Clinical trial NCT04311177
Conditions: Corona Virus Infection Acute Respiratory Distress Syndrome SARS-CoV Infection
Keywords: COVID-19 Corona Virus SARS-COV-2
Sponsor: University of Minnesota
Start date: 2020-04-09; Completion date: 2021-02-01
Enrollment: 117 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, double-blinded study of COVID-19 infected patients randomized 1:1 to daily losartan or placebo for 10 days or treatment failure (hospital admission).

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; 25 mg daily; oral administration intervention 2: Placebo (microcrystalline methylcellulose, gelatin capsule); oral administration

Protocol documents:
ICF_002.pdf: 
 
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                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 Not Requiring Hospitalization” 
 
Principal Investigator: 
(Study Doctor) 
 
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Telephone: 
 
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Address: 
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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 
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 tested positive for COVID-19 
(novel coronavirus) and you are recovering at home. 


 
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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 kidney disease 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 take study drug for 10 days 
or until you are admitted to the hospital, whichever comes first. 
 
What will I need to do to participate? 
Prior to being assigned to a treatment arm, we will need to do some additional safety screening 
procedures. If you do not have documentation of a blood pressure, creatinine and potassium levels in 
your medical record within the 7 days prior to enrollment, you will be asked to visit a clinic location 
prepared to accept known COVID-19 positive patients. The additional screening procedures at that visit 
will include: a blood pressure and a blood draw (1 teaspoon) to check creatinine, and potassium levels. 
Additional vials of blood (1 tablespoons and 2 teaspoons) will be drawn at this time for research to 
understand how the virus  affects the human body and to help guide future research to combat the 
virus. Once you are assigned to a treatment group in the study, you will be asked to take and record 
your temperature and blood pressure daily. You will also be asked to provide oral mouth swabs every 
three days (with a kit provided to you), answer questions about symptoms or side effects every other 
day, and take your study drug twice daily. If you are a woman capable of becoming pregnant, you will 
need to take a pregnancy test showing you are not pregnant, prior to taking any study medication. This 
will either be done with the blood draw at the screening clinic or you will be sent a urine pregnancy test 
to take at home. 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?” 


 
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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 or “minerals” in your blood (less common 
● Allergic reaction  (less common) 
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 that 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 as directed by your doctor. 
 
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 580 people will be in this research study. 
 
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 a bottle of 
study drug and asked to take 1 study pill either once or twice a day (1 or 2 pills per day total, depending 
on your kidney function) for 10 days or until you are admitted to the hospital, whichever comes first. 
During your participation you can expect the following procedures: 
● If you haven’t recently had your blood pressure taken or kidney function tested, you will need to 
come to clinic for a blood pressure measurement and a blood test. 
o You will have a blood draw of about 2 tablespoons at the screening visit (for Potassium, 
Creatinine, and research how COVID-19 affects the body). 
o You will have a pregnancy test either with screening labs or a urine pregnancy test at 


 
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home before starting medication.  
● 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 treatment, like flipping a coin. You will not 
know which 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 once you are enrolled in this study: 
o Study staff will ask you some questions about symptoms or side-effects 
o You will be asked to send the study team a swab of saliva samples taken from your 
mouth on days 0, 3, 6, and 9; this will be picked up from your home by a courier service. 
o You will be given a bottle of study medication (either Losartan or placebo) and asked to 
take 1 pill once or twice a day for 10 days (1 or 2 pills per day total) 
o You will be asked to take your blood pressure and temperature daily for the 10 days you 
are taking the study medication. You will be asked to return to the clinic for a blood 
draw for follow up creatinine and potassium levels and the research how COVID-19 
affects the body (about  2 tablespoons of blood) and a mouth swab around 15 days after 
you enroll in the study. 
● You have the choice to have your samples of blood, saliva stored for future research. You can 
choose if you want to give that permission at the end of this consent form. 
● You have the choice to participate in two optional blood draws (a little over 1 tablespoon) 2-3 
months and 5-7 months after starting the study. This blood will be used in the development of a 
vaccine against COVID-19 by the National Institute of Health. You can choose if you want to 
participate in this effort at the end of this 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. 
 


 
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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 
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, drug, 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 


 
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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 
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. 
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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. 
 
 
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.  


 
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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 
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 future research after this study is complete. The future 
research will be looking 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: 


 
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● 
By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
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: Pro00042760. 
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. 
 
Will I have a chance to provide feedback after the study is over?  
The University of Minnesota Human Research Protection Program (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. 
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 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. 


 
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Will I be compensated for my participation? 
You will be compensated $25  for your time spent on the day 15 study visit. This single payment will be 
made using a pre-paid debit card called Greenphire ClinCard. It works like a bank debit card. 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 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. 
Participant Phone Number: ______________________________________ 
 
Participant Email Address: 
___________________________________________________________________________________________ 
 
 
Are you signing this consent in person (at the hospital with study staff) or remotely?   
O Yes 
O No 
 
All of my questions have been answered, and I have been given the opportunity to decline this research.  
O Yes 
O No 
 
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 
 
 
 
____________________________________________            __________________ 
Signature of Person Obtaining Consent                                       Date 
 


 
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______________________________________________________ 
Printed Name of Person Obtaining Consent 
 
______________________________________________________________________ 
For the Consent of Non-English Speaking Participants when an Interpreter is Used: 
As someone who understands both English and the language spoken by the participant, I represent that 
the English version of the consent form was presented orally to the participant in their own language, 
and that they were given the opportunity to ask questions. 
 
__________________________________________       __________________ 
Signature of Interpreter  
 
 
 
Date 
 
___________________________________________    
Printed Name of Interpreter 
 
OR:  
 
 
 
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. These samples will not have any identifying information (name, date of birth, medical record 
number, SSN, etc.) with them.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 
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 
 


 
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_______________________________________________      __________________ 
Signature of Participant                                                                   Date 
 
 
 
____________________________________________            __________________ 
Signature of Person Obtaining Consent                                       Date 
 
______________________________________________________ 
Printed Name of Person Obtaining Consent 
 
Signature for Optional National Institute of Health (NIH) Vaccine Research 
We are asking you to take part in this optional NIH vaccine 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 by the NIH Vaccine Research Center (https://www.niaid.nih.gov/about/vrc) to find a 
vaccine against COVID-19. 
This optional part of this study includes two extra blood draws (around 2 teaspoons of blood) at 2-3 
months and 5-7 months after you start the study. Additionally 1 extra teaspoon of blood will be drawn 
at your day 0 and 15 blood draw. 
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.  These samples will not have any identifying information (name, date of birth, medical record 
number, SSN, etc.) with them. 
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 COVID-19 vaccine research. You may stay in the main study even if you decide not to take part in 
this vaccine research. Before you consent to give your sample for this optional 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 vaccine research.  You will be 
provided a copy of this signed document. 
 
_______________________________________________ 
Printed Name of Participant 
 
_______________________________________________      __________________ 
Signature of Participant                                                                   Date 
 


 
University of Minnesota  
Page 13 of 13  
 
 
«PiFullName» 
Advarra IRB Approved Version 7 Apr 2020 
Revised «PIApprovalDate» 
 
 
 
____________________________________________            __________________ 
Signature of Person Obtaining Consent                                       Date 
 
______________________________________________________ 
Printed Name of Person Obtaining Consent 
 

Prot_SAP_000.pdf: 
MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
 
Protocol Title 
Randomized Controlled Trial of Losartan for outpatients 
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 
Associate Professor of Emergency Medicine 
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: 1.8   
Date: 5APR2020 
 
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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
 
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 
         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, Past-President Minnesota Society  
of Health-System Pharmacists (MSHP) 
             Email: tsobask1@fairview.org 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent 
Change? 
1.7 
3/26/20 
Changes to I/E criteria, method of 
patient identification and screening 
procedures, data collected, and 
corrected inconsistencies. 
Additional sites added. Additional 
blood testing and home blood 
pressure cuffs added 
Y – updated 
biospecimens and 
risks 
1.8 
3/31/20 
Clarified I/E criteria, added 
stopping rules, expanded eligible 
clinics, clarified table of 
procedures, clarified reporting of 
protocol deviations 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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 
● FV 
 
Fairview Hospital System 
● HCMC  
Hennepin County Medical Center 
● ICD  
 
International Classification of Diseases 
● ICF 
 
Informed Consent Form 
● ICS 
 
Informatics Consulting Service 
● ICU  
 
Intensive care unit 
● LOS   
Length of stay 
● MHealth 
University of Minnesota Health 
● 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 outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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 outpatients with COVID-19 
VERSION DATE:5APR2020 
 
 
1.0 
Objectives 
1.1 
Title: Randomized Controlled Trial of Losartan for outpatients with COVID-19 
1.2 
Purpose: To determine the impact of losartan compared to placebo on the rate of 
hospitalization in outpatients diagnosed with COVID19 not requiring hospital admission 
at the time of initial presentation. 
1.3 
Hypothesis: Losartan will significantly reduce the rate of hospitalization at 15 
days in outpatients not requiring hospitalization after initial presentation. 
1.4 
Study design: Multi-center, prospective, randomized blinded interventional trial of 
losartan (25 mg orally twice daily) versus placebo administered for 10 days or until 
hospital admission. 
1.5 
Study procedures: 
● The trial emphasizes early intervention to prevent the progression of 
respiratory disease. Patients presenting to the emergency department or 
outpatient drive-thru COVID-19 clinics who test positive for the virus will 
be eligible for enrollment and randomization within 72 hours of test result 
and no more than 7 days from symptom onset. 
● Investigators and research coordinators will leverage already functional 
electronic consent procedures to enroll patients safely while also 
minimizing risk to study staff. Patients tested at all locations will be given 
a brochure with study information instructing them to contact the study 
team if interested in a clinical trial (see attached patient-facing study 
related materials). In addition, patients receiving test results by phone 
from the clinical care team will be alerted they may qualify for a research 
study and that study team members may contact the patient about 
eligibility. The patient may opt-out of such followup calls.The eConsent 
platform is currently used in NIH supported StrokeNet and SIREN 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 delivered study drug, a 
thermometer, oropharyngeal swabs, home blood pressure cuff, and a 
urine pregnancy test, if applicable, by courier service within 24 hours of 
randomization. Study personnel will call patients every other day during 
the intervention window to review study drug adherence, review 
symptoms for possible adverse events, remind patients to collect 
oropharyngeal swabs, and administer validated outpatient dyspnea 
assessments at predetermined time points. 
● Patient-collected oropharyngeal swabs will be retrieved using a courier 
service with capacity for transport of biologic specimens 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 the 
presence of any delayed adverse events. Follow-up phone contact and 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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 
measurements by patient self-report, obtained in the medical record, or 
obtained during an in person pre-screening visit 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 currently used by our 
group for this purpose in our group. The database, with the currently 
approved eConsent policy, and is HIPAA compliant. 
● Every other day follow-ups will be recorded by study personnel into a 
RedCap database and will include self-reported AEs and medication 
adherence and maximum daily temperature. On days 0, 4 and 10, a 
previously validated patient-reported outcomes measurement information 
system (PROMIS) dyspnea survey and SF-12 (survey’s attached in 
supplement). In the event the patient is not available or contacted on the 
day of survey administration, surveys administered +/- 1 day will be 
considered before this data point is considered missing. The following 
datapoints will also be collected, if available: 
o Name 
o Date of birth 
o Medical record number (if applicable) 
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 assessment  
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 (if recorded) 
o Clinical laboratory results at presentation (if recorded) 
o Patient-reported 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), 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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 Self-reported home medications [antihypertensives, insulin, non-
insulin diabetes medications, corticosteroids (inhaled or systemic), 
other immunosuppressants hydroxychloroquine, other COVID-
directed treatments] or home oxygen use 
o Use of outpatient COVID-directed treatments (such as 
hydroxychloroquine, Tylenol, ibuprofen, azithromycin, or others) 
o PROMIS Pool v1.0 Dyspnea Characteristics Survey (5 question 
Likert scale survey) (attached) with date/time of administration 
o Short form 12 (SF-12) health survey (attached) with date/time of 
administration 
o Oropharyngeal swab every third day (performed, yes or no) 
o Lowest home blood pressure daily  
o Highest home temperature daily 
o Medication adherence 
o Hospital admission (with date, if applicable) 
a. If admitted: initial vital signs, initial and highest method of 
respiratory support (oxygen by nasal cannula, facemask, 
high flow nasal cannula, CPAP, BIPAP, endotracheal 
intubation, ECMO), initial and worst measures of organ 
failure (SOFA score), and initial and worst markers of 
cardiac injury (troponin, BNP/pro-BNP. CXR or CT chest 
results will be recorded. If patients are admitted to non-
MHealth or HCMC hospitals, we will contact the patient to 
obtain permission to request data from their hospitalization. 
o Date of death (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 de-
identified data sets with all PHI removed will be shared for the purposes 
of data analysis.  
● Oropharyngeal swabs will be patient-collected and placed in pre-
packaged transport to be collected by a biosafety-trained courier service, 
transported and processed to the University of Minnesota BSL-3 lab, and 
frozen at -80 C until later analysis. All biospecimens will be labeled with a 
deidentified patient ID number to prevent inadvertent disclosure of PHI. 
The following data points will be collected for biospecimens:  
o Study ID number 
o Day of protocol 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
o Specimen tracking number 
 
 
2.0 
Background 
2.1 
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 
155,000 people with over 5,900 deaths to date across 100 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  
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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
with a well-established safety profile readily available for immediate clinical trial testing 
and rapid knowledge translation if efficacious. 
2.2 
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 
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.  
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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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.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.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).22 This finding that SARS-CoV results in downregulation of ACE2 has been 
validated in subsequent studies.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 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). 22  
 
 
In 2005, Imai et al 
showed that loss of 
ACE2 leads to 
significantly worse 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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 
(Figure 5, pink triangles) For this study ACE2 
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 doses equivalent to those used 
for clinical treatment of humans were associated with increased survival, decreased lung edema 
and lung injury scores, and decreased IL-6 for mice infected with 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  
 
 
 
 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
 
 
 
 
 
2.3 
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 proposed study will elucidate the role of losartan, this is based on strong 
physiologic and preclinical data as described in detail above.  
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 not sufficiently 
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 the need for hospital 
admission at 15 days from randomization. 
3.2 
Secondary Endpoint(s)/Event(s)/Outcome(s):  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
● Subjective improvement in dyspnea as measured by the dyspnea 
PROMIS measures (survey attached) at day 0, 4 and 10 
● Daily maximum temperature 
● Number of emergency department or clinic presentations within 28 days 
● Disease severity rating on the 7-point ordinal scale [ Time Frame: Day 7, 
15, 28 ] 
o 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 by oropharyngeal swab 
● Ventilator free days, oxygen free days 
● Need for hospital admission and oxygen therapy at 15 days 
3.3 
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. Prevention of acute lung 
injury with an angiotensin receptor blocker such as losartan may reduce the 
development of the primary need for hospitalization. This 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. It is important to emphasize the critical need for research studies that identify 
effective treatments that mitigate the progression of disease requiring hospitalization. To 
provide a specific example, Minneapolis has a metropolitan population of 3.4 million 
residents with approximately 5000 inpatient hospital beds and 500 ICU beds. If only 1% 
of the Minneapolis population developed symptomatic COVID-19 that would equate to 
34,000 patients. Studies support a 13-15% hospitalization rate both in the US (as of the 
time of this writing New York state has 421 cases, 50 hospitalized, 13 in ICU) and 
internationally30 which would constitute 4420 – 5100 beds, nearly the entire metropolitan 
hospital capacity.  
3.4 
Justification of the secondary outcomes: Validated study instruments to assess 
dyspnea and physical function will assess patient-centered outcomes and strengthen the 
biologic plausibility of the intervention. A decrease in inflammation through the reduction 
of pulmonary edema may be observed as a change in fever. The study drug could affect 
the number of presentations requiring evaluation but not result in hospital admission. 
The 7-point ordinal scale described is used by other ongoing COVID-19 clinical trials and 
will allow harmonization of the trial results. 
 
4.0 
Study Interventions / Interventional Agents 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
4.1 
Intervention arm: The intervention is losartan, an angiotensin receptor blocker, in 
microcrystalline methylcellulose, administered at 25 mg PO twice daily for 10 days 
(patients with eGFR 30-60 mL/min/1.73 m2 will be given 25 mg once daily) or until 
hospital admission, whichever comes first.  
● Rationale for the duration of the intervention: The average time from 
symptom onset to hospitalization based on reports to date is 8-9 days.7,31 
We expect participants to present with at least 1-2 days of symptoms. We 
expect most participants to reach their primary endpoint within 10 days of 
treatment (11-12 days from symptom onset), which represents our time of 
maximal efficacy of the intervention in this cohort. We have chosen to 
stop treatment at the time of hospitalization as the participant may or may 
not be admitted to a participating hospital, introducing significant logistical 
limitations.  
● Rationale for the dose of treatment: The lowest dose of losartan is 25 mg 
orally, which minimize risk of side effects and AEs to the patient. 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.32 Twice daily dosing 
has been shown to potentiate angiotensin-II receptor blockade compared 
with once daily dosing. We propose a dose of 25mg twice daily. At this 
dose, extrapolated data suggest 37% inhibition of angiotensin-II 
receptors, which we believe represents an excellent risk: benefit ratio for 
trial participants. At the highest maximum allowable clinical dose (50 mg 
twice daily) we would anticipate 50% inhibition of angiotensin-II 
receptor.32 Multiple early pharmacokinetic studies of losartan at the low-
dose demonstrates the drug has minimal side effects on blood pressure  
(consistently <10 mmHg reduction in maximal systolic blood pressure) in 
healthy patients33-36 without an overactive renin-angiotensin-aldosterone 
system. Clinical exclusion criteria has been added to identify patients who 
might be at increased risk for side effects.  Patients with moderate renal 
dysfunction (eGFR 30-60 mL/min/1.73 m2 will be given 25 mg once daily 
given impaired renal clearance.  
 
4.2 
Placebo arm. Placebo capsules will match, and contain microcrystalline 
methylcellulose only. 
4.3 
Investigational new drug. The study will undergo pre-IND review with the Food 
and Drug Administration to determine the need for an investigational new drug 
assessment, and will be assigned an IND number if required. 
4.4 
Timing of the intervention: Treatment will continue for 10 days or attainment of 
the primary outcome (hospital admission). 
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 pills (#20) will be placed in identical 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
bottles with a deidentified study number coded by site and patient number (e.g. 01-001, 
02-001, etc.). A site-specific randomization schema will be created (each site will 
undergo permuted block randomization with random block sizes stratified by site and 
age). Given significant differences in outcome by age, patients will be randomized by 
age strata (>=50, <50). 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: Following randomization, a courier service will 
ship drugs to study participants within 24 hours of randomization. Each dispensing will 
contain 20 capsules, enough to complete the 10-day therapy 
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. Patient screening will follow one 
of two screening procedures based on the location of their presentation. 
● Emergency department or COVID-specific clinic patients: 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 by delegated members of the 
research team in participating emergency departments. Providers may 
contact study personnel to conduct pre-screening, as well. 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 to determine eligibility 
criteria. Patients seen in the emergency department but whose test 
results did not result prior to discharge will be given a study brochure with 
information to contact the study team if their test results positive and they 
wish to be considered for study participation. In addition, each site has 
clinical staff to call and alert patients regarding positive test results. These 
staff will alert the patient that they are eligible for a research study and 
that they may be contacted by study personnel, and will be given the 
opportunity to opt-out of this research contact. Once contact has been 
made, study personnel will conduct a screening questionnaire to 
determine eligibility criteria. 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
● Drive-thru clinical patients: M Health Fairview will have 4 drive thru 
centers for SARS-CoV-2 screening. Patients presenting to one of the 
centers will be given a brochure informing them that if they test positive 
and are interested in enrolling in a clinical trial of a new treatment for 
COVID-19 to contact our study coordinators (see attached study related 
materials). Once contact has been made, study personnel will conduct a 
screening questionnaire to determine eligibility criteria. 
● Dashboard: In addition, participating sites have an electronic dashboard 
or electronic-medical record based report of all pending and confirmed 
positive COVID-19 tests that can be used for real-time prescreening of 
emergency department or COVID-clinic patients. 
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. Enrollment will similarly 
occur via one of two methods based on location of identification. In all cases, 
consent converations will occur via telemedicine, institutionally approved 
video connection platform, or phone call (drive through patients or ED 
patients discharged prior to randomization) which limit traditional face-to-
face contact. If the participant regains capacity to consent, we will reconsent the 
participant in the study. If they decline, further study procedures will stop but 
previously collected data under the LAR consent will be utilized. If the participant 
does not regain capacity to consent, study procedures will continue under consent 
of the LAR. 
● Rationale for the use of telemedicine, video connection, or 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 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. LARs will not be used for remote consent. Critically, the 
low-dose and established safety profile of losartan, with multiple studies 
demonstrating minimal side effects on blood pressure in healthy 
patients33-36 without an overactive renin-angiotensin-aldosterone system, 
combined with the close remote 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. 
● Emergency department or COVID-clinic patients (patient is still in the 
emergency department or clinic): 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 using tablets with 
telemedicine capabilities housed in the emergency department or with the 
study team.  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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
electronic consent, stored and maintained in a secure RedCap server 
(see departmental policy on eConsent, attached).  
● Non-emergency department or COVID-clinic patients (patient returned 
home) or drive-thru clinic patients: For the sake of healthcare provider 
safety, and to minimize the spread of the virus, pre-screening and 
consent will occur through a video connection or phone call. At this visit, 
consents will be reviewed in detail with the potential participant. The 
potential participant will have the opportunity to ask questions. If the 
participant 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).  
●  Eligible patients who meet inclusion criteria but do not have a 
documented creatinine and blood pressure reading within 7 days of the 
return of their positive COVID19 test results will undergo remote consent 
and enrolled. However, prior to randomization they will be required to 
participate in additional study screening at a clinic location prepared to 
accept known COVID-19 positive patients. The additional screening 
procedures will include: a blood pressure, creatinine, and potassium. 
 
5.3 
Administration of study drug: Patients will be given prepared components 
necessary for conduct of the study, including study drug (losartan or placebo), a 
thermometer, a home blood pressure cuff, and oropharyngeal swabs shipped 
supplies via same-day courier service. 
5.4 
Patient follow-up: Participants will receive phone calls by trained study personnel 
every other day for the 10 days of the intervention period to monitor for the 
development of complications including lowest daily blood pressure (measured at 
least once by home blood pressure cuff provided to the patient and medication 
compliance. Data will be documented into a Redcap database. The coordinators 
will have participants complete 2 qualitative surveys at enrollment, day 4, and day 
10 (both attached in supplement). Surveys and adverse event assessments 
conducted within 1 day of the time point will be counted as qualifying and not 
considered missing. At day 15 (+/- 2 day), patients will be asked to return for 
repeat research blood draw to include creatinine testing. Patients will be contacted 
by phone at day 28 (+/- 3 days) and 90 (+/- 3 days) for short and intermediate term 
outcomes. If there is no follow-up due to lack of patient response, this will be 
documented and not counted as a protocol deviation.  
 
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
5.5 
Table of events: 
 
 
  
Study Day 
  
Screening
/ 
Enrollmen
t* 
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 / 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
ADDITIONAL POST-ENROLLMENT PRESCREENING (IF NOT ALREADY AVAILABLE) 
Pregnancy 
assessment and 
birth control X 
plan** 
X 
 
 
 
 
 
 
 
 
 
 
Blood Pressure 
within 1 week of 
randomization 
X 
 
 
 
 
 
 
 
 
 
 
Creatinine / 
Potassium within 
1 week of 
randomization 
X 
 
 
 
 
 
 
 
 
 
 
Randomize 
subject if eligible 
after additional 
prescreening 
X 
 
 
 
 
 
 
 
 
 
 
POST-RANDOMIZATION 
Demographics 
X 
Medical History / 
CRF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense / 
administer study 
drug**  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
 
 
 
 
 
 
STUDY PROCEDURES (while outpatient)# 
Assessment of 
Hospitalization 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
Adverse event 
assessment 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
 
Review 
adherence 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Review and 
record blood 
pressures and 
temperatures 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
PROMIS Survey 
X 
X 
X 
Short Form 12 
Health Survey 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Oropharyngeal 
swabs 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Potassium / 
Creatinine 
Check  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Follow-up 
biospecimens 
(OP swab + 
blood draw) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
@ 
 
 
Electronic 
medical record / 
death index 
review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
 
*Within 72 hours of + COVID-19 test results,  
**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. For those capable of having children, a pregnancy test will be 
delivered to patients to confirm no pregnancy prior to initiation of study drug. 
#Outpatient follow-ups +/- 1 day are accepted.  
@ We will attempt to obtain oroopharygeal and blood biospecimens from patients hospitalized when they would otherwise 
have been planned  
 
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 sets with all PHI 
removed will be shared for data 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 monitor from Clinical Translational Science Institute (CTSI) 
or 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. 
●  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 
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 (oropharyngeal swabs) provided 
by patients will be transported via courier service with the capacity to 
transport biologic materials with due consideration of communicable 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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. 
● 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.  
8.0 
Study Population 
8.1 
Inclusion Criteria 
● Positive laboratory test for COVID-19 based on local laboratory standard  
● Age greater than or equal to 18 years of age 
● Upper respiratory symptoms (cough, rhinorrhea) or fever (>101.5) 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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. 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.  Patients must be symptomatic to avoid 
enrolling asymptomatic carriers unlikely to meet the primary outcome. 
8.3 
Exclusion Criteria 
● Randomization > 72 hours of meeting inclusion criteria 
● Randomization > 7 days of symptom onset 
● 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 
● Women able to have children 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, condom use or abstinence during the study. All women of child 
bearing age enrolled in this fashion will be informed of the teratogenic 
risks.   
● 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 III or IV 
o Estimated Glomerular Filtration Rate (eGFR) of < 30ml/min/1.73 
m2 (must be have been measured within 1 month of enrollment) 
o Other kidney disease that in the opinion of the investigator, would 
affect losartan clearance 
● Patient reported dehydration and significantly decreased urine output in 
the past 72 hours 
● Most recent systolic blood pressure prior to enrollment <110 mmHg  
● Patient reported history or electronic medical record history of severe liver 
disease, defined as: 
o Cirrhosis 
o History of hepatitis B or C 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
o Other liver disease that in the opinion of the investigator, would 
affect losartan clearance 
o Documented AST or ALT > 3 times the upper limit of normal within 
3 months of randomization (if available in electronic medical 
record) 
● Potassium >5.0 mmol/L (must have been measured within 1 month) of 
enrollment 
● Concurrent treatment with aliskiren 
● Inability to obtain informed consent 
8.4 
Rationale for exclusion criteria: We expect treatment results to be available within 
24 hours of sample collection related to delays in transport to a central facility. Coupled 
with delays in patient contact, 72 hours allows sufficient time for early outpatient 
intervention. Every effort will be made to minimize this window, however. Most patients 
will be hospitalized within 9 days of first symptoms, so patients with >7 days of 
symptoms have limited potential for benefit. 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 (14-40) without a history of hysterectomy 
must have a documented negative pregnancy test in the emergency department or clinic 
in the past 7 days or have had a prior history of hysterectomy. Alternatively, if interested 
in the study, women of childbearing age will be sent a urine pregnancy test and report 
the result by verbal report over telemedicine or phone. Patients returning for 
prescreening labs and vital signs may have a serum pregnancy test performed, instead. 
If negative, they will be considered eligible. Given the class D pregnancy class, women 
of childbearing age must be taking a study-allowed form of contraception for the study 
period. Patients will have potassium and creatinine screening to decrease the risk of 
both kidney injury and decreased clearance. Patients on dialysis or with and eGFR <30 
will be excluded, and 30-60 will have half-dosing. Patients with a documented potassium 
>5.0 will be excluded. Patients with hypotension will be excluded given an expected 
decrease of 6-8 mmHg in their blood pressure. Finally, all patients or their legally 
authorized representative will provide prospective 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.  
 
Population / Group 
Identify whether any of the following 
populations will be targeted, included (not 
necessarily targeted) or excluded from 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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 
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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
 
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 participants, 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 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 serious health condition for which there are no 
satisfactory standard treatments: 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. We will also employ the teach-back method to 
ensure participants understand risks and demands of study participation.  
● 
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 
10.1 
Locations: Enrollment will occur in the ED (or designated COVID19 areas) of 
MHealth Fairview Southdale Hospital, MHealth Ridges Hospital, University of Minnesota 
Medical Center East Bank and West Bank, Hennepin County Medical Center, Bethesda 
Hospital (COVID designated hospital, Mayo Clinic St. Mary’s Hospital, or remotely via 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
the previously described methods for interested participants presenting to one of the 4 
drive-thru clinics or stand-alone COVID clinic. 
 
10.2 Number of participants: We will enroll 580 participants; this will provide adequate 
statistical power for testing our primary hypothesis and allows for 10% loss-to-follow-up. 
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: Patients presenting to either the emergency department 
of the drive-thru clinic tested for COVID-19 will receive an informational brochure 
(attached as addendum) which provides information about testing, call-back, and the 
study. A phone number, email, and website will be created to allow participant to 
express interest in the study.  
11.4 
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. 
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 be withdrawn from the study for repeated 
treatment non-adherence. Participants may also withdraw from the study at any time for 
any reason. All data from 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 remote nature of this study, 
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 patients 
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 circumstances 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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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 
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.34-37 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. 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. 
However, this will be monitored carefully through admission rates and AE/SAE 
reporting to the DSMB, in addition to continuous monitoring of the primary outcome 
by the DSMB. 
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 phone. If a face-to-face evaluation or physical examination is required due to 
concern for adverse events, participants will be directed to a clinic or emergency 
department that is prepared for management of patients with COVID-19, and 
instructed on techniques to minimize exposure of others. 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 
treat,emt group using mean, standard deviation, median, and interquartile range 
(IQR) for continuous variables and frequencies and percentages for categorical 
variables. The primary outcome, hospitalization at day 15, will be summarized by 
group using the sample proportion with 95% asymptotic confidence intervals. 
Treatment groups will be compared using the Chi-square test and the treatment 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
effect will be summarized by the absolute difference in the hospitalization rate 
between groups.  Secondary endpoints will be summarized by the mean and 
standard deviation and compared using the two-sample unequal variance t-test, 
potentially after appropriate data transformations to assure that assumptions of the 
t-test 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. In addition, we 
will perform a preplanned pooled analysis with a planned national outpatient trial of 
losartan versus placebo targeting the same patient population with harmonized 
assessments and outcomes.  
15.2 Power Analysis: Previously published literature from China suggest a 15% 
hospitalization rate for patients infected with coronavirus.7,30 To detect a difference 
in hospital admission rate of 15% in control vs. 7% in the intervention group, with 
alpha of 0.05 and 80% power using a two-sided test, we will need 264 patients in 
each group. We will enroll a total of 290 patients in each group (total sample size of 
580) to account for the possibility of 10% loss-to-follow-up. 
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)   
 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
☐ 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 
☒ 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.). HCMC will enter data 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: 580, BPIC will be used to 
extract structured data, for unstructured data or patients that are not admitted to the 
hospital phone calls by study coordinators will collect data which will be manually 
entered into Redcap. 
 
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)  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
 ☒ Store 
☒ Analyze 
☒ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) Database  
 ☐ Store 
☐ Analyze 
☐ Share 
☒ 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 smart device (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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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. 
 
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 Data 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. A monitor from Clinical Translational Science 
Institute (CTSI) 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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
results of diagnostic procedures are considered to be AEs if the 
abnormality: 
o results in study withdrawal, 
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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
personal physician, believes might reasonably be related to participation 
in this study.  
● 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, hospitalization, 
cardiovascular events (need for vasoactive drugs or fluids for 
hypotension), or respiratory events (worsening hypoxia, worsening acute 
respiratory distress syndrome, or new respiratory failure). 
● Other clinical 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 adverse event reporting can be 
sporadic and inconsistent, so 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 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. 
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) 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
● 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. 
● 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 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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 recognition, while 
SAEs will be reported within 24 hours in the appropriate AE 
module of the case report form (CRF) on Redcap.  
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 hospitalization, the primary SAE of interest) will be 
reported within 24 hours, allowing for continuous study monitoring. We will conduct 
formal interim analyses for safety at 5%, 10%, 15%, 20%, 30%, and 50% of 
enrollment. With a baseline event rate of 15%, this corresponds to formal analyses 
after every ~5 events initially, decreasing to every ~10 as data accumulates. 
Despite the lower number of formal preplanned analyses, the DSMB will still 
receive near real-time reporting of hospitalizations and deaths, and can deviate 
from this strategy and perform earlier testing if desired. 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. 
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. 


MEDICAL PROTOCOL (HRP-590) 
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VERSION DATE:5APR2020 
 
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. 
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 platform with an accompanying phone call or video feed to conduct 
the consent conversation. 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 during the consent conversation and a signed copy will be emailed 
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  


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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): These patient groups 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: The enrollment of these patients will necessarily by affected by the 
location of presentation and timing of assessment. The identification of patients 
who lack consent capacity will not be possible in ED patients discharged or in 
patients presenting to drive-through clinics in this study since capacity 
assessments, such as the UBACC or the MacArthur Competence Assessment 
tool, are difficult to conduct over telemedicine or the phone, and methods of 
administering capacity screening tools in these settings have not yet been 
validating. Patients screened in the ED still physically present could be enrolled. To 
establish capacity in this setting, the MacArthur 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: These patients will be evaluated using the same 
process as 21.6, and may be eligible for consent via an LAR if physically present in 
the ED. 
21.8 
Assent and dissent in adults with fluctuating or limited mental capacity:  
● 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: 
● Emergency Departments 
o M Health Fairview Ridges Hospital - Emergency Department 
o M Health Fairview Southdale Hospital - Emergency Department 
o M Health Fairview University of Minnesota - East Bank 
Emergency Department 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
o M Health Fairview University of Minnesota - West Bank 
Emergency Department 
o M Health Fairview Clinics performing COVID testing 
o Hennepin County Medical Center - Emergency Department 
o Hennepin County Medical Center – Outpatient / COVID-Clinics 
o North Memorial Hospital and Clinics 
o Mayo Clinic – Emergency Department 
o Mayo Clinic – Outpatient / COVID clinics 
● M Health Fairview Drive through COVID-19 testing clinic sites 
o Brooklyn Park Urgent Care 
o Woodwinds Walk-in Clinic 
o Maplewood Walk-in Clinic 
o Oxboro Clinic Urgent Care 
22.2 International Research: N/A  
23.0 Multi-Site Research 
23.1 Study-Wide Number of Participants: 580 
23.2 Study-Wide Recruitment Methods: N/A 
23.3 Study-Wide Recruitment Materials:  Study brochures (attached) will be made 
available at all sites. 
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 
 
25.0 Resources Available 


MEDICAL PROTOCOL (HRP-590) 
SHORT PROTOCOL TITLE: Randomized control trial of losartan for outpatients with COVID-19 
VERSION DATE:5APR2020 
 
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. In addition, more personnel are available if funds are 
released for conduct of this study. 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. 
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