An Open Label Phase 1 Trial of Losartan for Worsening Respiratory Illness in COVID-19
Phase: PHASE1
Conditions: COVID-19
Sponsor: University of Kansas Medical Center

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
 
An open label phase 1 trial of losartan for worsening respiratory illness in COVID-19 
 
 
PROTOCOL 
VERSION 6.0 dated 29May2020 
 
Principal Investigator:  
Matthias Salathe, MD 
Professor 
University of Kansas Medical Center  
Department of Internal Medicine  
Division of Pulmonary, Critical Care and Sleep Medicine  
3901 Rainbow Blvd., Delp 4032 
Kansas City, KS 66160 
 
Sponsor:  
 
 
Matthias Salathe, MD 
Professor 
University of Kansas Medical Center  
Department of Internal Medicine  
Division of Pulmonary, Critical Care and Sleep Medicine  
3901 Rainbow Blvd., Delp 4032 
Kansas City, KS 66160 
 
Medical Monitor:  
 
Mario Castro, MD 
Professor 
University of Kansas Medical Center  
Department of Internal Medicine  
Division of Pulmonary, Critical Care and Sleep Medicine  
3901 Rainbow Blvd., Delp 4032 
Kansas City, KS 66160 
 
Co-PIs:   
 
 
Usman Nazir, MD 
Assistant Professor 
University of Kansas Medical Center  
Department of Internal Medicine  
Division of Pulmonary, Critical Care and Sleep Medicine  
3901 Rainbow Blvd., Delp 4032 
Kansas City, KS 66160 
 
Charles Bengtson, MD 
Assistant Professor 
University of Kansas Medical Center  
Department of Internal Medicine  
Division of Pulmonary, Critical Care and Sleep Medicine  
3901 Rainbow Blvd., Delp 4032 
Kansas City, KS 66160 
 
Lewis Satterwhite, MD 
Associate Professor 
University of Kansas Medical Center  
Department of Internal Medicine  
Division of Pulmonary, Critical Care and Sleep Medicine  
3901 Rainbow Blvd., Delp 4032 
Kansas City, KS 66160 
 
Funding:  
 
 
None 
 

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
Background 
 
As of March 11, 2020, COVID-19 caused by the coronavirus SARS-CoV-2 reached pandemic status. 
Worldwide, there are 121,564 confirmed cases with 4,373 deaths and both numbers are rapidly rising. While our 
understanding of the disease continues to increase, the clinical picture in China can be summarized as follows:1 
median age is 47 years (41.9% females), most common symptoms are fever (88.7% during hospitalization) and 
cough (67.8%), radiographic findings include ground-glass opacities on CT scans (56.4%), and lymphocytopenia 
(83.2%), ICU admissions are required in 6.1% of the cases with 2.3% needing mechanical ventilation and 1.4% 
are dying. In Italy, the numbers are slightly different: median age 65, up to 15% ICU admissions, and current 
death rate up to 6%.  
As the name of the virus indicates, death is usually associated with respiratory failure. Thus, the question is 
how to mitigate the development of lung disease in COVID-19 since no SARS-CoV-2, FDA approved 
therapeutics are available as yet. While trials with anti-viral and other therapies are being conducted, e.g., 
remdesivir2 and chloroquine3, additional safe and nontoxic therapies to prevent progression of lung disease are 
needed. We therefore propose a proof of concept clinical trial with losartan to block angiotensin II type 1 
receptors (AT1R) in the lung of patients with worsening respiratory function due to SARS-CoV-2.  
Arguments to use angiotensin receptor blockers (ARBs) for persons with COVID-19 were recently published in 
at least two opinion pieces.4, 5 More importantly the premise is based on scientific data assembled over years in 
multiple models of viral pneumonia. Like other coronaviruses, SARS-CoV-2 infects cells by binding to 
angiotensin-converting enzyme 2 (ACE2),6, 7 a protein highly expressed in the lung.8 The enzyme is thereby 
downregulated in the setting of viral infection causing dysregulation of the renin-angiotensin axis that results in 
more angiotensin II9 and less angiotensin 1–7, a vasodilator. This finding was confirmed in the systemic 
circulation of patients with H7N9 influenza in whom elevated plasma angiotensin II is associated with worse 
outcome.10 Disproportionate AT1R stimulation has been shown to mediate pulmonary capillary leak and AT1R 
blockade or knockdown is associated with better outcomes in animal models.11, 12 Furthermore, ACE2 null mice 
develop an angiotensin II-mediated cardiomyopathy through unopposed stimulation of AT1R.13 
Since AT1R blockade increases ACE2,14-16 one could be concerned about possibly worsening viral entry with 
worsening outcome. In this context, hypertension is a risk factor for severe COVID-19 disease and hypertension 
rates are high in China. However, ARBs are not commonly used in China to treat hypertension.17 In addition and 
maybe paradoxically, ACE2 upregulation may still be beneficial in disease models,18 possibly by increased 
angiotensin 1–7 production. Interestingly, upregulation of viral binding sites for HIV is also associated with a 
decrease rather than an increase in HIV virulence.5, 19  
 
Thus, good evidence suggests that at least acute treatment with ARBs could ameliorate lung injury in COVID-
19. We therefore propose to test losartan in a Phase I proof of concept and safety trial. The primary hypothesis 
to be tested is that losartan treatment is safe in the setting of acute SARS-CoV-2 infection. Secondarily, losartan 
can potentially reduce the length of respiratory failure due to SARS-CoV-2.  
 
Significance  
Importance of the problem: As outlined above, there is currently no data that supports specific treatment 
options for respiratory failure in COVID-19. There are active or soon to be active clinical trials that may show 
promise in this space such as blocking IL-6 with tocilizumab20 or using hydroxychloroquine. None of these 
therapies are without side effects and alternative or additional approaches could lessen the burden of respiratory 
failure in this patient population.  
 
 
Approach and Protocol  
 
This is an open label, phase 1 clinical trial to evaluate the safety of losartan in respiratory failure due to COVID-
19.  
 
Clinical Trial setup:  
Detailed inclusion and exclusion criteria are listed below. Briefly, 50 patients with COVID-19 and respiratory 
failure who meet criteria and agree to participation in the study will be placed on losartan 25 mg daily on study 
day 0. If parameters are met the dose of losartan will be increased to 50 mg on study day 3. Participants will 
continue losartan until they experience resolution of respiratory failure (normal oxygen levels on room air), are 
discharged from the hospital, meet stoppage criteria (detailed below) or complete 14 days of therapy.  
 
 

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
Primary hypothesis and endpoint:  
• 
Losartan is safe in acute respiratory failure due to SARS-CoV-2.  
 
Secondary endpoints: 
• 
Losartan reduces the number of days on supplemental oxygen in respiratory failure due to COVID-19 
• 
Incidence of mechanical ventilation use 
• 
Days on mechanical ventilation 
• 
Incidence of non-invasive positive pressure ventilation or heated high flow nasal cannula use 
• 
Days on non-invasive positive pressure ventilation or high flow nasal cannula 
• 
Incidence of transfer to ICU from non-ICU hospital bed 
• 
ICU length of stay (days) 
• 
In-hospital mortality 
• 
Hospital length of stay (days) 
• 
Cumulative incidence of severe adverse events 
• 
Cumulative incidence of adverse events 
• 
Change from baseline in oxygenation 
• 
Incidence of medications with possible antiviral activity (hydroxychloroquine, lopinavir/ritonavir, ribavirin 
or remdesivir) or adjunctive therapy use (e.g., tocilizumab)  
• 
Incidence (and length in days) of extracorporeal membrane oxygenation use 
• 
Incidence (and length in days) of renal replacement therapy use 
• 
Intolerance of high dose (50mg) losartan after tolerating 25mg 
• 
Change in SARS-CoV-2 viral load determined by quantitative PCR 
 
Inclusion criteria: 
1.Age >18 years admitted to the University of Kansas Health System. 
2.Confirmation of infection with SARS-CoV-2 by PCR testing. 
3.Hypoxic respiratory failure  
Requiring mechanical ventilation or oxygen OR a SpO2 ≤94% on room air or a PaO2/FiO2 (P/F) ratio 
<300 OR tachypnea (respiratory rate ≥24 breaths/min).  
4.Other concomitant medications such as antivirals and hydroxychloroquine are allowed. 
5.Participants prescribed standard of care (SOC) losartan (25mg QD) within 48 hours of consenting may be 
considered for enrollment if eligibility criteria are met based on EMR data assessment, i.e. no other ARB or 
ACE prior to SOC medication administration. If participant is eligible and signs consent form, investigational 
losartan 25mg QD will be ordered to replace SOC prescription on the following scheduled dose.   
 
Exclusion criteria:  
1.Pregnancy. 
2.Respiratory failure due to a process other than COVID-19. 
3.Intolerance to ARBs. 
4.Previous treatment with an ARB or ACE inhibitor (see exception in inclusion criteria). 
5.Current chronic use of medication with known interactions with losartan including NSAIDs (intermittent prior 
use is acceptable), potassium supplementation aliskiren. 
6.Blood pressure less than 90 mm Hg systolic or 60 mm Hg diastolic recorded on at least two readings 30 min 
apart. 
7.Need for vasopressors, unless norepinephrine ≤0.1 µg/kg/min 
8.Hyperkalemia (serum K+ >5.5 mM). 
9.Known cardiac failure (left ventricular ejection fraction ≤35%), renal insufficiency (Cockcroft-Gault <30 
mL/min/1.73 m2 or urinary output <20 mL/h), hepatic failure (LFTs > 5x normal upper limit). 
10.Known renal artery stenosis. 
11.Neurological, psychiatric, endocrine or neoplastic diseases that are judged to interfere with participation in 
the study. 
12.On another interventional trial (including one for COVID-19) that excludes participation. 
13.Meeting all inclusion criteria for more than 48 hours prior to Day 0 
 
Patients and/or surrogate decision maker who do not give consent to treatment will be asked to allow collection 
of data from their medical record for use as a control group. Patients or surrogate decision makers who cannot 
consent in person, will be consented in accordance to the KUMC remote consent guidelines. 
 

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
Parameters to be collected: 
General: Demographics, clinical symptoms, history of other medical conditions, routine blood work, and 
concomitant medications. Baseline characteristics will include age, sex, race, ethnicity and body mass index, 
Simplified Acute Physiology Score (SAPS) II, National Early Warning Signs (NEWS), Sequential Organ Failure 
Assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II. The APACHE II will be 
collected only for participants admitted in the ICU. 
 
Physical examination: We will record vital signs such as highest and lowest temperatures (˚C), highest 
respiratory rate, highest heart rate, lowest mean arterial pressure (mmHg), highest oxygen requirements and 
body mass index (BMI).  
 
Confirmation of infection with SARS-CoV-2 by PCR testing by chart. Also, documentation of other infections if 
present.  
 
Blood samples: We will collect laboratory values throughout the study (hemoglobin, platelet count, white blood 
cell count, lymphocyte count, liver enzymes, glucose, blood urea nitrogen, creatinine, creatine kinase, lactate, 
and arterial blood gas) and as indicated (LDH, ferritin, troponin), potassium and other values available in EMR. 
Store plasma at beginning and at the end of study for later analysis (possibly IL-6 etc.).  
 
Nasopharyngeal swabs: We will collect nasopharyngeal swabs at study enrollment and end of study to 
determine SARS-CoV-2 viral load by quantitative PCR.  
 
Radiographic imaging will be recorded upon presentation and subsequently thereafter as indicated.  
 
Monitor for deteriorating acute respiratory failure and determine the indication the need for mechanical 
ventilation.  
 
Study procedures (see schematic) 
Day 0 
• 
Labs collected for routine clinical care and the medical record will be reviewed to screen for eligibility. 
Assuring pre-menopausal women have a negative pregnancy test.  
• 
Consenting participants who meet enrollment criteria will be started on losartan 25 mg once daily per 
mouth.  
• 
Treatment group will have nasaopharyngeal swab and research plasma collected for analysis. 
• 
Control group will be followed only for data collection until study completion. 
 
Day 1-2; 
• 
Monitor subject for safety and losartan stoppage criteria. 
• 
For participants following inclusion criteria #5: Day 0 assessments should be performed on enrollment 
day as well as day 1 or day 2 based on first dose of SOC losartan administration. 
 
Day 3: 
• 
Dose escalation: On study day 3 if none of the parameters listed below are met the dose of losartan will 
be increased to 50 mg once daily.  
 
Day 4 until study completion: 
• 
Monitor subject for safety and losartan stoppage criteria. 
• 
Treatment group will have nasopharyngeal swab and research plasma collected at end of study. 
 
Stoppage criteria for losartan 
• 
Hyperkalemia (persistent values >5.5 mM recorded on at least 2 readings). 
• 
Worsening renal function (Cockcroft-Gault <30 mL/min/1.73 m2) or urinary output <20 mL/h. 
• 
Skin rashes, palpitations or other moderate or severe adverse events (interference with usual daily 
activities) without clear explanation should warrant immediate cessation of treatment and notification of 
study personnel. 
• 
Development of sustained hypotension defined as SBP <90 mmHg, DBP <60 mmHg recorded on at least 
two readings 30 min apart or use of norepinephrine >0.1 µg/kg/min. 

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
• 
Any change in monitor lab parameters deemed significant and potentially related to study drug by the 
Investigator. 
 
Dose de-escalation criteria 
• 
Any change in monitoring parameter after dose increase from 25 mg to 50 mg that is considered 
significant by the investigator will trigger a decrease dose back to 25 mg 
• 
If abnormal parameter is resolved and, in the opinion of the investigator, is unlikely to be related to 
losartan will increase dose back to 50 mg 
• 
If de-escalation criteria is met after re challenging 50mg dose, the dose will be once more decreased to 
25mg until the end of the study. 
 
Criteria for resuming after stopping 
• 
If stoppage criteria have resolved and reason for stoppage is felt to be unlikely or possibly related to 
losartan, discussion of resumption of losartan with medical monitor 
• 
Dose resumption will start at 25 mg. If stopped at 25 mg  the dose will be continued for three days 
followed by increase to 50 mg if tolerated. If stopped at 50 mg, 25 mg will be started and escalated to 
50 mg the day after if tolerated.  
 
 
 
Control 
Patients that request to not be treated with Losartan will be approached by the study team to request permission 
for their standard of care treatment and data be followed and recorded by the research team for this study. 
Patients that agree, will sign the consent form, but will not provide a blood sample for research. We will also 
collect medical information relating to safety criteria on historical controls treated at the University of Kansas 
Hospital in the 30 days prior to the study start date (3/25/2020) and during the study period. These controls will 
be retrospectively identified through query of the electronic health record. We will attempt to include controls that 
meet all criteria for enrollment into the study but to achieve a ratio of controls to study participants of 2:1 may 
need include some with exclusion criteria (excluding prior ACE inhibitor or ARB use). Controls identified 
retrospectively will not undergo informed consent as this represents minimal risk.   
 

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
Losartan 
Losartan is an FDA-approved ARB widely prescribed for treatment of hypertension, heart failure, and for renal 
protection in patients with diabetes. The doses proposed in this study are well tolerated by non-hypertensive 
patients without significant effect on blood pressure. The proposed starting dose of losartan is 25 mg orally per 
day with increase to 50 mg orally per day on day 3 if tolerated until they patient is discharged from the hospital, 
met stoppage criteria (above) or completed 14 days of therapy.  
 
The most common side effects are fatigue and dizziness. Serious adverse events that are rare include 
angioedema, hypotension, renal dysfunction or failure, blood dyscrasias, hepatitis, or rhabdomyolysis. The 
following are meant to mitigate risk to the subjects: Dosing will be done in an inpatient setting with clinically 
indicated close observations of blood pressure and organ dysfunction (blood work). Subjects with hyperkalemia, 
renal dysfunction, or who are taking potassium supplements will not be enrolled into the study. Participants will 
be given written descriptions of potential side effects and potential responses to the side effects. 
 
Sample size and Statistics 
Since there is no information on the effects of losartan in human beings suffering from COVID-19, a statistical 
analysis based on efficacy is not possible. From a safety perspective, we would accept considering losartan 
equivalent or superior to the comparison group not receiving losartan (historical or no consent) if there is a ±20% 
difference in total AE/SAEs. Historical controls will be matched with study participants based on upon age, sex 
and disease severity in a 2:1 ratio for safety comparison. From a safety perspective, losartan’s long track record 
as a safe medication is reassuring. See section on DSMB for further details on safety monitoring and analysis.  
 
Confidentiality 
All information provided by the subject to the investigators, and all information that is collected about the 
subjects by the investigators, shall be kept confidential to the extent that is provided by law. Computer data files 
will be stored and backup up to secure, HIPPA compliant, password protected computers and servers. Electronic 
data capture into REDCap system will be used. Access to these databases will be restricted to individuals 
associated with the study who require access to the data to perform their duties. These individuals will be named 
by the principal investigator prior to initiation of the clinical trial. The subject's actual identity cannot be 
ascertained exclusively from these data and the subject's name shall not be used in any publications. All 
investigators and staff involved in the research protocol will be bound by this agreement of confidentiality. 
 
Adverse Event and Serious Adverse Event Documentation  
Definition of an Adverse Event  
For the purpose of this protocol, an AE will be defined as any untoward medical occurrence in a subject during 
the study listed under DMSB - Anticipated Adverse Events and Grading Scale section of this protocol as well 
as safety monitoring data listed on table 1 as well as stoppage criteria for losartan.  
The event does not necessarily have a causal relationship with the treatment. AEs will be collected for both 
study groups, treatment and control from the time the ICF is signed until the subject completes study 
participation.  
Definition of a Serious Adverse Event  
An SAE is any AE that meets any of the following outcomes:  
•  Fatal (death, regardless of cause, that occurs during participation in the study or occurs after participation in 
the study and is suspected of being a delayed toxicity due to administration of the study drug)  
•  Life-threatening, such that the subject was at immediate risk of death from the reaction as it occurred  
•  Inpatient hospitalization or prolongation of hospitalization  

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
•  Persistent or significant disability/incapacity (disability is defined as a substantial disruption of a person’s 
ability to conduct normal life functions)  
•  Congenital anomaly or birth defect  
•  Important medical event that, based upon appropriate medical judgment, may jeopardize the subject or may 
require medical or surgical intervention to prevent 1 of the outcomes listed above (e.g., an allergic 
bronchospasm requiring intensive treatment)  
 
Data Safety and Monitoring Plan and Internal DSMB 
Anticipated Adverse Events and Grading Scale 
Losartan side effects: The most common side effects are fatigue and dizziness. Serious adverse events that 
are rare include angioedema, hypotension, renal dysfunction or failure, blood dyscrasias, hepatitis, or 
rhabdomyolysis (clinical assessment of muscle pain). Skin rashes, palpitations or other moderate or severe 
adverse events without other clear explanation warrants immediate cessation of treatment and notification of 
study personnel, who will take appropriate reporting actions.  
 
Grading Scale 
Grade 1:  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL*Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self care ADL**. 
 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE. 
Activities of Daily Living (ADL) 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
 
Table 1 
 
Adverse event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hemoglobin 
Hemoglobin (Hgb) <LLN - 
10.0 g/dL; <LLN - 6.2 
mmol/L; <LLN - 100 g/L  
Follow up 
Hgb <10.0 - 8.0 g/dL; <6.2 - 
4.9 mmol/L; <100 - 80g/L  
; follow up 
Hgb <8.0 - 6.5 g/dL; <4.9 - 4.0 
mmol/L; <80 - 65 g/L; transfusion 
indicated; stop losartan, follow up 
Life-threatening consequences; 
urgent intervention indicated; 
stop losartan 
Death  
Leukocytes 
<LLN - 3000/mm3; <LLN - 
3.0 
x 10e9 /L; follow closely 
<3000 - 2000/mm3; <3.0 - 2.0 
x 10e9 /L; stop losartan; follow 
up 
<2000 - 1000/mm3; <2.0 - 1.0 
x 10e9 /L; stop losartan; follow up 
and further investigation  
<1000/mm3; <1.0 x 10e9 /L; 
stop losartan; follow up and 
further investigation  
 
Platelets  
<LLN - 75,000/mm3; <LLN 
- 
75.0 x 10e9 /L; follow 
closely 
<75,000 - 50,000/mm3; 
<75.0 
- 50.0 x 10e9 /L; follow 
closely, stop losartan  
<50,000 - 25,000/mm3; <50.0 
- 25.0 x 10e9 /L; follow closely, 
stop losartan,  
<25,000/mm3; <25.0 x 10e9 
/L; follow closely, stop 
losartan, transfer to ICU 
 
Angioedema 
N/A 
N/A 
Angioedema occurs – mild: stop 
losartan, transfer to ICU 
Angioedema occurs – severe 
tongue swelling: stop losartan, 
transfer to ICU 
Death 
Hypotension (for 
participants in ICU on 
sedation for mechanical 
ventilation ONLY) 
Initiation of vasopressors 
 
Increase in vasopressor 
dose to >0.1; stop losartan, 
follow up 
Persistent hypotension without 
alternative cause; stop 
losartan, follow up 
Irreversible end organ 
damage related to 
hypotension; stop losartan, 
follow up 
Death 
Hypotension (for 
participants NOT in ICU on 
sedation for mechanical 
ventilation) 
Asymptomatic, intervention 
not indicated 
Non-urgent medical 
intervention indicated; stop 
losartan, follow up 
Urgent medical intervention or 
transfer to ICU indicated; stop 
losartan, follow up 
Life-threatening and urgent 
intervention indicated; 
losartan, follow up 
Death 

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
Creatinine 
>1 - 1.5 x baseline; >ULN - 
1.5 x ULN; follow up 
>1.5 - 3.0 x baseline; >1.5 -3.0 
x ULN; close follow up 
>3.0 baseline; >3.0 - 6.0 x ULN; 
stop losartan, nephrology 
intervention 
>6.0 x ULN; stop losartan, 
nephrology intervention 
 
Potassium& 
>ULN to 5.5 mmol/L; monitor 
>5.5 - 6.0 mmol/L, stop 
losartan, close follow up 
>6.0 - 7.0 mmol/L; 
urgent intervention indicated, 
stop losartan, intervention 
>7.0 mmol/L; life-threatening 
consequences; stop losartan, 
intervention 
 
AST, ALT,  
alkaline phosphatase 
>ULN - 3.0 x ULN; monitor 
closely  
Asymptomatic with AST,ALT, 
alk.P. >3.0 -5.0 x ULN; >3 x 
ULN with the appearance of 
worsening of fatigue, nausea, 
vomiting, right upper quadrant 
pain or tenderness, fever, rash, 
or eosinophilia or bilirubin 
elevation; stop losartan, 
monitor 
>5.0 - 20.0 x ULN; >5 x ULN for 
>2 weeks; stop losartan, monitor  
>20.0 x ULN; stop losartan, 
monitor, other interventions  
 
CPK# 
>ULN - 2.5 x ULN; monitor 
closely 
>2.5 x ULN - 5 x ULN; stop 
losartan, monitor closely 
>5 x ULN - 10 x ULN; stop 
losartan, monitor closely 
>10 x ULN; stop losartan, 
monitor closely, possible 
admission with other 
abnormalities  
 
& Given that hyperkalemia occurs with patients on Losartan and there could be patients with renal dysfunction that falls 
just under the 1.5 mmol/L creatinine exclusion point, the DMC would recommend a modification to the reporting of 
abnormal results of serum potassium. We suggest that upon receipt of a level greater than 5.5 mM, the blood draw be 
repeated within 24 hours and that the PI for the study respond to the repeat level by either reassuring the patient that all 
is well or if the level is still rising discontinuing the study drug. Since there will be blood draws frequently during this study, 
we feel that continuing the study subject on study drug if the level returned to normal on repeat testing is safe, especially 
in the expected monitored setting. 
#  Only done when clinically indicated  
 
Pregnancy  
Female subjects will be tested for pregnancy by hospital policy. If pregnant they will be excluded.  
 
It is not expected that a female subject becomes pregnant while participating in the study. In the rare case this 
does occur, study drug must be stopped immediately and permanently discontinued. Losartan does not have 
effects on a fetus in the 1st trimester but could later on. The investigator must notify the DSMB and IRB within 24 
hours of the site's knowledge of the subject's pregnancy and other agencies as by law. Pregnancy itself does 
not constitute an AE. Pregnancy test will be performed at all site visits. 
 
Data monitoring plan will be implemented as follows: 
• 
Safety monitoring will be done: 
o All SAEs attributable to study drug will be reported to the study investigator(s) and discussed with 
an internal safety and monitoring group of 5 experts consisting of an intensivist(s), infectious disease 
specialist(s), ethicist and biostatistician. These experts may not report to the PI directly. 
o Any serious AE or SAE attributable to study drug will be shared with the medical monitor and safety 
and monitoring group within 24 hrs. The members will make the decision whether or not to stop the 
trial. 
• 
All SAEs will be reported to the safety and monitoring group and the appropriate agencies including FDA 
and IRB as required.  
• 
All adverse effects will be reported according to the rules to the FDA, the IRB and our internal DMSB 
• 
Initial interim analysis on safety will be done after the first 5 patients and reviewed by the internal DSMB. 
• 
The DSMB may stop the study due to safety or futility. 
• 
All DSMB reports will be shared with the IRB. 
 
Safety Reporting  
Data monitoring plans will be implemented as follows: The study will be closely monitored by the PI and Co-
PIs. Any relevant AE or SAE will be reported to the medical monitor and to the DSMB (separate charter).  
• 
DSMB meeting will occur after the first 5 patients, 25 patients and at end of study, or more frequently if 
needed.  
o Safety monitoring will be done by the DSMB. Safety monitoring will be done as follows: The 
investigators will continuously monitor the study for side effects. If any AE or serious adverse 
events (SAEs) occur, the physicians will assess the event and report them to the appropriate 
authorities if needed as per Good Clinical Practice. Subjects might be withdrawn from the study if 
they experience intolerance to the study medication, initially based on the investigators’ discretion.  
o All adverse effects will be discussed among the investigators 
 
If deemed severe the data will be shared with the medical monitor and the safety and 
monitoring group. The group will make the decision whether or not to stop the trial based on 
safety data. 
• 
All SAEs will be reported to the IRB and the appropriate agencies including FDA as required.  

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
• 
All adverse effects will be reported according to the rules to the FDA (if needed), the IRB and the DSMB. 
 
Safety Reviews  
Safety review will occur at least every month and/or if a SAE occurs. The internal safety and monitoring group 
will meet after the first 5 patients, 25 patients and at end of study or more frequently if needed. If needed, the 
biostatics core will assist in data analysis for adverse events as well (fee for service basis). However, this is a 
small study.   
 
Removal of Subjects from Study 
A subject withdrawal is defined as a discontinuation from the study for any reason. Subjects may withdraw or 
be withdrawn from this study for the following reasons: 
• 
At their own request or at the request of their authorized representative at any time for any reason 
• 
If, in the investigator's opinion, continuation in the study would be detrimental to the subject's well-being 
 
Subjects must be withdrawn from the study for the following reasons: 
• 
Subjects with an occurrence of any medical condition which, either because of its severity or duration or 
necessary change in treatment, contravenes the condition of the study or puts the patient at unnecessary 
risk or harm.  
• 
Subjects with an occurrence of an AE/SAE, which in the opinion of the investigator and/or subject requires 
termination of treatment 
• 
Subjects who are noncompliant with the protocol per the investigator’s discretion 
• 
Pregnancy 
 
In all cases, the reason for withdrawal will be recorded in the subject's medical records and case report forms. 
Subjects who terminate the clinical study prematurely, either at their own request or on the recommendation of 
the clinical investigator, will be considered early terminations. Subjects who withdraw from the study will not be 
replaced but asked that their progress off drug can be followed as well. The DSMB should be notified of all early 
withdrawals and/or termination in the trial.   
 
REGULATORY CONSIDERATIONS 
The protocol will be submitted to the KUMC IRB. The study was registered on clinicaltrials.gov. 
 
ADMINISTRATIVE SECTION 
Protocol Amendments 
Any amendments to the protocol will be approved by the PI and co-investigators and the independent Data 
Monitoring Committee and the DSMB. All amendments will be submitted to the IRBs for review and approval 
prior to implementation unless the amendment details changes related to safety. 
 
Protocol Deviations 
The investigator will only make changes to the protocol procedures when necessary to protect the safety, rights, 
and welfare of the subjects. In such an event where protocol procedures are changed, the investigators are 
responsible for notifying the IRBs and the internal DSMB. 
In the event that an isolated, unforeseen instance occurs resulting in a protocol deviation, the investigators are 
to document this deviation and notify IRBs as by the rules at KUMC.  
 
Case Report Form (CRF) 
All clinical data will be recorded on the CRFs for this study, including their electronics versions (Red Cap and 
Velos databases). 
 
Study Documentation and Records Retention 
The Good Clinical Practice guidelines issued by the Committee for Proprietary Medicinal Products state that 
“The investigator must arrange for retention in strict confidence of the subjects’ identification codes, names and 
addresses for at least 15 years after the completion or discontinuation of the trial.” Subjects’ files and other 
pertinent documentation (i.e., study protocol, signed informed consent forms, drug dispensing logs, 
correspondence, and other documents pertaining to the conduct of the study) must be kept for the maximum 

 
Losartan COVID-19 | V5.0 | 27 APR 2020 
period permitted by the hospital or private office in accordance with the local requirements, but not less than 15 
years.  
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