Conditions: Corona Virus Infection Acute Respiratory Distress Syndrome SARS-CoV Infection
Keywords: COVID-19 Corona Virus SARS-COV-2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 205
Healthy volunteers: no

Brief summary:
This is a multi-center, double-blinded study of COVID-19 infected patients requiring inpatient hospital admission randomized 1:1 to daily Losartan or placebo for 7 days or hospital discharge.

Detailed description:

Arms:
arm 1: Participants in this arm will receive the study drug, Losartan. arm 2: Participants in this arm will receive a placebo treatment.

Interventions: intervention 1: Losartan intervention 2: Placebo
Intervention descriptions: intervention 1: Losartan; 50 mg daily; oral administration intervention 2: Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration

Protocol document:
Prot_SAP_000.pdf: 
MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 1
 
 
Protocol Title 
Randomized Controlled Trial of Losartan for inpatients with 
COVID-19 
Principal 
Investigator/Faculty 
Advisor -1  
Name: Christopher Tignanelli, MD 
Department: Surgery 
Telephone Number:612 625 7911 
Email Address: ctignane@umn.edu 
Principal 
Investigator/Faculty 
Advisor -2 
Name:  Michael Puskarich, MD, MS 
Current Academic Status (Student, Fellow, Resident): NA 
  
Department:  Emergency Medicine 
Telephone Number: 612 626 6911 
Email Address:  mike-em@umn.edu  
Scientific 
Assessment 
HRPP facilitated scientific assessment 
IND/IDE # (if 
applicable) 
148365 
IND/IDE Holder 
Michael Puskarich, MD MS 
Investigational Drug 
Services # (if 
applicable) 
NA 
Version 
Number/Date: 
Version: 2.0  
Date: 22APR2020 
 
Co-Investigators: 
Jeffrey Chipman, MD 
         Department: Surgery 
         Title: Professor and Chief, Division of Critical Care / Acute Care Surgery 
                
M Health Fairview Critical Care Domain Lead 
         Email: chipm001@umn.edu 
 
Timothy Shacker, MD 
         Department: Medicine and Infectious Diseases 
         Title: Vice Dean for Research, University of Minnesota Medical School 
                    
Director, Program in HIV Medicine 
         Email: schac008@umn.edu 
 
Nicholas Ingraham, MD 
         Department: Medicine 
         Title: Pulmonary Critical Care, Fellow 
         Email: ingra107@umn.edu 
 
David Wacker, MD 
         Department: Medicine 
         Title: Assistant Professor of Medicine 
         Email: wack0012@umn.edu 
 
Ron Reilkoff, MD 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 2
         Department: Medicine 
         Title: Assistant Professor of Medicine, Medical Director M Health Fairview ICU 
         Email: rreilkoff@umn.edu 
 
Michelle Biros, MD, MS 
         Department: Emergency Medicine 
         Title: Professor and Research Director, Department of Emergency Medicine; Deputy 
                   
Institutional Official, University of Minnesota Biomedical Research 
         Email: biros001@umn.edu 
 
John Connett, PhD 
 
Department: Biostatistics 
 
Title: Professor of Biostatistics and Director of CTSI Biostatistical Design and Analysis         
                        Center (BDAC) 
 
Email: john-c@umn.edu 
 
Tamara Bezdicek, PharmD 
 
Department: Pharmacy 
Title: Clinical Manager at Fairview Southdale 
             Email: tsobask1@fairview.org 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 3
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent 
Change? 
1.7 
3/26/20 
Changes to I/E criteria, method of 
patient identification, data 
collected, and corrected 
inconsistencies. Additional sites 
added. 
Y – updated 
biospecimens and 
risks 
1.8 
04/07/20 
Updated I/E, change in primary 
efficacy outcome measurement, 
increased dose, updated optional 
PK substudy, decreased frequency 
of blood draws from daily to every 
other day, clarified table of study 
procedures 
Y – updated 
optional PK 
substudy 
1.9 
04/13/20 
Updated enrollment window to 48 
hours, new language regarding 
compensation for study-related 
damages due to recent federal 
government issued orders, 
clarified conflicting exclusion 
criteria and protocol 
inconsistencies 
Yes 
2.0 
04/22/2020 
Updated approved viral swab 
methods to include oropharyngeal 
(OP) swabs, clarification of P/F 
ratio calculations for subjects 
discharged prior to Day 7 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 4
ABBREVIATIONS/DEFINITIONS 
● COVID-19  
Disease caused by the virus SARS-CoV-2, or “Wuhan coronavirus” 
● ACE2   
Angiotensin converting enzyme 2 
● ACE   
Angiotensin converting enzyme 
● ACEi   
Angiotensin converting enzyme inhibitor 
● AE 
 
Adverse event 
● ALI 
 
Acute lung injury 
● ARDS   
Acute Respiratory Distress Syndrome 
● ARF   
Acute respiratory failure 
● ARB   
Angiotensin receptor blocker 
● AT1R   
Angiotensin 1 receptor 
● CDR   
Clinical Data Repository 
● CDSS   
Clinical decision support systems 
● CTSI   
Clinical and Translational Science Institute  
● D & I   
Dissemination and Implementation 
● DUA 
 
Data Use Agreement 
● EBP   
Evidence-based best practice 
● eConsent 
Electronic consent 
● ECMO  
Extracorporeal membrane oxygenation 
● ED  
 
Emergency department 
● EHR   
Electronic health record 
● FiO2 
 
Fraction of inspired oxygen 
● ICD  
 
International Classification of Diseases 
● ICF 
 
Informed Consent Form 
● ICS 
 
Informatics Consulting Service 
● ICU  
 
Intensive care unit 
● LOS   
Length of stay 
● NETT  
Neurological Emergencies Treatment Trials 
● PaO2  
Partial pressure of arterial oxygen 
● SAE   
Severe adverse event 
● PETAL  
Prevention and Early Treatment of Acute Lung injury   
● SaO2  
Saturation of oxygen 
● SIREN  
Strategies to Innovate Clinical Trials Network 
● SOFA   
Sequential organ failure assessment 
● UMMC  
University of Minnesota Medical Center 
 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 5
Table of Contents 
 
1.0 
Objectives 
8 
2.0 
Background 
11 
3.0 
Study Endpoints/Events/Outcomes 
15 
4.0 
Study Intervention(s)/Investigational Agent(s) 
17 
5.0 
Procedures Involved 
18 
6.0 
Data and Specimen Banking 
21 
7.0 
Sharing of Results with Participants 
23 
8.0 
Study Population 
24 
10.0 Local Number of Participants 
32 
11.0 Local Recruitment Methods 
32 
12.0 Withdrawal of Participants 
33 
13.0 Risks to Participants 
34 
14.0 Potential Benefits to Participants 
35 
15.0 Statistical Considerations 
35 
16.0 Health Information and Privacy Compliance 
36 
17.0 Confidentiality 
40 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
40 
19.0 Provisions to Protect the Privacy Interests of Participants 
41 
20.0 Compensation for Research-Related Injury 
42 
21.0 Consent Process 
42 
22.0 Setting 
43 
23.0 Multi-Site Research 
44 
24.0 Coordinating Center Research 
45 
25.0 Resources Available 
45 
26.0 References 
45 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 6
 
1.0 
Objectives 
1.1 
Title: Randomized Controlled Trial of Losartan for inpatients with COVID-19 
1.2 
Purpose: To determine the impact of early losartan compared to placebo on the 
change in respiratory failure in inpatients diagnosed with COVID19 requiring hospital 
admission at the time of initial presentation. 
1.3 
Hypothesis: Losartan will significantly improve respiratory failure, as measured 
by change in estimated (PEEP adjusted) P/F ratio, in patients requiring hospitalization. 
1.4 
Study design: Multi-center, prospective, randomized blinded interventional trial of 
losartan (50 mg orally twice daily) versus placebo administered for 10 days or until 
hospital discharge. 
1.5 
Study procedures: 
● The trial emphasizes early intervention to prevent the progression of 
respiratory disease. Patients presenting to the emergency department (or 
transferred) who test positive for Covid-19 will be eligible for enrollment 
and randomization within 48 hours of admission to the hospital or within 
48 hours of a positive test result, whichever is later. Patients transferred 
from another facility will be eligible.  
● Investigators and research coordinators will leverage already functional 
electronic consent procedures to enroll patients safely while also 
minimizing risk to study staff. The telemedicine and eConsent platforms to 
be leveraged in this trial are actively used in NIH supported StrokeNet 
clinical trials, and are HIPAA compliant. 
● Enrolled patients will be randomized to losartan or placebo, and undergo 
daily assessment by study personnel with built-in safety and efficacy 
assessments. Enrolled participants will be administered study drug twice 
daily while hospitalized. Study personnel will evaluate patients every day 
during the intervention window to review symptoms for possible adverse 
events and administer validated patient-reported dyspnea assessment at 
predetermined time points. If in-person examinations are necessary, 
study investigators trained for appropriate PPE use will perform the 
examinations. 
● Nasopharyngeal or oropharyngeal swabs and blood samples will be 
collected from the same nostril and transported to a BSL-3 laboratory 
(https://www.researchservices.umn.edu/services-name/biosafety-level-3-
program). These will be stored for public health and viral research 
purposes.  
● Patients will be followed for 90 days to determine outcomes and review 
delayed adverse events. Follow-up phone contact and electronic medical 
record review will determine the primary and secondary efficacy 
endpoints, and provide additional safety data.  
1.6 
Data and specimen collection method 
● Inclusion and exclusion criteria, patient demographics, baseline 
comorbidities, symptoms, and validated symptom assessment 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 7
measurements by patient self-report (if patient is able) will be collected at 
the time of enrollment and maintained in a RedCap database. In addition, 
electronic consent forms will be maintained in a University of Minnesota 
RedCap database with established functionality for this purpose in our 
group. The database, with the currently approved eConsent policy, is 
HIPAA compliant. 
● Daily follow-ups will be recorded by study personnel into a RedCap 
database and will include data points from the electronic medical record, 
and self-reported AEs. At enrollment and on day 4 and 10, standardized 
patient-reported dyspnea and SF-12 surveys will be administered. In the 
event the patient is not available or unable to participate on the day of 
survey administration, surveys administered +/- 1 day will be considered 
before this data point is considered missing. If the patient is unable to 
participate, this will be recorded. The following data points will also be 
collected, if available: 
o Name 
o Date of birth 
o Medical record number  
o Phone number 
o Email address 
o Age 
o Gender 
o Race 
o Ethnicity 
o Insurance status (if available) 
o Zip code 
o Location of initial sample collection for diagnosis  
o Location of enrollment  
o Date and time of initial sample collection for diagnosis 
o Date and time of positive test result for Covid-19 
o Date of first symptoms  
o Date of first fever (temperature >101.5) 
o Vital signs at presentation and daily 
o Comorbidities [hypertension (requiring or not requiring 
medication), diabetes mellitus (insulin or non-insulin dependent), 
coronary artery disease, myocardial infarction, congestive heart 
failure (with preserved or reduced ejection fraction, if known), 
pacemaker or AICD, asthma (with or without emergency 
department evaluation and / or hospital admission in the past 
year), chronic obstructive pulmonary disease, chronic bronchitis, 
chronic steroid use, history of transplant (with type), arrhythmias 
including atrial fibrillation, dialysis, angina, pulmonary 
hypertension and obstructive sleep apnea, renal disease, liver 
disease, tobacco and alcohol use history, recent pregnancy or 
breastfeeding history, height and weight] 
o Home medications [antihypertensives, insulin, non-insulin 
diabetes medications, corticosteroids (inhaled or systemic), other 
immunosuppressants, Use of outpatient COVID-directed 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 8
treatments (such as hydroxychloroquine, Tylenol, ibuprofen, 
azithromycin, or others) or home oxygen use 
o Concurrent inpatient medications, including COVID-directed 
treatments, as well as study medication administration timing 
o PROMIS Pool v1.0 Dyspnea Characteristics Survey (5 question 
Likert scale survey) (attached) with date/time of administration 
o Short form 12 health survey (attached) with date/time of 
administration 
o Nasopharyngeal or oropharyngeal swab every third day 
(performed, yes or no, reason if not) 
o Research blood samples (performed, yes or no, reason if not) 
o Hospital and ICU utilization (with discharge date, if applicable) 
o Clinical laboratory results daily for 10 days, if available (creatinine, 
total bilirubin, platelet count, white blood count, hemoglobin, 
sodium, potassium, chloride, glucose, lactate, procalcitonin, 
albumin, AST, ALT, partial pressure of oxygen on arterial blood 
gas, troponin, BNP or proBNP, urine pregnancy test, influenza or 
viral testing results) 
o Radiographic findings of CXR, CT chest 
o EKG QTc (if performed) 
o Ventilatory support: type of ventilatory support (nasal cannula, 
high flow nasal cannula, face mask, CPAP, BiPAP, endotracheal 
intubation, ECMO), fraction of inspired oxygen, oxygen flow rate (if 
applicable), ventilator settings (if applicable, including tidal volume 
and PEEP) 
o Vasopressor usage (daily type and dose) 
o Need for renal replacement therapy 
o Evidence of bacterial co-infection 
o Glasgow coma scale (daily, if available)  
o Death (with date, if applicable) 
o Study withdrawal, with date and time (if applicable) 
● Final outcome follow-ups will be determined through a combination of 
patient report, electronic medical record review, and review of the social 
security death index (SSDI). 
● All data will be stored in a password protected Redcap database, with 
customizable tiered access and an audit trail. All protected health 
information (PHI) will be marked with a PHI tag that will prevent export, so 
only deidentified data can be exported from the database. Only 
deidentified data with no PHI will be exported for analysis. 
● Nasopharyngeal or oropharyngeal swabs (day 1,4,8,10,15); 30 patients 
will receive blood draws for pharmacokinetic analysis (day 1, hours 2, 4, 
and 6) and patients will provide blood samples for RAAS, RNASeq, flow 
cytometry, and cytokine assays, collected by study personnel or bedside 
nurse and placed in pre-packaged transport containers to be collected by 
biosafety-trained transporters, transported and processed to the 
University of Minnesota’s BSL-3 laboratory noted above, and frozen at -
80 C until later analysis for local sites. Blood samples will not exceed 30 
mL day 1, and will equal ~21-24 mL on days 2, 4, 6, 8, 10, and 15). All 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 9
biospecimens will be labeled with a deidentified patient ID number to 
prevent inadvertent disclosure of PHI. Participants will be given the 
opportunity to contribute to an optional study using genetic material for 
future studies of patient-level responses to COVID-19. These samples will 
likewise be deidentified, but are theoretically identifiable biologic 
information. 
o Cytokine assays will be conducted by Timothy Schacker’s 
laboratory at the University of Minnesota 
o RAAS pathway assays will be conducted at the Wake Forest 
Hypertension and Vascular Research Biomarker Analytical Core  
o Pharmacokinetics will be conducted at Courtney Fletcher’s 
Antiviral Pharmacology Laboratory at the University of Nebraska  
 
 
2.0 
Background 
1.2 
Significance of Research Question/Purpose:  
Since appearing in Wuhan, China in December 2019, the severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) has caused disease (COVID-19) in over 
800,000 people with over 40,000 deaths to date across 180 countries.1-3 The mortality is 
estimated at 3.7%,4 with infectivity (R0) estimated at 2.24 to 3.585,5 with morbidity and 
mortality disproportionately affecting the elderly.6 Most severely affected patients are 
admitted for respiratory support and die of respiratory failure.7,8 At present there is no 
current specific treatment for patients with COVID-19.9 The novel coronavirus is closely 
related to the severe acute respiratory syndrome coronavirus (SARS-CoV) which caused 
an outbreak of disease (SARS) in 2003; this may inform the development of novel 
treatments.9,10 Attempts to develop vaccines since SARS or middle eastern respiratory 
virus (MERS) have been unsuccessful, will take time, and may or may not be effective 
for this or future coronavirus pandemics.11 Extensive efforts to date, therefore, have 
been appropriately focused on screening, identification, and containment with 
collaboration and coordination within and between governments to combat its spread.12  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 10
Due to the nature of coronavirus cellular binding, there exist several promising novel 
pharmacotherapeutic strategies that differentiate this virus from seasonal or pandemic 
influenza. Similar to the 
2002-2003 SARS-CoV, the 
SARS-CoV-2 virus binds the 
spike protein of angiotensin-
converting enzyme 2 
(ACE2), a critical component 
of the renin-angiotensin-
aldosterone (RAAS) system, 
in order to enter the cell.13 
(Figure 1 – red arrow on 
right) Multiple proposed 
interventions to combat 
SARS-CoV-2 under 
development focus on this 
pathway with the goal of 
blocking viral entry into cells, 
and include anti-viral 
agents,14 anti-malarial 
medications,15 vaccines,16  
and viral protein inhibitors.9 
While these therapies are 
promising, immediate use of these interventions are not feasible. In many cases, drugs 
are still under development and lack a clinical indication, with limited safety and efficacy 
data in humans to date. These factors will necessarily lead to delays in drug 
development. Given the rapid spread of SARS-CoV-2, patients would greatly benefit 
from interventions with a well-established safety profile readily available for immediate 
clinical trial testing and rapid knowledge translation if efficacious. 
1.3 
Rationale and Scientific Hypothesis: 
Renin-aldosterone blockade has been proposed as a potential treatment for COVID-
19.17-19 This hypothesis was originally published by Sun et al19 on February 16, 2020 
(manuscript published in Chinese) and in the British Medical Journal on February 4, 
2020.18 This hypothesis was reinforced in Drug Development Research on March 4, 
2020.17 To the best of our knowledge, our study is the first investigating this hypothesis.  
As opposed to ongoing clinical trials targeting viral binding and entry, the proposed 
clinical trial proposes to mitigate the respiratory consequences of SARS-CoV-2, thereby 
reducing morbidity and mortality. As illustrated in Figure 1, SARS-CoV-2 binds to 
angiotensin converting enzyme 2 (ACE2), similar to 2002-2003 SARS-CoV. Molecular 
simulation has shown SARS-CoV-2 has a higher affinity for ACE2 compared with SARS-
CoV.20  
Healthy State:  
In states of health, ACE2 converts Angiotensin 2 (ATII) into lung-protective angiotensin 
(AT) 1-7 and 1-9, thus preventing unopposed ATII activation of AT1R. Unopposed AT1R 
activation triggers a downstream pro-inflammatory cascade, characterized by increased 
lung permeability, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), 
and death (Figure 2).4,18 AT1R activation also leads to type II pneumocyte apoptosis, a 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 11
common feature of ARDS.12,13 Therefore, under usual conditions of health, ACE2 
prevents lung injury. 
Infection with SARS-CoV-2: 
Impaired ACE2 
activity due to 
binding with 
SARS-CoV-2 
results in 
excessive ATII 
allowing 
unopposed 
binding of AT1R 
without 
generation of 
lung-protective 
AT1-7 and AT1-
9 (Figure 2).21,22 
An ongoing 
clinical trial is 
attempting to 
exploit this 
mechanism by treating 24 patients with recombinant human ACE2 (rhACE2) infusions.23 
Infusions of ACE2 have previously been shown to result in decreased AT2 and 
increased AT1-7.24 Unfortunately, protein recombinant human infusions are costly and 
scaling production will take significant time.  
2.1 
Given this, we propose to leverage a readily available angiotensin receptor 
blocker (ARB) with an excellent safety profile, losartan, to mitigate this pathway with the 
aim of decreasing ALI/ARDS. While ACE inhibitors (ACEi) could also be considered for 
trial, ACEi are frequently associated with cough which could exacerbate the spread of 
the disease. In 2 8 week studies, studies, losartan had 17% and 27% rates of cough vs 
69% and 62% (see package insert). Furthermore, ACE inhibitors can induce expression 
of ACE2 secondary to low local angiotensin II levels, potentially increasing viral uptake. 
Preclinical Supporting Data:  
 
SARS-CoV specific preclinical work: 
In 2003, ACE2 was identified as the binding protein for SARS-CoV (Li et al, Nature, 2003).25 
This was validated in 2005 by Kuba et al. This same study identified that SARS-CoV injury 
worsens acute lung injury and can be attenuated by Renin-Angiotensin (RAS) pathway inhibition 
(Kuba et al, Nature Med, 2005).22 Kuba first identified that ACE2 knockout mice had significantly 
lower viral loads in the lung following infection, whereas wildtype (wt) mice had very high viral 
loads.22 Additionally, wt mice had significantly higher lung injury scores following SARS-CoV 
infection.22 SARS-CoV infection results in downregulation of its binding protein ACE2 (ACE2 
has been shown to be lung protective in its action of converting AT2 -> AT1-7) (Kuba et al, 
Nature Med, 2005).22 This finding that SARS-CoV results in downregulation of ACE2 has been 
validated in subsequent studies (Glowacka et al, Journal of Virology, 2010).26 Kuba et al, then 
showed that treatment with Losartan 15 mg/kg attenuated lung injury (Figure 3B) and the 
development of pulmonary edema (Figure 3C) in mice infected with SARS-CoV Spike-FC.22 For 
this study 2.5-3 month old mice received SARS-CoV Spike-FC. 30 minutes later they received 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 12
HCL to expedite lung injury. Mice were then randomized to Losartan vs vehicle. 1 and 2 hours 
later SARS-CoV Spike-FC. Mice then received 3 hours of mechanical ventilation and were 
sacrificed. (Figures 3B and C) (Kuba et al, Nature Med, 2005).22  
 
In 2005, Imai et al showed that loss of ACE2 leads to significantly worse oxygenation, massive 
lung edema, and inflammatory cell infiltration in mice compared to wildtype mice in response to 
acid aspiration.21 They then performed a rescue experiment and showed that supplementation 
with rhACE2 rescued infected mice (Figure 4A, B: green circles vs purple triangle and dark 
pink diamond).21  
Imai et al. 
demonstrated 
inhibition of AT1R 
via losartan 
reduced lung 
injury (Figure 5, 
light purple 
triangle) 
compared with 
vehicle (Figure 5, 
purple square). 
This pathway was 
specific to 
inhibition of AT1R 
as, inhibition of 
AT2R did not 
reduce lung injury  
 
Imai et al. then 
showed that 
inhibition of AT1R via losartan reduced lung injury (Figure 5, light purple triangle) compared 
with vehicle (Figure 5, purple square). This pathway was specific to inhibition of AT1R as, 
inhibition of AT2R did not reduce lung injury (Figure 5, pink triangles) For this study ACE2 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 13
knockout (KO) mice were given AT1R (losartan) or AT2R 30 minutes prior to acid-induced acute 
respiratory distress syndrome (ARDS).21   
 
 
Preclinical supporting data for Renin-Angiotensin 
inhibition in other viral pneumonias that interact with 
ACE2:  
 
Both influenza H7N9 and H5N1 have been implicated 
to cause lung injury through ACE2 with resultant 
upregulation of angiotensin-2 and AT1R induced lung 
injury (Zou et al., Nature Communications, 2014 and 
Yang et al, Sci Rep, 2014).27,28 Yiwu et al found that 
Losartan at clinically equivalent doses to humans was 
associated with increased survival, decreased lung 
edema and lung injury scores, and decreased IL-6 for 
mice infected with influenza H5N1 (Figure 6 A-E) 
(Yiwu et al, Sci China Life Sci, 2015).29  
 
 
 
Yang et al infected 4 week 
old mice with either 
influenza H7N9 or 
placebo.28 Mice were given 
Losartan 30 minutes prior 
to viral infection. They 
identified that inhibition of 
AT1R attenuates H7N9 
lung injury and was 
associated with lower wet-
dry ratios and lower 
infiltrative cell counts (Yang 
et al, Sci Rep, 2014).28  
 
 
 
 
 
2.2 
Existing Literature:  
 There is no existing literature regarding the effect of losartan in COVID-19. To that 
effect there is limited literature regarding the effectiveness of any treatments on 
COVID-19. Data of relevance to are summarized in 2.1-2.3.  
 There is an urgency to identify effective and readily available treatments for patients 
with COVID-19. This study will elucidate the role of losartan, this is based on strong 
physiologic and preclinical data as described in detail above.  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 14
There is a critical and dire need to identify and evaluate all possible methods to 
minimize the burden of COVID-19 on our society and healthcare system. At the 
current rate of growth (as of 3/13/2020) America is 1 week from widespread outbreak 
similar to Italy and Iran. Unfortunately, current community efforts are now slowing down 
spread as our slope (see Figure below) is higher in the last few days than the rest of the 
world. 
 
3.0 
Study Endpoints/Events/Outcomes 
3.1 
Primary Endpoint/Event/Outcomes: The primary endpoint is to determine the 
impact of losartan on respiratory failure. This will be determined by measuring the 
difference in estimated (PEEP adjusted) P/F ratio at 7 days, a validated routinely 
used in critical care research derived from the partial pressure of oxygen or 
peripheral saturation of oxygen by pulse oximetry divided by the fraction of inspired 
oxygen (PaO2 or SaO2 : FiO2 ratio).30,31 PaO2 is preferentially used if available. A 
correction is applied for endotracheal intubation and/or positive end-expiratory 
pressure. Patients discharged prior to day 7 will have a home pulse oximeter sent 
home for measurement of the day 7 value, and will be adjusted for home O2 use, if 
applicable. Patients who died will be applied a penalty with a P/F ratio of 0.  
3.2 
Secondary Endpoint(s)/Event(s)/Outcome(s):  
3.3 There will be 7 secondary endpoints: 
● To ensure losartan is safe and well tolerated in hospitalized patients with 
COVID-19, we will:  
o Compare daily hypotensive episodes (MAP < 65 mmHg) prompting 
intervention (indicated by a fluid bolus >=500 mL) 
o Hypotensive episodes requiring intervention (vasopressors or fluid 
bolus) 
o Determine the incidence of new or worsening renal failure 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 15
● Daily Sequential Organ Failure Assessment (SOFA) score to day 10. If data 
are unavailable for any given organ failure, we will use the last value carried 
forward approach.  
● Change in estimated P/F ratio daily between groups 
● In-hospital, 28, and 90-day mortality (by using state death certificate or 
social security death index data) 
● Resource utilization as assessed by: ICU admission, ventilator free days, 
oxygen free days, vasopressor free days, ICU and hospital length of stay 
● Respiratory failure as measured by the utilization of Bilevel Positive Airway 
Pressure (BiPAP), high flow nasal cannula, mechanical ventilation or 
extracorporeal membranous oxygenation (ECMO) utilization, as well as 
trends in S/F ratio.  
● Symptomatic improvement as assessed by the dyspnea PROMIS and SF-
12 assessments of dyspnea and functional status 
● Percentage of subjects reporting each severity rating on the 7-point ordinal 
scale [ Time Frame: Day 15 ]  
▪ 
The 7-point ordinal scale is an assessment of the clinical status at the first 
assessment of a given study day. The scale is as follows: 1) Death; 2) 
Hospitalized, on invasive mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive 
ventilation or high flow oxygen devices; 4) Hospitalized, requiring 
supplemental oxygen; 5) Hospitalized, not requiring supplemental 
oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no 
limitations on activities. 
▪ 
Change in viral load (nasopharyngeal or oropharyngeal swab and blood) 
1.4 
Justification of the primary outcome: This trial seeks to mitigate lung injury from 
Covid-19 rather than treating the viral infection. Most patients present to the hospital 
secondary to dyspnea and pneumonia, and the primary mechanism of death is via 
respiratory failure progressing to multi-system organ failure.7 Prevention of progression 
of acute lung injury with an angiotensin receptor blocker such as losartan may decrease 
estimated P/F ratio, a validated measure of lung dysfunction that accounts for 
differences in the level of ventilatory support. We considered respiratory SOFA score, 
but this crude ordinal measurement is estimated off of the estimated P/F ratio, which will 
provide a more precise measurement of the same physiology. Estimated P/F is a 
clinically relevant outcome not only to patients, but also to the healthcare system 
due to overwhelming surge of patients straining hospital resources which not 
only puts patients with COVID-19 at risk, but also those admitted to the hospital 
for other reasons.  
 
● Rationale for the timing of the primary endpoint: The average time from 
hospitalization to mechanical ventilatory support is 2-3 days, and average 
length of hospital stay is 10 days.32 We considered a 3 day outcome time 
point to minimize the need for home measurement and early death. 
However, >24 hours is required to reach steady state levels of drug, and 
3 days is likely too early to detect a treatment benefit. We also considered 
10 days, but this increases competing risks and decreases the sensitivity 
and strength of using the continuous primary outcome but increasing the 
proportion of patients who either die or recover, skewing the data.  We 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 16
believe 7 days to represent the optimal balance of these competing 
concerns. 
3.4 
Justification of the secondary outcomes: Patients severely infected with 
respiratory dysfunction may be at increased risk of volume depletion, acute kidney injury, 
or the development of hypotension, so we will systematically track these measured 
instead of relying upon adverse event reporting which introduces the potential for bias. 
We will measure P/F ratios daily in case our choice of 7 days proves incorrect. SOFA 
score is a validated measuring of organ failure in critically ill populations that can be 
determined. Death is clinically important, but we do not believe our sample size is 
adequately powered to detect a difference in this outcome. Resource utilization and 
respiratory support are critical in surge capacity situations and of relevance to this 
disease process. Validated study instruments to assess dyspnea and physical function 
will assess patient-centered outcomes and strengthen the biologic plausibility of the 
intervention. The 7-point ordinal scale described is used by other ongoing Covid-19 
clinical trials and will allow harmonization of the trial results. Changes in viral load are 
important to assess the theoretical possibility of losartan induced ACE2 expression 
leading to increased viral entry, propagation, and shedding.  
 
4.0 
Study Interventions / Interventional Agents 
4.1 
Intervention arm: The intervention is losartan, an angiotensin receptor blocker 
prepared in suspension per the package insert, administered at 50 mg PO twice daily for 
10 days (patients with eGFR 30-59 mL/min/1.73 m2 will be given 50 mg once daily) or 
until hospital discharge, whichever comes first. The supply of suspension is stable for 4 
weeks refrigerated according to the package insert. Any unused doses will be discarded 
if unused by the 28 day time point.   
● Rationale for the duration of the intervention: The average duration of 
mechanical ventilation caused by Covid-19 is approximately 14 days. We 
expect that if a benefit is observed, it will become apparent in that time 
frame. We have chosen to stop treatment at the time of discharge as the 
participant will have already demonstrated significant clinical 
improvement, and would introduce significant logistical limitations. 
● Rationale for the dose of treatment: The lowest dose of losartan is 25 mg 
orally. The maximum clinical dose is 100 mg daily. Losartan has a half-life 
of 2 hours with an active metabolite E3174 of 6-9 hours. The threshold for 
blockade of angiotensin-II receptor is at least 20 mg per day.33 Twice daily 
dosing has been shown to potentiate angiotensin-II receptor blockade 
compared with once daily dosing. At this dose, extrapolated data 
suggests <70% inhibition of angiotensin-II receptors. At the highest 
maximum allowable dose (50 mg twice daily) we would anticipate >80% 
inhibition of angiotensin-II receptor.  We believe this is necessary as these 
patients have significant pro inflammatory response. Recent reports 
indicate that patients with COVID19 have increased plasma Ang II levels 
and that Ang II levels correlate with COVID19 disease severity and viral 
load. AT1R inhibition is associated with decreased activity of STAT1 and 
NFkB downstream signaling as confirmed by western blot analysis. 
Furthermore, since our initial submission Losartan has been identified for 
its potential inhibitory effects on SARS-CoV2 viral life cycle based on 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 17
molecular docking analysis of the coronavirus macrodomain. We propose 
a dose increase to 100 mg daily (50 mg PO BID in patients without renal 
dysfunction). We have previously utilized this dose in previous RCTs in 
HIV (Schacker/Fletcher). These studies confirmed the safety profile of 
Losartan with a mean systolic blood pressure (SBP) reduction of only 7 
mmHg at 100 mg daily and excellent tolerability and safety profile. Our 
findings confirm prior reports of 6 mmHg mean SBP reduction for 
Losartan when doses at 100mg daily. Patients will receive intensive 
safety monitoring as this will be delivered in the inpatient setting with 
blood pressure checks multiple times per day and minimum required 
potassium, creatinine and GFR checks prior to enrollment, day 1, 3, and 7 
(or prior to discharge). In addition, patients will have routine creatinine 
and potassium monitored if ordered clinically We hypothesize significant 
benefit as 4 preliminary and observational reports out of China and the 
UK suggest significant reductions in disease severity and inflammatory 
profile for patients treated with ACEi or ARBS with no preliminary reports 
suggesting harm from ACEi or ARBS in Covid19 patients. 
● We propose a dose of 50 mg twice daily, given significantly improved 
RAS blockade. This is a higher dose than we are proposing for study in 
outpatients, as patients will be carefully monitored with regular blood 
pressures and renal function testing. Furthermore, patients will have a 
higher severity of illness and are more likely to benefit from more robust 
blockade. Patients with moderate renal dysfunction (eGFR 30-59 
mL/min/1.73 m2 will be given 50 mg once daily given impaired renal 
clearance.  
4.2 
Placebo arm: The same volume of suspension prepared according to the 
package insert will be administered without the active ingredient. Any unused doses of 
placebo will be discarded if unused by the 28 day time point.   
4.3 
Investigational new drug. The study will be conducted under IND 148365. 
4.4 
Timing of the intervention: Treatment will continue for 10 days or hospital 
discharge. 
4.5 
Duration of study participation: The final follow-up will occur at 90 days after 
randomization to determine episodes of delayed hospitalization. Data analysis is 
expected to be completed within 1 year of enrollment of the final patient. 
4.6 
Drug Handling, blinding, and randomization:  
Fairview Investigational Drug Services (IDS), part of M Health Fairview will oversee the 
preparation of treatment drug and placebo. Identical suspensions (#20) will be prepared 
in identical syringes and labeled with a deidentified study number coded by site and 
patient number. A site-specific randomization schema will be created (each site will 
undergo block randomization in variable permuted blocks by site and age strata). Given 
significant differences in outcome by age, patients will be randomized by age strata 
(>=60, <60). Randomization allocation will be 1:1. IDS will not be blinded to patient 
randomization. All other members of the study, the participants, and the clinical care 
team will be blinded to treatment allocation. 
4.7 
Provision of study drug to patients: The local Fairview or HCMC pharmacy will 
dispense the patient specific supply to each patient after consent has been obtained and 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 18
a prescription has been received from an authorized prescriber. The investigational drug 
or placebo will be provided to the bedside nurse twice daily for the duration of study 
participation. 
4.8 
Study unblinding: MHealth Fairview, East bank Inpatient Pharmacy UMMC 
campus, will hold the blind for all subjects on study. In the event of an emergency and 
unblinding is necessary, study staff can contact 612-273-3066, option 1, then option 2. 
This information is included on each label. 
4.9 
Biosafety: N/A. The intervention is not a biohazard. 
 
4.10 
Stem Cells: N/A 
4.11 
Fetal Tissue: N/A 
4.12 
Use of radiation: N/A 
4.13 
Use of Center for Magnetic Resonance Research: N/A 
5.0 
Procedures Involved 
5.1 Screening: Screening logs containing non-identifiable information (age, gender, 
race, ethnicity, location of presentation, and reason for exclusion) will be 
maintained for patients screened but not enrolled. Initial pre-screening to 
determine study eligibility will necessarily proceed under waiver of informed 
consent and waiver of HIPAA authorization through the screening of electronic 
medical records. In addition, sites will have an electronic dashboard of all pending 
and confirmed positive COVID-19 tests that can be used for real-time prescreening 
of patients. If the patient appears to be eligible based on pre-screening, and if 
acceptable to the treating physician, the patient will be approached by a study 
investigator or delegated study coordinator or research nurse. For the sake of 
healthcare provider safety, and to minimize the spread of the virus, this visit will 
occur via a HIPAA compliant telemedicine consultation or phone.   
5.2 Enrollment: Patients or their legally authorized representative, with due 
consideration of vulnerable patient populations, (see section 9) will be eligible for 
consent by delegated members of the study team with appropriate training and 
experience in the conduct of human subjects research. At this visit, consents will 
be reviewed in detail with the subject or LAR. The subject or LAR will have the 
opportunity to ask questions. If the patient (or LAR) agrees to become a study 
participant, electronic consent will be obtained using HIPAA and rule 11 compliant 
electronic consent, stored and maintained in a secure RedCap server (see 
departmental policy on eConsent). For patients who are enrolled via a LAR, we will 
attempt to reconsent the patient for ongoing study participation. If they decline, 
previous information gathered will be utilized but no further information will be 
collected. If the patient is unable to be contacted prior to discharge or by phone 
following discharge, or they do not regain capacity to consent, the participant will 
continue to participate in study procedures under LAR consent.   
● Rationale for the use of telemedicine / phone consent: We have chosen 
this method of consent in order to minimize risk to research team and 
healthcare providers, and to decrease community spread of the disease. 
We have prior experience using telemedicine and phone consent coupled 
with electronic consent form review for time-sensitive clinical trials of 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 19
stroke. While the rationale for eConsent is different in this case 
(minimization of disease spread during a pandemic), we believe it is 
appropriate for the disease and intervention being studied. Critically, the 
established safety profile of losartan, with minimal side effects of effects 
on blood pressure in healthy patients without an overactive renin-
angiotension-aldosertone system, combined with the close telemedicine 
and EMR based follow-up methods proposed in this study make the risk : 
benefit ratio for the alteration of traditional consent process acceptable for 
participants, providers, and the public. 
5.3 
Administration of study drug: Study drug will be dispensed to bedside nurses twice 
daily for administration. Patients unable to take the suspension (due to 
endotracheal intubation) will have it administered via an orogastric or nasogastric 
tube, or G-tube. If the patient is unable to receive the study drug for respiratory 
distress, we will allow for +/- 3 hours from the scheduled time of drug 
administration. If this is not possible, the patient will not receive that dose, and this 
will be tracked. 
5.4 
Patient follow-up: Participants will receive remote telemedicine, phone, or in 
person evaluation by trained study personnel every day for the 10 days of the 
intervention period to monitor for the development of complications as well as day 
15. In addition, electronic medical record labs and notes will be monitoring for the 
development of AE and SAEs. Data will be documented into a Redcap database. 
The coordinators will have patients complete 2 surveys at enrollment, day 4, day 
10, and day 28 (both attached in supplement), if the patient can cooperate. If not, 
the reason for failure to complete the survey will be recorded. Surveys conducted 
within 1 day of the time point will be counted as qualifying and not missing. 
Patients will be contacted at day 28 (+/3 days) and 90 (+/- 3 days) for intermediate 
term outcomes. If follow-up procedures are not completed due to inability (patient 
unavailable or intubated), or due to loss to follow-up, these will not be counted as 
protocol deviations. 
5.5 
Pharmacokinetics: Patients undergoing this voluntary substudy will have up to 
another 9 mL of total blood drawn (30 mL total day 1 instead of 21-24 mL day 1. 
The remainder of the samples will be the same for the duration of the study). Blood 
will be processed, frozen at -80 C until shipping to Dr. Courtney Fletcher at the 
University of Nebraska for analysis.    
 
5.6 
Table of events: 
 
  
  
Study Day 
  
Screening/ 
Enrollment
* 
1 2 
3 4 
5 
6 
7 
8 
9 
1
0 
1
1 
1
2 
1
3 
1
4 
1
5 
2
8 
9
0 
ELIGIBILITY  
Covid-19 Result 
confirmation 
X 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
Inclusion/Exclusi
on 
X 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
PRESCREENING / RANDOMIZATION 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 20
Additional labs 
(pregnancy, Cr, 
potassium) if 
applicable 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomize 
subject 
X 
 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
POST-RANDOMIZATION 
Enrollment Day 0 
CRFs 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Dispense / 
administer study 
drug**  
 
X X X 
X 
X 
X 
X 
X 
X 
 X 
  
  
  
  
  
 
  
MINIMUM STUDY PROCEDURES (while inpatient, if applicable)# 
Daily CRFs 
  
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine, 
Potassium$ 
X$ 
X$ X X$ X 
X 
X 
X$ 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SOFA score 
assessment 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
 
  
Estimated P/F 
X 
X X X 
X 
X 
X X& X 
X 
X 
 
 
 
 
X 
 
 
Ordinal scale 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
Blood draws%  
X X 
X 
X 
X 
X  
 
 
X 
 
  
Nasopharyngeal 
or oropharyngeal  
swabs% 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Adverse event 
assessment 
  
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
X 
 
X 
PROMIS Survey 
X 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
Short Form 12 
Health Survey 
X 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
 
STUDY PROCEDURES FOLLOWING DISCHARGE (if applicable) 
Assessment of 
Hospitalization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Estimated P/F& 
 
 
 
 
 
 
 
&  
 
 
 
 
 
 
X 
 
 
Follow-up 
biospecimens 
(NP/OP swab + 
blood draw) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
@  
  
Electronic 
medical record / 
death index 
review 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
Adverse event 
assessment 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
X 
X 
 
PROMIS Survey 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
Short Form 12 
Health Survey 
 
  
  
  
X 
  
  
  
  
  
X 
  
  
  
  
  
X 
 
OPTIONAL STUDY PROCEDURES  
Pharmacokinetic 
Lab Draw*** 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Within 48 hours of hospital admission or a positive test result, whichever is later,  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 21
**In women of child-bearing age, patients must confirm negative test with study personnel prior to beginning treatment as 
well as confirmation of acceptable birth control method 
*** A subset of patients will opt-in to an additional pharmacokinetic substudy 
$ Record clinical potassium and creatinine. Required measurements occur pre-enrollment, day 1, day 3 (+/- 1 day), day 7 
(+/- 1 day). 
# Only to be performed if patient is an inpatient. Otherwise move to Study procedures following discharge 
% Nasopharngeal swabs and blood draws should be collected if local logistical and biosafety procedures allow. Day 1 and 
4 and 10 blood and days 1 and 10 NP or OP swabs are preferred if limited.  
@ We will attempt to coordinate follow-up clinic visits within 1-2 weeks from hospital discharge to obtain nasopharygeal 
and blood biospecimens 
& Subject discharged before D7 will be sent home with a pulse oximeter to calculate P/F ratio and a phone call will be 
made at this time 
 
6.0 
Data and Specimen Banking 
6.1 
Data management: 
● Storage and Access: Data collection is the responsibility of the clinical 
research staff under the supervision of Drs. Tignanelli and Puskarich. 
Study data will be recorded within a RedCAP database with study 
personnel being granted access to the database based on the tasks listed 
in the Delegation of Authority log. Only deidentified data with no PHI will 
be exported for analysis. The electronic consent (eConsent) forms, which 
will be maintained in a University of Minnesota RedCap database with 
established functionality for this purpose in our group. The database is 
HIPAA compliant. 
● Monitoring: A designated study monitor will review 100% of electronic 
consent documents, study drug administration data, and SAE reporting. 
Additionally, a random sampling of 5% of subjects will undergo full 
evaluation and comparison of source documentation with data entered 
into the study database. The first data monitoring visit will be scheduled 
once 10% of the cohort has been enrolled, with repeat monitoring after 
50% and 100% of enrollments. Monitors will evaluate 100% of users to 
ensure assigned access is consistent with training and delegation of 
authority logs. Remote clinical monitoring with source verification of the 
electronic health record will be allowed given limitations in local site 
access in the setting of the COVID epidemic limiting in person monitoring 
consistent with risk-based monitoring principles. 
● Release/Sharing: Data will be shared among members of the study team 
with appropriate access assigned in Redcap based on study role, training, 
and delegation of authority. Data will be made available to assigned study 
monitors, the data safety monitoring board, the appropriate University of 
Minnesota oversight authorities, the Food and Drug Administration, and 
other state and federal regulatory authorities as required by state and 
federal law.  
● Data sharing: Requests for data following study completion for sharing 
will be evaluated by a steering committee that will be established and will 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 22
include the principal investigators. Requests will be evaluated on a case-
by-case basis. If data are shared, only deidentified data will be shared.  
6.2 
Biospecimen management:  
● Specimen banking: Biologic specimens (nasopharyngeal or 
oropharyngeal swabs and blood samples) provided by patients will be 
transported via courier service with the capacity to transport biologic 
materials with due consideration of communicable diseases. Specimens 
will be transported and processed by the University of Minnesota BSL-3 
laboratory and frozen at -80 C until the time of analysis. Samples will be 
deidentified and labeled only with a patient ID number. Other sites will be 
encouraged to also obtain these specimens using local resources, with 
transfer of collected materials as they are able.   
● Biospecimens and protocol deviations: Baseline clinical laboratory results 
will be required to establish inclusion and exclusion criteria, and missing 
data will be reported as protocol deviations. However, significant barriers 
exist to the collection and processing of other biospecimens due to the 
increased containment required, meaning that not every study site may 
be able to accomplish these procedures. In addition, patient self-
collection will lead to missing samples. While every effort will be made to 
obtain these biospecimens, failure to do so will not constitute protocol 
deviations. 
● Specimen sharing:  Requests for specimen sharing during or following 
study completion for sharing will be evaluated by a steering committee 
that will be established and will include the principal investigators. 
Requests will be evaluated on a case-by-case basis. If specimens are 
shared, human genetic analysis will only proceed on those patients who 
opt-in to genetic testing. Genetic testing of viral genomes will be allowed 
to proceed on all patients.  
 
7.0 
Sharing of Results with Participants 
7.1 
Sharing of results: Data collected within this study will be obtained from the 
participants themselves and recorded on collection templates or directly into 
Redcap, or will be obtained from the electronic medical record and thus are 
already available to the patient and treatment team. Any testing of biospecimens 
will occur at a later time point and do have specific clinical relevance and will not 
be shared with the patient. 
7.2 
Sharing of genetic testing 
● Disclosure of results: There is no plan to disclose genetic results to the 
patients as none is yet planned.  
● If returning results to participants: N/A 
7.3 
Future analysis of genotypes: Genetic testing, while potentially an area of future 
investigation as a means to determine if participants with specific genetic differences are 
more or less susceptible to COVID-19, is not currently planned nor funded. As such, 
data will not be disclosed to the participants. To the extent possible in future work, 
participants or families with rare variants will undergo attempts at anonymization.  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 23
8.0 
Study Population 
8.1 
Inclusion Criteria 
● Presumptive positive laboratory test for Covid-19 based on local 
laboratory standard  
● Age greater than or equal to 18 years of age 
● Admission to the hospital with a respiratory SOFA >=1 and increased 
oxygen requirement compared to baseline among those on home O2  
● Randomization within 48 hours of presentation of hospital admission or 
within 48 hours of a positive test result, whichever is later 
8.2 
Rationale for inclusion criteria: This is a pragmatic trial looking to enroll a diverse 
cohort of participants so the results may be broadly applicable to a wide patient 
population if efficacious. We do not have sufficient data to support lack of efficacy in a 
specific subgroup at this time to justify their exclusion. However, a respiratory SOFA of 
at least 1 is included to provide room for improvement to meet the primary efficacy 
endpoint. Patients on home oxygen therapy must demonstrate an acute deterioration 
under the same rationale. While we currently propose to exclude children due to 
insufficient time at the writing of this protocol to closely scrutinize safety and dosing in 
that group, along with logistical challenges of having different doses, we have plans to 
evaluate the possibility of expanding to include that patient population as soon as 
logistically feasible.   
8.3 
Exclusion Criteria 
● Randomization > 48 hours of admission order or positive test result, 
whichever is later 
● Currently taking an angiotensin converting enzyme inhibitor (ACEi) or 
Angiotensin receptor blocker (ARB) 
● Prior reaction or intolerance to an ARB or ACE inhibitor, including but not 
limited to angioedema 
● Pregnant or breastfeeding women 
● Lack of negative urine or serum pregnancy test 
● Not currently taking a protocol allowed version of contraception: 
intrauterine device, Depo-formulation of hormonal contraception (e.g. 
medroxyprogesterone acetate / Depo-Provera), subcutaneous 
contraceptive (e.g. Nexplanon), daily oral contraceptives with verbalized 
commitment to taking daily throughout the study period; use of condoms 
or agree to abstain from sexual intercourse during the study. All women of 
child bearing age enrolled in this fashion will be informed of the 
teratogenic risks. If enrolled under LAR, they will be informed of the risks 
after regaining capacity.   
● Patient reported history or electronic medical record history of kidney 
disease, defined as: 
o Any history of dialysis 
o History of chronic kidney disease stage IV 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 24
o Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 
m2 at the time of randomization  
● Severe dehydration at the time of enrollment in the opinion of the 
investigator or bedside clinician 
● Most recent mean arterial blood pressure prior to enrollment <65 mmHg  
● Patient reported history or electronic medical record history of severe liver 
disease, defined as: 
o Cirrhosis 
o History of hepatitis B or C 
o Documented AST or ALT > 3 times the upper limit of normal 
measured within 24 hours prior to randomization 
● Potassium >5.0 within 24 hours prior to randomization unless a repeat 
value was <=5.0 
● Treatment with aliskiren  
● Inability to obtain informed consent from participant or legally authorized 
representative 
● Enrollment in another blinded randomized clinical trial for COVID 
8.4 
Rationale for exclusion criteria: We expect treatment results to be available within 
24 hours of testing given the acuity of the patient, though delays are expected so this 
window is open until 48 hours for logistical considerations. We wish to limit interventions 
to an early window, as progression from admission to mechanical ventilatory support 
occurs within days, and we intend to maximize potential efficacy of the treatment to 
mitigate respiratory failure. Patients already taking or with prior adverse events to either 
an ACE inhibitor or ARB are excluded for risk of side effects. Losartan is a class D drug. 
Women of child bearing age (14-60) without a history of hysterectomy must have a 
documented negative pregnancy test in the emergency department or have had a prior 
history of hysterectomy. We will exclude patients with significantly elevated creatinine or 
liver enzymes expected to affect drug clearance. Aliskiren is contraindicated for losartan 
co-treatment. Patients with hypotension will be excluded given an expected decrease of 
6-8 mmHg in their blood pressure that might necessitate the need for cardiovascular 
interventions. Finally, all patients or their legally authorized representative will give 
written informed consent. 
 
9.0 
Vulnerable Populations 
9.1 
Vulnerable Populations: By nature of the disease and the fact COVID-19 is a 
rapidly evolving pandemic, with uncertain clinical course but potentially significant 
morbidity and mortality, all participants enrolled in this study are considered to be 
vulnerable. Some participants have additional characteristics that add to this 
vulnerability. Our criteria for inclusion and exclusion of each of these groups is 
summarized below, followed by our rationale and additional safeguards built into our 
study design. Our group has significant experience enrolling vulnerable patients in 
emergency care trials, and experience with a diverse population of potential participants 
in high stress situations.  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 25
 
Population / Group 
Identify whether any of the following 
populations will be targeted, included (not 
necessarily targeted) or excluded from 
participation in the study.  
Children 
Excluded from Participation 
Pregnant women/fetuses/neonates 
Excluded from Participation 
Prisoners 
Excluded from Participation 
Adults lacking capacity to consent and/or adults 
with diminished capacity to consent, including, 
but not limited to, those with acute medical 
conditions, psychiatric disorders, neurologic 
disorders, developmental disorders, and 
behavioral disorders 
Included/Allowed to Participate 
Non-English speakers 
Included/Allowed to Participate 
Those unable to read (illiterate) 
Included/Allowed to Participate 
Employees of the researcher 
Included/Allowed to Participate 
Students of the researcher 
Included/Allowed to Participate 
Undervalued or disenfranchised social group 
Included/Allowed to Participate 
Active members of the military (service 
members), DoD personnel (including civilian 
employees) 
Included/Allowed to Participate 
Individual or group that is approached for 
participation in research during a stressful 
situation such as emergency room setting, 
childbirth (labor), etc. 
Included/Allowed to Participate 
Individual or group that is disadvantaged in the 
distribution of social goods and services such as 
income, housing, or healthcare. 
Included/Allowed to Participate 
Individual or group with a serious health 
condition for which there are no satisfactory 
standard treatments. 
Included/Allowed to Participate 
Individual or group with a fear of negative 
consequences for not participating in the 
research (e.g. institutionalization, deportation, 
disclosure of stigmatizing behavior). 
Included/Allowed to Participate 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 26
Any other circumstance/dynamic that could 
increase vulnerability to coercion or exploitation 
that might influence consent to research or 
decision to continue in research. 
Excluded from Participation 
 
9.2 
Additional safeguards: 
● 
Non-English speakers: Excluding this group would compromise the principle of 
justice in clinical research. For groups likely to be enrolled given our known 
demographics (Spanish-speaking and Somali-speaking), we will translate 
informed consent forms (ICF) and use professional interpreters during both the 
consent and follow-up periods. These interpreters are available to our group 
during daytime hours by telephone. We will request the use of the Short Form 
Consent for non-English speaking particiapnts, and adhere to the regulations 
surrounding its use. When the translated ICsF become available, they will be 
used for non-English speakers. 
● 
Employees or students of the researcher: To minimize the potential for coercion, 
any employee or student of the research will undergo screening and informed 
consent by study personnel, but not by the investigator who is the direct 
supervisor of the vulnerable participant. The screening will not be performed by 
the study physicians or investigators, so this group may opt out in a deidentified 
fashion at that stage. Furthermore, if the potential participant wants to enroll, all 
interactions will occur with a different study investigator (such as the other co-
principal investigator. These two clinical investigators work in different 
departments with different staff).   
● 
Undervalued or disenfranchised social group: We will assure confidentiality, that 
they have the right to withdraw at any time without penalty, and they have the 
freedom to refuse to answer questions.  
● 
Active members of the military (service members), DoD personnel (including 
civilian employees): The status of participants of this group is not asked during 
the study nor known by study staff, and therefore vulnerability is not increased for 
anyone in this group.  
● 
Individual or group that is disadvantaged in the distribution of social goods and 
services such as income, housing, or healthcare: We will assure participants that 
participation in this study will be treated with the strictest confidentiality, that they 
have the right to withdraw at any time without penalty, and they have the freedom 
to refuse to answer questions. 
● 
Individual or group with a serious health condition for which there are no 
satisfactory standard treatments: We will assure that information from 
participants in this study will be treated with the strictest confidentiality, that 
participants have the right to withdraw at any time without penalty, and they have 
the freedom to refuse to answer questions. 
● 
Individual or group with a fear of negative consequences for not participating in 
the research (e.g. institutionalization, deportation, disclosure of stigmatizing 
behavior): The status of participants from these groups is not asked during the 
study nor known by study staff, and that vulnerability is not increased for anyone 
in this group. 
10.0 Local Number of participants 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 27
10.1 
Locations: Enrollment will occur on the ED (or designated COVID19 areas) of 
participating study sites see section 22.1). 
 
10.2 
Number of participants: We expect to enroll a minimum of 200 participants, with 
up to 220 participants when considering screen failures and withdrawals.  
 
11.0 Local Recruitment Methods 
11.1 
Recruitment Process: See section 5.0 
11.2 
Identification of Potential Participants: See section 5.0 
11.3 
Recruitment materials: N/A 
1.5 
Payment: Patients will be eligible for a $25 gift card for their time to return for the 
15-day blood draw for renal function testing if allowed by local site. 
 
12.0 Withdrawal of Participants 
12.1 
Withdrawal Circumstances: Participants may be withdrawn from research without 
their consent if they develop SAEs that the investigator believes to be likely related to 
the study drug. Participants may also withdraw from the study at any time for any 
reason. All patients withdrawn from the study will be analyzed using intent to treat 
principles. 
12.2 
Withdrawal Procedures: If patients choose to withdraw, study procedures 
including intervention and follow-ups will stop. Given the risks of transmission of 
infectious disease, written notification is not required. If the patient chooses to withdraw, 
the study team will ask if the patient is willing to allow continued electronic medical 
record evaluation for the determination of study endpoints (partial withdrawal). We will 
also ask if the patient wishes to withdraw consent for the use of future biologic 
specimens. If the patient declines to participate in any component of research, no further 
study data will be collected, biologic samples will be destroyed, but existing study data 
may be used. Each of these will be documented and stored as a study document. 
12.3 
Termination Procedures: Upon trial termination, study outcomes will be followed 
until completion. Case report forms and collection templates will be maintained in paper 
format (when application) and electronically for 7 years in accordance with regulations. 
Collected data will be used for secondary analyses with approval of the principal 
investigators in a deidentified fashion. Data entry will be completed, checked for 
accuracy, and locked for analysis within 1 year of enrollment of the final patient. 
13.0 Risks to Participants 
13.1 Foreseeable Risks: Potential risks of losartan are detailed in consent forms. The 
most severe risks of losartan use include teratogenicity in the setting of pregnancy, 
hypersensitivity including angioedema, symptomatic hypotension, worsening of 
renal function, and electrolyte abnormalities.  The most common side effects of 
losartan include fatigue, weakness, diarrhea, chest pain and anemia.  Subjects will 
be rigorously screened to ensure that they are at low risk for complications due to 
losartan and they will be monitored closely for side effects and signs of toxicity. 
The package insert for Losartan has been included with this protocol. Clinical trial 
and post-marketing surveillance data (see package insert) demonstrate an 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 28
excellent safety profile. In over 4,000 patients, there was a low incidence of 
adverse events (2.3%) comparable to placebo (3.7%). The effects more common 
in losartan than placebo were clinically minor, including dizziness (3% vs 2%), 
upper respiratory infection (8% vs 7%), nasal congestion (2% vs 1%) and back 
pain (2% vs 1%). While losartan has the potential to cause symptomatic 
hypotension, four studies have identified losartan has a negligible effect on resting 
blood pressure and heart rate in healthy volunteers.33-36 While there may be a 
higher risk in critically ill patients, we will exclude patients with bedside clinician 
assessment of volume depletion that might increase the risk of side effects. It has 
been theorized there may be an increase risk of cardiac dysfunction in patients 
taking an ACE-I or ARB in COVID-19, though evidence for this effect is lacking. 
We will monitor troponin and BNP/pro-BNP levels in participants and report these 
data to the DSMB if measured clinically. In fact, the most recent preprinted (non-
peer reviewed) data from China now suggest a protective effect based on 
retrospective data compared to other antihypertensive regiments. Nevertheless, 
based on this recent suggestion, we will track troponin and BNP/proBNP 
measurements in addition to our previously planned assessments of new episodes 
of hypotension and shock, and report these data to the DSMB. In addition, all 
patients are closely monitored for clinical purposes given their severity of illness, 
combined with daily assessments for AEs and SAEs will allow for early detection of 
side effects and reduce the risks to patients.  
13.2 Reproduction Risks: Losartan is class D in pregnancy. Women of childbearing age 
will only be eligible for enrollment with a negative pregnancy test prior to 
enrollment. In addition, women breastfeeding will be excluded from the study. 
13.3 Risks to Others: The primary risk to others is the risk to study personnel of 
becoming infected with COVID-19. To overcome this barrier, patients will be 
enrolled using an electronic consent process already established among our group 
for other studies. In addition, follow-up evaluations will preferentially be performed 
by telemedince evaluation or phone evaluation. If a face-to-face evaluation or 
physical examination is required due to concern for adverse events, investigators 
trained and fitted with N95 masks or equivalent will perform a face-to-face 
examination. Participants will generate potential biohazards (oropharyngeal 
swabs), the safety steps surrounding which are discussed in section 6.2. 
14.0 Potential Benefits to Participants 
14.1 Potential Benefits: If randomized to the intervention arm, and if losartan is 
demonstrated to prevent the progression of acute lung injury, patients may benefit 
by having reduced lung injury, decreased need for oxygen or mechanical 
ventilation, or possibly lower mortality. If randomized to the control arm, there is no 
direct potential benefit to the patient. However, the proposed research has the 
potential to significantly benefit people infected with COVID-19. 
15.0 Statistical Considerations 
15.1 Data Analysis Plan: All analysis will focus on comparisons between the treatment 
and control groups. Demographics and other baseline clinical characteristics will be 
summarized using descriptive statistics. Descriptive statistics will be presented by 
treatment group using mean, standard deviation, median, and interquartile range 
(IQR) for continuous variables and frequencies and percentages for categorical 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 29
variables. The primary outcome, change in estimated P/F ratio at 7 days, will be 
summarized by group using the sample mean with 95% asymptotic confidence 
intervals. Patients discharged home will be given a pulse oximeter and called for 
the value at 7 days, adjusted for home O2 use as applicable. Patients who died will 
be penalized with a P/F of 0 (lower values indicate higher degree of respiratory 
failure) in order to address competing risks. Like respiratory SOFA, an adjustment 
is applied based on the use of PEEP. For the primary statistical analysis, 
Treatment groups will be compared using the two-sample t-test for unequal 
variances and the treatment effect will be summarized by the mean difference 
between groups.  As a secondary statistical approach, we will also jointly model the 
longitudinal and time to event outcome under the assumption of informative 
missingness, jointly modeling P/F ratio measured daily and time to death using a 
shared random effects model. Finally, we will analyze these data on an ordinal 
scale (the respiratory SOFA score), which is a 0-4 ordinal scale derived from the 
estimated P/F ratio. In addition, patients who die prior to the day 7 assessment will 
be assigned a 5 for this analysis.  
Secondary endpoints will be summarized by the sample mean or sample 
proportion, as appropriate, and compared using the unequal variance two-sample 
t-test or Chi-square test, as appropriate. Appropriate data transformations will be 
used to assure that assumptions of all statistical tests are met. Time-to-event 
endpoints will be summarized by Kaplan-Meier curves and compared using Cox 
proportional hazards regression. For all endpoints, we will complete secondary 
analyses comparing for important baseline variables that are unequally distributed 
between treatment groups. Preplanned subgroup analyses are planned by age 
(dichotomized at 50 and by decade), history of hypertension, sex, and smoking 
history, timing of randomization from symptom onset, and respiratory support 
needed at the time of randomization. 
15.2 Power Analysis: Assuming a fixed sample size, we analyzed power using a 
number of assumptions. In general, studies with a similar degree of acute lung 
injury that we expect in this study have a standard deviation of estimated P/F ratio 
of 100-125. ARDS trials tend to have smaller SD due to narrowed inclusion criteria, 
while a single study of H1N1 with a lower severity of illness had a SD of 150. We 
calculated power for a variety of assumptions. If the SD is 125 or less, we will have 
>0.8 power to detect a difference in P/F of 50. Differences of less than this are of 
uncertain clinical significance. This method and outcome has more power than our 
alternative approach of respiratory SOFA, which is a more crude measure of the 
estimated P/F ratio.  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 30
 
15.3 Data Integrity: The principal investigator will manage oversight of quality control for 
collected data.  Recruitment of subjects will be performed using inclusion/exclusion 
criteria defined above. Study data will be recorded within a RedCAP database, 
which is HIPAA compliant, password protected with variable assignable security 
access and an audit trail consistent with all regulatory requirements for 
maintenance of clinical trial data. Data summaries and quality control checks will 
be run routinely. 
16.0 Health Information and Privacy Compliance 
16.1 
Select which of the following is applicable to your research: 
☐ My research does not require access to individual health information and 
therefore assert HIPAA does not apply.   
 
☒ I am requesting that all research participants sign a HIPCO approved HIPAA 
Disclosure Authorization to participate in the research (either the standalone 
form or the combined consent and HIPAA Authorization). 
☐ I am requesting the IRB to approve a Waiver or an alteration of research 
participant authorization to participate in the research. 
☒ An external IRB (e.g. Advarra) is reviewing and we are requesting use of the 
authorization language embedded in the template consent form in lieu of the U 
of M stand-alone HIPAA Authorization.  Note: External IRB must be serving as 
the privacy board for this option. 
 
16.2 
Identify the source of Private Health Information you will be using for your 
research (Check all that apply)   
 
☐ I will use the Informatics Consulting Services (ICS) available through CTSI 
(also referred to as the University's Information Exchange (IE) or data shelter) to 
pull records for me 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 31
☒ I will collect information directly from research participants. 
☐ I will use University services to access and retrieve records from the Bone 
Marrow Transplant (BMPT) database, also known as the HSCT (Hematopoietic 
Stem Cell Transplant) database. 
☒ I will pull records directly from EPIC. 
☐ I will retrieve record directly from axiUm / MiPACS 
☐ I will receive data from the Center for Medicare/Medicaid Services  
☒ I will receive a limited data set from another institution 
☒ Other.  Describe: CTSI’s BPIC will be used to pull structured data directly from 
EPIC into redcap (ED vitals, labs, etc.), or data will be transcribed by 
coordinators into our Redcap research database. Study coordinators will contact 
patients daily to obtain data and will input it directly into the Redcap research 
database.   
16.3 
Explain how you will ensure that only records of patients who have agreed to 
have their information used for research will be reviewed: Study coordinators and 
BPIC will review if patients have opted out of research by using the opt-out flag 
within Epic to determine research status. Only patients that have opted-in to 
research or have expressed that they wish to delay opt-out status will be included 
in this study. 
16.4 
Approximate number of records required for review: 220. 
 
16.5 
Please describe how you will communicate with research participants during the 
course of this research.  Check all applicable boxes: 
☐ This research involves record review only. There will be no communication 
with research participants. 
☒ Communication with research participants will take place in the course of 
treatment, through MyChart, or other similar forms of communication used 
with patients receiving treatment.  
☐ Communication with research participants will take place outside of treatment 
settings. If this box is selected, please describe the type of communication and 
how it will be received by participants.  
16.6 
Explain how the research team has legitimate access to patients/potential 
participants: Informed consent will be obtained from patients granting access to clinical 
data for study participants. 
16.7 Location(s) of storage, sharing and analysis of research data, including any links to 
research data (check all that apply).   
☒ In the data shelter of the Information Exchange (IE)  
 ☒ Store 
☒ Analyze 
☒ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) Database  
 ☐ Store 
☐ Analyze 
☐ Share 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 32
☒ In REDCap (recap.ahc.umn.edu)  
 ☒ Store 
☒ Analyze 
☐ Share 
☐ In Qualtrics (qualtrics.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In OnCore (oncore.umn.edu)  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In the University’s Box Secure Storage (box.umn.edu) 
 ☐ Store 
☐ Analyze 
☒ Share 
☐ In an AHC-IS supported server. Provide folder path, location of server and IT 
Support Contact: 
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In an AHC-IS supported desktop or laptop.  
Provide UMN device numbers of all devices:  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ Other. Describe:  
Indicate if data will be collected, downloaded, accessed, shared or stored using a 
server, desktop, laptop, external drive or mobile device (including a tablet 
computer such as an iPad or a smartdevice (iPhone or Android devices) that you 
have not already identified in the preceding questions 
☐I will use a server not previously listed to collect/download research data 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) not 
previously listed  
☐I will use a mobile device such as an tablet or smartphone not previously listed 
 
16.8 Consultants. Vendors. Third Parties. N/A 
16.9 Links to identifiable data: All information that identifies study subjects will be 
handled in accordance with regulatory bodies including HIPAA regulations and the 
cIRB. This information will be made only available to the principal investigators and 
study personnel who directly participate in the research calls. Prior to enrollment, 
participants will sign an authorization to use and disclose PHI for research 
purposes. All staff will have been trained in the use of PHI. Subjects will be 
assigned a random subject ID number and a link between identifiers will be 
maintained in an excel log which will be stored in a secure folder in the AHC-IE 
data shelter, the University of Minnesota’s most secure healthcare research 
environment.  Only the principal investigators and study nurses will have access to 
this file. 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 33
16.10 Sharing of Data with Research Team Members: A fully de-identified (of all PHI) 
database will be generated which will be used for statistical analysis and for 
monitoring by our DSMB. This database will exist within Redcap. 
16.11 Storage and Disposal of Paper Documents: At this time we do not anticipate any 
paper documents related to this study. Everything, including consents will be done 
electronically. If the need for paper collection templates becomes evident, these 
documents will be stored in locked rooms where only study personnel have 
access. They will be maintained for 7 years as legally required, after which time 
they will either be destroyed or moved to long-term storage. 
17.0 Confidentiality 
17.1 Data Security: All data will be stored on servers (Redcap and CTSI AHC-IE data 
shelter) managed by the University of Minnesota IS. No data will be stored on 
individual research computers, flash drives, etc. These servers Redcap and the 
data shelter meet all data regulatory requirements and are HIPAA compliant. 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
18.1 Integrity Monitoring: Data entry will be performed by trained members of the 
research team who have received documented delegation of authority. Data 
integrity will be overseen by the PIs and the Minnesota CCBR. A study monitor will 
review 100% of electronic consent documents, study drug administration data, and 
SAE reporting. Additionally, a random sampling of 5% of subjects will undergo full 
evaluation and comparison of source documentation with data entered into the 
study database. The first data monitoring visit will be scheduled once 10% of the 
cohort has been enrolled, with repeat monitoring after 50% and 100% of 
enrollments. Monitors will evaluate 100% of users to ensure assigned access is 
consistent with training and delegation of authority logs. The project research 
coordinators at the sites will maintain binders containing pertinent documents and 
information including IRB approval letters, documentation of GCP training, 
licenses, human subjects research ethics training certificates, curriculum vitae, and 
correspondence. 
18.2 Adverse events reporting 
● Definition of an Adverse Event (AE): An AE is any symptom, sign, illness, 
or experience that develops or worsens in severity during the course of 
the study but does not necessarily have a causal relationship with study 
agent/intervention or procedures.  A clinical trial adverse event is defined 
as any untoward medical event associated with the use of a drug or study 
procedure. The Investigators will determine daily if any adverse events 
occur during the period from enrollment (signing of the informed consent) 
through study day 15. Investigators will determine if the event is serious 
or related to the study drug. The rationale for this time window is the half-
life of 2 hours for losartan and 6-9 hours for its metabolite.  Even in the 
setting of impaired clearance, 3 days after study drug cessation is more 
than adequate to help to define the period at risk from losartan. Abnormal 
results of diagnostic procedures are considered to be AEs if the 
abnormality: 
o results in study withdrawal, 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 34
o is associated with a serious adverse event (SAE), 
o leads to additional treatment or to further diagnostic tests, or 
o is considered by the Investigator to be of clinical significance. 
● Definition of a Serious Adverse Event: Adverse events are classified as 
serious or non-serious.  An SAE is any AE that is: 
o Fatal, 
o life-threatening, 
o requires or prolongs a hospital stay, 
o results in persistent or significant disability or incapacity, 
o a congenital anomaly or birth defect, or 
o an important medical event. 
Important medical events are those that may not be immediately 
life threatening, but are clearly of major clinical significance.  They 
may jeopardize the subject, and may require intervention to 
prevent 1 of the other serious outcomes noted above.  For 
example, drug overdose or abuse, a seizure that did not result in 
in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered 
serious. Serious adverse events will be collected during the first 
15 study days, regardless of the investigator's opinion of 
causation. Thereafter, serious adverse events are not required to 
be reported unless the investigator feels the events were related 
to either study drug or a protocol procedure. 
Study site personnel must alert a study investigator of any serious and 
study drug or study procedure related adverse event within 24 hours of 
investigator awareness of the event. Alerts issued via telephone are to be 
immediately followed with official notification on the adverse event case 
report form.  
All AEs that do not meet any of the criteria for serious should be regarded 
as non-serious AEs. 
● Preexisting Condition: A preexisting condition is one that is present at the 
start of the study.  A preexisting condition will be recorded as an AE if the 
frequency, intensity, or the character of the condition worsens during the 
study period. 
● Post-study Adverse Event: All unresolved AEs will be followed by the 
Investigator until the events are resolved, the subject is lost to follow-up, 
or the AE is otherwise explained.  At the last scheduled visit, study 
personnel will instruct each subject to report any subsequent event(s) 
within 3 months of study completion that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation 
in this study.  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 35
● Abnormal Laboratory Values: A clinical laboratory abnormality should be 
documented as an AE if any 1 of the following conditions is met: 
o  The abnormality suggests a disease and/or organ toxicity that 
worsened from the time of enrollment, or 
o The abnormality is of a degree that requires active management; 
e.g., change of dose, discontinuation of the drug, more frequent 
follow-up assessments, further diagnostic investigation, etc. 
● Continuous SAEs of interest monitoring: The following SAEs will be 
continuously reported to the DSMB: deaths. Cardiovascular events (need 
for vasoactive drugs or fluids for hypotension), and respiratory events 
(worsening hypoxia, worsening acute respiratory distress syndrome, or 
new respiratory failure) will be continuously reported to the DSMB within 
24 hours of recognition for safety reasons. While they will be reported 
continuously, they will not necessarily be filed as SAEs unless the 
investigator deems it to be related to study procudures (see below)  
● Other outcomes that may be exempt from adverse event reporting: Study 
specific outcomes as outlined in 5.1 and 5.2 are exempt from adverse 
event reporting unless the investigator deems the event to be related to 
the study procedures (or of uncertain relationship) or if the event leads to 
discontinuation of study procedures. The following are examples of 
events that will be considered study specific clinical outcomes and will be 
systematically tracked through the study design. The rationale for this 
criteria is that these events are likely to be present in a large proportion of 
the study population, and relatedness will be subject to significant 
subjective assessment, making adverse event reporting can be sporadic 
and inconsistent. Therefore, events more likely to be truly related to a 
study intervention are better treated by consistent tracking through the 
systemic design and collection of potentially related adverse events: 
o Respiratory events: decreased PaO2/FiO2, hypoxia, worsening 
acute respiratory distress syndrome, or respiratory failure. 
o Cardiovascular events: (need for vasoactive drugs or fluids for 
hypotension) 
o Hepatic events: hepatic injury or liver dysfunction that leads to an 
increase from baseline in the serum level of bilirubin. 
o Renal events: renal failure, renal insufficiency, or renal injury that 
leads to an increase from baseline in serum creatinine. 
o Hematologic/coagulation events: coagulopathy, disseminated 
intravascular coagulation, thrombocytopenia, or thrombocytosis. 
o Changes in serum sodium and potassium 
● Scales Used to Grade Severity of Adverse Events: All AEs will be graded 
in the following manner: 
o Grade 1 (Mild): Events require minimal or no treatment and do not 
interfere with the participant’s daily activities. 
o Grade 2 (Moderate): Events result in a low level of inconvenience 
or concern.  Moderate events may cause some interference with 
functioning. 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 36
o Grade 3 (Severe): Events interrupt a participant’s usual daily 
activity and may require systemic drug therapy or other 
treatment.  Severe events are usually incapacitating. 
o Grade 4 (Life-threatening): Any adverse drug experience that 
places the participant, in the view of the Investigator, at immediate 
risk of death from the reaction as it occurred (i.e., it does not 
include a reaction that had it occurred in a more severe form, 
might have caused death). 
o Grade 5 (Death) 
● Scales Used Attribute Adverse Events: The Principal Investigator will 
assess the relationship of all AEs to any drug or study procedure: 
o Definitely Related: There is clear evidence to suggest a causal 
relationship, and other possible contributing factors can be ruled 
out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study 
agent/intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to 
withdrawal of the study agent/intervention (de-challenge) should 
be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory re-
challenge procedure if necessary. 
o Probably Related: There is evidence to suggest a causal 
relationship, and the influence of other factors is unlikely. The 
clinical event, including an abnormal laboratory test result, occurs 
within a reasonable time sequence to administration of the study 
agent/intervention, is unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (de-challenge). Re-challenge 
information is not required to fulfill this definition. 
o Possibly Related: There is some evidence to suggest a causal 
relationship (e.g., the event occurred within a reasonable time 
after administration of the trial medication). However, the influence 
of other factors may have contributed to the event (e.g., the 
subject’s clinical condition, other concomitant events). Although an 
adverse drug event may rate only as “possible” soon after 
discovery, it can be flagged as requiring more information and 
later be upgraded to probable or certain as appropriate. 
o Unlikely: A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to study agent/intervention 
administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of 
the trial medication) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the 
subject’s clinical condition, other concomitant treatments). 
o Not related: The AE is completely independent of study 
agent/intervention administration, and/or evidence exists that the 
event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 37
● Response to possibly, probably, or definitely related AEs and SAEs: 
SAEs determined to be probably or definitely related will prompt 
discontinuation of study drug. AEs determined to be probably or definitely 
related with prompt a) decrease in study drug from twice a day to once a 
day if currently dosing twice daily, b) discontinuation of study drug if only 
taking once daily, or c) discontinuation for study drug at the discretion of 
the investigator.  
● Anticipated Adverse Events: Adverse events are not expected from any of 
the study procedures.  We do not expect any serious adverse events due 
to losartan. 
● Recording and Documentation 
o At each contact with the subject, personnel must seek information 
as to discomforts or adverse experiences by specific questioning 
and, as appropriate, by examination. This will typically occur via 
phone or telemedicine due to concerns regarding infectious 
contagion. Information about AEs to be recorded includes event 
description, time of onset, investigator assessment of severity, 
relationship to Study Agent(s)/Intervention(s), and time of 
resolution/stabilization of the event.  All AEs occurring during the 
study period (from time of consent signing to study day 15) must 
be documented appropriately regardless of relationship to study 
products or procedures unless included on the list of clinical 
outcomes that may be exempt from adverse outcomes reporting 
as part of the study protocol and outcomes.  Information on all 
identified AEs will be recorded within 5 days of recognition in the 
appropriate AE module of the case report form (CRF) on Redcap, 
and within 24 hours in the event of a SAE.  
18.3 Data Safety Monitoring: A data safety monitoring board (DSMB) has been 
convened and includes 4 individuals meeting the key element criteria below, and 
includes a biostatistician with prior clinical trials DSMB experience.  The DSMB will 
follow the guidance as outlined in the application and the attached charter unless 
there is a compelling, unanticipated reason to deviate from these rules. Data 
regarding the primary outcome (hospitalization) will be reported to the DSMB 
continuously, consistent with continuous study monitoring principles. The DSMB 
may recommend stopping the trial early only for safety, following these guidelines: 
[Patient Safety] A recommendation to suspend, alter the study, or stop for harm 
would occur if during continuous monitoring there is strong evidence that the rate 
of IRB-reported SAEs was significantly higher in the experimental group than in 
the placebo group. SAEs (including increasingly level of ventilator support and 
initiation of vasopressors, the two SAEs of interest) will be reported within 24 
hours, allowing for continuous study monitoring. For the inpatient cohort, we 
propose formal interim analyses for safety at 10%, 20%, and 30% of enrollment. A 
50% preplanned interim analysis for safety, efficacy, and futility is planned with 
specific stopping rules provided to the DSMB as a guide. Assuming a baseline 
mortality rate of 10%, this corresponds to formal hypothesis testing after every ~2 
events initially, and decreasing as data accumulate. Despite the lower number of 
formal preplanned analyses, the DSMB will still receive near real-time reporting of 
deaths, and can deviate from this strategy and perform earlier testing if desired. 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 38
They retain authority to change this plan if the continuous reporting suggests 
harm prior to the first formal planned assessment if they feel that a formal 
hypothesis test is warranted. In addition, the DSMB may request additional safety 
assessments after the 50% assessment, if they feel that additional formal testing 
is needed. 
[Efficacy] – A preplanned interim analysis at 50% of enrollments will assess for 
early efficacy or futility. 
 The DSMB will operate in accordance with guidelines established by the FDA in 
“Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data 
Monitoring Committee” jointly published by the CBER, CDER and CDRH of the FDA 
(https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/establishment-and-operation-clinical-trial-data-monitoring-committees) . The 
key elements include: 
1. Expertise and independence: The members must have expertise in the area of 
study, not be study authors and have no financial conflict of interest. 
2. Members will sign a confidentiality agreement. 
3. It is preferred that the DSMB have a face-to-face initial meeting, but can meet 
by telephone thereafter more frequently. 
4. All meetings must follow standard operating procedures (SOPs). 
If the DSMB recommends closure of the study, then the DSMB Chair will email the 
principal investigator and IRB. If the trial is stopped for patient safety and a repairable 
cause of unacceptably high adverse events can be identified, the action must be 
reviewed and approved by the DSMB and IRB prior to resuming enrollment. For 
example, if one additional exclusion criterion is discovered that would account for the 
majority of unexpected events, this new exclusion criterion could be added, and the 
study could proceed. 
19.0 Provisions to Protect the Privacy Interests of Participants 
19.1 Protecting Privacy: Conversations will be held in a private room whenever 
possible. Telephone calls will be performed one on one.  The electronic consent 
process takes place using a secure RedCAP server that is HIPAA compliant. 
19.2 Access to Participants:  Conduct of the study and determination of both safety and 
efficacy of the intervention requires access of the medical records. All study 
personnel undergo human subjects protection training and understand and value 
privacy standards set forth by HIPAA. Participants enrolled in the trial are made 
aware during the informed consent procedure that study personnel will be required 
to access this private information for trial conduct, and consent to this access prior 
to agreeing to participate. 
20.0 Compensation for Research-Related Injury 
20.1 Compensation for Research-Related Injury: There is no compensation available for 
research related injury from the study team. Due to the coronavirus public health 
crisis, the federal government has issued an order that may limit your ability to 
recover damages if you are injured or harmed while participating in this COVID-19 
clinical study. If the order applies, it limits your ability to recover damages from the 
University, researchers, healthcare providers, study sponsor, manufacturer or 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 39
distributor involved with the study. However, the federal government has a program 
that may provide compensation to you or your family if you experience serious 
physical injuries or death due to this study. To find out more about this 
“Countermeasures Injury Compensation Program” go to 
https://www.hrsa.gov/cicp/about/index.html or call 1-855-266-2427. 
20.2 Contract Language: N/A. 
21.0 Consent Process 
21.1 Consent Process (when consent will be obtained): All subjects participating in this 
study or their LARs will be required to provide prospective informed consent using 
an eConsent platofrm.  Prior to doing so, will discuss the study with study 
personnel who have been specially trained in obtaining informed consent. Our 
team has significant experience in this process, with due consideration of 
vulnerable patient populations. The subject or LAR will review the eConsent in 
detail and have the chance to ask questions.  The personnel will then ask the 
subject questions to ensure that they understand the information presented in the 
consent discussion using a teach back method.  The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this 
study. A copy of the informed consent document will be available electronically to 
the participants for their records.  The participants may withdraw consent at any 
time throughout the course of the trial (see withdrawal procedures). The eConsent 
forms are included in this IRB submission. 
21.2 Waiver or Alteration of Consent Process (when consent will not be obtained): N/A 
21.3 Waiver of Written/Signed Documentation of Consent (when written/signed consent 
will not be obtained): N/A  
21.4 Non-English Speaking Participants: Spanish and Somali speaking persons, who 
represent the vast majority of non-English speaking patients in the study hospitals 
and clinics, will be included as described above.  
21.5 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 years of 
age): Patients will be excluded per the study protocol. If logistical and scientific 
concerns can be adequately addressed, we will submit a revised application with 
an ethical framework, scientific support, and logistical considerations. 
21.6 Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to 
consents: To establish capacity in this setting, the MacArther Competence 
Assessment tool will be administered by trained study personnel. If the patient 
lacks capacity, a LAR may provide consent for these participants on their behalf. 
For adults unable to consent, consent will be obtained from a legally authorized 
representative in the following order of priority consistent with Minnesota State 
Law: health care agent previously assigned via a health care power of attorney, 
spouse, parents, adult children, and then adult siblings. An incapacitated adult who 
has a court appointed guardian would require permission of the court for 
enrollment, and these participants will be excluded practically from the trial.  
21.7 Adults Unable to Consent: The same process will be applied as in 21.6. 
21.8 Assent and dissent in adults with fluctuating or limited mental capacity:  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 40
● Assent: If patients might have capacity, we use the MacArthur 
Competence Assessment Tool for Clinical Research. If they do not reach 
the pre-specified threshold for capacity, we seek from an LAR. We do not 
seek further assent, as these patients are frequently intubated, delirious, 
or medically sedated 
● Dissent: However, even if the LAR consents to the trial, if the patient is 
awake and alert, but dissent, we will exclude the patient. 
22.0 Setting 
22.1 
Research Sites: 
● Participating study sites will undergo a standardized screening process to 
ensure they can participate in necessary aspects of the study protocol, 
and comply with safety and remote oversight, legal, and regulatory 
procedures. All sites will cede to the central (Advarra) IRB in addition to 
undergoing local context review, as appropriate. 
22.2 International Research: N/A  
23.0 Multi-Site Research 
23.1 Study-Wide Number of Participants: 200 minimum, up to 220 including screen 
failures 
23.2 Study-Wide Recruitment Methods: N/A 
23.3 Study-Wide Recruitment Materials:  N/A 
23.4 
Communication Among Sites: 
23.5 
All sites have the most current version of the protocol, consent document(s), and, 
when applicable, HIPAA authorization. 
●              All required approvals (initial, continuing review, and modifications) have been 
obtained at each site (including by the site’s IRB of record). 
●              All modifications have been communicated to sites, and approved (including 
approval by the site’s IRB of record) before the modification is implemented. 
●              All engaged participating sites will safeguard data, including secure 
transmission of data, as required by local information security policies. 
●              All local site investigators conduct the study in accordance with applicable 
federal regulations and local laws. 
●              All non-compliance with the study protocol or applicable requirements will be 
reported in accordance with university or local policy. 
●              All other reportable events in accordance with university or local policy 
23.6 Communication to Sites: Personnel from all sites will participate in monthly 
progress meeting calls, which will include discussion of any problems including 
reportable events, interim results, and completion of the study. More frequent 
communications may be planned, as becomes necessary. 
24.0 Coordinating Center Research: N/A 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 41
25.0 Resources Available 
25.1 
Resources Available: It is difficult to estimate how many patients will develop 
COVID-19 in Minneapolis; however, given estimates from other countries it is likely to be 
1000’s if the virus is not contained.  
The study PIs and research team will contribute at least 20% of their research time 
towards conducting and completing this study, we will leverage the rich resources of the 
UMN SIREN network hub and HCMC emergency department research infrastructure (of 
note, Dr. Puskarich is research director at HCMC, as well as associate research director 
at the University of Minnesota). In total across sites, this include >8 FTE of highly trained 
research nurses, coordinators, and research assistants across sites managed by the co-
I plus an additional on-call pool of 8 additional trained associates providing 24/7 
coverage for this and other studies. All study members have completed all required 
responsible conduct in research coursework and have extensive research experience. 
The research team is built for mobile, multi-site enrollment in time-sensitive emergency 
care research, and has been a consistent top enroller in the NIH supported emergency 
care SIREN, StrokeNET, NETT, and PETAL clinical trial networks for years. Additional 
expansion sites will undergo additional screening and training prior to expansion to 
ensure they are capable of executing the protocol as described. 
 
26.0 References 
 
 
1. 
Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in 
real time. Lancet Infect Dis. 2020. 
2. 
John Hopkins C. Coronavirus COVID-19 (2019-nCoV). 2020; 
https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48
e9ecf6. 
3. 
World Health Organization. Novel Coronavirus (2019-nCoV) situation reports. 2020; 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports. 
4. 
Wang Y, Wang Y, Chen Y, Qin Q. Unique epidemiological and clinical features of the 
emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control 
measures. J Med Virol. 2020. 
5. 
Zhao S, Lin Q, Ran J, et al. Preliminary estimation of the basic reproduction number of 
novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in 
the early phase of the outbreak. Int J Infect Dis. 2020;92:214-217. 
6. 
World Health O. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 
(COVID-19). In:2020. 
7. 
Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in 
China. N Engl J Med. 2020. 
8. 
Liu W, Tao ZW, Lei W, et al. Analysis of factors associated with disease outcomes in 
hospitalized patients with 2019 novel coronavirus disease. Chin Med J (Engl). 2020. 
9. 
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 
(ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic 
target. Intensive Care Med. 2020. 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 42
10. 
Severe Acute Respiratory Syndrome (SARS) and Coronavirus Testing—United States, 
2003. JAMA. 2003;289(17):2203-2206. 
11. 
de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights 
into emerging coronaviruses. Nature reviews Microbiology. 2016;14(8):523-534. 
12. 
Fang Y, Nie Y, Penny M. Transmission dynamics of the COVID-19 outbreak and 
effectiveness of government interventions: A data-driven analysis. J Med Virol. 2020. 
13. 
Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel 
coronavirus: implications for virus origins and receptor binding. Lancet. 
2020;395(10224):565-574. 
14. 
Zhang L, Liu Y. Potential interventions for novel coronavirus in China: A systematic 
review. J Med Virol. 2020;n/a(n/a). 
15. 
Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent 
efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci 
Trends. 2020;advpub. 
16. 
Patel A, Jernigan DB, nCo VCDCRT. Initial Public Health Response and Interim Clinical 
Guidance for the 2019 Novel Coronavirus Outbreak - United States, December 31, 2019-
February 4, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(5):140-146. 
17. 
Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug 
Dev Res. 2020. 
18. 
Kickbusch I, Leung G. Response to the emerging novel coronavirus outbreak. BMJ. 
2020;368:m406. 
19. 
Sun ML, Yang JM, Sun YP, Su GH. [Inhibitors of RAS Might Be a Good Choice for the 
Therapy of COVID-19 Pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 
2020;43(0):E014. 
20. 
Chen Y, Guo Y, Pan Y, Zhao ZJ. Structure analysis of the receptor binding of 2019-
nCoV. Biochem Biophys Res Commun. 2020. 
21. 
Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe 
acute lung failure. Nature. 2005;436(7047):112-116. 
22. 
Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) 
in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875-879. 
23. 
ClinicalTrials.Gov. Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as 
a Treatment for Patients With COVID-19 - Full Text View - ClinicalTrials.gov. 2020; 
https://clinicaltrials.gov/ct2/show/NCT04287686. 
24. 
Khan A, Benthin C, Zeno B, et al. A pilot clinical trial of recombinant human 
angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 
2017;21(1):234. 
25. 
Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional 
receptor for the SARS coronavirus. Nature. 2003;426(6965):450-454. 
26. 
Glowacka I, Bertram S, Herzog P, et al. Differential downregulation of ACE2 by the 
spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus 
NL63. J Virol. 2010;84(2):1198-1205. 
27. 
Zou Z, Yan Y, Shu Y, et al. Angiotensin-converting enzyme 2 protects from lethal avian 
influenza A H5N1 infections. Nat Commun. 2014;5:3594. 
28. 
Yang P, Gu H, Zhao Z, et al. Angiotensin-converting enzyme 2 (ACE2) mediates 
influenza H7N9 virus-induced acute lung injury. Sci Rep. 2014;4:7027. 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for inpatients with COVID-19 
VERSION DATE:22APR2020 
 
 43
29. 
Yan Y, Liu Q, Li N, et al. Angiotensin II receptor blocker as a novel therapy in acute 
lung injury induced by avian influenza A H5N1 virus infection in mouse. Sci China Life 
Sci. 2015;58(2):208-211. 
30. 
Rice TW, Wheeler AP, Bernard GR, et al. Comparison of the SpO2/FIO2 ratio and the 
PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest. 2007;132(2):410-
417. 
31. 
Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of 
Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the 
Sequential Organ Failure Assessment score. Crit Care Med. 2009;37(4):1317-1321. 
32. 
Zhou FY, T. Du, R. Fan, G. Liu, Y. Liu Z, et al. Clinical Course and risk factors for 
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort 
study. Lancet, Epub Ahead of Print, March 11, 2020. . 
33. 
Sica DA, Gehr TW, Ghosh S. Clinical pharmacokinetics of losartan. Clin Pharmacokinet. 
2005;44(8):797-814. 
 
 

ICF_001.pdf: 
University of Minnesota  
Page 1 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
INFORMED CONSENT FORM AND AUTHORIZATION TO USE AND DISCLOSE PROTECTED 
HEALTH INFORMATION 
 
Sponsor / Study Title: 
  
University of Minnesota / “Randomized Controlled Trial of Losartan 
for Patients with COVID-19 Requiring Hospitalization” 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
This form is for use in a research study that may involve participants who may or may not have the 
capacity to consent to take part in the study.  When the participant cannot legally consent to take part, 
pronouns “you” and “your” should be read as referring to the participant rather than the person (legally 
authorized representative) who is signing this form for the participant. In cases where the participant’s 
representative gives consent, the participant should be informed about the study to the extent possible 
given his/her understanding. During the course of the study, if the participant regains the capacity to 
consent, informed consent will be obtained from the participant and the participant offered the ability 
to leave the study if desired. 
 
If your doctor is also the person responsible for this research study, please note that he is interested in 
both your clinical care and the conduct of this research study. You have the right to discuss this study 
with another person who is not part of the research team before deciding whether to participate in the 
research. 
 
Key Information About This Research Study 
The following is a short summary to help you decide whether or not to be a part of this research study. 
More detailed information is listed later on in this form.  
What is research?  
 
Doctors and investigators are committed to your care and safety. There are important differences 
between research and treatment plans: 
 
 
 
 
 
 
 
● The goal of research is to learn new things in order to help groups of people in the future. 
Investigators learn things by following the same plan with a number of participants, so they do 
not usually make changes to the plan for individual research participants. You, as an individual, 
may or may not be helped by volunteering for a research study.   
● The goal of clinical care is to help you get better or to improve your quality of life. Doctors can 


University of Minnesota  
Page 2 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
make changes to your clinical care plan as needed. 
 
 
 
 
 
Research and clinical care are often combined. One purpose of this informed consent document is to 
provide you clear information about the specific research activities of this study.  
 
 
 
Why am I being asked to take part in this research study? 
We are asking you to take part in this research study because you have either tested positive for COVID-
19 (novel coronavirus) or your treating provider thinks you may have this infection, and you are in the 
hospital for care.  
 
What should I know about a research study? 
● Someone will explain this research study to you. 
● Whether or not you take part is up to you. 
● You can choose not to take part. 
● You can agree to take part and later change your mind. 
● Your decision will not be held against you. You will not be penalized or lose benefits you are 
otherwise entitled to. 
● You can ask all the questions you want before you decide. 
 
Why is this research being done? 
The virus COVID-19 uses a specific protein on the surface of your cells to enter the cell. This protein is 
important to protect your lung from circulating hormones. COVID-19 blocks this protein and damages 
your lungs. In this study, we want to see if giving you a study drug (called Losartan) that can block this 
lung damaging hormone helps reduce problems with breathing while you recover from COVID-19.  
Losartan is approved by the U.S. Food and Drug Administration (FDA) to treat high blood pressure and 
diabetic neuropathy in patients with type 2 diabetes and high blood pressure. Losartan has not been 
approved to treat COVID-19 or its symptoms. The use of this drug in this study is considered 
experimental. 
 
How long will the research last? 
We expect that you will be in this research study for up to 90 days. You will receive study drug for 10 
days unless you are sent home from the hospital, whichever comes first.  
 
What will I need to do to participate? 
You will be asked to have a physical exam, provide blood samples, mouth swab samples, answer daily 
questions about symptoms or side effects, and take your study drug daily.  You will be randomly 
assigned to receive either Losartan or a placebo (a pill that looks just like Losartan but doesn’t have any 
active drug in it). You have a 50:50 chance of taking either pill during this study, like flipping a coin. 
Neither you nor the study staff will know what you are taking, but they can find out if they need to. 
More detailed information about the study procedures can be found under “What happens if I say yes, I 
want to be in this research?” 


University of Minnesota  
Page 3 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
Is there any way that being in this study could be bad for me? 
Risks of Losartan include: 
• 
Feeling tired, weak, or dizzy  (more common, 2-3 out of 100 people) 
• 
Diarrhea (less common) 
• 
Chest pain (more common, 1-2 out of 100 people) 
• 
Low red blood cell count (less common) 
• 
Low blood pressure (more common) 
• 
Worsening kidney function (less common) 
• 
Abnormal levels of electrolytes (minerals in your blood, less common) 
• 
Allergic reaction (less common) 
Blood draws may cause pain, bleeding, or bruising where the needle pokes your skin. There is a small 
risk of infection at the needle site, and sometimes people feel lightheaded or faint during a blood draw. 
The team will try to draw your blood from IVs you already have, but might need to perform a needle 
stick. 
There is also a small risk that someone who is not part of the study team might see information 
collected about you for this research. We store your data securely to try to avoid this. 
You will be emailed a PDF copy of this signed and dated consent form. There may be risks of loss of 
privacy and confidentiality if the PDF copy of this consent form is viewed and/or stored on a personal 
electronic device (PED), especially if that PED is shared with other users or is lost, hacked, or subject to a 
search warrant or subpoena. Also, the PDF copy of the consent may not be able to be permanently 
removed from a PED. 
Since the use of this study drug is experimental, there may be other risks that are unknown. 
Additionally, there may be unknown risks to a pregnancy, embryo, or fetus if you become pregnant. 
Any new important information that is discovered during the study and which may influence your 
willingness to continue participation in the study will be provided to you. 
Will being in this study help me in any way? 
We cannot promise any benefits to you or others from your taking part in this research. However, if you 
receive Losartan and if this study drug works, you might need less oxygen or mechanical ventilation.  
What happens if I do not want to be in this research? 
You do not have to participate in this research.  Instead of being in this research study, you can continue 
to receive supportive care in the hospital.  
 
Detailed Information About This Research Study 
The following is more detailed information about this study in addition to the information listed above. 
How many people will be studied? 
We expect about 220 people here will be in this research. 
 
What happens if I say “Yes, I want to be in this research”? 
If you decide you want to be in this research, you will participate for 90 days. You will receive study drug 
for 10 days or until you are sent home from the hospital, whichever comes first. During your hospital 
stay, you can expect the following procedures: 
• 
You will have a physical exam to determine if you are eligible for this study. If you are a woman 


University of Minnesota  
Page 4 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
who is able to become pregnant, you will also have a urine pregnancy test. 
• 
If you are eligible for this study, you will be randomly assigned to receive either Losartan or a 
placebo. You have a 50:50 chance of receiving either study treatment, like flipping a coin. You 
will not know which study treatment you are receiving; study staff will not know but if they need 
to find out during an emergency, they can.  
• 
You will have the following done every day that you are in the hospital, beginning as soon as you 
sign and date this consent form: 
o Study staff will ask you some questions about symptoms or side-effects 
o You will have a blood draw of about a tablespoon plus a teaspoon of blood daily 
o You will have a swab of saliva samples taken from your mouth on days 0, 3, 6, 9, and 15 
o You will be given study drug (either Losartan or placebo) twice a day while in the 
hospital.  
o You will be asked to return to the clinic for a blood draw for follow up creatinine and 
potassium levels (about 2 tsp of blood) around 15 days after you enroll in the study. If 
you are still in the hospital this visit can occur while you are in the hospital. 
• 
You have the choice to have your samples of blood, saliva and lung fluid stored for future 
research. You can choose if you want to give that permission at the end of this consent form.  
Around day 30 and 90, the study team may contact you by phone to complete end of study 
assessments.  
 
What happens if I say “Yes”, but I change my mind later? 
If you take part in this research study, and want to leave, you should tell us.  Your choice not to be in this 
study will not negatively affect your right to any present or future medical care, your academic standing 
as a student, or your present or future employment.   
 
We will make sure that you stop the study safely.  We will also talk to you about follow-up care, if 
needed.    
 
If you decide to leave the research study, study staff will ask you if it is okay to conduct a final study visit 
for safety testing.   
 
If you stop being in the research, information about you that has already been collected may not be 
removed from the study database. You will be asked whether the study doctor can collect information 
from your routine medical care, such as your medical records after you leave the study. If you agree, you 
will be asked to sign and date an additional consent form (Clinical Data Collection after Withdrawal 
Consent Addendum) and HIPAA authorization to document your agreement to participate in ongoing 
data collection.   
 
Can I be removed from the research? 
It’s possible that we will have to ask you to leave the study before you finish it.  If this happens, we will 
tell you why.  We will also help arrange other care for you, if needed. 
 
What do I need to know about reproductive health and/or sexual activity if I am in this 
study?   
Losartan has additional risks to a fetus or baby. Women who are pregnant or breastfeeding are not 
eligible to participate in this study.  Women of child bearing potential must already be using highly 


University of Minnesota  
Page 5 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
effective contraception and continue to use it until the study is completed. 
 
Will it cost me anything to participate in this research study? 
 
There will be no cost to you for any of the study activities or procedures. 
 
There will be no cost to you for the lab tests, drugs, and follow-up visits that are done for 
research purposes only and are not part of your regular care. 
 
You will have to pay for basic expenses like any childcare, food, parking, or transportation 
related to study activities. 
 
You or your insurance company will have to pay for all costs for medical care not related to 
participation in this study, including copayments and deductibles.  You will have to pay for any 
costs your insurance does not cover.  If you have any questions about these costs, or what out-
of-pocket expenses you may have to pay, you should contact your insurance company.  If you do 
not have health insurance, you will have to pay all costs for your medical care just as you would 
if you did not take part in this study.  
 
If you need treatment for side effects while you are on the study, you or your insurance will 
need to pay for this treatment. 
 
What happens to the information collected for the research, including my health 
information? 
 
We try to limit the use and sharing of your information, including research study records, any medical 
records and any other information about you, to people who have a need for  this information.  But 
we cannot promise complete confidentiality.   
 
Overview 
 
If you participate in this study, your information, including your health information, will be used and 
shared for purposes of conducting this research.  As described later in this Consent Form, your 
information may also be used and shared for publishing and presenting the research results, future 
research, and any optional elements of the research you agree to in this Consent Form, which may 
include creating audio and video recordings of you.   If you sign this Consent Form, you are giving us 
permission to use and share your health information for these purposes, and if we are using your 
medical records, you are giving permission to any health care providers who are treating you to share 
your medical records with us.   
 
What health information will be made available? 
 
Health information about you to be used and shared for the research includes those items checked by 
the research team below: 
 
☒ Your medical records, which may include records from hospital and clinic visits, emergency room 
visits, immunizations, medical history and physical exams, medications, images and imaging reports, 
progress notes, psychological tests, EEG/EKG/ECHO reports, lab and pathology reports, dental records 
and/or financial records.  These records may be used and shared for as long as this research continues. 
☒ Information collected as part of this research study, including research procedures, research visits, 
and any optional elements of the research you agree to, all as described in this Consent Form.  This 


University of Minnesota  
Page 6 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
information might not be part of your medical record, and may include things like responses to surveys 
and questionnaires, and information collected during research visits described in this Consent Form. 
What about more sensitive health information? 
Some health information is so sensitive that it requires your specific permission.  If this research study 
requires any of this sensitive information, the boxes below will be marked and you will be asked to initial 
to permit this information to be made available to the research team to use and share as described in 
this Consent Form. 
☐ My drug & alcohol abuse, diagnosis & treatment records ______ (initial) 
☐ My HIV/AIDS testing records  ______ (initial) 
☐ My genetic testing records  ______ (initial) 
☐ My mental health diagnosis/treatment records  ____ (initial) 
☐ My sickle cell anemia records  _______ (initial) 
Who will access and use my health information? 
If you agree to participate in this study, your information will be shared with: 
● The University of Minnesota research team and any institutions or individuals collaborating on 
the research with us; 
 
● Others at the University of Minnesota and M Health/Fairview who provide support for the 
research or who oversee research (such as the Institutional Review Board or IRB which is the 
committee that provides ethical and regulatory oversight of research at the University, systems 
administrators and other technical and/or administrative support personnel, compliance and 
audit professionals (Such as the Quality Assurance Program of the Human Research Protection 
Program (HRPP)) , individuals involved in processing any compensation you may receive for your 
participation, and others); 
 
● The research sponsor(s), any affiliates, partners or agents of the sponsor(s) involved in the 
research, organizations funding the research, and any affiliates, partners or agents of the 
funding organization(s) involved in the research; 
 
● Organizations who provide accreditation and oversight for research and the research team, and 
others authorized by law to review the quality and safety of the research (such as U.S. 
government agencies like the Food and Drug Administration, the Office of Human Research 
Protections, the Office of Research Integrity, or government agencies in other countries); and 
 
● Organizations that process any payments that may be made to you for participating in this 
study, and any other individuals or organizations specifically identified in this Consent Form. 
 
 
 


University of Minnesota  
Page 7 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
Additional sharing of your information for mandatory reporting 
If we learn about any of the following, we may be required or permitted by law or policy to report this 
information to authorities: 
● Current or ongoing child or vulnerable adult abuse or neglect; 
● Communicable, infectious or other diseases required to be reported under Minnesota’s 
Reportable Disease Rule; 
● Certain wounds or conditions required to be reported under other state or federal law; or 
● Excessive use of alcohol or use of controlled substances for non-medical reasons during 
pregnancy. 
 
How will my information be used in publications and presentations? 
 
We may publish the results of this research in scientific, medical, academic or other journals or reports, 
or present the results at conferences.  Information that makes it easy to identify you (such as your name 
and contact information, SSN and medical records number) will not be part of any publication or 
presentation.  If you have an extremely unique or rare condition that is not shared by many others, it is 
possible that some people may be able to determine your identity even without these identifiers. 
 
Once your health data has been shared with authorized users, it may no longer be protected by federal 
privacy law and could possibly be used or disclosed in ways other than those listed here.  
 
Your permission to use and share health data about you will end in 50 years unless you revoke it (take it 
back) sooner.  
 
You may revoke (take back) your permission to use and share health data about you at any time by 
writing to the study doctor at the address listed on the first page of this form. If you do this, you will not 
be able to stay in this study. No new health data that identifies you will be gathered after your written 
request is received. However, health data about you that has already been gathered may still be used 
and given to others as described in this form. 
 
Certificate of Confidentiality  
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. The 
researchers with this Certificate may not disclose or use information, documents, or biospecimens that 
may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other action, 
suit, or proceeding, or be used as evidence, for example, if there is a court subpoena, unless you have 
consented for this use. Information, documents, or biospecimens protected by this Certificate cannot be 
disclosed to anyone else who is not connected with the research except, if there is a federal, state, or 
local law that requires disclosure (see below); if you have consented to the disclosure, including for your 
medical treatment; or if it is used for other scientific research, as allowed by federal regulations 
protecting research subjects.  
 
The Certificate cannot be used to refuse a request for information from personnel of the United States 
federal or state government agency sponsoring the project that is needed for auditing or program 
evaluation by the agency which is funding this project or for information that must be disclosed in order 
to meet the requirements of the federal Food and Drug Administration (FDA).  You should understand 


University of Minnesota  
Page 8 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
that a Certificate of Confidentiality does not prevent you from voluntarily releasing information about 
yourself or your involvement in this research. If you want your research information released to an 
insurer, medical care provider, or any other person not connected with the research, you must provide 
consent to allow the researchers to release it. 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, state, or 
local law of, for instance, child abuse or neglect, harm to self or others, and communicable diseases.  
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you have 
consented to in this informed consent document. 
What will be done with my data and specimens when this study is over? 
Your data and/or samples may be used for any future research after this study is complete. The future 
research will be look at the virus and your health status during the study. 
 
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include your name or any other direct identifiers such as your contact 
information.  The Web site may include a summary of the results of this research. You can search this 
Web site at any time. 
 
Will I receive research test results? 
Most tests done on samples in research studies are only for research and have no clear meaning for 
health care. The investigator(s) will not contact you or share your individual test results.  
 
Will anyone besides the study team be at my consent meeting?   
You may be asked by the study team for your permission for an auditor to observe your consent 
meeting. Observing the consent meeting is one way that the University of Minnesota makes sure that 
your rights as a research participant are protected. The auditor is there to observe the consent meeting, 
which will be carried out by the people on the study team. The auditor will not document any personal 
(for example, name, date of birth) or confidential information about you. The auditor will not observe 
your consent meeting without your permission ahead of time.    
 
Whom do I contact if I have questions, concerns or feedback about my experience? 
During the study, if you experience any medical problems, suffer a research-related injury, or have 
questions, concerns or complaints about the study, please contact the Investigator at the telephone 
number listed on the first page of this consent document.  If you seek emergency care, or hospitalization 
is required, alert the treating physician that you are participating in this research study.   
An institutional review board (IRB) is an independent committee established to help protect the rights of 
research subjects.  If you have any questions about your rights as a research subject, and/or concerns or 
complaints regarding this research study, contact: 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 


University of Minnesota  
Page 9 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
Columbia, MD 21046 
• 
or call toll free:        877-992-4724 
• 
or by email:              adviser@advarra.com 
Please reference the following number when contacting the Study Subject Adviser: Pro00042757. 
To share feedback privately with the University of Minnesota Human Research Protection Program 
(HRPP) about your research experience, call the Research Participants’ Advocate Line at 612-625-1650 (Toll 
Free: 1-888-224-8636) or go to z.umn.edu/participants. You are encouraged to contact the HRPP if:  
● Your questions, concerns, or complaints are not being answered by the research team. 
● You cannot reach the research team. 
● You want to talk to someone besides the research team. 
● You have questions about your rights as a research participant. 
● You want to get information or provide input about this research. 
The University of Minnesota HRPP may ask you to complete a survey that asks about your experience as 
a research participant. You do not have to complete the survey if you do not want to. If you do choose 
to complete the survey, your responses will be anonymous.  If you are not asked to complete a survey, 
but you would like to share feedback, please contact the study team or the University of Minnesota 
HRPP. 
Will I have a chance to provide feedback after the study is over?  
The HRPP may ask you to complete a survey that asks about your experience as a research participant. 
You do not have to complete the survey if you do not want to. If you do choose to complete the survey, 
your responses will be anonymous.   
If you are not asked to complete a survey, but you would like to share feedback, please contact the 
study team or the HRPP. See the “Investigator Contact Information” of this form for study team contact 
information and “Whom do I contact if I have questions, concerns or feedback about my experience?” of 
this form for HRPP contact information. 
What happens if I am injured while participating in this research? 
In the event that this research activity results in an injury, treatment will be available, including first aid, 
emergency treatment and follow-up care as needed. Care for such injuries will be billed in the ordinary 
manner to you or your insurance company. If you think that you have suffered a research related injury, 
let the study doctor know right away. By signing this document, you will not lose any of your legal rights 
or release anyone involved in the research from responsibility for mistakes. 
 
Will I be compensated for my participation?  
«Compensation» 
You will be compensated $25 your time spent on the 15 day study visit. Payment will be made using a 
pre-paid debit card called Greenphire ClinCard. It works like a bank debit card. We will give you a 
ClinCard and each time you receive a payment for participation in this study, the money will be added to 
the card after each completed visit. You may use this card at any store that accepts MasterCard or you 
can use a bank machine to remove cash. However, there may be fees drawn against the balance of the 
card for cash withdrawals (ATM use) and inactivity (no use for 3 months). We will give you the ClinCard 
Frequently Asked Questions information sheet that answers common questions about the debit card. You 


University of Minnesota  
Page 10 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
will also receive letters with additional information on how you can use this card and who to call if you 
have any questions. Be sure to read these letters, including the cardholder agreement, for details about 
fees. The debit card system is administered by an outside company. The company, Greenphire, will be 
given your name, address, and date of birth. They will use this information only as part of the payment 
system. Your information will not be used for any other purposes and will not be given or sold to any other 
company. Greenphire will not receive any information about your health status or the study in which you 
are participating. Payment you receive as compensation for participation in research is considered 
taxable income. If payment from the University of Minnesota to an individual equals or exceeds $600 in 
any one calendar year, the University of Minnesota is required to report this information to the Internal 
Revenue Service (IRS). Research payments to study participants that equal or exceed $600 during any 
calendar year will result in a FORM 1099 (Miscellaneous Income) being issued to you and a copy sent to 
the IRS. 
 
Signature Block: 
 
Your signature documents your permission to take part in this research.  You will be provided a copy of 
this signed and dated document. 
 
_______________________________________________ 
Printed Name of Participant 
 
_______________________________________________      __________________ 
Signature of Participant                                                                   Date 
 
_______________________________________________ 
Printed Name of Legally Authorized Representative (if applicable) 
 
 
_______________________________________________      __________________ 
Signature of Legally Authorized Representative  
 
Date 
 
 
____________________________________________            __________________ 
Signature of Person Obtaining Consent                                       Date 
 
______________________________________________________ 
Printed Name of Person Obtaining Consent 
 
Signature Block for Witness: 
WITNESS STATEMENT: 
The participant or legally authorized representative (LAR) was unable to read or sign this consent form 
because of the following reason: 
 
☐ The participant/LAR is illiterate 
☐ The participant/LAR is visually impaired 
☐ The participant/LAR is physically unable to sign the consent form. Please describe:  


University of Minnesota  
Page 11 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
______________________________________________________________________ 
☐ Other (please specify): 
______________________________________________________________________ 
For the Consent of Non-English Speaking Participants or LARs when an Interpreter is Used: 
As someone who understands both English and the language spoken by the participant or LAR, I 
represent that the English version of the consent form was presented orally to the participant of LAR in 
their own language, and that they were given the opportunity to ask questions. 
 
__________________________________________       __________________ 
Signature of Interpreter  
 
 
 
Date 
 
___________________________________________    
Printed Name of Interpreter 
 
OR:  
 
Statement from a Non-Interpreter: 
As someone who understands both English and the language spoken by the participant or LAR, I 
represent that the English version of the consent form was presented orally to the participant or LAR in 
their own language, and that they were given the opportunity to ask questions. 
 
__________________________________________       __________________ 
Signature of Individual  
 
 
 
Date 
 
___________________________________________    
Printed Name of Individual 
Signature for Optional Future Scientific Research 
We are asking you to take part in this optional future scientific research because you have already 
agreed to take part in the main study, named above. You are now being asked to give permission for 
your biologic samples to be used for future scientific research which may include examining your genes.  
This future research will examine how individuals respond to COVID-19 infection.   
Your biologic samples will be stored indefinitely.  You have the right to change your mind at any time 
about participating in this optional research.  And your biological samples will be destroyed if you ask.  
Any information gained from your biological samples before you change your mind will not be 
destroyed. 
This portion of the study is optional.  
All of your rights as a research participant are covered in the main study Consent Form 
This form only provides additional information for you to decide if you want to give your permission for 
this future scientific research. You may stay in the main study even if you decide not to take part in this 


University of Minnesota  
Page 12 of 12  
 
«PiFullName» 
Advarra IRB Approved Version 2 Apr 2020 
Revised «PIApprovalDate» 
 
future research. Before you consent to give your sample for future research, please read this form. Ask 
as many questions as you need to before you decide if you want to take part. 
Your signature documents your permission to take part in this optional research.  You will be provided a 
copy of this signed document. 
 
_______________________________________________ 
Printed Name of Participant 
 
_______________________________________________      __________________ 
Signature of Participant                                                                   Date 
 
_______________________________________________ 
Printed Name of Legally Authorized Representative (if applicable) 
 
 
_______________________________________________      __________________ 
Signature of Legally Authorized Representative  
 
Date 
 
 
____________________________________________            __________________ 
Signature of Person Obtaining Consent                                       Date 
 
______________________________________________________ 
Printed Name of Person Obtaining Consent