Clinical trial NCT04360551
Conditions: COVID-19
Sponsor: University of Hawaii
Start date: 2020-07-01; Completion date: 2022-04-26
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will enroll 40 symptomatic outpatients tested positive for Coronavirus 2019 (COVID-19). Patients to be randomized 1:1 to Telmisartan (40 mg) vs placebo to be administered orally once daily x 21 days. Daily, the study patients will be asked to keep a record of the severity of their fever, dyspnea and fatigue and take their blood pressure (BP) and temperature. Study visits to occur on day 1 (entry), day 4, day 10 and day 21. Oro-pharyngeal swabs, and approximately 25 cc of blood will be collected at each study visit for safety labs and for the evaluation of the renin-angiotensin system (RAS) system and for various blood biomarkers of inflammation, coagulation and fibrosis.

Detailed description:

Arms: arm 1: Telmisartan 40 mg po daily x 21 days arm 2: Placebo
Interventions: intervention 1: Telmisartan 40mg intervention 2: Placebo
Intervention descriptions: intervention 1: Angiotensin Receptor Blocker (ARB) intervention 2: Placebo once daily

Protocol documents:
Prot_SAP_000.pdf: 
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HAWAII CENTER FOR AIDS (HICFA) 
CLINICAL STUDY PROTOCOL: H051 
Randomized, Double-Blind, Placebo-Controlled Pilot 
Clinical Trial of the Safety and Efficacy of Telmisartan 
for the Mitigation of Pulmonary and Cardiac 
Complications in COVID-19 Patients 
 
 
 
 
 
 
Principal Investigator: 
 
Cecilia M. Shikuma MD 
 
 
 
 
 
Professor of Medicine 
 
 
 
 
 
John A. Burns School of Medicine 
 
 
 
 
 
University of Hawaii - Manoa 
 
Funding: 
HICFA Discretionary Funds; grant application to NIH pending 
 
Version Number:   3.0 (March 25, 2021) 
 


 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................................................... ii 
LIST OF ABBREVIATIONS ....................................................................................................................................... 5 
STATEMENT OF COMPLIANCE ............................................................................................................................. 6 
PROTOCOL SUMMARY ........................................................................................................................................... 7 
SCHEMATIC OF STUDY DESIGN .......................................................................................................................... 8 
1 
KEY ROLES .................................................................................................................................................... 9 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................... 12 
2.1 
Background Information .................................................................................................................... 12 
2.2 
Potential Risks and Benefits ............................................................................................................ 15 
2.2.1 
Known Potential Risks ................................................................................................... 15 
2.2.2 
Known Potential Benefits .............................................................................................. 16 
3 
OBJECTIVES AND PURPOSE .................................................................................................................. 17 
4 
STUDY DESIGN AND ENDPOINTS ......................................................................................................... 18 
4.1 
Description of the Study Design ...................................................................................................... 18 
4.1.1 
Primary Endpoint ............................................................................................................ 18 
4.1.2 
Secondary Endpoint ...................................................................................................... 20 
4.1.3 
EXPLORATORY ENDPOINTS .................................................................................... 20 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................................... 21 
5.1 
Participant Inclusion Criteria ............................................................................................................ 21 
5.2 
Participant Exclusion Criteria ........................................................................................................... 21 
5.3 
Strategies for Recruitment and Retention ...................................................................................... 21 
5.4 
Participant Withdrawal or termination ............................................................................................. 22 
5.4.1 
Reasons for Withdrawal or Termination ..................................................................... 22 
5.4.2 
Handling of Participant Withdrawals or termination .................................................. 22 
5.5 
Premature Termination or Suspension of Study ........................................................................... 22 
6 
STUDY AGENT ............................................................................................................................................ 23 
6.1 
Study Agent and Control Description.............................................................................................. 23 
6.1.1 
Formulation, Appearance, Packaging, and Labeling ................................................ 23 
6.1.2 
Product Storage and Stability ....................................................................................... 23 
6.1.3 
Preparation ...................................................................................................................... 23 
6.1.4 
Dosing and Administration ............................................................................................ 23 
6.1.5 
Route of Administration ................................................................................................. 23 
6.1.6 
Starting Dose and Dose Escalation Schedule ........................................................... 23 
6.1.7 
Dose Adjustments/Modifications/Delays .................................................................... 23 
6.1.8 
Duration of Therapy ....................................................................................................... 24 
6.1.9 
Tracking of Dose ............................................................................................................ 24 
6.1.10 
Device Specific Considerations ................................................................................... 24 
6.2 
Study Agent Accountability Procedures ......................................................................................... 24 
6.3 
Study Procedures/Evaluations ......................................................................................................... 24 
6.3.1 
Study specific procedures ............................................................................................. 24 
6.3.2 
Standard of care study procedures ............................................................................. 24 


 
 
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6.4 
Laboratory Procedures/Evaluations ................................................................................................ 24 
6.4.1 
Clinical Laboratory Evaluations .................................................................................... 24 
6.4.2 
Other Assays or Procedures ........................................................................................ 25 
6.4.3 
Specimen Preparation, Handling, and Storage ......................................................... 26 
6.4.4 
Specimen Shipment ....................................................................................................... 26 
6.4.5 
Screening ........................................................................................................................ 26 
6.4.6 
Follow-up Screen and Enrollment/Baseline [Entry Visit (Visit 1, Day 1)] ............... 27 
6.4.7 
Follow-up Study Visits ................................................................................................... 28 
6.4.8 
Final Study Visit .............................................................................................................. 29 
6.4.9 
Follow Up Phone CallS ................................................................................................. 29 
6.4.10 
Discontinuation of study treatment .............................................................................. 30 
6.4.11 
Schedule of Events Table ............................................................................................. 31 
6.5 
Concomitant Medications, Treatments, and Procedures ............................................................. 31 
6.6 
Prohibited or Precautionary Medications, Treatments, and Procedures ................................... 31 
6.7 
Participant Access to Study Agent At Study Closure ................................................................... 31 
7 
ASSESSMENT OF SAFETY ...................................................................................................................... 32 
7.1 
Specification of Safety Parameters ................................................................................................. 32 
7.1.1 
Definition of Adverse Events(AE) ................................................................................ 32 
7.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 32 
7.1.3 
Definition of Unanticipated Problems (UP) ................................................................. 32 
7.2 
Classification of an Adverse Event ................................................................................................. 33 
7.2.1 
Severity of Event ............................................................................................................ 33 
7.2.2 
Relationship to Study Agent ......................................................................................... 33 
7.2.3 
Expectedness ................................................................................................................. 34 
7.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 34 
7.4 
Reporting Procedures ....................................................................................................................... 34 
7.4.1 
Adverse Event Reporting .............................................................................................. 34 
7.4.2 
Serious Adverse Event Reporting ............................................................................... 35 
7.4.3 
Unanticipated Problem Reporting ................................................................................ 35 
7.4.4 
Events of Special Interest ............................................................................................. 36 
7.4.5 
Reporting of Pregnancy ................................................................................................ 36 
7.5 
Study Halting Rules ........................................................................................................................... 36 
7.6 
Safety Oversight ................................................................................................................................ 36 
7.6.1 
Routine Safety Oversight .............................................................................................. 36 
7.6.2 
Data Safety Monitoring Board (DSMB) ....................................................................... 36 
8 
CLINICAL MONITORING ............................................................................................................................ 37 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 38 
9.1 
Statistical Hypotheses ....................................................................................................................... 38 
9.2 
Analysis Datasets .............................................................................................................................. 38 
9.3 
Description of Statistical Methods ................................................................................................... 38 
9.3.1 
General Approach .......................................................................................................... 38 
9.3.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 39 


 
 
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9.3.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 39 
9.3.4 
Safety Analyses .............................................................................................................. 39 
9.3.5 
Adherence and Retention Analyses ............................................................................ 39 
9.3.6 
Baseline Descriptive Statistics ..................................................................................... 40 
9.3.7 
Planned Interim Analyses ............................................................................................. 40 
9.3.8 
Additional Sub-Group Analyses ................................................................................... 40 
9.3.9 
Multiple Comparison/Multiplicity................................................................................... 40 
9.3.10 
Tabulation of Individual Response Data ..................................................................... 40 
9.4 
Sample Size ....................................................................................................................................... 40 
9.5 
Measures to Minimize Bias .............................................................................................................. 41 
9.5.1 
Enrollment/ Randomization/ Masking Procedures .................................................... 41 
9.5.2 
Evaluation of Success of Blinding ............................................................................... 41 
9.5.3 
Breaking the Study Blind/Participant Code ................................................................ 41 
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 42 
11 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 43 
11.1 
Ethical Standard ................................................................................................................................. 43 
11.2 
Institutional Review Board ................................................................................................................ 43 
11.3 
Informed Consent Process ............................................................................................................... 43 
11.3.1 
Consent/assent and Other Informational Documents Provided to Participants.... 43 
11.3.2 
Consent Procedures and Documentation .................................................................. 43 
11.4 
Participant and data Confidentiality ................................................................................................ 44 
11.4.1 
Research Use of Stored Human Samples, Specimens or Data ............................. 44 
11.5 
Future Use of Stored Specimens .................................................................................................... 45 
12 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 46 
12.1 
Data Collection and Management Responsibilities ...................................................................... 46 
12.2 
Study Records Retention .................................................................................................................. 46 
12.3 
Protocol Deviations............................................................................................................................ 46 
12.3.1 
Definitions ........................................................................................................................ 46 
12.3.2 
Procedures for Reporting Protocol Violations ............................................................ 47 
12.4 
Publication and Data Sharing Policy ............................................................................................... 48 
12.4.1 
Use of Study Findings ................................................................................................... 48 
12.4.2 
Publication ....................................................................................................................... 48 
13 
STUDY ADMINISTRATION ........................................................................................................................ 49 
13.1 
Study Leadership ............................................................................................................................... 49 
14 
CONFLICT OF INTEREST POLICY .......................................................................................................... 50 
15 
LITERATURE REFERENCES.................................................................................................................... 51 
16 
VERSION HISTORY .................................................................................................................................... 53 
 


 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
ACE 
Angiotensin Converting Enzyme  
ARB 
Angiotensin Receptor Blocker 
CBC 
Complete Blood Count 
CLIA 
Clinical Laboratory Improvement Amendments 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HICFA 
Hawaii Center for AIDS 
HIPAA 
Health Insurance Portability and Accountability Act 
IATA 
International Air Transportation Association 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
NP 
Naso-Pharyngeal 
NSAID 
Non-steroidal Anti-inflammatory Drug 
OHRP 
Office for Human Research Protections 
OP 
Oro-Pharyngeal 
PBMC 
Peripheral blood mononuclear cell(s) 
PD-1 
Programmed death receptor-1 
PI 
Principal Investigator 
PID 
Patient identifier number 
QA 
Quality Assurance 
QC 
Quality Control 
qd 
Daily 
SAE 
Serious Adverse Event 
SID 
Subject identifier number 
SOP 
Standard Operating Procedures 
Sub-I 
Sub-Investigator(s) 
UP 
Unanticipated Problem 
US 
United States 
WBC 
White Blood Cell count 
WHO 
World Health Organization 
 
 
 


 
 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
The principal investigator, co-investigators and clinical trial site staff who are responsible for the 
conduct, management, or oversight of this clinical trial have completed Human Subjects Protection and 
ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the protocol 
and the consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the study. 
In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
Principal Investigator:  Cecilia M. Shikuma MD 
Signed: 
 
Date: 
 
 


 
 
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PROTOCOL SUMMARY 
Title: 
Randomized, Double-Blind, Placebo-Controlled Pilot Clinical 
Trial of the Safety and Efficacy of Telmisartan for the Mitigation 
of Pulmonary and Cardiac Complications in COVID-19 Patients 
Study Description: 
This study will enroll 40 symptomatic outpatients tested positive for COVID-
19. Participants to be randomized 1:1 to Telmisartan (40 mg) vs placebo to 
be administered orally once daily x 21 days. Daily, the study participants will 
be asked to keep a record of the severity of their fever, dyspnea, and fatigue 
and to take their blood pressure (BP) and temperature. Study visits will occur 
on day 1 (entry), day 4, day 10 and day 21. Oro-pharyngeal swabs, and 
approximately 25 cc of blood will be collected at each study visit for safety 
labs and for the evaluation of the renin-angiotensin system (RAS) system and 
for various blood biomarkers of organ function/coagulation, inflammation, 
leukocyte chemotaxis, tissue remodeling/fibrosis and immune exhaustion.  
Objectives: 
Primary Objective:  
Compare the maximum clinical severity of disease between the telmisartan 
and the placebo arms utilizing a modified WHO COVID-19 7-point ordinal 
scale 
Hypothesis: Overall severity of disease will be less on the telmisartan arm 
compared to the placebo arm  
 
Secondary Objectives:  
 
Evaluate the safety and tolerability of Telmisartan when given over 
21 days to patients with COVID-19 disease 
 
Compare the circulating RAS metabolites between the 2 arms; assess 
the ability of RAS metabolites to predict clinical status 
 
Compare plasma biomarkers between the 2 arms; assess the ability 
of plasma biomarkers to predict clinical status  
 
Exploratory Objective: 
 
Longitudinally assess the detectability of SARS-CoV-2 virus  
Endpoints: 
Primary Endpoint: Maximal clinical severity of disease utilizing a modified 
WHO 7-point ordinal scale 
Secondary Endpoints:  
 
Number of grade II or higher adverse events (AE) through day 21 of 
study  
 
Levels of various components of the RAS system including Ang(1-12), 
AngI, AngII and Ang(1-7)  
 
Levels of various blood biomarkers  
Exploratory Endpoint: 
 
SARS-CoV-2 detectability in OP samples  
Study Population: 
Forty (40) symptomatic participants diagnosed positive for COVID-19. 


 
 
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Phase: 
Phase II trial 
Description of 
Sites/Facilities Enrolling  
Single site study at the John A. Burns School of Medicine – Kakaako campus, 
University of Hawaii  
Description of Study 
Intervention: 
Telmisartan is a member of a family of angiotensin receptor blockers (ARB) 
anti-hypertensive medications.  
Study Duration: 
One year total duration of study 
Participant Duration: 
21 day participation for each patient 
 
 
SCHEMATIC OF STUDY DESIGN 
 


 
 
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1 
KEY ROLES 
 
Principal Investigator 
Cecilia Shikuma, MD 
Professor, Medicine 
Hawaii Center for AIDS 
John A. Burns School of Medicine 
University of Hawaii - Manoa 
651 Ilalo Street, Suite 231 
Honolulu, HI 96813 
phone: (808) 692-1310 
fax: (808) 692-1345 
email: shikuma@hawaii.edu 
Clinical Sub-Investigator 
Dominic Chow, MD, PhD 
Professor, Medicine 
Hawaii Center for AIDS 
John A. Burns School of Medicine 
University of Hawaii - Manoa 
651 Ilalo Street, Suite 231 
Honolulu, HI 96813 
phone: (808) 692-1310 
fax: (808) 692-1345 
email: dominicc@hawaii.edu 
Other Investigators 
Chunrong Lin MD 
Pulmonology/Critical Care Medicine 
Queen’s Medical Center 
1601 Punchbowl St 
Honolulu, HI 96813 
email: chunronglin@yahoo.com 
Corey Lum MD 
Cardiology 
Queen’s Medical Center 
1601 Punchbowl St 
Honolulu, HI 96813 
email: coreylumdo@gmail.com 
Brooks Mitchell PhD 
Lecturer, Department of Tropical Medicine, Medical Microbiology 
and Pharmacology 
Hawaii Center for AIDS 
John A. Burns School of Medicine 
University of Hawaii – Manoa 


 
 
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email: brooksim@hawaii.edu 
Rui Sun PhD 
Assistant Professor, Dept of Chemistry 
University of Hawaii – Manoa 
email: ruisun@hawaii.edu 
Iain MacPherson PhD 
Assistant Professor, Dept. of Tropical Medicine, Medical 
Microbiology and Pharmacology 
John A. Burns School of Medicine 
University of Hawaii – Manoa 
Email: iain@hawaii.edu 
Collaborator 
 
 
 
Stan Louie PharmD 
Professor, Clinical Pharmacy & Director of Clinical Experimental 
Therapeutics Program 
Clinical Pharmacy 
University of Southern California 
email: slouie@usc.edu 
Biostatistician 
 
 
 
Chathura Siriwardhana Ph.D. 
Assistant Professor, Dept of Quantitative Health Sciences  
John A. Burns School of Medicine 
University of Hawaii – Manoa 
cksiri@hawaii.edu 
Research Unit Coordinator 
Debra Ogata-Arakaki, RN 
Hawaii Center for AIDS 
John A. Burns School of Medicine 
University of Hawaii at Manoa 
651 Ilalo St., BSB 231  
Honolulu, Hawaii 96813 
phone: (808) 692-1332  
fax: (808) 692-1345 
email: ogataara@hawaii.edu 
Research Nurse 
Cris Milne RN 
Hawaii Center for AIDS 
John A. Burns School of Medicine 
University of Hawaii at Manoa 
651 Ilalo St., BSB 231  
Honolulu, Hawaii 96813 
phone: (808) 692-1336  
fax: (808) 692-1345 
email: cmilne@hawaii.edu 
Research Pharmacist 
Scott Souza, PharmD 


 
 
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Adjunct Assistant Professor of Medicine 
Hawaii Center for AIDS 
John A. Burns School of Medicine 
University of Hawaii at Manoa 
651 Ilalo St., BSB 231  
Honolulu, Hawaii 96813 
phone: (808) 691-7542  
fax: (808) 691-4098  
email: ssouza@hawaii.edu 
Processing Lab Technician 
Clay McClure 
Hawaii Center for AIDS 
John A. Burns School of Medicine 
University of Hawaii at Manoa 
651 Ilalo St., BSB 231  
Honolulu, Hawaii 96813 
phone: (808) 692-1334  
fax: (808) 692-1345  
email: claymc@hawaii.edu 


 
 
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2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
BACKGROUND INFORMATION 
COVID-19 Pandemic  As of the writing of this protocol, there  2,394,278 cases  of Covid-19 in 185 
countries and regions throughout the world and approximately 83,764 new cases occur daily. In the 
largest cohort of >44,000 persons with COVID-19 from China, while disease severity was mild to 
moderate in 81%, pulmonary and multi-organ system dysfunction complications account for the 
majority of the morbidity and mortality of this disease. Severe disease (dyspnea, hypoxia, or >50% lung 
involvement on imaging) occurred in 14%, and critical disease (respiratory failure, shock, or multiorgan 
system dysfunction) occurred in 5%. Among U.S. COVID-19 cases with known disposition, the proportion 
of persons who were hospitalized was 19%1. Among patients who developed severe disease, the 
medium time to dyspnea ranged from 5 to 8 days, the median time to acute respiratory distress 
syndrome (ARDS) ranged from 8 to 12 days, and the median time to ICU admission ranged from 10 to 12 
days2-5. Age is a strong risk factor for severe illness, complication and death1, and the case fatality is 
higher for patients with co-morbidities: 10.5% for those with cardiovascular disease, 7.3% for diabetes, 
and approximately 6% each for chronic 
respiratory disease, hypertension and cancer6. 
Compared to other states, Hawaii has had 
relatively few cases (574 confirmed COVID-19 
cases as of April 19, 2020). Early institution of 
public health measures including the mandatory 
14-day quarantine for all individuals flying into 
Hawaii have been credited for these low number. 
However, without an effective vaccine, as 
normalization of the economy and re-opening of 
our state to visitors are attempted, more cases of 
COVID-19 may be inevitable.  
Renin-Angiotensin System (RAS) RAS is 
a hormonal system best known for its ability to 
regulate blood pressure, fluid and electrolyte 
balance and systemic vascular resistance. As 
shown in very simplistic form in Figure 1, 
angiotensinogen, released by the liver, is 
converted by the action of renin into angiotensin 
I [AngI; also known as Ang-(1–10)]. AngI is 
subsequently converted to angiotensin II [AngII; 
Ang-(1–8)] by the angiotensin-converting enzyme 
(ACE1) found on the surface of vascular 
endothelial cells, predominantly in the lung.  
The effect of AngII is receptor-specific with 2 predominant receptors: angiotensin II type 1 receptor 
(AT1R) and angiotensin II type 2 receptor (AT2R). AngII/ AT1R binding leads to the classic ‘deleterious’ 
Figure 1. ‘Deleterious’ and ‘Protective’ Aspects of the 
Renin-Angiotensin System (RAS) 
 
 


 
 
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effects of AngII, including hypertension, arterial wall thickening, impaired lung function and fibrosis. It 
has increasingly been demonstrated that AngII/AT1R binding also plays an important role in lung 
inflammation, impaired function and fibrosis. In mouse models of ARDS, AngII/AT1R binding leads to 
impaired lung function and fibrosis7. Elevated circulating AngII concentrations in influenza A (H7N9) 
pneumonia were associated with higher mortality rates8. Angiotensin receptor blockers (ARB) 
medications such as telmisartan used for the treatment of hypertension and cardiovascular risk 
reduction exerts its known anti-hypertensive, cardio -protective effect by blocking the binding of AngII 
to AT1R. There is evidence that ARB may also have lung-protective effects9. 
Accumulating evidence suggests that, in contrast, an alternative, counter-regulatory ‘protective’ arm of 
the RAS system exists and that it is mediated by 2 alternative pathways as shown in Figure 1 which may 
be inter-related: (1) an alternative interaction of angiotensin II with AT2R;  and (2) the activity of the 
enzyme angiotensin-converting enzyme 2 (ACE2) to cleave AngI and AngII ultimately to angiotensin (1-7) 
[Ang(1-7)]. Both the angiotensin II/AT2R and the angiotensin (1-7) /Mas receptor (MasR) interactions 
promote the counter-regulatory ‘protective’ effects of RAS that includes vasodilation, anti-inflammatory 
and anti-fibrotic responses. Our collaborator for this project (S Louie PharmD) and his colleagues have 
published that increased activity of this counter-regulatory RAS system as measured circulating 
angiotensin peptide levels correlate with survival of Acute Respiratory Distress Syndrome (ARDS) 
patients10. 
SARS-CoV2 and ACE2 Severe Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) responsible for the 
SARS epidemic in 2002 to 2004, and the SARS-CoV-2 virus responsible for the current COVID-19 
pandemic, both utilize ACE2 as the receptor to enter the cells it infects11,12. ACE2 is found attached to 
the cell membrane of lung alveolar epithelial cells, enterocytes of the small intestines, arterial and 
venous endothelial cells and arterial smooth muscle cells in most organs13. It has been postulated that 
the lack of ACE2 may lead to unopposed AngII accumulation and local unfavorable RAS activation, and 
therefore may be responsible for much of the organ injury in COVID-19 disease14. Several data support 
this view. Down-regulation of ACE2 abundance on cell surfaces has been demonstrated in mouse studies 
after the initial engagement of SARS-CoV-2 spike protein15. Down-regulation of ACE2 activity in the lung 
in response to bacterial endotoxin in a murine model has been shown to promote the release of 
proinflammatory chemokines, increase neutrophil infiltration, and exaggerate lung injury16. Elevated 
levels of plasma AngII have been demonstrated in a small study of patients with COVID-19 which in turn 
correlated with total viral load and degree of lung injury17. In autopsies of patients who died from SARS, 
35% of heart samples showed the presence of viral RNA, which in turn was associated with reduced 
ACE2 protein expression18. 
Telmisartan  an ARB approved in 1998 for the treatment of hypertension and for cardiovascular risk 
reduction.  It is marketed by Boehringer Ingelheim Pharmaceuticals, Inc as Micardis but is also available 
in generic form. The dosage of 40 mg once daily is the recommended starting dose. The drug has been 
evaluated for safety in more than 3700 patients in clinical trials. Adverse events are generally mild with 
overall rates similar to that in placebo and rarely require discontinuation of therapy. The adverse events 
most commonly seen were upper respiration infection, back pain, sinusitis, diarrhea and pharyngitis. 
There are only a few contraindications to its use in the package insert. It is contraindicated in individuals 
with diabetes who are also receiving concomitant aliskiren, has a black box warning to discontinue 
telmisartan when pregnancy is detected because of fetal toxicity and should not be used while breast 
feeding.  Telmisartan may also increase digoxin and lithium levels upon co-administration. Nonsteroidal 


 
 
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anti-inflammatory agents and COX2 inhibitors could reduce the antihypertensive effects of telmisartan 
and can decrease renal function. Evidence for potential antiviral activity of Telmisartan Computational 
methods for screening and identifying candidate therapeutic compounds are a reliable and productive 
approach in drug discovery. Our group implemented a structure based virtual screening method to 
identify compounds that may have activity against SARS-CoV-2. Of the over 1900 compounds screened, 
we identify an angiotensin receptor blocker with binding affinity for the viral 3 Chymotrypsin-like 
protease (3CLPro) (Souza, unpublished data. comparable to the N3 inhibitor of the crystal structure (PDB 
6LU7). Its lowest energy conformer places the benzoic acid moiety of telmisartan over the active site of 
3CLpro defined by Cys 145 and His 4119. By amino acid sequence alignment of SARS CoV pp1ab with 
SARS-CoV-2 pp1ab, 3CLpro is thought to be responsible for cleaving the SARS-CoV-2 pp1ab at 11 sites 
that result in the formation of 11 non-structural proteins (Nsp)20. Among these proteins are Nsp12, the 
RNA dependent RNA polymerase (RdRp), a key enzyme responsible for replication of SARS-CoV-2 RNA,  
Nsp7 and Nsp8 (cofactors for RdRp) and Nsp 13 (Helicase). 
We further characterized the interaction between telmisartan and 3CLpro using an atomistic molecular 
dynamics simulation. The N3 ligand associated with the crystal structure was used to locate the 
substrate binding cleft of 3CLpro and study the interaction with telmisartan. One monomer (the 3CL 
protease exists as a dimer, but the binding site is far from the monomer-monomer interaction area and 
one telmisartan molecule were solvated in water and were allowed to interact in unbiased simulations 
over a timeframe of microseconds. Preliminary data suggest that telmisartan forms a favored interaction 
with the 3CLpro  binding site. It is important to note that further inside from the initial binding site, 
there is a hollow area that includes hydrophilic residues, making further tight binding possible. Our 
results support the bioinformatics study which suggests telmisartan shows a promising binding 
propensity for 3CLpro. 
RATIONAL FOR THE STUDY: 
There is a need for a therapeutic modality to minimize the severity of COVID-19 disease Currently 
there are no FDA-approved drugs demonstrated safety and efficacy in randomized controlled trials in 
patients with COVID-19. As of April 10, 2020, there were over 440 clinical trials of COVID-19 registered 
on ClinicalTrials.gov. While there were a few trials proposing to utilize another ARB losartan singly or in 
combination, to the best of our knowledge this is the only trial to propose telmisartan.  
Telmisartan is an FDA-approved drug. Repurposing FDA approved drugs can expedite the treatment of 
diseases particularly for conditions of unmet needs. The safety of these drugs has already been 
evaluated by the FDA and the risk associated with their use is well documented. Repurposed drugs can 
lower development costs and shorten the time it takes to treat patients. 
Our central hypothesis is that the 
use of telmisartan will mitigate the 
symptomatic severity of COVID-19 
disease by influencing the balance 
between the pathologic and 
counter-regulatory aspects of RAS. 
As shown in Figure 2A (left), the 
binding of the SARS-CoV2 virus to 
ACE2 results in an imbalance in the 
Figure 2. (Left) Unopposed SARS-CoV2 viral influence on the RAS and 
(Right) SARS-CoV2 viral influence on RAS with the addition of 
Telmisartan (Adapted from Stone, RE et al Journal of Neuroimmune 
Pharmacology 2019) 
 
 


 
 
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RAS with an increase in the pathologic effects mediated by a decrease in ACE2, i.e. an increase in AngII 
with excessive binding to AT1R and a decrease in the counter-regulatory protective effects of angII/AT2R 
and A(1-7)/MasR binding. We hypothesize that telmisartan (Figure 2 right) will block the AT1R receptor, 
and correct this imbalance, i.e. resulting in a decrease in AngII/AT1R binding and an increase in 
AngII/AT2R and A(1-7)/MasR binding.  
In addition, we hypothesize that telmisartan may have an anti-viral effect against SARS-CoV-2. By 
computer simulation, telmisartan appears to have the ability to bind to the 3CL protease and may 
effectively prevent the creation of discrete viral proteins necessary for the development of infectious 
SARS-CoV-2 virions.  
This pilot study will provide important preliminary data on the pathogenesis of COVID-19 disease. We 
propose assays of RAS peptides performed by a laboratory with demonstrated expertise in this area 
Assays of circulating angiotensin peptides levels conducted in Dr. S Louie’s laboratory have been used to 
correlated clinical outcomes in patients with Acute Respiratory Distress Syndrome10. We also propose to 
assay various plasma biomarkers of organ function/coagulation, inflammation, leukocyte chemotaxis, 
tissue remodeling/fibrosis and immune exhaustion. 
2.2 
POTENTIAL RISKS AND BENEFITS 
2.2.1 KNOWN POTENTIAL RISKS 
According to the FDA- approved package insert, telmisartan is contraindicated in individuals with a 
history of known hypersensitivity to the drug or its components and in individuals with diabetes who are 
also receiving concomitant aliskiren. It is not recommended in pregnant or breast feeding female 
because it can reduce fetal renal function and increase fetal and neonatal morbidity and death. NSAIDs 
is believed to increase risk of renal impairment and loss of anti-hypertensive effect. Co-administration 
with digoxin increases the digoxin peak plasma concentration (49%) and in trough concentrations (20%). 
Reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium.  
The drug has been evaluated for safety in more than 3700 subjects in clinical trials, including 1900 for 
over 6 months and more than 1300 for over one year. Adverse experiences have generally been mild 
and transient in nature and have infrequently required discontinuation of therapy. In placebo-controlled 
trials, the overall incidence of adverse events was similar to that in patients treated with placebo. 
Adverse events occurring at an incidence of > 1% in in patients treated with telmisartan and at a greater 
rate than in patients treated with placebo, irrespective of their casual association, were as below: 
 
The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of 
patients. Warning and precautionary measures recommended in the package insert include the need to 
correct or follow closely patients who are volume- or salt-depleted; and to monitor for risk of 
hyperkalemia particularly in those with advanced renal impairment, heart failure or on renal 
replacement therapy. 


 
 
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2.2.2 KNOWN POTENTIAL BENEFITS 
Telmisartan is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood 
pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial 
infarctions. According to the package insert, the antihypertensive effects of Telmisartan have been 
demonstrated in six principal placebo-controlled clinical trials, studying a range of 20 to 160 mg; one of 
these examined the antihypertensive effects of Telmisartan and hydrochlorothiazide in combination. 
The studies involved a total of 1773 patients with mild to moderate hypertension (diastolic blood 
pressure of 95 to 114 mmHg), 1031 of whom were treated with Telmisartan. Following once daily 
administration of Telmisartan, the magnitude of blood pressure reduction from baseline after placebo 
subtraction was approximately (SBP/DBP) 6 to 8/6 mmHg for 20 mg, 9 to 13/6 to 8 mmHg for 40 mg, 
and 12 to 13/7 to 8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further 
decrease in blood pressure. 
Some beneficial effects not related to its anti-hypertensive effects have also been reported at least for 
ARB medications in general. ARB medications have been reported to suppress mediators of 
inflammation, including ROS and C-reactive protein, and they increase expression of inhibitory κB (an 
inhibitor of nuclear factor-κB)21,22. It has also been reported that the use of ARBS lower progression of 
emphysema and lower incidence of inflammatory complications including rates of pneumonia and 
influenza9. In animal models, inhibition of AT1 signaling has been shown to attenuate experimental 
pulmonary fibrosis induced by bleomycin, radiation, and hyperoxia. In a pilot clinical study, Couluris et 
al. evaluated the effect losartan, an AT1 antagonist, on idiopathic pulmonary fibrosis progression over 
12 months23. The study demonstrated stable or improved pulmonary function testing in 12 of the 17 
patients treated with losartan. The authors concluded that losartan is a promising low-toxicity agent for 
treatment of idiopathic pulmonary fibrosis that requires more extensive evaluation in a placebo-
controlled multicenter trial. 


 
 
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3 
OBJECTIVES AND PURPOSE 
 
Primary Objective: 
Compare the maximum clinical severity of disease between the telmisartan 
and the placebo arms utilizing a modified WHO COVID-19 7-point ordinal scale 
Secondary Objectives: 
 
 
Evaluate the safety and tolerability of Telmisartan when given over 21 
days to participants with COVID-19 disease 
 
 
Compare the circulating RAS metabolites between the 2 arms; assess 
the ability of RAS metabolites to predict clinical status 
 
 
Compare plasma biomarkers between the 2 arms; assess the ability of 
plasma biomarkers to predict clinical status  
 
Exploratory Objective: 
 
Longitudinally assess the detectability of SARS-CoV-2 virus  
 


 
 
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4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
A 21 day, randomized, double-blind, placebo-controlled pilot study of Telmisartan in patients with 
symptomatic COVID-19 disease. The study is structured as a pilot study to assess whether telmisartan 
may be effective in mitigating the pulmonary and cardiac complications of COVID-19 disease. Forty 
study participants will be randomized 1:1 to receive Telmisartan 40 mg or Placebo once daily for 21 
days. Study specific procedures include daily log of fever, dyspnea and fatigue symptomology and daily 
blood pressure and temperature monitoring to be performed by the participant. Oro-pharyngeal swab, 
and blood draw for safety labs and research assays will be obtained at day 1 (entry), day 4 (72 hours 
post entry), day 10 and day 21 (end of study).  
4.1.1 PRIMARY ENDPOINT 
The primary endpoint is the maximum clinical severity of disease for each participant as assessed on a 7-
point Clinical Status ordinal scale adapted from the WHO MASTER PROTOCOL for the Treatment of 
COVID-19 in Hospitalized Patients. The WHO 7-point scale was modified by adding sub-categories for the 
categories of ‘Not hospitalized, limitation on activities’ (based on scoring on a Symptom Scale to be 
filled out by participants daily, as explained below), as well as for the ‘Hospitalized, requiring 
supplemental oxygen’ and ‘Hospitalized, on non-invasive ventilation or high flow oxygen devices’ 
categories. For non-hospitalized participants, the maximum clinical severity recorded for any day > day 3 
of study will be used. For participants who become hospitalized, the maximum clinical severity prior to 
discharge will be used. 


 
 
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‘Symptom Scale’ to be used for sub-classification of the ‘Not hospitalized, limitation on activities’ 
category on the modified WHO 7-point ordinal scale is as shown below. The participant will be asked to 
daily grade each symptom by severity to obtain a total score. For example, the assessment of grade 2 
fever (2 points), grade 1 breathing (1 point) and grade 3 fatigue (3 points) will result in a total score on 
the symptom scale of 6 for that day. Referring back to the Clinical Status classification above, the clinical 
status on the 7 point ordinal scale would be ‘not hospitalized, limitation on activities (b) 4-6 points’ for a 
clinical status score for the participant on that day of 2.25. 


 
 
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4.1.2 SECONDARY ENDPOINT 
o Number of grade II or higher adverse events (AE) through day 21 of study  
o Levels of various components of the RAS system including Ang(1-12), AngI, AngII and Ang(1-7)  
o Levels of various blood biomarkers  
4.1.3 EXPLORATORY ENDPOINTS 
o  SARS-CoV-2 detectability in OP samples  
 


 
 
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5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 
• 
Able to provide written informed consent prior to initiation of any study procedures. 
• 
Understands and agrees to comply with planned study procedures including self testing of blood 
pressure daily 
• 
Male or non-pregnant female adult ≥18 years of age at time of enrolment. 
• 
Subject reported positive SARS-CoV-2 test by a commercial laboratory or public health assay in 
any specimen collected ideally < 72 hours prior to randomization. Exceptions to the <72 hr 
inclusion criteria may be made at the discretion of the investigator. 
• 
Positive for COVID-19 symptoms: fever defined as a temperature of >100.4 on study screening 
or self-report of daily fever at home OR shortness of breath of any degree OR fatigue causing 
greater than minimal interference with usual social & functional activities 
• 
Women of childbearing potential must agree to use at least one primary form of contraception 
for the duration of the study 
• 
Able to easily swallow pills  
5.2 
PARTICIPANT EXCLUSION CRITERIA 
• 
Immediate need for hospitalization on screening 
• 
Systolic blood pressure less than 100 mmHg 
• 
Self-reported presence of chronic kidney disease or requiring dialysis  
• 
Self-reported history of liver failure or untreated hepatitis B or C 
• 
Pregnancy or breast feeding 
• 
Allergy to the study medication 
• 
Current use of ARB or ACE Inhibitor medications. Other blood pressure medications will be 
permitted in the systolic BP is higher than 90 mmHg 
• 
Prior reaction or intolerance to ARB or ACE Inhibitor 
• 
Use of aliskiren participant 
• 
Current use of and on-going need for lithium, digoxin, potassium sparing diuretics such as 
spironolactone 
• 
Current use of and need for potassium supplements 
• 
Current or past participation in a research study within 12 weeks prior to the Screening Visit 
unless cleared by Study Team 
• 
Inability to arrange a safe environment for study visits 
• 
Subjects, who, in the opinion of the investigator, are unable to comply with the protocol 
evaluation, or for whom study participation may not be advisable 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Information about the study will be circulated widely to community physicians and medical 
establishments. Information about the availability of the study may be distributed at SARS-CoV-2 test 
sites or made known by public advertisement including by web. All advertisement materials will be 
approved by the UH Human Subjects Committee prior to its use.  


 
 
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To compensate participants for time and effort, participants will be given $60 at each study visit, for a 
maximum of $240 total ($60 x 4 visits) for participation in the study. 
 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Each participant may discontinue study drug and/or withdraw completely from the study for any reason. 
The date and reason for termination or withdrawal will be documented.  
Premature Termination of Study Drug for a study participant may occur for the following reasons: 
o Possible drug-related AE or toxicity which, in the judgment of the PI or Sub-I, is 
considered to not be in the subject’s best interest 
o Request by the subject to terminate study drugs 
o Subject cannot make scheduled visit(s) 
o Subject does not provide OP or blood sample(s) 
Withdrawal completely from the study may occur for the following reasons: 
o Failure to comply with the provisions of the protocol 
o Request by the subject to withdraw. 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
Participants may withdraw or terminate involvement at any time for any reason, and that request will 
be honored.  
No discontinuation visit is necessary. However, participants who terminate or withdraw for toxicity 
reasons will be followed for that toxicity until the toxicity is resolved.  
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated at the discretion of the study 
team. Study participants will be informed of study suspension or termination and whether the 
circumstances that led to this decision confers possible added risk to study participants. 
Regulatory authorities including the IRB, the Food and Drug Administration (FDA), and ClinicalTrials.gov 
will be notified as warranted. 


 
 
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6 
STUDY AGENT 
6.1 
STUDY AGENT AND CONTROL DESCRIPTION 
6.1.1 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Telmisartan is a non-peptide angiotensin II receptor (type AT1) antagonist. 
It is chemically described as 4'-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-
biphenyl]-2-carboxylic acid. Its empirical formula is C33H30N4O2, its molecular weight is 514.63, and its 
structural formula is: 
 
Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 
3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base 
Telmisartan is available as a patented drug originally FDA approved in 1998 and marketed under the 
trade name Micardis. Multiple different generics are also available with tablets varying in size, color, and 
shape. The appearance, packaging and labeling also differs by the generics on the market. This study will 
select and utilize one specific formulation for all its needs.  
6.1.2 PRODUCT STORAGE AND STABILITY 
 Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) 
6.1.3 PREPARATION 
Study medication to be dispensed to participants will be prepared by the research pharmacist.  
Telmisartan and matching placebo will be prepared using over-encapsulation. 
6.1.4 DOSING AND ADMINISTRATION 
Telmisartan will be dosed in this study as one tablet of 40 mg to be taken by mouth daily. All study 
medication will be dispensed to the study participant by the research pharmacist provided to the 
participant by the research nurse.  
6.1.5 ROUTE OF ADMINISTRATION 
Study drug will be taken orally with or without food. 
6.1.6 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Participants will be randomized to one 40 mg tablet of Telmisartan daily or one placebo tablet daily. 
There is no dose reduction or escalation for this study.  
6.1.7 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
The toxicity grading system that will be used is the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Version 2.0, November 2014, located at:  


 
 
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https://rsc.tech-res.com/docs/default-source/safety/daids-aegrading-table-v2-nov2014.pdf 
6.1.8 DURATION OF THERAPY 
The study medication will be given for a duration of 21 days. 
6.1.9 TRACKING OF DOSE 
Subjects will be asked to bring back any medication not taken.  
6.1.10 DEVICE SPECIFIC CONSIDERATIONS 
Not applicable. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
Drug Accountability 
The pharmacist will be responsible for ensuring adequate accountability of all used and unused study 
drug. This includes ordering and acknowledgment of receipt of study product (quantity and condition), 
subject dispensing records and returned or destroyed study product. Accountability records will 
document quantities including lot number, date dispensed, subject identifier number, subject initials, 
and the initials of the person dispensing the medication. Study drug will not be supplied to any person 
who has not consented to participate in the study. Persons authorized to distribute and control the 
study medication include the PI or Co-I listed on the FDA 1572 and designated staff. 
Unused Study Drug 
Upon study completion, unused study drug will be destroyed at the research unit (verified by witness). 
Original drug accountability records must be maintained in the site’s records. 
Placebo  
Tentative plans for placebo call for the use of gelatin capsules filled with an inactive ingredient. To 
provide a similar appearance, telmisartan tables will be over-encapsulated with the gelatin capsules.  
6.3 
STUDY PROCEDURES/EVALUATIONS 
6.3.1 STUDY SPECIFIC PROCEDURES 
Study specific procedures include obtaining oropharyngeal swabs and research blood specimens. 
 
6.3.2 STANDARD OF CARE STUDY PROCEDURES 
Other than monitoring safety labs to assess lack of adverse events on study medication, this protocol is 
not meant to provide clinical care of patients with COVID-19 disease. 
6.4 
LABORATORY PROCEDURES/EVALUATIONS 
6.4.1 CLINICAL LABORATORY EVALUATIONS 
Hematology: Complete blood count (CBC)  
Chemistries: Chemistry to include sodium (Na), potassium (K), chloride (Cl), bicarbonate (HCO3), 
creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), aminotransferase (AST), 
alkaline phosphatase (ALK-P), total bilirubin, albumin, and glucose. In addition, LDH and hs-CRP will be 
assessed serially.  


 
 
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6.4.2 OTHER ASSAYS OR PROCEDURES 
Research bloods will be drawn, processed to separate into viably preserved PBMC and plasma, and 
banked for batch analyses of the following: 
RAS assessments: Assessments of various components of the RAS system will be performed in Dr. Stan 
Louie’s lab. This is anticipated to include RAS peptides to be drawn in protease inhibitor containing 
tubes to include AngI, AngII, Ang(1-9) and Ang(1-7); ACE1 and ACE2 in plasma; and ACE1, ACE2, AT1R, 
AT2R and MasR in PBMC. In addition, one cc of plasma will be forwarded to Dr. Louie’s lab for ACE1 and 
ACE2 enzymatic evaluation. A vial of 5 million cells will be forwarded for RT-PCR for AT1R, AT2R, MasR, 
ACE1 and ACE2 as well as neprilysin (NEP) and aminopeptidase A (APA). 
 
Plasma Biomarkers:  Blood plasma will be assessed for plasma biomarkers of organ 
function/coagulation, inflammation, leukocyte chemotaxis, tissue remodeling/fibrosis and immune 
exhaustion by Luminex multiplexing assays. While subject to change the following analytes are planned: 
 
Oro-pharyngeal Swab: Oro-pharyngeal swabs will be obtained at each study timepoint. These will be 
collected using a foam swab and placed in a multi microbe media (M4, M4RT, M5, M6), VCM (UTM) 
medium (green-top) tube, Amies liquid elution swab (ESwab), or equivalent Viral Transport Media 
(VTM). Once placed in the appropriate viral media, the specimens will be frozen at -70C and sent out for 
batch analysis at a later date. While it is currently anticipated that the study will utilize oro-pharyngeal 
swabs for determination of viral persistence, it is possible that naso-pharyngeal swabs or saliva testing 
or other means of viral detection may be substituted depending on sensitivity/specificity, availability, 
and cost. 


 
 
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6.4.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
6.4.3.1 Blood Draw  
Collection of blood will occur at the specified time points for clinical laboratory assessments and for 
research blood for assays to be conducted on cryopreserved blood. The quantity of blood to be drawn at 
each setting is defined in the Schedule of Events. 
Whole blood will be obtained by venous puncture and processed by the Processing Laboratory ideally 
within 1 hour of collection. If processing will be delayed (2-3 hours), the collection tube should be placed 
on a slow rocking table until processed. 
6.4.3.2 Blood for RAS assessments 
Blood will be drawn in specific tubes pre-filled with protease solution to enable to determine of various 
RAS components. These pre-filled tubes will be obtained from Dr. Stan Louie’s laboratory and will be 
forwarded to his lab in Los Angeles for RAS analyses.  
6.4.3.3 Plasma (EDTA tube) for banking 
Plasma is separated from whole blood collected in EDTA vacutainers.    
1. Spin vacutainer at 900xg for 10 minutes at room temperature (RT) to separate plasma from 
blood cells. 
2. Remove plasma and save tube to process white blood cell separation. 
3. Transfer plasma to a labelled 15mL conical Falcon tube and centrifuge at 820xg for 10 minutes 
at 4°C. 
4. Aliquot plasma into 1mL labelled cryovials (3 to 4 aliquots). 
5. Cryovials are stored at -20°C for 24 hours before being transferred to long-term cryobox storage 
at -80°C or placed in liquid nitrogen Dewar to snap freeze. 
6.4.3.4 Peripheral Blood Mononuclear Cells (PBMC)(EDTA tube) 
1. Resuspend EDTA blood pellet after plasma separation with 2x DMSO freezing medium in 1:1 
ratio and freeze in 1 mL aliquots at -80°C after counting total WBCs for use in chloramine 
analysis assay. 
2. Follow standard Ficoll Hypaque procedure to separate PBMC from 10 mL of heparinized blood. 
3. Perform a cell count of the isolated PBMC. 
4. Add appropriate DMSO/FBS solution for a final concentration of 5x106 cells/mL. 
5. Transfer 1mL aliquots (5x106 cells) to 1.25 mL cryovials. Store in Mr. Frosty at -80°C for at least 
24 hours before transferring samples to long-term -140°C storage. 
6.4.4 SPECIMEN SHIPMENT 
Blood tubes for RAS assessment will be shipped to Dr. Stan Louie’s lab at a minimum of q monthly 
intervals. Plasma and viably preserved PBMC will also be forwarded to Dr. Louie’s lab for the planned 
extended analysis of the RAS components.  
6.4.5 SCREENING 
6.4.5.1 Initial Medical History by Phone Interview 
Verbal informed consent and medical history will be obtained by phone or video-conference (selected at 
caller preference) interview with the potential participant. The interview will record: 


 
 
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o Current Illness: Obtain date of onset of current illness, date of SARS-CoV2 testing and date the 
positive test was reported back to the participant. Review participant’s signs and symptoms 
associated with the illness with a focus on presence, course, and severity of fever, dyspnea and 
fatigue. Record grade of fever, dyspnea and fatigue on symptoms scale. 
o History of co-morbidities including history of cardiovascular disease including history of 
hypertension, history of pulmonary diseases; history of pre-diabetes or diabetes, history liver, 
kidney disease or auto-immune/ immune deficiency diseases and history of alcohol, tobacco, or 
illicit substance abuse 
o Current prescription and over-the-counter medications and medication allergies 
o Self-reported weight and height 
The potential participant will be asked to bring his or her COVID-19 test result to the person-to-person 
screening/entry visit. If documentation of the COVID-19 test result is unavailable, the potential 
participant will be given the option of obtaining it or providing the researchers permission to obtain the 
test result (this will be done at the Entry visit).   
6.4.6 FOLLOW-UP SCREEN AND ENROLLMENT/BASELINE [ENTRY VISIT (VISIT 1, DAY 1)] 
Potential participants who have verbally consented to the study will be given an appointment for a 
follow-up person-to-person screening/entry visit as soon as possible – preferably the same day. The 
screen/entry visit should occur within 24 hrs of the telephone screening visit. 
This screen/entry in-person visit will preferably be conducted outside with the participant in his/her car 
or sitting comfortably in a portable tent set up in the clinic parking area of the UH Clinics at Kakaako. 
Study visits in other venues will be considered on a case-by-case basis. It is envisioned that such visits in 
other venues may occur if the participant is not able to come to the UH Clinics at Kakaako parking area 
in a safe manner. Study visits in other venues will occur only if the participant is willing and the setting 
can a) ensure participant safety; b) will not increase risk of infection or pose any other safety issues for 
our clinical research staff; c) will ensure adequate privacy for the participant; d) the location will allow 
satisfactory performance of all study mandated procedures; and e) will not break any state or county 
law or ordinance. A ‘safe’ study visit location away from the UH Clinics at Kakaako premises may include, 
for example, an outside patio open to outside air flow attached to the participant’s home located within 
the immediate Honolulu area (i.e. not a distance which may make blood transport back within a 
reasonable time frame difficult) that could be assessed without entering the home and would ensure 
adequate privacy and acceptability for the participant.  We will mandate that the PI (C. Shikuma), clinical 
Sub-Investigator (D Chow), unit coordinator (D Ogata-Arakaki), research nurse and all staff physically 
planning to conduct this study visit in a different venue must ALL be in agreeable that the venue is safe 
BEFORE a different venue is permitted. If all members of the research team are fully vaccinated (are at 
least 14 days beyond completion of his/her COVID-19 vaccine series), it may be decided that completing 
most of the interview by phone but entering the home in full PPE briefly to complete certain research 
needs (such as a blood draw) may be acceptable. 
o Informed consent document will be reviewed. The participant will be provided with the 
informed consent document, asked to sign and a photo taken of the informed consent signature 
page. 


 
 
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o The current signs and symptoms will be reviewed and the presence of symptoms sufficient to 
meet entry requirements will be confirmed. Entry Symptom Scale and Clinical Status to be 
recorded. 
o A photo of the person’s COVID-19 test result will be taken. If unavailable and the person opts to 
have the researchers request it, the person will provide signed permission Consent to Release 
Information and a photo will be taken of the document.  This will permit researchers to obtain 
the test result document. Also, the person will be asked to sign the Consent to Release in case of 
hospitalization. 
With confirmation of study eligibility:  
o Vitals signs will be taken to include temperature, pulse, blood pressure, respiratory rate, and O2 
sat. 
o Oro-pharyngeal swab will be obtained 
o Blood draw for clinical safety labs and for research assays in quantity as specified in the 
Schedule of Events. 
o The participant will be given a Symptoms log and instructed to daily take and record his/her own 
blood pressure and temperature. Temperature should also be taken whenever there is tactile 
fever. The participant will be provided with a digital thermometer and BP monitor as needed 
and instructed in their use. The participant will be asked to call immediately if systolic blood 
pressure falls below 90 mmHg and to NOT take further study medications unless advised by the 
study team that it is safe to do so.  
o The pharmacist will randomize study participant to telmisartan or placebo; then the study 
medication will be dispensed to the participant. Participant will be instructed to take first dose 
as soon as he or she is home. 
o Provide the following instructions to participants: 
o Take BP daily at generally the same time of the day and record on Symptoms log. Call 
research team if SBP is <90 and do not take further study medication unless instructed 
to do so by the research team. 
o Take temperature whenever a fever is suspected but at least once daily and record 
o Record appropriate fever, dyspnea and fatigue symptoms daily 
o Record the time study medication is taken daily 
o Participants will be advised to take particular effort to remain hydrated, and to be 
judicious with the use of aspirin or other NSAIDS for fever/symptomatic treatment 
because it may increase risk for renal problems if excessive amounts are taken with 
study medication. 
6.4.7 FOLLOW-UP STUDY VISITS 
The participant will be asked to daily: 
o take BP generally at the same time of day and record  


 
 
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o measure temperature prn tactile fever but at least daily and record 
o record fever, dyspnea and fatigue 
The research nurse will phone or video-conference the participant daily or at least 3x/week during the 
first week to monitor how the participant is doing especially if there are concerns regarding the 
participant’s status and to reinforce the need to take daily study medications and to record BP, 
temperature and symptom status. 
The participant will also be instructed to call the research nurse (or Physician-on-call on weekends or 
after-hours via the Physician Exchange Service) if side effects, problems or concerns arise.  
Day 4 (+/- 1 day) and Day 10 (+/- 1 day) Study Visit  At this visit, nurse will: 
o Take photo of participant’s log for temperature, BP and symptoms; assess current signs and 
symptoms and clinical status 
o Update medication list 
o Record adherence with study medication 
o Record AEs as reported by participant or observed by investigator 
o Record vital signs (temperature, pulse, blood pressure, respiratory rate and O2 sat) and conduct 
targeted PE if warranted 
o Collect OP swab 
o Draw blood for clinical safety labs and for research assays in quantity as specified in the 
Schedule of Events.  
6.4.8 FINAL STUDY VISIT 
Day 21 Study Visit (+/- 2 days) At this visit:  
o Take photo of participant’s log for temperature, BP and symptoms; assess current signs and 
symptoms and clinical status 
o Update medication list 
o Record adherence with study medication 
o Collect unused medication 
o Record AEs as reported by participant or observed by investigator 
o Record vital signs (temperature, pulse, blood pressure, respiratory rate and O2 sat) and conduct 
targeted PE if warranted 
o Collect OP swab 
o Draw blood for clinical safety labs and for research assays in quantity as specified in the 
Schedule of Events.  
6.4.9 FOLLOW UP PHONE CALLS 
Post Day 21  
o Research nurse may contact the participant after the last study visit if further follow-up 
information on participant status is needed 


 
 
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6.4.10 DISCONTINUATION OF STUDY TREATMENT 
The study treatment will be prematurely discontinued for the following reasons: 
o Participant becomes pregnant or starts breast-feeding 
o Participant is admitted to the hospital 
o Participant requires a prohibited medication  
 
The participant will be asked to continue to be followed and attend the study visits after discontinuation 
of study treatment. No study procedures will be performed on the participant during hospitalization.   
 


 
 
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6.4.11 SCHEDULE OF EVENTS TABLE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*If possibility of pregnancy is solicited from participant 
6.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES 
The participant’s ‘usual medications’ may be continued unless specifically contra-indicated in this study. 
Antipyretics and other symptomatic medications and treatments will be allowed although participants 
will be asked to use judiciously and in moderation. The participant will be asked to call the Study Team 
if/when antibiotics or other medications are prescribed by the participant’s own physician. In general 
these will be allowed except if drug-drug interaction with Telmisartan or if increased toxicity is of 
concern.  
6.6 
PROHIBITED OR PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
Use of ARBs (other than Telmisartan/Placebo being provided by the Study), ACE Inhibitors, Aliskiren, 
eplerenone, triamterene, amiloride, spironolactone and potassium supplements are prohibited.  
6.7 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE 
Telmisartan will not be provided to any person outside the context of the study or following the closure 
of the study. 
 
Schedule of Events 
 
 
 
 
 
 
Phone 
Screen 
Entry 
(Day 1) 
Day 4 
Day 10 
Day 21 
Review COVID-19 symptoms and date of 
COVID-19 testing; Obtain Demographics, 
verbal Ht and Wt and Co-Morbid Medical 
History; Obtain Verbal Informed Consent 
x 
 
 
 
 
Update current illness and confirm eligibility for 
study; verify signing of Informed Consent 
 
x 
 
 
 
Complete Symptom Scale and Clinical Status 
 
x 
x 
x 
x 
Vital Signs (Temp, Pulse, BP, Resp Rate, 
O2sat) 
 
x 
x 
x 
x 
Pregnancy test (except in post-menopausal 
state) 
 
x 
x* 
x* 
x* 
Oro-pharyngeal Swab 
 
x 
x 
x 
x 
Safety Labs (CBC with diff, chem, hsCRP, LDH) 
[10 ml] 
 
x 
x 
x 
 
x 
RESEARCH Bloods including for RAS 
assessment (volume to be drawn) [25 ml] 
 
x 
x 
x 
x 
TOTAL BLOOD VOLUME (ml) 
 
35 
35 
35 
35 


 
 
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7 
ASSESSMENT OF SAFETY 
7.1 
SPECIFICATION OF SAFETY PARAMETERS 
7.1.1 DEFINITION OF ADVERSE EVENTS(AE) 
Adverse event (AE) means any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention-related [21 CFR 312.32 (a)]. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a study drug. 
Collection of AEs will begin at the start of the study drug infusion and continue until the Final Visit. 
AEs may be volunteered spontaneously by the subject or discovered as a result of general questioning 
by the study staff, by physical examination, or through procedures or laboratory testing. At each 
evaluation, the subject will be asked, “Have you experienced any problems or changes in your health 
since the last evaluation?” In addition, open-ended queries will help elicit information about possible 
AEs. All AEs will be recorded on the source documents and subsequently the CRF. For all AEs, the PI or 
Sub-I must pursue and obtain information adequate to determine the outcome of the AE and to assess 
whether it meets the criteria for classification as a serious AE requiring immediate notification. Follow-
up of the AE is required until the event resolves, the condition stabilizes, the event is otherwise 
explained, or the subject is lost to follow-up. 
To avoid vague, ambiguous, or colloquial expressions, all AEs should be recorded in standard medical 
terminology on the CRF and on the medical record rather than in the subject’s own words. Each AE will 
also be described in terms of duration, frequency, severity, association with the study drug, assessment 
of possible causes, actions taken, and outcome, using choices given on the CRF. Specific guidelines for PI 
or Sub-I classification of AEs by severity and relationship to study drug are given below. 
The toxicity grading system that will be used to grade the AE is the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014, located at:  
https://rsc.tech-res.com/docs/default-source/safety/daids-aegrading-table-v2-nov2014.pdf 
7.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
Serious adverse event or serious suspected adverse reaction (SAE) is an AE or suspected adverse 
reaction that is considered "serious" if, in the view of either the PI or Sub-I, it results in any of the 
following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
7.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
OHRP considers unanticipated problems (UP) involving risks to participants or others to include, in 
general, any incident, experience, or outcome that meets all of the following criteria:  


 
 
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• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being 
studied.  
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and  
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized.  
This study will use the OHRP definition of UP. 
7.2 
CLASSIFICATION OF AN ADVERSE EVENT 
7.2.1 SEVERITY OF EVENT 
The following guidelines will be used to describe AE severity. 
• 
Mild (Grade 1) – An event that is easily tolerated by the subject, causing minimal discomfort, 
and not interfering with everyday activities. 
• 
Moderate (Grade 2) – An event that is sufficiently discomforting to interfere with normal 
everyday activities. 
• 
Severe (Grade 3) – An event that prevents normal everyday activities. 
• 
Life-Threatening (Grade 4) - An event that causes extreme limitation in activity or an event 
where significant medical intervention/therapy is required. 
• 
Death Related to AE (Grade 5)- An event that results in a fatal outcome. 
7.2.2 RELATIONSHIP TO STUDY AGENT 
For all collected AEs, the PI or Sub-I who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below.  
• 
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 drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary.  
• 
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 after administration of the drug, is unlikely to be attributed 
to concurrent disease or other drugs or chemicals, and follows a clinically reasonable 
response on withdrawal (dechallenge). Rechallenge information is not required to fulfill this 
definition.  
• 
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, 


 
 
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other factors may have contributed to the event (e.g., the participant’s clinical condition, 
other concomitant events). Although an AE may rate only as “possibly related” soon after 
discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug 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 participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study drug 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. 
7.2.3 EXPECTEDNESS 
Dr. Shikuma and Sub-Investigator will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study agent. 
7.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care. During each study visit or phone call, 
research nurse coordinator, PI, or Sub-I will query the participant for unsolicited and solicited AEs. All 
AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate CRF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while 
on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution.  
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE. UPs will be recorded in the CRF throughout the study.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode.  
The PI or Sub-I will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 days for non-serious AEs and 30 days for SAEs after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit. Events will be followed for outcome information until resolution or stabilization. 
7.4 
REPORTING PROCEDURES 
7.4.1 ADVERSE EVENT REPORTING 
All AEs will be recorded on the source documents and subsequently the CRF. For all AEs, the PI or Sub-I 
must pursue and obtain information adequate to determine the outcome of the AE and to assess 


 
 
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whether it meets the criteria for classification as a serious AE requiring immediate notification. Follow-
up of the AE is required until the event resolves, the condition stabilizes, the event is otherwise 
explained, or the subject is lost to follow-up. 
To avoid vague, ambiguous, or colloquial expressions, all AEs should be recorded in standard medical 
terminology on the CRF and on the medical record rather than in the subject’s own words. Each AE will 
also be described in terms of duration, frequency, severity, association with the study drug, assessment 
of possible causes, actions taken, and outcome, using choices given on the CRF. Specific guidelines for 
Investigator classification of AEs by severity and relationship to study drug outlined in Sections 7.2.1, 
7.2.2, 7.2.3 and 7.3. 
When changes in the severity of an AE occur more frequently than once a day, the maximum severity for 
the experience that day should be noted. If the severity category changes over a number of days, then 
those changes will be recorded separately (with distinct onset dates). 
AE will be reported to the IRB. The PI or designee is responsible for assessing each event and signing off 
on the AE report. 
7.4.2 SERIOUS ADVERSE EVENT REPORTING 
The PI, Sub-I, or research nurse coordinator is responsible for recording and reporting SAEs. The 
following procedure will be followed for reporting and handling SAEs: 
The research nurse coordinator will notify the PI or Sub-I immediately on becoming aware of a potential 
SAE. After business hours, PI or Sub-I can be reached via pager system at 808-522-4000 or 808-566-
5036. PI or Sub-I is responsible for assessing each event and will determine if the event meets the 
criteria for an SAE, the SAE severity, its relationship to the study intervention, and if the event was 
expected. PI or Sub-I assessment will be communicated to the research nurse coordinator who will 
record the event on the SAE form. Because each federal and local have their own reporting 
requirements, SAE reports will be filed in accordance with their respective time requirements.  
The SAE will be followed until satisfactory resolution or the PI or Sub-I believe the situation is stable or 
chronic. Any other supporting documents or follow-up reports will be completed and submitted if 
warranted. The IRB will be notified of any unexpected fatal or life-threatening SAE within 7 calendar 
days of receipt notification.  
7.4.3 UNANTICIPATED PROBLEM REPORTING 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP 
report form. PI or designee will be responsible for reporting UPs to the IRB. The UP report will include 
the following information:  
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number. 
• 
A detailed description of the event, incident, experience, or outcome. 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP. 
• 
A description of any changes to the protocol or other corrective actions that have been taken 
or are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  


 
 
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• 
All UPs, whether they are SAEs or not, will be reported to the IRB within the institution’s specific 
time frame of the PI or Sub-I becoming aware of the event. 
7.4.4 EVENTS OF SPECIAL INTEREST 
Not applicable. 
7.4.5 REPORTING OF PREGNANCY 
Pregnant females are excluded from the study. Women of child bearing age will undergo pregnancy 
testing on entry and will be asked to be on at least one form of contraception. Pregnancy testing will be 
done at each study visit if there is any suspicion of possible pregnancy. Study medications will be 
terminated immediately upon the discovery of pregnancy.  
7.5 
STUDY HALTING RULES 
A halt to the study will be considered by the study team if new information becomes available or 
adverse events connected with the study suggest that continuation of the study is not in the best 
interest of the participants. Should this happen, the PI or Sub-I will inform the IRB within 24 hours of the 
decision and will provide the IRB with written documentation detailing the circumstances leading to this 
decision. The PI or Sub-I will notify all regulatory bodies, ClinicalTrials.gov, and the FDA of the disposition 
of the study. 
7.6 
SAFETY OVERSIGHT 
7.6.1 ROUTINE SAFETY OVERSIGHT 
Safety oversight will be under the direction of the PI from first participant screening through study 
completion. Safety labs are done at entry (to establish baseline) and at each subsequent study visit at 
day 4, 10 and 21. The results of these safety labs are reviewed by the research nurse within 24 hrs of the 
blood draw and any concerning abnormality reviewed with the research physician. The status of all 
participants on study are reviewed at weekly staff meetings. 
7.6.2 DATA SAFETY MONITORING BOARD (DSMB) 
As this is a small single-site pilot study and not a phase III study, a DSMB will not be convened for this 
study. It is anticipated that safety of the participants can be ensured by close monitoring and review of 
all participants on study at weekly staff meetings.  


 
 
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8 
CLINICAL MONITORING 
Quality assurance monitoring will be performed by the Unit Coordinator of the Hawaii Center for AIDS to 
ensure the safety of the participants, to ensure that the rights and well-being of human subjects are 
being protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and 
with applicable regulatory requirement(s).  
Careful attention will be paid to GCP, applicable regulatory requirements, and the need to ensure the 
safety of the participants. All efforts will be expended to make sure that procedures are followed and 
that appropriate documentation is in place should site monitoring be requested by the IRB or other 
regulatory bodies. 


 
 
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9 
STATISTICAL CONSIDERATIONS 
 
9.1 
STATISTICAL HYPOTHESES 
 
Primary hypothesis 
Maximum severity of disease, as assessed by the modified 7-point Clinical 
Status ordinal scale, will be less in the telmisartan arm compared to the 
placebo arm  
Secondary hypotheses 
o Telmisartan will be safe and well tolerated in symptomatic patients 
with COVID-19 over the 21 day study period 
  
o Telmisartan will increase Ang(1-9), AngII and Ang(1-7); Elevated 
levels of these peptides in relation to angiotensin peptide 
receptors such as MasR, AT1R and AT2R expression will be 
important predictors of improved clinical outcomes 
o Differences in biomarker levels will be seen between the 2 arms; 
Certain baseline values may predict clinical outcomes  
 
Exploratory hypothesis: 
o Loss of viral detectability will be faster in the telmisartan arm 
compared to the placebo arm 
 
9.2 
ANALYSIS DATASETS 
The analysis dataset will include all subjects enrolled into the study with data from entry to the final day 
21 study visit.  
9.3 
DESCRIPTION OF STATISTICAL METHODS 
9.3.1 GENERAL APPROACH 
This is a prospective, randomized, double-blind 3-week study of telmisartan vs placebo in symptomatic 
individuals diagnosed with COVID-19 disease. Subjects will be randomized 1:1 to receive telmisartan vs 
placebo for 3 weeks (21 days). A block randomization will be applied to ensure the balance of 
participant numbers and baseline severity between treatments. 
The baseline characteristics of participants will be summarized by descriptive statistics and compared 
between the two groups to check any imbalance. The primary efficacy endpoint for the study is an 
ordinal outcome corresponding to the maximum clinical status of the study subject. The proportional 
odds model and logistic regression techniques will be applied to compare the ordinal outcome between 
treatments, based on odds ratios. There are several secondary efficacy endpoints defined for the study. 
For those measures, averages and rates will be compared between groups, appropriately. Longitudinal 
mixed-effects models will be utilized to handle longitudinal outcome measures observed at days 1, 4, 10, 
and 21. The covariate use in regression models will be limited due to the relatively small sample size. 
Tests of normality will be performed on continuous data and transformation applied where applicable. 
Type-I error for hypothesis tests will be fixed at 5% nominal level. All efficacy and safety estimates (e.g. 


 
 
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average and proportions) will be provided with 95% confidence intervals (95% CI). The multiplicity error 
in exploratory analyses will be corrected via the false discovery rate. All efforts will be taken to minimize 
loss-to-follow-up. However, small amounts of missing data may occur. In such cases, participants 
without final outcome data will be excluded from the analysis. Sensitivity analysis with multiple 
imputations will be performed for confirming results. Statistical analyses will be performed using the R 
software 3.5.1 version.  
9.3.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The efficacy primary endpoint of the study is the maximum clinical severity of disease as assessed by the 
clinical status ordinal scale. The primary efficacy analysis will be performed using a proportional odds 
model. This model allows comparing odds ratios on ordinal categories between the experimental 
treatment and the placebo via a set of regression parameters. The statistical significance of regression 
parameters will be tested using a one-sided test for the superior efficacy by telmisartan Alternatively, 
several ordinal categories can be combined to obtain a composite binary class outcome, in case if 
insufficient class representations observed. In this situation, group comparison with respect to a binary 
outcome can be performed using the logistic regression model.  
In addition to the primary analysis, longitudinal outcomes obtained at baseline (day 1), days 4, 10, and 
21 will be used in a generalized mixed-effect regression model (i.e., cumulative link mixed model) that 
contains treatment and days, and treatment: days interaction as fixed effects. In the model, treatment: 
days interaction represents the difference in longitudinal trajectories between the two treatment 
groups. The statistical significance of interactions will be determined. The regression models used for 
analysis can be further adjusted for any unbalanced covariates observed at baseline. 
9.3.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary efficacy endpoints for the study are given by a set of continuous/count measures observe at 
days 4, 10 and 21 (i.e., components of the RAS and blood biomarkers indicative of pro-inflammatory and 
coagulation disturbances, circulating T cell (CD4 and CD8), NK cell, and monocytes). A shift in 
distribution location parameter will be tested for the group companion, using two sample t-test or the 
Wilcoxon rank-sum test selected upon the outcome distributions. Additionally, longitudinal secondary 
outcomes obtained at baseline (day 1), days 4, 10, and 21 will be analyzed using generalized mixed 
effect models and together with a proper link function (i.e., identity, log, etc.). In those models, days: 
treatment interactions, will be tested for the differences in trajectories. Covariate adjustments will be 
applied if required.     
 
AEs are categorical data. AEs will be summarized as frequencies and percentages within telmisartan and 
placebo groups. Chi-squared test or Fisher’s exact test will be used to test for differences in proportions 
between two groups. 
9.3.4 SAFETY ANALYSES 
The number of adverse events will be tabulated by grade and symptom/lab parameters. Proportions and 
corresponding 95% exact confidence intervals will be provided. 
9.3.5 ADHERENCE AND RETENTION ANALYSES 
Participants compliance to study medication will be monitored at each study visit via Symptom Form 
that is completed by the participant daily. The participant is asked to enter the date and time they take 
the study medication each day on the Symptom Form. The number of subjects who discontinue study 


 
 
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drug, withdraw completely from the study, or are lost to follow-up will be summarized in a table as 
counts and proportions with 95% exact confidence intervals. The specific reasons for withdrawing or lost 
to follow-up will also be presented.  
9.3.6 BASELINE DESCRIPTIVE STATISTICS 
Demographic and clinical variables will be summarized using descriptive statistics. Continuous variables 
will be summarized with means and standard deviations. Categorical variables will be summarized with 
frequencies and proportions. To understand if imbalance at the baseline, clinical and demographic 
variables will be compared between two-groups, appropriately, using T-tests (or Wilcoxon Rank Sum 
test) and chi-squared test (or Fisher’s exact test). Additionally, graphical techniques will be used to 
visualize longitudinal profiles of study participants, stratified by treatment groups. 
9.3.7 PLANNED INTERIM ANALYSES 
The proposed study will be a pilot study to explore early evidence for the clinical efficacy and safety of 
telmisartan in mitigating the pulmonary and cardiac severity of disease due to COVID-19. Since the study 
will be conducted using a relatively small sample size, the research team does not intend to propose a 
pre-planned interim analysis for stopping for the efficacy. However, the study can be stopped at any 
point for the safety of participants.  
9.3.8 ADDITIONAL SUB-GROUP ANALYSES 
Sub-group analysis by age, sex, race/ethnicity will be performed as possible within the relatively small 
sample size of this study. Average treatment effect differences among subgroups (e.g. baseline severity) 
will be summarized, along with 95% confidence intervals. Additionally, subgroup analysis results will be 
visualized using graphical techniques. 
9.3.9 MULTIPLE COMPARISON/MULTIPLICITY 
The multiplicity error in exploratory analyses will be corrected via the false discovery rate. 
9.3.10 TABULATION OF INDIVIDUAL RESPONSE DATA 
Individual participant data will be listed by measure and time point. 
9.4 
SAMPLE SIZE 
The sample size estimation for the proposed study is not provided considering that this is a pilot study. A 
total sample of 40 participants will be used in the study (20 per group). The above sample size was 
determined based on the feasibility assessment. Suppose, in the placebo group, the vector of 
probabilities for observing the ordinal scale outcomes is {0.40, 0.40, 0.05, 0.04, 0.04, 0.04, 0.03}, 
respectively for categories 1-7. If we assume the corresponding vector for the experimental treatment 
group as {0.76, 0.18, 0.02, 0.01, 0.01, 0.01, 0.01}, that will produce an odds ratio of 5.0 between the two 
groups. In this scenario, we will have about 80% power to detect a treatment difference using the 
proportional odds model at 5% type-I error. Also, the selected sample size will allow us to detect a 
standardized effect size of 0.9 at Cohen’s d scale, above 80% power, for a mean comparison between 
two groups via a two-sample T-test for a Gaussian outcome. 


 
 
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9.5 
MEASURES TO MINIMIZE BIAS 
9.5.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
After signing the Informed Consent Form (ICF), the subject is assigned a unique patient identifier 
number (PID). At the time of enrollment (randomization), the subject is assigned a unique subject 
identifier number (SID). PIDs and SIDs are not re-assigned. Screening Numbers and Subject Numbers are 
not re-assigned. Subjects are randomly allocated (1:1) to active medication (telmisartan) or placebo. 
Randomization may occur after verbal informed consent has been obtained from the subject or 
representative, and subject eligibility has been confirmed. A study enrollment form will be sent to the 
research pharmacist to initiate the randomization process and assign the treatment to the participant. 
The research pharmacist will obtain the randomized treatment allocation from a computer-generated 
randomized treatment list for the subject and the pharmacist or designated staff will prepare the study 
medication. The study medication will not be provided to the participant however until a written 
informed consent is obtained. The site research staff and investigators (with the exception of the 
research pharmacist) will not have access to the treatment assignments and investigational drug 
products are over-encapsulated to blind the study drugs. 
Since the research pharmacist is unblinded in order to provide the assigned treatment, the research 
pharmacist will not be involved with the assessment of outcomes or data capture except as necessary to 
manage drug distribution, control and accountability. 
9.5.2 EVALUATION OF SUCCESS OF BLINDING 
Not applicable.  
9.5.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
Blinded Treatment assignments will be made available to the Investigators only in the event of a medical 
emergency where knowledge of the blinded treatment is necessary for further medical management of 
the participant (for instance in the event of serious adverse event). The rationale for unblinding and 
circumstances supporting unblinding must be documented in the research record. A written request to 
unblind will be sent by the investigator to the research pharmacist or designated pharmacy staff. The 
treatment assignment will be revealed to the investigator in writing and documentation will be filed in 
the accountability record. 
 


 
 
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10 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Source data is defined as information, original records of clinical findings, observations, or other 
activities in a study necessary for the reconstruction and evaluation of the study. CRF will be designed by 
the research nurse coordinator and will serve as source documents for some of the required data except 
for the source data from participant’s medical records, hematology, chemistry, and EKG results.  
The research nurse coordinator and research pharmacist will maintain the source data, CRF, and all 
regulatory documents in compliance with ICH E6 and regulatory and institutional requirements for the 
protection of confidentiality of participants. The participant’s research records will be stored in a locked 
file cabinet in the research unit’s main office. PI, Co-I, research nurse coordinator, research pharmacist, 
and research staff working on the protocol or data analyses will have access to all documents and will 
adhere to all requirements for subject confidentiality as outlined in the ICF. QUALITY ASSURANCE AND 
QUALITY CONTROL 
This section indicates the plans for quality management, the system for assessing the quality of 
processes within the study. Quality management will encompass quality assurance (QA) and quality 
control (QC). QA is defined as all planned and systematic actions that are established to ensure that the 
trial is performed and the data are generated, documented (recorded), and reported in compliance with 
Good Clinical Practice (GCP) and the applicable regulatory requirement(s) (ICH E6 1.46). QC is defined as 
the operational techniques and activities undertaken within the quality assurance system to verify that 
the requirements for quality of the trial-related activities have been fulfilled (ICH E6 1.47). 
The research unit has a written QA and QC management plan that will be used for this protocol. 
QC procedures will be implemented beginning with the data entry system and data QC checks that will 
be run on the database will be generated. Any missing data or data anomalies will be clarified/resolved 
by the PI in collaboration with the research nurse coordinator and research pharmacist. 
The PI, research nurse coordinator, and research pharmacist will verify that the clinical trial is conducted 
and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, 
and the applicable regulatory requirements (e.g., Good Laboratory Practices, GLP).  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by local and regulatory authorities. 


 
 
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11 ETHICS/PROTECTION OF HUMAN SUBJECTS 
11.1 ETHICAL STANDARD 
The PI will ensure that this study is conducted in full conformity with Regulations for the Protection of 
Human Subjects codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and the ICH E6. 
11.2 INSTITUTIONAL REVIEW BOARD 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form by 
the IRB must be obtained before any participant is enrolled.  
Any amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. All changes to the consent form will be IRB approved; a determination will be 
made regarding whether previously consented participants need to be re-consented. 
11.3 INFORMED CONSENT PROCESS 
11.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
IRB-approved informed consent document describing in detail the study intervention, study procedures, 
and risks will be given to the participant and written documentation of informed consent will be 
required prior to starting intervention/administering study intervention.  
The informed consent document for this study is submitted with this protocol. 
11.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
For each study subject, an oral consent will be obtained prior to obtaining any patient information 
needed to determine eligibility requirements and for any specific protocol related information.  A signed 
written informed consent will be obtained at the Entry visit. The process will be fully documented in the 
source documents.  
The research nurse coordinator, PI or Co-I will explain orally the nature, duration, and purpose of the 
study, and the action of the drug in such a manner that the subject is aware of the potential benefits, 
risks, inconveniences, and adverse effects that may occur because of their participation. They will be 
informed that the subject may withdraw from the study at any time. They will receive all information 
that is required by federal, state, and local laws and regulations and ICH guidelines. 
The participant will also be asked to read and review the IRB-approved informed consent document and 
to ask questions prior to signing. An opportunity will be given for the participant to discuss the study 
with their significant other and/or primary care physician or think about it prior to agreeing to 
participate. The participant will sign the informed consent document prior to invasive procedures 
specifically for the study. The participant may withdraw consent at any time throughout the course of 
the trial. 
The participant will retain the signed informed consent document and a photo will be taken of the 
signed consent for the research record. 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. 


 
 
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11.4 PARTICIPANT AND DATA CONFIDENTIALITY 
Participant confidentiality is strictly held in trust by the participating investigators and research staff. 
This confidentiality is extended to cover testing of biological samples in addition to the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without the permission of the Principal Investigator.  
All subjects will be assigned a unique patient identifier number (PID) and at the time of enrollment 
(randomization), each subject will be assigned a unique subject identifier number (SID). PID and SIDs are 
not re-assigned. The log that links the subject’s name to the PID is stored in a locked file cabinet. This 
information is also stored on a separate flash drive and not on a computer hard drive or server. The 
locked file cabinets housing these confidential documents will be stored in research unit’s main office, 
which is in a 24-hour secured building. The only individuals who have access to these locked files are 
authorized personnel of the research staff directly involved in this study.  
Representatives of the IRB or FDA may inspect all documents and records required to be maintained by 
the PI, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for 
the participants in this study.  
If the study participant elects to have their clinical laboratory data sent to their primary care providers, 
they will be asked to sign a separate consent covering release of his/her data to their physician.  
The study participant’s contact information will be securely stored in a locked file cabinet for internal 
use during the study. At the end of the study, all records will continue to be kept in a locked file cabinet 
in the main office of the research unit for as long a period as dictated by local IRB and Institutional 
regulations.  
A study database containing de-identified study participant research data only will be utilized for the 
purposes of statistical analysis and scientific reporting. The database will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by research staff will be secured and password protected.  
11.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
Intended Use of Stored Human Samples, Specimens, or Data: The ability to conduct studies on the 
mechanisms underlying COVID-19 pathologic effects by accessing the banked specimens together with 
de-identified data is an integral part of this clinical study.  Therefore, the willingness to have specimens 
stored for future use is part of the permission we are seeking from participants prior to entry into this 
study.  
Storage of Stored Human Samples, Specimens, or Data: Blood samples will be stored in the research 
unit’s processing laboratory. Access to stored samples will be limited to laboratory staff of the research 
unit. No genetic testing will be performed. 
Tracking of Stored Human Samples, Specimens, or Data: De-identified data will be tracked using 
subject’s unique identifier code. Data will be kept in password-protected computers. 


 
 
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11.5 FUTURE USE OF STORED SPECIMENS 
Stored specimens may be used for research of COVID-19.  


 
 
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12 DATA HANDLING AND RECORD KEEPING 
12.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection is the responsibility of the PI, Co-I, research nurse coordinator, and research pharmacist 
at the site under the supervision of the PI. The PI is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data. Black ink is required to ensure clarity of reproduced copies. When making changes or 
corrections, cross out the original entry with a single line, and initial and date the change. ERASURE, 
OVERWRITE, OR USE OF CORRECTION FLUID OR TAPE ON THE ORIGINAL WILL NOT BE ALLOWED. 
Copies of the CRF will be provided for use as source documents and maintained for recording data for 
each participant enrolled in the study. Data reported in the CRF derived from source documents should 
be consistent with the source documents or the discrepancies should be explained and captured in a 
progress note and maintained in the participant’s official electronic study record.  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into REDCap and/or Microsoft Excel, a 21 CFR Part 11-compliant data 
capture system provided by the University of Hawaii John A. Burns School of Medicine. The data system 
includes password protection and internal quality checks, such as automatic range checks, to identify 
data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
12.2 STUDY RECORDS RETENTION 
Study documents will be maintained and retained in accordance with applicable federal, state, and local 
laws, rules, regulations, guidelines, and regulatory requirements.  
12.3 PROTOCOL DEVIATIONS 
The following describes the managing of Non-Compliance that may affect the rights or welfare of human 
subject participants. 
12.3.1 DEFINITIONS 
Non-compliance is defined as conducting research involving human participants in a manner that 
disregards or violates federal regulations and/or the institutional human research protection program 
policies governing such research.  
Continuing Non-Compliance is defined as a pattern of non-compliance that suggests the likelihood that, 
without intervention, situations of non-compliance will recur, a repeated unwillingness to comply, or a 
persistent lack of understanding of how to comply. Serious Non-Compliance is defined as non-
compliance that adversely affects the rights or welfare of human research participants.  
Protocol Violation is defined as a type of non-compliance, any deviation or departure from the IRB-
approved protocol or proposal that does not have prior approval by the IRB unless the change is 
necessary to remove an apparent immediate hazard to one or more study participants.  
• 
Minor Protocol Violation (also known as “Protocol Deviation”) is defined as a protocol violation 
that does not impact the safety or welfare of study participants, compromise the integrity of 


 
 
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study data, or affect participants’ willingness to participate in the study. Examples of protocol 
deviations include the following (not an all-inclusive list): 
o Use of an outdated version of the consent form if risks to participants described in the 
form do not differ from those described in the current form.  
o A study procedure conducted out of sequence.  
o A study visit conducted outside the required time period.  
o Failure to perform a required procedure, assessment, or lab test that, in the opinion of 
the PI, is unlikely to have an adverse impact on participant safety or welfare or the 
integrity of the data collected; and  
o Enrollment of more than the IRB-approved number of participants.  
 
• 
Major Protocol Violation is defined as a protocol violation that may impact the safety or welfare 
of study participants, compromises the integrity of study data, or affects participants’ 
willingness to participate in the study. Examples of major protocol violations include the 
following: 
o Failure to obtain informed consent, or obtaining informed consent from a participant 
after initiation of study procedures.  
o Using an outdated version of the consent form when risks to participants described 
differ from those described in the current consent form.  
o Performing a study procedure not approved by the IRB.  
o Modifying a study without prior IRB approval unless to remove an apparent immediate 
hazard to one or more study participants.  
o Enrollment of a subject who did not meet any inclusion/exclusion criteria.  
o Failure to perform a required procedure, assessment, or lab test that, in the opinion of 
the PI, may affect the safety or welfare of one or more participants or the integrity of 
the data collected.  
o A drug dispensing or dosing error.  
o A study visit conducted outside of the required time period with a potentially adverse 
effect on the safety or welfare of one or more study participants.  
o Failure to follow applicable federal regulations or IRB policies and procedures, including 
those for reporting Unanticipated Problems and Adverse Events.  
o Failure to follow an IRB-approved safety monitoring plan.  
Corrective Action Plan (CAP) is defined as a plan developed in response to a protocol violation that 
outlines the steps to be taken to: (1) reduce the risk to participants affected by the violation, and (2) 
prevent a recurrence of the violation.  
12.3.2 PROCEDURES FOR REPORTING PROTOCOL VIOLATIONS 
Minor Protocol Violations will not require reporting to the IRB at the time of each occurrence per 
institution Standard Operating Procedures (SOP).  
The PI will provide to the IRB a summary of minor or major protocol violations that occurred during the 
prior IRB approval period at the time of continuing review. 


 
 
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Timeframe of Reporting Major Violations. The PI will notify the IRB of major protocol violations no later 
than 24 hours after the PI becomes aware of the event by phone or email, and report the event to the 
IRB no later than 10 business days after discovery of the violation using the protocol violation report 
form by a member of the study team.  
Changes to Remove a Hazard. If a protocol change has been initiated to remove an apparent immediate 
hazard to one or more study participants, the PI will report this change to the IRB no later than 5 
business days after initiation of the change. 
12.4 PUBLICATION AND DATA SHARING POLICY 
12.4.1 USE OF STUDY FINDINGS 
This study is registered with www.clinicaltrials.gov (ID: NCT04360551) and will be updated as study 
findings become available. 
It is also anticipated that if beneficial impact of telmisartan is seen in this study, grant applications 
proposing further research into the potential use of telmisartan in COVID-19 would be submitted.  
12.4.2 PUBLICATION 
It is anticipated that multiple publications will result from this study. The Investigative Team research-
team will be responsible for assigning the primary author responsible for leading the writing of the 
manuscript, for developing publication procedures and resolving authorship issues. 


 
 
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13 STUDY ADMINISTRATION 
13.1 STUDY LEADERSHIP 
The clinical protocol will be implemented with Dr. Cecilia Shikuma as Principal Investigator and Dr. 
Dominic Chow as Physician Sub-Investigator. 


 
 
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14 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial. 


 
 
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15 LITERATURE REFERENCES 
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2019 (COVID-19) - United States. MMWR Morbidity and mortality weekly report. 2020. 
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Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in 
Wuhan, China. Lancet. 2020;395(10223):497-506. 
3. 
Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel 
Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. 
4. 
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 
pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet 
Respir Med. 2020. 
5. 
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. 
6. 
Novel Coronavirus Pneumonia Emergency Response Epidemiology T. [The epidemiological 
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Lim DS, Lutucuta S, Bachireddy P, et al. Angiotensin II blockade reverses myocardial fibrosis in a 
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791. 
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Huang F, Guo J, Zou Z, et al. Angiotensin II plasma levels are linked to disease severity and 
predict fatal outcomes in H7N9-infected patients. Nat Commun. 2014;5:3595. 
9. 
Parikh MA, Aaron CP, Hoffman EA, et al. Angiotensin-Converting Inhibitors and Angiotensin II 
Receptor Blockers and Longitudinal Change in Percent Emphysema on Computed Tomography. 
The Multi-Ethnic Study of Atherosclerosis Lung Study. Ann Am Thorac Soc. 2017;14(5):649-658. 
10. 
Reddy R, Asante I, Liu S, et al. Circulating angiotensin peptides levels in Acute Respiratory 
Distress Syndrome correlate with clinical outcomes: A pilot study. PLoS One. 
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11. 
Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for 
the SARS coronavirus. Nature. 2003;426(6965):450-454. 
12. 
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and 
TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020. 
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Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 
protein, the functional receptor for SARS coronavirus. A first step in understanding SARS 
pathogenesis. J Pathol. 2004;203(2):631-637. 


 
 
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14. 
Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-
Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020. 
15. 
Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS 
coronavirus-induced lung injury. Nat Med. 2005;11(8):875-879. 
16. 
Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, et al. Attenuation of pulmonary ACE2 activity 
impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil 
infiltration. Am J Physiol Lung Cell Mol Physiol. 2018;314(1):L17-L31. 
17. 
Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients 
linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364-374. 
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Oudit GY, Kassiri Z, Jiang C, et al. SARS-coronavirus modulation of myocardial ACE2 expression 
and inflammation in patients with SARS. Eur J Clin Invest. 2009;39(7):618-625. 
19. 
Zhang L, Lin D, Sun X, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for 
design of improved alpha-ketoamide inhibitors. Science. 2020. 
20. 
Wu C, Liu Y, Yang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of 
potential drugs by computational methods. Acta Pharm Sin B. 2020. 
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Benicky J, Sanchez-Lemus E, Pavel J, Saavedra JM. Anti-inflammatory effects of angiotensin 
receptor blockers in the brain and the periphery. Cell Mol Neurobiol. 2009;29(6-7):781-792. 
22. 
Dandona P, Dhindsa S, Ghanim H, Chaudhuri A. Angiotensin II and inflammation: the effect of 
angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum 
Hypertens. 2007;21(1):20-27. 
23. 
Couluris M, Kinder BW, Xu P, Gross-King M, Krischer J, Panos RJ. Treatment of idiopathic 
pulmonary fibrosis with losartan: a pilot project. Lung. 2012;190(5):523-527. 
 


 
 
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16 VERSION HISTORY 
 
Version 
Date 
Significant Revisions  
1.0 
Approval: ______ 
Original