcomes of COVD-1	 support models of
immunopathology and suggest routes of intervention. Absolute counts and relative proportions of
immune cell and lymphocyte subsets are aberrant in COVD-1	
 especially in severe cases1

7
	
–
8. nflammatory cytokines
 chemokines
 and other markers of inflammation including L-
 L-
L-7
L-8
soluble
L-
receptor
(CD)
interferon-
inducible
protein
1
monocyte
chemoattractant protein 1
 granulocyte-colony stimulating factor
 macrophage inflammatory
protein 1-α
 tumor necrosis factor-α
 C-reactive protein
 procalcitonin
 ferritin
 and D-dimer are
also increased in severe cases1
7–1
–3. L- specifically diverges between non-survivors and
survivors and is predictive of COVD-1	 severity and in-hospital mortality1
13
1. The levels of these
markers mirror those seen in cytokine storm induced by SAS-CoV-1 and MES-CoV infection31–
3. Cytokine storm is associated with ADS
 the primary driver of mortality in SAS and
MES3
37. COVD-1	 cytokine profiles also resemble the hyperinflammation state seen in
hemophagocytic
lymphohistiocytosis
(HLH)
a
hyperinflammatory
syndrome
caused
by
underlying defects in perforin signaling pathways1
38–1. Furthermore
 the profile of immune


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dysregulation of COVD-1	 resembles CS seen as an adverse effect of biologic and cellular
immunotherapies
 including CA-T cells–.
Pending data from randomized controlled trials
 retrospective data from 1 patients with severe
or critical COVD-1	 treated with tocilizumab suggests that inhibition of the L- signaling axis is
highly effective18. However
 considerable cost
 limited availability
 the potential for serious adverse
events
 and the risk of prolonged immunosuppression limit the application of biological therapies
targeting the L- axis in COVD-1	.
Tocilizumab is available in only limited quantities
 and its use in COVD-1	 must be weighed
against the competing use for treating patients undergoing CA-T therapy experiencing CS.
The use of tocilizumab will therefore likely be limited to patients who have progressed to severe
or critical COVD-1	1
3
. Hospital and critical care capacities have already been exceeded in
certain regions and are likely to be exceeded in others
7. Preventative therapies that could
reduce the risk of severe COVD-1	 prior to disease onset would alleviate both hospital capacity
and critical care capacity and need for advanced supportive measures. Furthermore
 in those
patients who survive COVD-1	-associated ADS
 reducing pulmonary inflammation and
secondary lung fibrosis may prevent long-term morbidity and functional disability while increasing
quality of life8–.
Another drawback
of biological therapies that
target the
L- axis is their
prolonged
immunosuppressive effect. Use could lead to impaired viral clearance or favor secondary bacterial
infection and viral co-infection or reactivation1. As secondary infections are a predictor of
mortality with COVD-1	
 broadly immunosuppressive therapies such as glucocorticoids
 anti-L-
 receptor antibodies
 or Janus kinase (JAK) inhibitors carry not insignificant risk in the critically-
ill patient with COVD-1	8
. ndeed
 use of glucocorticoids in SAS and MES was associated
with delayed viral clearance and did not reduce mortality3–.
Considering the pathophysiology of severe COVD-1	 and the limitations of current treatments
there is a critical need for other host-directed therapies8. Targeting the catecholamine axis is a
promising route.
We have recently shown that CS observed with bacterial infections
 CA-T cells
 and other T
cell-activating therapies is accompanied by a surge in catecholamines1	. Catecholamines
enhance inflammatory injury by augmenting the production of L- and other cytokines through a
self-amplifying feed-forward loop in immune cells (macrophages and T cells) that requires alpha-
1 adrenergic receptor signaling. Other studies have demonstrated in animal models that
production of catecholamines from immune cells increases downstream cytokine production and
enhances inflammatory lung injury whereas blockade of catecholamine signaling decreases lung
inflammation
7.
Prophylactic inhibition of catecholamine synthesis by treatment with metyrosine
 a tyrosine
hydroxylase antagonist
 reduced levels of catecholamines and cytokine responses and resulted
in markedly increased survival following various inflammatory stimuli in mice1	. Similar protection
against a hyper-inflammatory stimulus was observed after prazosin administration
 demonstrating
that alpha-1 receptor antagonists can also prevent cytokine storms in mice.
Additional studies have explored the effects of alpha-adrenergic blockade with prazosin in
prevention or protection of inflammatory cascades and cytokine-induced injuries. n models of
pulmonary edema that are characterized by inflammation and neutrophil accumulation
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cytokines in the lung and peripheral blood
 and resulted in restoration of normal fluid transport
capacity of alveolar epithelium after hemorrhagic shock8
	. n a model of brainstem encephalitis
early alpha-1-receptor blockade using prazosin allowed for preservation of cardiac output
reversed neutrophil infiltration in lungs
 and prevented hemorrhagic pulmonary edema
1.
Prazosin was also found to suppress the clinical and histological expression of experimental
autoimmune encephalomyelitis (EAE) in preclinical models–. n a mouse model of ischemia-
reperfusion injury
 prazosin administration led to a decrease in the expression levels of L-
 TNF-
α
 L-1
 and L-1
 and prevented mortality. n humans
 prazosin is a first-line treatment in
scorpion envenomation
 a process that involves dysregulated inflammatory responses that can
progress to ADS. Expression of alpha-1 adrenergic receptors are increased during sepsis7
and catecholamine levels are elevated in septic shock8. Finally
 elevated catecholamines in
enterovirus A71-related hand
 foot
 and mouth disease may contribute to cardiopulmonary failure
and mortality8–71.
Together
 these findings offer a rationale for studying alpha-1 receptor antagonists in the
prophylaxis of patients with COVD-1	. Prospective
 randomized clinical trials of alpha-1 receptor
antagonists administered prior to the onset of severe symptoms
 as proposed herein
 are needed
to assess their utility in preventing CSS and reducing mortality in patients with COVD-1	.
2.3.
Kw pa rsks
Prazosin is a quinazoline derivative and commonly used drug in the long-term treatment of
patients with benign prostatic hyperplasia
 arterial hypertension
 post-traumatic stress disorder
(PTSD) and other conditions7. Similar to other alpha-1 receptor antagonists
 prazosin is
inexpensive and relatively safe. Given the role of alpha-adrenergic signaling on vascular tone and
blood pressure regulation
 adverse reactions related to a decrease in total peripheral resistance
and hypotension are predicted to be most common. Thus
 the administration of prazosin requires
careful dose escalation.
Although the safety profile of prazosin for the modulation of hyperinflammation is unknown
 its
common use for hypertension and psychiatric disorders has been well-documented
 particularly
in the older age cohort that COVD-1	 has impacted most seriously. More recently
 prazosin was
used for treatment of post-traumatic stress disorder (PTSD) in a cohort of 3 military veterans
(	  male
 mean age  years) for  weeks73. For dosing in men and women
 prazosin was
safely escalated up to  mg and 1 mg
 respectively. Of importance
 the number of serious
adverse events did not differ significantly between prazosin and placebo. As expected
 only
dizziness
 lightheadedness
 and urinary incontinence occurred significantly more often in the
prazosin group (3  vs 1 
 3  vs  
 and 1  vs   respectively).
n a double-blind randomized clinical trial for alcohol use disorder
 prazosin in a cohort of 
individuals (mean age 	.1 years) was escalated to three doses daily ( mg
  mg
 and 8 mg per
day) for 1 weeks7. A greater proportion of participants with prazosin experienced drowsiness
and edema than those with placebo. Five serious adverse events occurred; however
 none of
which were determined by the institutional review board to be related to participation in the study.
n a pilot study with Alzheimer’s disease
 prazosin (up to  mg) was well-tolerated in twenty-two
nursing home participants (mean age 8. years) with no significant differences in adverse effects
between prazosin and placebo groups7. Early reports of prazosin use in patients with prostate
obstruction also indicated oral prazosin to be safe and effective in long-term treatment7. The
reported side effects of prazosin and other alpha-blockers by manufacturers are summarized in
Tab 1. Prazosin has a similar side effect profile to other alpha-blockers. Due to the lack of


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reported serious adverse events such as stroke and myocardial infarctions in current published
trials
 we believe prazosin will be well-tolerated within our cohort.
Tab 1. Rprd advrs vs fr dffr apha-1 rcpr aass77
Prazosin
Terazosin
Doxazosin
Tamsulosin
Alfuzosin
Dizziness
1.3 
	.1 
1. 
1.	 
.7 
Somnolence
7. 
3. 
Fatigue
. 
7. 
8. 
7.8 
.7 
Postural Hypotension
1- 
3.	 
1.7 
Edema
1- 
.7 
Dyspnea
1- 
. 
ash
1- 
Syncope
1. 
Tachycardia/radycardia
<1 
hinitis
<1 
1.	 
3. 
Erectile Dysfunction
<1 
1. 
1. 
Allergic eaction
<1 
Headache
3. 
2.4.
Kw pa bfs
2.4.1. Pa bfs f ram
The potential benefits of treatment with prazosin in patients at risk for developing severe COVD-
1	 are unknown. To date
 no controlled trials have examined the role of alpha-1 adrenergic
receptor antagonists for the prevention of cytokine storm syndromes and ADS in human
subjects.
To investigate a potential role for alpha-1 adrenergic receptor antagonists in preventing poor
outcomes in ADS
 we performed a case-control study analyzing the potentially protective effect
of alpha-1 receptor antagonists on ventilator dependence in adults with ADS. Using data from
the Truven Health MarketScan esearch Database (1-17)
 we conducted a case-control
study of 18
	 patients (age 18-) with a diagnosis of ADS that was seen in an inpatient
setting. ADS was determined using codes from the nternational Statistical Classification of
Disease and elated Health Problems (CD)
 	th and 1th revision
 respectively. Our analysis
included 3
87 cases with invasive mechanical ventilation and 1
877 controls nested within a
population of ADS patients. The alpha-1 adrenergic receptor antagonists included were
doxazosin
 prazosin
 silodosin
 terazosin
 and tamsulosin. Logistic regression models were used
to calculate odds ratios (O) and confidence intervals (C) correlating any prior use of alpha-1
adrenergic receptor antagonists with the risk of ventilator dependence.


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The majority of patients in our cohort were women (3 )
 with a mean age of .7 (SD=11.).
We found that patients with prior use of alpha-1 adrenergic receptor antagonists experienced a
1.8  reduced risk of invasive mechanical ventilation compared to non-users (O .8
 	  C
.7-.	
 p=.) (Fur 1A). This association remained significant after adjustment for
several potential confounders including age
 year
 sex
 hypertension
 chronic obstructive
pulmonary disease
 and diabetes mellitus (adjusted O .83
 	 C .71-.	). We performed
a subsequent analysis investigating the possible association between alpha-1 receptor antagonist
use and mortality. This analysis included 
8 adult inpatients with ADS between 1-1
with an average age of 1.	 (SD=11.). Strikingly
 we found that patients with prior use of alpha-
1 adrenergic receptor antagonists experienced a 8.	  reduced risk of mortality compared to
non-users (O .	
 	  C .7-.81
 p=.	8) (Fur 1B). This association remained
significant after adjustment for the aforementioned list of confounders (O .
 	 C .-
.77). Using the same data set
 in-hospital mortality in patients with ADS was .7  for
individuals treated with alpha-1 adrenergic receptor antagonists vs 	.8  for patients not on this
class of drugs (test of proportions: p=.11) (Fur 1C).
Mirroring findings from pre-clinical models
 these data suggest a strong clinical rationale to study
alpha-1 adrenergic receptor antagonists in the prophylaxis of ADS and states of local and
systemic immune dysregulation. n patients with COVD-1	
 we expect that preemptive treatment
with prazosin will decrease the risk of developing severe complications of disease (e.g. ADS
cytokine storm
 and death) and reduce morbidity should they develop.
Fur 1. Logistic regression of invasive mechanical ventilation (A) and in-hospital mortality () in patients
with ADS who are using alpha-1 adrenergic receptor antagonists in a preliminary case control-study using
data from MarketScan esearch Database. (C) Percent in-hospital mortality in patients with ADS who
were taking any as compared to no alpha-1 adrenergic receptor antagonists using the same data set.
2.4.2. Pa bfs f cca mr ad vrc s
Subjects enrolled in the study will undergo close clinical and laboratory monitoring that could
facilitate improved management of COVD-1	 with associated benefit to the individual
 their family
and the community at large.
3. PATIENT POPUATION
3.1. Icus Crra fr Erm
1.
Subjects must be  years of age or older


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. Provide consent to participate
3. Subjects who tested positive for SAS-CoV- AND have clinical symptoms of COVD-
1	1 AND have been hospitalized
 but are not requiring more than  liters/minute of
supplemental oxygen by nasal cannula and are not requiring CU/CCU-level care at time
of enrollment
3.2. Excus Crra fr Erm
1. Female subjects who identify as pregnant
 self-reported positive pregnancy testing
 or
who are breastfeeding during the study period
. Age >8 years
3. Subjects whose primary reason for hospitalization was not for clinical symptoms of
COVD-1	 although tested positive for SAS-CoV-.
. 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
. Currently enrolled in another clinical trial for COVD-1	
. Need for vasopressors
 inotropes
 or intra-aortic balloon pump at time of enrollment
7. Allergy or intolerance to quinazolines (including prazosin)
8. equires oxygen supplementation beyond  liters of oxygen/minute per nasal cannula
at time of enrollment (i.e. not requiring oxygenation by non-rebreather
 high-flow nasal
cannula
 CPAP/iPAP
 or invasive mechanical ventilation)
	. Patients who are in the custody of state or federal entities (prisoners)
4.
INVE
TIGATIONA PAN
4.1. Dfs
.
Enrolled: From time consented to initiation of study therapy until designated as off
study either through discontinuation or completion of the study.
.
andomized: when a subject D number is assigned through randomization.
.
Screen Failures: signed informed consent
 but then determined to be ineligible or
withdraws before initiation of study therapy.
V.
Discontinued: randomized
 but then withdrawn by investigator or withdraws
consent.
A subject may be discontinued from treatment but continue to be
monitored in the post-treatment follow-up portion of the trial
 or discontinued from
the trial.
V.
Completed: Subjects are considered completed when they are followed through to
Day  or died before that.
1	
eespi
y

ife
i(s	ese
f
les
ef
hefllwig:feve,hills,se
h
,mylgi,
ihe,	gh,sh
essfbe
h)NDwi
h
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h
f	llyexplis
heliilpese

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Fur 2	 
ummary f Ivsaa Pa


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4.2. Radmza
andomization will be done by block randomization.
4.3. Irv
.
Subjects will be randomized in a 1:1 ratio to receive treatment vs standard of care
.
Study drug: Prazosin
.
Active arm will receive prazosin given by mouth three times a day with dose escalation
over  days to target dose of  mg or as tolerated
V.
Control arm will receive standard of care
V.
Once the patient is discharged
 they should be instructed to complete the 
udy Dru
ad Bd Prssur Pa Dary.
4.4. Raa fr mdca ds
Prazosin is FDA-approved for the treatment of arterial hypertension
 either alone or in combination
with other antihypertensive drugs. The initial dose of prazosin is 1 mg two or three times a day
with therapeutic dosages most commonly employed ranging from  mg to 1 mg daily given in
divided doses. Doses higher than  mg usually do not increase efficacy. Effective therapeutic
doses of prazosin for the treatment of benign prostatic hyperplasia and arterial hypertension
commonly range from 1 mg by mouth every 8 hours to  mg by mouth every 8 hours. At these
doses
 the medication is typically well tolerated. Clinical trials were conducted on more than 	
patients. During these trials and subsequent marketing experience
 the most frequent reactions
associated with prazosin therapy are: dizziness 1.3 
 headache 7.8 
 drowsiness 7. 
 lack
of energy .	 
 weakness . 
 palpitations .3 
 and nausea .	 . n most instances
 side
effects have disappeared with continued therapy or have been tolerated with no decrease in dose
of drug.
Less frequent adverse reactions which are reported to occur in 1-  of patients are:
●
Gastrointestinal: vomiting
 diarrhea
 constipation.
●
Cardiovascular: edema
 orthostatic hypotension
 dyspnea
 syncope.
●
Central Nervous System: vertigo
 depression
 nervousness.
●
Dermatologic: rash.
●
Genitourinary: urinary frequency.
●
EENT: blurred vision
 reddened sclera
 epistaxis
 dry mouth
 nasal congestion.
n addition
 fewer than 1  of patients have reported the following (in some instances
 exact causal
relationships have not been established):
●
Gastrointestinal: abdominal discomfort and/or pain
 liver function abnormalities
pancreatitis.
●
Cardiovascular: tachycardia.
●
Central Nervous System: paresthesia
 hallucinations.
●
Dermatologic: pruritus
 alopecia
 lichen planus.
●
Genitourinary: incontinence
 impotence
 priapism.
●
EENT: tinnitus.
●
Other: diaphoresis
 fever
 arthralgia


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ased on a pre-clinical model of treating hyperinflammation
 we estimate the required total daily
dose of prazosin to be less than 1 mg daily. This dosing range is further supported by data from
a cohort study of patients with ADS which showed that use of alpha-1 adrenergic receptor
antagonists at commonly prescribed doses was indeed associated with a reduction of outcome
severity.
Given the role of alpha-adrenergic signaling on vascular tone and blood pressure regulation
adverse reactions related to a decrease in total peripheral resistance and hypotension are most
common. Careful dose escalation of prazosin over a period of  days will therefore be employed
to achieve a target total daily treatment dose of 1 mg daily
 given in divided doses of  mg daily
as outlined below. The protocol further allows for individualized dosing based on the highest
tolerated daily dose of prazosin identified following the dose escalation protocol outlined below.
We are aware that the titration of most anti-hypertensive agents is often performed during weeks
and not days as proposed in our trial
 yet the need for maximizing benefits before week  of the
disease have made us adopt this more aggressive escalation schema. The fact that patients’
blood pressure will be monitored routinely
 and a de-escalation schema is also in place
 reinforces
our decision.
4.5. 
pcfc ds ad ds scaa csdras fr prazs
1.
First dose: A single loading dose of prazosin 1 mg by mouth should be given to
observe whether the medication is tolerated or whether signs or symptoms of
hypotension develop (e.g. dizziness
 lightheadedness).
○
Prazosin may cause syncope with sudden loss of consciousness due to an
excessive postural hypotensive effect. Syncopal episodes usually occur
within 3 to 	 minutes of the initial dose of the drug.
○
t is expected that the arterial blood pressure can decrease by -1 mmHg
with the first dose of prazosin.
○
The patient should be counseled about possible adverse effects of prazosin
and advised what measures to take should they develop symptoms of
hypotension
 namely
 dizziness and lightheadedness. The patient should be
counseled that mild lightheadedness with rapid change of position is
common. Accordingly
 they should be instructed to slowly change position
and take 3 seconds to move from supine to a sitting position
 from a sitting
to standing position
 and from standing to ambulation (until they completed
the dose escalation protocol and know that their current dose is tolerated).
Patients should be counseled that caution should be taken when getting up
and walking to the bathroom at night since they are at increased risk of
syncope
 falling
 and injury. Patients should be counseled to sit down to
urinate until they have completed the dose escalation protocol and they have
tolerated stable doses for several days.
.
The blood pressure (P) should be measured prior to the next dose: if the patient
remains asymptomatic and P ≥11/ mmHg
 continue prazosin 1 mg by mouth
every 8 hours
3.
The blood pressure (P) should be measured prior to the next dose on Day 3: if the
patient remains asymptomatic and P ≥11/ mmHg
 the dose will be increased
to  mg by mouth every 8 hours


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.
lood pressure measurement on Day : if the patient remains asymptomatic and
P ≥11/ mmHg
 the dose will be increased to a target dose of  mg by mouth
every 8 hours
.
f the BP s <110/60 mmH a ay m on spot measurement
 the next dose of
prazosin should be held
 and the patient instructed to continue with the highest
previously tolerated dose 8 hours later:
a. For patients who have received  mg dosing
 the next dose will be  mg TD
b. For patients who have received  mg dosing
 the next dose will be 1 mg TD
c.
For patients who are still on 1 mg dosing
 the next dose will be 1 mg D
d. Patients will be dose de-escalated to 1 mg D until P is stable
 or be
removed from study treatment if not able to tolerate this lowest schedule
e. There will be no intra-patient re-escalation
 excepts scenario described in 
below
.
f the patient did not tolerate dose escalation to  mg by mouth every 8 hours and
is persistently hypertensive (P ≥13/8 mmHg for  subsequent days)
 one
attempt can be made to increase the dose of prazosin to 3 mg by mouth every 8
hours. f this is not tolerated
 the patient is instructed to continue with the highest
previously tolerated dose 8 hours later.
7.
The maximum total daily dose of prazosin should not exceed 1 mg by mouth.
8.
If bd prssur mr s  avaab a sudy s, rpad
ccurrcs f psura dzzss shud rr dru ds rduc r BP
mr.
	.
efore the patient is discharged
 he/she will receive an automated blood pressure cuff
and instructions on how to monitor and record blood pressure at home at least once
daily. He/she will remain on the highest tolerated dose at discharge and be instructed to
complete the 
udy Dru ad Bd Prssur Pa Dary with each dose. There
will be no dose titration at home.
4.6. Df f a Ovrds fr hs Prc
Overdose of prazosin is defined as:
An overdose is defined as the accidental or intentional administration of any dose of a product
that is considered both excessive and medically important. Appropriate supportive treatment
should be provided if clinically indicated.
All reports of overdose (with and without an AE) must be reported within  hours as an SAE per

c 9.
Should overdosage lead to hypotension
 support of the cardiovascular system is of first
importance. estoration of blood pressure and normalization of heart rate may be accomplished
by keeping the patient in the supine position. f this measure is inadequate
 shock should first be
treated with volume expanders. f necessary
 vasopressors should then be used. enal function
should be monitored and supported as needed. Laboratory data indicate prazosin is not dialysable
because it is protein bound.
4.7. Prhbd Mdcas	
Approved or investigational drug with established activity against SAS-CoV-.


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4.8. 
ubjc Whdrawa
The reason for study removal and the date the subject was removed will be documented in the
CF. A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as parent or legal guardian) withdraws
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the post-
treatment follow-up portion of the trial) for any of the following reasons:

The subject or legal representative (such as legal guardian) withdraws consent.

ntercurrent illness that prevents further administration of treatment

Severe or life-threatening prazosin-related AE(s)
 including but limited to:
Gastrointestinal: Severe persistent (more than  hrs) vomiting
 diarrhea
Cardiovascular: Severe orthostatic hypotension
 dyspnea
 syncope
 angina
Central Nervous System: vertigo

f in the opinion of the nvestigator
 a change or temporal or permanent discontinuation
of therapy would be in the best interest of the patient

Noncompliance with trial treatment or procedure requirements

Patient is lost to follow-up

Patient becomes pregnant
andomized subjects who withdraw from the study will not be replaced.
5. PHARMACEUTICA INFORMATION
5.1. A Accuaby
The ND Sponsor or the ND Sponsor’s representative shall take responsibility for and shall take
all steps to maintain appropriate records and ensure appropriate supply
 storage
 handling
distribution and usage of investigational product in accordance with the protocol and any
applicable laws and regulations.
5.2.
Md f Ac
Prazosin (MNPESS®)
 a quinazoline derivative
 is an oral alpha-blocker; used primarily to treat
hypertension. The exact mechanism of the hypotensive action of prazosin is unknown. ecent
animal studies
 however
 have suggested that the vasodilator effect of prazosin is also related to
blockade of postsynaptic alpha-adrenoceptors.
5.3.
Dscrp
Prazosin is supplied as the following:

rh
Capsu Cr
Packa 
z
MNPESS® 1 mg
White
	’s
MNPESS®  mg
Pink and White
	’s


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MNPESS®  mg
lue and White
	’s
5.4.
Packa
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
5.5.

ra
Prazosin should be stored at room temperature (between 8 and 77 degrees F) while protected
from light and moisture and in a secure
 limited access storage area
 accessible only by
authorized personnel.
5.6.
Ru f Admsra
Prazosin is administered orally. The dose of prazosin should be adjusted according to the
patient’s individual blood pressure response. The initial dose will be 1mg TD starting on Day 1
and dose escalated to  mg TD on Day 3 and  mg TD on Day  if tolerated per 
c 4.5.
Once the patient is discharged
 he/she will remain on the highest tolerated dose and should be
instructed to complete the 
udy Dru ad Bd Prssur Pa Dary at home. There will
be no dose titration at home.
5.7.

ubjc Car Impcas
As with all alpha-blockers
 prazosin may cause syncope with sudden loss of consciousness. n
most cases
 this is believed to be due to an excessive postural hypotensive effect
 although
occasionally the syncopal episode has been preceded by a bout of severe tachycardia with heart
rates of 1–1 beats per minute. Syncopal episodes have usually occurred within 3 to 	
minutes of the initial dose of the drug; occasionally
 they have been reported in association with
rapid dosage increases or the introduction of another antihypertensive drug into the regimen of a
patient taking high doses of prazosin. The incidence of syncopal episodes is approximately 1  in
patients given an initial dose of  mg or greater. Clinical trials conducted during the investigational
phase of this drug suggest that syncopal episodes can be minimized by limiting the initial dose of
the drug to 1 mg
 by subsequently increasing the dosage slowly
 and by introducing any additional
antihypertensive drugs into the patient’s regimen with caution. Hypotension may develop in
patients given prazosin who are also receiving a beta-blocker such as propranolol.
f syncope occurs
 the patient should be placed in the recumbent position and treated supportively
as necessary. This adverse effect is self-limiting and in most cases does not recur after the initial
period of therapy or during subsequent dose titration.
Patients should always be started on the 1 mg capsules of prazosin. The  and  mg capsules
are not indicated for initial therapy.
More common than loss of consciousness are the symptoms often associated with lowering of
the blood pressure
 namely
 dizziness and lightheadedness. The patient should be cautioned
about these possible adverse effects and advised what measures to take should they develop.
The patient should also be cautioned to avoid situations where injury could result should syncope
occur during the initiation of prazosin therapy.


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Addition of a diuretic or other antihypertensive agent to prazosin has been shown to cause an
additive hypotensive effect. This effect can be minimized by reducing the prazosin dose to 1 to 
mg three times a day
 by introducing additional antihypertensive drugs cautiously
 and then by
retitrating prazosin based on clinical response.
Should overdosage lead to hypotension
 support of the cardiovascular system is of first
importance. estoration of blood pressure and normalization of heart rate may be accomplished
by keeping the patient in the supine position. f this measure is inadequate
 shock should first be
treated with volume expanders. f necessary
 vasopressors should then be used. enal function
should be monitored and supported as needed. Laboratory data indicate prazosin is not dialysable
because it is protein bound.
f a dose of prazosin is missed for more than 1 hour or if a patient vomits after the dose
 the dose
should be skipped and dosing should resume at the next scheduled dose.
5.8.
Rurs ad Rccas
Each local investigator is responsible for keeping accurate records of the clinical supplies
 the
amount dispensed to
 and returned by the subjects and the amount remaining at the conclusion
of the trial.
Upon completion or termination of the study
 all unused and/or partially used investigational
product will be destroyed at the local site per institutional policy. t is the nvestigator’s
responsibility to arrange for disposal of all empty containers
 provided that procedures for proper
disposal have been established according to applicable federal
 state
 local and institutional
guidelines and procedures
 and provided that appropriate records of disposal are kept.
6.

TATI
TICA CON
IDERATION
6.1.

amp 
z ad Pwr Csdras
As per recommendation of the COVD-1	 eview Committee at The Johns Hopkins University
School of Medicine
 an initial interim analysis will be performed after 3 patients have completed
8 days of follow-up (1 in each arm; 13  of recruitment) to analyze safety endpoints and early
signs of efficacy. f the intervention is deemed safe
 after discussion with the centralized Data and
Safety Monitoring oard (DSM)
 recruitment may continue to the next interim analysis (33  and
7  completion of 8 day follow-up) to reach a target enrollment of  patients (11 in each
arm). The estimated sample size that is required based upon the assumptions below is 
participants. We have a planned sample size of  subjects to allow for losses or withdrawals.
Participants will be randomized in a 1:1 ratio to prazosin (Arm 1) vs standard of care (Arm ).
To evaluate the power of the study
 the following assumptions were made:
1.
The primary analysis will compare the prazosin and standard of care using the formula
presented by Palta and Amini for survival analysis8 and a one-sided Type  error rate
(alpha) of . and Type  error rate (beta) of .. Therefore
 we have power of 8 . A
one-sided test was chosen as we hypothesize that prazosin will be beneficial and are not
interested in whether prazosin is worse than standard of care. That is
 the null hypothesis
is: There is no significant difference between prazosin and standard of care in the
prevention of severe COVD-1	. The alternative hypothesis is: Prazosin use is superior to
standard of care in the prevention of severe COVD-1	.


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. t is anticipated that very few of these subjects will be randomized and not start the study
(and so be excluded from the primary analysis) or be lost to follow-up prior to Day 8 (and
so have missing data for the primary endpoint) as they are all hospitalized patients.
3.
Among those randomized to receive standard of care
 by day 8
 3.  incidence of
severe symptomatic disease among individuals that were symptomatic at time of
randomization. This results in an overall hazard rate of .11.
.
Among those randomized to receive prazosin
 by day 8
 17.3  incidence of severe
symptomatic disease
 a   reduction in risk of progressing to severe disease. This
results in an overall hazard rate of .8.
6.2.

asca Aayss
Aayss f AE daa
Analysis of AE data will primarily be descriptive based on CTCAE version . coding of events.
The proportion of subjects experiencing an SAE and the proportion experiencing a Grade 3 or
higher. AE will be compared between randomized arms using Fisher’s Exact Test.
6.3.
Edps
Prmary Edp	 Clinical event scale of disease severity (evaluated up to Day ):
1.
Death
.
Hospitalized
 requiring mechanical ventilation  high flow nasal cannula 
CU/CCU admission (or equivalent setting)  ECMO
Prmary 
afy Edps	
1.
Cumulative incidence of grade 3 and  adverse events during the study period
.
Cumulative incidence of serious adverse events during the study period
3. Cumulative incidence of symptomatic hypotension (SP <	 mmHg) or hypotension
requiring cessation of prazosin
The primary endpoint is progression of disease from being hospitalized with no more than 
liters/minute of supplemental oxygen to either requiring mechanical ventilation
 high flow nasal
cannula
 CU/CCU admission
 or ECMO
 or death. Our primary hypothesis that the COVD-
1	 disease severity will be mitigated among participants taking prazosin. Specifically
 we
hypothesize that prazosin will mitigate the more severe levels of disease outcomes including
the requirement of mechanical ventilation  high flow nasal cannula  CU/CCU
admission
 and death. These outcomes will be captured in continuous time (i.e. day of
requiring mechanical ventilation
 day of death) from randomization. Our main analysis will be
the cumulative incidence of these severe outcomes from the point of randomization to
standard of care or prazosin treatment arms. Our primary approach for estimating the overall
cumulative incidence function is a non-parametric Kaplan-Meier estimator that is unadjusted
as well as an adjusted analysis using inverse probability of treatment weights. The risk
eq	iigxygebyhigh-flwsl	l,eq	iigi
	b
i,eq	iigmehilve
il
i,eq	iig
ICUCCU-leveleq	ivle
e,eq	iig
iliz	mbsil	mbsil
	ximb,e
h


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difference of severe disease progression to hospitalization
 mechanical ventilation/CU/CCU
or death
 will be estimated at day 8 from the cumulative incidence curve as well as along the
entire cumulative incidence curve. Furthermore
 we can obtain the restricted mean survival
time from the non-parametric survival curves
 which provides the expected time to severe
disease within a limited period of follow-up time from randomization (e.g.
 at 8 days)8. To
obtain the confidence interval on the risk scale
 we will bootstrap the survival curves especially
as we will be adjusting for the variables that are related to the outcome but would estimate
the marginal survival curve7	
8.
As exploratory analysis
 we will then move to a flexible Weibull parametric model that allows
for a variety of curvature to the hazard function and thus reduce the required distributional
assumptions for parametric time-to-event models78 but yet still increase efficiency and
precision by the fact that some distributional assumption is being made. Furthermore
 we will
allow for interaction between covariates and time to allow for non-proportionality. n order to
check the fit of the parametric model
 we will graphically assess the parametric cumulative
incidence curves to that of the non-parametric estimator. f a good fit is not achieved
 we will
add additional splines to the flexible Weibull parametric model and/or modify the interaction
between covariates and time to allow for additional flexibility in the model over follow-up time.
Additionally
 to increase power in a clinical trial
 we can adjust for baseline covariates that are
related to the outcome7	
8. Therefore
 we will adjust for factors that likely contribute to more
severe disease such as age
 immune compromised
 and whether an individual has
comorbidities. Comorbidities may be summarized using an index such as the Charlson
Comorbidity ndex if deemed appropriate. Depending on the amount of losses-to-follow-up
we will use inverse probability of censoring weights to mitigate the potential for informative
censoring81-83.
Furthermore
 in addition to calculating the overall cumulative incidence curves
 as a further
exploratory analysis
 we will examine moving from being hospitalized without the more severe
disease to the more severe outcomes as a multistate model
 if the study goes to completion
and is not stopped early by the DSM. That is each individual starts in the initial state of being
symptomatic and hospitalized but not requiring more than  liters/minute of supplemental
oxygen by nasal cannula. Participants may then move from being symptomatic and
hospitalized to mechanical ventilation/HFNC/CU/CCU care/ECMO
 discharged from hospital
alive
 and finally they may then transition to death which is an absorbing state. Therefore
 we
have the following states that individuals may be in: i) hospitalization with or without
supplemental oxygen by nasal cannula (but not high flow nasal cannula
 non-rebreather
CPAP/iPAP)
 ii) mechanical ventilation and/or high flow nasal cannula and/or CU/CCU
admission and/or ECMO
 iii) discharged alive
 and iv) death. We will allow transition from
states i or ii to any of the other states. We will estimate the transition probability given the
treatment arm and therefore be able to estimate the probability of transitioning to a more
severe state as well as whether individuals transition to a less severe state by study arm.
All analyses will be conducted with a modified intention-to-treat approach
 which excludes
randomized subjects who do not begin prazosin treatment.
Finally
 statistical inference will use a one-sided Type 1 error rate of . and 	 
confidence intervals (note that we will use an O’rien and Flemming type spending function
to preserve the Type 1 error for interim analyses see below under 
c 9.3 Halting Criteria
for Study). ecause the analysis requires multiple steps to properly study the multiple levels


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of the outcome
 we will use bootstrap methods to estimate the p-value and 	  confidence
intervals.

cdary Objcvs	
1.
Compare rates and duration of laboratory abnormalities in peripheral blood including
lymphopenia
 leukocytosis
 anemia
 thrombocytopenia
 creatinine
 AST/ALT
 troponin 
pro-NP
 D-dimer
 ferritin
 interleukin (L-)
 soluble L- receptor
.
Compare rates and duration of laboratory abnormalities in peripheral blood including
fractionated
plasma
catecholamines
(adrenaline
noradrenaline
dopamine)
and
fractionated plasma metanephrines (metanephrine
 normetanephrine)
3.
Analyze the interaction between prazosin and D-dimer
The analysis of secondary endpoints will be descriptive. Specifically
 we will look for laboratory
abnormalities and compare the prevalence between the treatment arms using a logistic model
and adjusting for factors related to these outcomes. n order to determine the duration of
abnormalities
 we will use a discrete time to event model to examine how long participants remain
at abnormal levels. A discrete time to event model will be used due to the discrete time points at
which laboratory markers will be measured. These models will be adjusted for factors such as
age
 race
 and sex
 as well as additional factors that may be related to laboratory abnormalities.
While we are not powered to find an interaction between disease severity
 as a secondary
outcome
 we will examine the potential for treatment effect heterogeneity by COVD-1	 disease
severity at time of randomization D-dimer has been indicated to be a marker for COVD-1	
disease progression1. Therefore
 we will assess whether the treatment effect of prazosin is
different by level of D-dimer. This will be done by allowing for D-dimer to be a continuous variable
and include interaction term(s) in the model. To allow for non-linearity between D-dimer and
disease progression
 we will allow for cubic splines for the main effect of D-dimer as well as for
the interaction terms with the treatment arm indicator variable.
Aayss f Prmary 
afy Edps
We will track the primary safety endpoints that occur during follow-up by treatment arms. Of
particular interest is the cumulative incidence of hypotension (SP<	 mmHg) or hypotension
requiring cessation of prazosin among those in the treatment arm. For the interim analyses of
safety endpoints
 we will provide the DSM with the cumulative incidence of each type of primary
safety endpoints by treatment arms as well as the risk difference and the 	  confidence interval
for the difference between treatment arms.


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7.

TUDY PROCEDURE
7.1.

udy Cadar

udy Prcdurs

cr
(Day -2  0)
Bas
(Day 0)
Day
1
Day
3
Day
7
Day
14
Day
21
Day
28
Day
60
Day f
Dschar
Visit Window (days)
-
-
-
-
± 1
± 
± 
± 
± 
-
nformed consent
X
Demographics R Medical
History
X
nclusion/Exclusion
X
andomization
X
Prazosin1
X Dose escalation up to  mg Q8H
lood Pressure Monitoring
X
Vitals signs
 height
 weight3
X
X
X
X
X
X
X
X
X
Physical examination or
assessment
X
X
X
X
X
X
X
X
X
COVD-1	 Symptom Screen
X
X
X
X
X
X
X
X
X
X
AE Monitoring
X
X
X
X
X
X
X
X
Complete Metabolic Panel
X
X
X
X
X
X
X
Complete lood Count w/
Differential
X
X
X
X
X
X
X
Pregnancy Test7
X
Serum L-
X
X
X
X
X
X
X
Serum soluble L- receptor
X
X
X
X
X
X
X
Fractionated Plasma
Catecholamine
X
X
X
X
X
X
X
Fractionated Plasma
Metanephrine
X
X
X
X
X
X
X
D-Dimer
 Pro-NP
Troponin-
X
X
X
X
X
X
X
Ferritin
X
X
X
X
X
X
X
SAS-CoV- Antibody8
X
JHH site only: ank Plasma
for Future Testing if co-
consented to CCPSE study	
X
X
X
X
X
X
1See Sections . and . for details regarding Prazosin dose titration plan.
See Sections . for details regarding blood pressure monitoring while admitted and after discharge to home.
3lood pressure
 pulse
 respiratory rate
 pulse oximetry
 temperature
 and weight will be collected per standard of care
while patients are admitted. Once discharged
 vital signs will be collected if available as part of their regular clinical
care. Height will be obtained at or prior to baseline only.
Complete physical examination at baseline; focused physical examinations or assessments thereafter. Physical exams
and assessments will be collected per standard of care while the patient is admitted. Once discharged
 these will be
collected if available as part of their regular clinical care and may be completed remotely via telemedicine
 phone
email
 or chart review.
Can be completed remotely via telemedicine
 phone
 email or chart review.
Laboratory values will be collected per standard of care at each participating center while the patient is admitted. Once
discharged
 labs will be collected if available as part of their regular clinical care.
7Women of child bearing potential only
8Measured via serum SAS CoV- S1 subunit gG and gA. Test result will be collected if conducted as part of standard
of care on or after day 1.


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	While inpatient at JHH
 sample collection will be conducted per Dr. Lauren Sauer’s  “Clinical
characterization protocol for severe infectious diseases (CCPSE)”. esearch sample collection will be discontinued
once the patient is discharged.
7.2.
Effcacy Ad abrary Masurs
Cca Effcacy
1.
Death
.
equiring mechanical ventilation and/or in CU level care
3.
equiring supplemental oxygen more than  liters/minute
 including non-rebreather
iPAP/CPAP but not mechanical ventilation.
.
Non-CU hospitalization
 requiring supplemental oxygen no more than  liters/minute
.
Non-CU hospitalization
 not requiring supplemental oxygen;
8. ADVER
E EVENT
, RI
K
, AND BENEFIT
8.1. Pa Bfs f ram
The potential benefits of anti-adrenergic treatment with prazosin in patients with COVD-1	 are
unknown. However
 it is anticipated that treatment will decrease the risk of developing severe
complications of symptomatic disease (i.e. requiring oxygen by high-flow nasal cannula
respiratory supplementation requiring mechanical ventilation
 requiring CU/CCU-level or
equivalent care
 ECMO
 or death) and decrease the severity of illness should it develop.
8.2. Pa bfs f cca mr
Subjects enrolled in the study will undergo close clinical and laboratory monitoring that could
facilitate improved management of COVD-1	 with associated benefit to the individual
 their family
and the community at large.
8.3. Pa rsks
1.
isks of prazosin: dizziness 1.3 
 headache 7.8 
 drowsiness 7. 
 lack of energy
.	 
 weakness . 
 palpitations .3 
 and nausea .	 
 lightheadedness
.
isks of phlebotomy: local discomfort
 bruising
 hematoma
 bleeding
 fainting
3.
Total blood draws will not exceed  mL
8.4. Aravs
The alternative to participation in this study is routine care and monitoring of COVD-1	.
8.5. Dfs
8.5.1. Advrs Ev (AE)
Adverse event is defined as any undesirable sign
 symptom or medical condition occurring after
starting the study drug (or therapy/intervention) even if the event is not considered to be related
to the study. An undesirable medical condition can be symptoms (e.g.
 nausea
 chest pain)
 signs
(e.g., tachycardia
 enlarged liver) or the abnormal results of an investigation (e.g., laboratory
findings
 electrocardiogram). Medical conditions/diseases present before starting the study
treatment are only considered adverse events if they worsen after starting the study treatment


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(any procedures specified in the protocol). Adverse events occurring before starting the study
treatment but after signing the informed consent form will not be recorded. Abnormal laboratory
values or test results constitute adverse events only if they induce clinical signs or symptoms or
require therapy.
This study will use the descriptions and grading scales found in the revised CTCAE version .
for AE reporting.
8.5.2. 
rus Advrs Ev (
AE)
A serious adverse event is an undesirable sign
 symptom or medical condition which:
• esults in death
• s life threatening (defined as an event in which the subject was at risk of death at the
time of the event; it does not refer to an event which hypothetically might have caused
death if it were more severe)
 equires inpatient hospitalization or causes prolongation of existing hospitalization (see
note below for exceptions)
• esults in persistent or significant disability/incapacity
• s a congenital anomaly/birth defect (note: reports of congenital anomalies/birth defects
must also be reported on the Pregnancy Supplemental Form)
• s an important medical event (defined as a medical event(s) that may not be immediately
life-threatening or result in death or hospitalization but
 based upon appropriate medical
and scientific judgment
 may jeopardize the subject or may require intervention [e.g.
medical
 surgical] to prevent one of the other serious outcomes listed in the definition
above.). Examples of such events include
 but are not limited to
 intensive treatment in
an emergency room or at home for allergic bronchospasm; blood dyscrasias or
convulsions that do not result in hospitalization.)
 s associated with an overdose
 s a pregnancy
Events  considered to be serious adverse events are hospitalizations for the:
• Admissions as per protocol for a planned medical/surgical procedure or to facilitate a
procedure
• outine health assessment requiring admission for baseline/trending of health status
(e.g.
 routine colonoscopy)
• Medical/surgical admission for purpose other than remedying ill health state and was
planned prior to entry into the study. Appropriate documentation is required in these
cases
• Admission encountered for another life circumstance that carries no bearing on health
status and requires no medical/surgical intervention (e.g.
 lack of housing
 economic
inadequacy
 care-giver respite
 family circumstances
 administrative).
• Admissions for monitoring of treatment-related infusion reactions that do not otherwise
meet the criteria for a SAE.
8.6.
Rashp
The relationship of an AE to the administration of the study drug is to be assessed by the
investigator according to the following definitions:


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 No (unrelated
 not related
 no relation): The time course between the administration of
study drug and the occurrence or worsening of the adverse event rules out a causal
relationship and another cause (concomitant drugs
 therapies
 complications
 etc.) is
suspected.
 Yes (related): The time course between the administration of study drug and the
occurrence or worsening of the adverse event is consistent with a causal relationship
and no other cause (concomitant drugs
 therapies
 complications
 etc.) can be
identified.
The following factors should also be considered:
 The temporal sequence from study drug administration - The event should occur after
the study drug is given. The length of time from study drug exposure to event should
be evaluated in the clinical context of the event.
 Underlying
 concomitant
 intercurrent diseases - Each report should be evaluated in the
context of the natural history and course of the disease being treated and any other
disease the subject may have.
 Concomitant medication - The other medications the subject is taking or the treatment
the subject receives should be examined to determine whether any of them might be
recognized to cause the event in question.
 Known response pattern for this class of study drug - Clinical and/or preclinical data
may indicate whether a particular response is likely to be a class effect.
 Exposure to physical and/or mental stresses - The exposure to stress might induce
adverse changes in the recipient and provide a logical and better explanation for the
event.
 The pharmacology and pharmacokinetics of the study drug - The known pharmacologic
properties (absorption
 distribution
 metabolism
 and excretion) of the study drug
should be considered.
Assssm f Grad	
The investigator will make an assessment of grade for each AE and SAE reported during the
study
 which will be recorded in the CF. The assessment will be based on the National Cancer
nstitute’s CTCAE (Version .) and graded as shown below:

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated

Grade : Moderate; minimal
 local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living

Grade 3: Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care
activities of daily living

Grade : Life-threatening consequences; urgent intervention indicated

Grade : Death related to AE
Any AE that changes in grade during its course will be recorded in the CF at the highest level
experience by the subject.
8.7.
Expcdss


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Unexpected adverse event: An adverse event
 which varies in nature
 intensity or frequency from
information on the investigational drug/agent provided in the nvestigator’s rochure
 package
insert or safety reports. Any adverse event that is not included in the informed consent is
considered “unexpected”.
Expected (known) adverse event: An adverse event
 which has been reported in the package
insert. An adverse event is considered “expected”
 only if it is included in the informed consent
document as a risk.
8.8.
Had f Expdd 
afy Rprs
n accordance with local regulations
 the ND Sponsor or designee will notify investigators of all
SAEs that are unexpected (i.e.
 not previously described in the )
 and related to prazosin. This
notification will be in the form of an expedited safety report (ES) that is to be emailed to the
investigators and the study coordinators. Upon receiving such notices
 the investigator must
review and retain the notice with the  and where required by local regulations
 the investigator
will submit the ES to the appropriate . The investigator and  will determine if the informed
consent requires revision. The investigator should also comply with the  procedures for
reporting any other safety information.
8.9.
Rpr
nformation about all adverse events
 whether volunteered by the subject
 discovered by
investigator questioning
 or detected through physical examination
 laboratory test or other
means
 will be collected
 recorded
 and followed as appropriate.
All adverse events experienced by subjects will be collected and reported from the first dose of
prazosin
 throughout the study
 and will only be followed for 3 days unless related to the
investigational agent.
Subjects who have an ongoing adverse event related to the study procedures and/or
medication(s) may continue to be periodically contacted by a member of the study staff until the
event is resolved or determined to be irreversible by the investigator.
8.9.1. Ru Advrs Ev Rpr
f an ongoing AE changes in its intensity or in its perceived relationship to investigational product
a new AE entry for the event should be completed. Adverse events should be followed to
resolution or stabilization
 or reported as SAEs if they become serious. Follow-up is also required
for AEs that cause interruption or discontinuation of investigational product
 or those that are
present at the end of study participation. Subjects with AEs at study completion should receive
post-treatment follow-up as appropriate.
All identified non-serious AEs must be recorded and described on the appropriate Adverse Event
Case eport Form (CF).
8.9.2. abrary Ts Abrmas
Laboratory abnormalities present at the screening visit will be recorded as pre-treatment signs
and symptoms. After study treatment administration
 all grade 3 and  clinical laboratory results
that represent an increase in severity from baseline will be reported as adverse events. A grade


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1 or  clinical laboratory abnormality should be reported as an adverse event only if it is
considered clinically significant by the investigator.
n addition
 the following laboratory abnormalities should also be captured on the AE CF page
as appropriate:

Any laboratory test result that is clinically significant or meets the definition of an SAE

Any laboratory abnormality that required the subject to have the investigational product
discontinued or interrupted

Any laboratory abnormality that required the subject to receive specific corrective
therapy
t is expected that wherever possible
 the clinical
 rather than the laboratory term would be used
by the reporting investigator (e.g.
 anemia versus low hemoglobin value).
8.9.3. 
rus Advrs Ev Rpr
All SAEs (including deaths) occurring from the first dose of the study drug through 3 days after
the last dose of study drug will be collected and recorded on the Adverse Event Case eport
Form (CF).
All SAEs should be reported to the ND Sponsor (cbetteg1@jhmi.edu) within  hours of
becoming aware of the event occurrence. The SAE eporting Form should be completed for all
SAEs that are deemed related and unexpected. 
c 9.2 outlines reporting requirements for
the DSM.
SAEs will be reported to the Johns Hopkins Medicine  per institutional guidelines.
Adverse events that are serious
 unexpected
 and assessed by the investigator to be related to
the study drug will be reported within  hours of becoming aware of the event occurrence to the
post-marketing departments of the drug manufacturer (Pfizer).
After the initial SAE report
 the investigator is required to proactively follow each subject and
provide further information in regards to the subject’s condition.
All AE(s) and SAE(s) will be followed until:
• esolution
• The condition stabilizes
• The event is otherwise explained
• The subject is lost to follow-up
• Death
8.9.3.1 Expdd IND 
afy Rprs  h FDA
All reporting to the FDA will be completed by the ND Sponsor.
7Cle-DyTelepheFxRep
:
The ND Sponsor is required to notify the FDA of any fatal or life-threatening adverse event that
is unexpected and assessed by the investigator to be possibly related to the investigational agent.


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3
Such reports are to be submitted to the FDA within 7 calendar days of first learning of the event.
Follow-up information will be submitted to the FDA as soon as relevant information is available.

15Cle-DyWi

eRep
:
The ND Sponsor is required to notify the FDA of any SAE that is unexpected and related to the
investigational agent in a written ND Safety eport.
Written ND Safety eports should include an Analysis of Similar Events in accordance with
regulation 1 CF § 31.3. All safety reports previously filed with the ND concerning similar
events should be analyzed. The new report should contain comments on the significance of the
new event in light of the previous
 similar reports.
Written ND safety reports with Analysis of Similar Events are to be submitted to the FDA within
1 calendar days of first learning of the event. Follow-up information will be submitted to the FDA
as soon as relevant information is available.
IND	lRep
s:
n accordance with the regulation 1 CF § 31.33
 the ND Sponsor shall within  days of the
anniversary date that the ND went into effect submit a brief report of the adverse events and
progress of the investigation. Please refer to Code of Federal egulations
 1 CF § 31.33 for
a list of the elements required for the annual report. All ND annual reports will be submitted to
the FDA by the ND Sponsor.
9. 
AFETY OVER
IGHT
9.1.
Mr Pa
1. outine monitoring at both Hopkins and Participating Sites will be conducted quarterly
or more as needed. Monitoring will be conducted remotely by a qualified study team
member.
. All AE and grade 1-3 SAE will be reviewed by the protocol team twice monthly
 or more
if needed. All grade - SAEs will be reviewed by the protocol team within -8 hours
of being received.
3. A data safety monitoring board (DSM)
 composed of independent experts without
conflict of interests
 will be established. The oard will review study data to evaluate the
safety
 efficacy
 study progress
 and conduct of the study. Additional details can be found
in 
c 9.2 and the Data and Safety Monitoring Plan.
9.2.
Ha Crra fr h 
udy
The study enrollment and dosing will be stopped
 and an ad hoc review will be performed if any
of the specific following events occur or
 if in the judgment of the study physician
 subject safety
is at risk of being compromised:
.
Unexpected death of a dosed subject.
.
Occurrence of a life-threatening allergic/hypersensitivity reaction (anaphylaxis)
manifested by bronchospasm with or without urticaria or angioedema requiring
hemodynamic support with pressor medications or mechanical ventilation.


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31
.
For a reported unexpected SAE or trend of unexpected SAEs related to the study
product.
V.
Two subjects with a Grade 3 or higher lab toxicity for the same parameter
associated with the study product.
V.
An overall pattern of symptomatic
 clinical
 or laboratory events that the DSM
consider associated with study product and that may appear minor in terms of
individual events but that collectively may represent a serious potential concern for
safety.
V.
Any other event(s) which is considered to be a serious adverse event in the good
clinical judgment of the responsible physician. This will be appropriately
documented.
Upon completion of this review
 the DSM will determine if the study enrollment or study dosing
should be interrupted or if study enrollment and study dosing may continue according to the
protocol. Should the trial not be stopped at this time point
 the final analysis would need to account
for the number of interim analyses that were conducted. Therefore
 we will use the O’rien and
Flemming type spending function to preserve the overall Type 1 error. This will allow for stopping
the trial earlier should the intervention arm be shown to be superior at an interim analysis.
Irm aayss	 We plan to provide the number and proportion of the primary outcome of
participants who have completed 8 days of follow up from randomization
 by masked treatment
arms to the DSM
 as well as participant accrual rate
 and withdrawals from study at the time of
the DSM meetings. We will ask whether the DSM would like a formal interim analysis where
analysis is done including adjustment for factors related to worse disease outcomes (age
cardiopulmonary comorbidities
 gender
 etc.) and the results are provided masked to the DSM.
The DSM may then ask for unmasking of the data and decide whether to halt the trial or not. We
plan to do interim analyses at 13 
 33 
 and 7  of final sample size reaching day 8. For the
primary safety endpoints
 we will provide the cumulative incidence of each type of safety endpoint
by study arm in addition to the risk difference and 	  confidence interval of the risk difference
between study arms.
10.
ETHIC
/PROTECTION OF HUMAN 
UBJECT
10.1.
Ehca 
adard
The JHU is committed to the integrity and quality of the clinical studies it coordinates and
implements. JHU will ensure that the legal and ethical obligations associated with the conduct of
clinical research involving human subjects are met. The information provided in this section
relates to all JHU sites participating in this research study.
As the Department of Health and Human Services continues to strengthen procedures for human
subjects’ protections via new regulations
 JHU will review these evolving standards in relation to
the proposed activities and will advise the investigators on those that may apply.
n addition
 JHU has a Federal wide Assurance (FWA) number on file with the Office for Human
esearch Protections (OHP). The FWA number for JHU is FWA83.
This assurance commits a research facility to conduct all human subjects’ research in accordance
with the ethical principles in The elmont eport and any other ethical standards recognized by
OHP. Finally
 per OHP regulations
 the research facility will ensure that the mandatory renewal
of this assurance occurs at the times specified in the regulations.


	
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10.2.
Isua Rvw Bard
The JHU  will review this protocol and all protocol-related documents and procedures as
required by OHP and local requirements before subject enrollment. The JHU  currently
holds and will maintain a US FWA issued by OHP for the entirety of this study.
10.3.
Ifrmd Cs Prcss
The informed consent process will be initiated before a volunteer agrees to participate in the study
and should continue throughout the individual’s study participation. The subject will sign the
informed consent document before any procedures are undertaken for the study. A copy of the
signed informed consent document will be given to the subject for their records. The consent will
explain that subjects may withdraw consent at any time throughout the course of the trial.
Extensive explanation and discussion of risks and possible benefits of this investigation will be
provided to the subjects in understandable language. Adequate time will be provided to ensure
that the subject has time to consider and discuss participation in the protocol. The consent will
describe in detail the study interventions/products and risks/benefits associated with participation
in the study. The rights and welfare of the subjects will be protected by emphasizing that their
access to and the quality of medical care will not be adversely affected if they decline to participate
in this study.
10.4.

ubjc Cfday
Subject confidentiality is strictly held in trust by the participating investigators and their staff. No
information concerning the study or the data will be released to any unauthorized third party
without prior written approval of the ND Sponsor. The results of the research study may be
published
 but subjects’ names or identifiers will not be revealed. ecords will remain confidential.
To maintain confidentiality
 the P will be responsible for keeping records in a locked area and
results of tests coded to prevent association with subjects’ names.
Data entered into
computerized files will be accessible only by authorized personnel directly involved with the study
and will be coded. Subjects’ records will be available to the FDA
 the NH
 the manufacturer of
the study product and their representatives
 investigators at the site involved with the study
 and
the .
10.5.
Fuur Us f 
rd 
pcms
While inpatient at JHH
 sample collection will be conducted per Dr. Lauren Sauer’s 
“Clinical characterization protocol for severe infectious diseases (CCPSE)”. Subjects will be
asked to co-consent to CCPS biorepository study () when joining this trial. They
will consent to use their samples for future testing before any research sample is obtained. The
confidentiality of the subject will be maintained. There will be no plans to re-contact them for
consent or to inform them of results. The risk of collection of the sample will be the small risk of
bruising or fainting associated with phlebotomy. However
 these samples will be taken at the
same time as other protocol required samples. No human genetic testing will be performed on
the samples.
Under this protocol
 research samples will be collected at 7 time points (see 
cs 7.1 and
7.2). Plasma will be frozen in 1-mL aliquots. These samples will be used to answer questions that
may arise while the study is underway or after it is completed. f for instance
 there were


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33
unanticipated AEs
 serum could be used to run tests that might help determine the reason for the
AEs. Cytokines of relevance may be measured
 for example.
Samples would not be shared with investigators other than investigators at JHU unless outside
investigators had relevant assays or expertise not available to the study investigators. The
specimens would remain linked and at JHU. Any use of these specimens not specified in the
current protocol will be reviewed by the JHU .
esearch sample collection will be discontinued once the patient is discharged.
10.6.
Daa maam ad mr
10.6.1.

urc Dcums
The primary source documents for this study will be the subjects’ medical records. f the
investigators maintain separate research records
 both the medical record and the research
records will be considered the source documents for the purposes of auditing the study. The
investigator will retain a copy of source documents. The investigator will permit monitoring and
auditing of these data
 and will allow the  and regulatory authorities access to the original
source documents. The investigator is responsible for ensuring that the data collected are
complete
 accurate
 and recorded in a timely manner. Source documentation (the point of initial
recording of information) should support the data collected and entered into the study
database/case report form and must be signed and dated by the person recording and/or
reviewing the data. All data submitted should be reviewed by the site investigator and signed as
required with written or electronic signature
 as appropriate. Data entered into the study database
will be collected directly from subjects during study visits or will be abstracted from subjects’
medical records. The subjects’ medical records must record their participation in the clinical trial
and what medications (with doses and frequency) or other medical interventions or treatments
were administered
 as well as any AEs experienced during the trial.
10.6.2.
Daa Maam Pa
Study data will be collected at the study site(s) and entered into the study database. Data entry
is to be completed on an ongoing basis during the study.
10.6.3.
Daa Capur Mhds
The data system includes password protection and internal quality checks to identify data that
appear inconsistent
 incomplete
 or inaccurate.
10.6.4.

udy Rcrd R
The site investigator is responsible for retaining all essential documents listed in the CH GCP
Guidelines. The FDA requires study records to be retained for up to  years after marketing
approval or disapproval (1 CF 31.)
 or until at least  years have elapsed since the formal
discontinuation of clinical development of the investigational agent for a specific indication. These
records are also to be maintained in compliance with /EC
 state
 and federal medical records
retention requirements
 whichever is longest. All stored records are to be kept confidential to the
extent provided by federal
 state
 and local law. t is the site investigator’s responsibility to retain
copies of source documents.


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No study document should be destroyed without prior approval from the Principal nvestigator.
Should the investigator wish to assign the study records to another party and/or move them to
another location
 the site investigator must provide written notification of such intent to sponsor
with the name of the person who will accept responsibility for the transferred records and/or their
new location. The sponsor must be notified in writing and written permission must be received by
the site prior to destruction or relocation of research records.
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