Conditions: COVID-19
Keywords: COVID-19 multi-organ failure acute kidney injury
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 22
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if administration of angiotensin-(1-7) (TXA127) prevents acute kidney injury and deterioration into multi-organ failure in patients with severe COVID-19. Participants will undergo a 10-day treatment with either placebo or study drug. The drug will be administered intravenously for 3 hours once each day for 10 days consecutively.

Detailed description:
Corona virus disease 2019 (COVID-19) has been associated with severe respiratory and multiorgan failure. Research shows that COVID-19 reduces levels of angiotensin-converting enzyme-2 (ACE-2), an enzyme that converts angiotensin II to angiotensin 1-7 (known as TXA127). COVID-19 reduces levels of ACE-2 and therefore angiotensin 1-7 and as a result, angiotensin II levels are going to be increased. Many clinical observations in COVID-19 have shown the high incidence of acute kidney injury that may be due to excessive levels of angiotensin II. The investigators hypothesize that administration of angiotensin (1-7) replaces levels of ACE-2 in COVID-19 and thereby ameliorates deterioration of multi-organ failure and specifically acute kidney injury.

Arms:
arm 1: Participants will receive one 3-hour dosage (0.5 mg/kg per day), intravenously, for 10 days consecutively (or until discharge if less than 10 days). arm 2: Participants will receive one 3-hour dosage (0.5 mg/kg per day), intravenously, for 10 days consecutively (or until discharge if less than 10 days).

Interventions: intervention 1: TXA127 intervention 2: Placebo
Intervention descriptions: intervention 1: 0.5 mg/kg per day intervention 2: 0.5 mg/kg per day

Protocol document:
Prot_SAP_000.pdf: 
AAAT0535 – TXA Trial 
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Randomized controlled trial of Angiotensin 1-7/ TXA127 for 
the treatment of severe COVID-19 
 
 
 
 
 
 
CUIMC Protocol Number: 
AAAT0535 
 
Drug Sponsored by: 
Constant Therapeutics LLC 
 
 
Principal Investigator: 
Jeanine D’Armiento, MD, PhD 
 
 
 
NCT#:  
NCT04401423 
 
 
 
 
 
 
Version Number: Version 2.0 
Date: 25 August 2021 
 


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Statement of Compliance 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46) 
• 
ICH GCP E6 
• 
Completion of Human Subjects Protection Training 


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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Principal Investigator: Jeanine D’Armiento, MD, PhD 
 
Signed: 
 
Date: 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
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iii 
Statement of Compliance ............................................................................................................. i 
Signature Page ........................................................................................................................... ii 
List of Abbreviations .................................................................................................................... v 
Protocol Summary ..................................................................................................................... vi 
 
1 
Key Roles ........................................................................................................................... 1 
2 
Background Information and Scientific Rationale................................................................ 2 
2.1 
Background Information .......................................................................................... 2 
2.2 
Rationale ................................................................................................................ 3 
2.3 
Objective ................................................................................................................. 4 
3 
Study Design ...................................................................................................................... 6 
4 
Study Population ................................................................................................................ 7 
4.1 
Selection of the Study Population ........................................................................... 7 
4.2 
Inclusion/Exclusion Criteria ..................................................................................... 7 
5 
Study Procedures/Evaluations ............................................................................................ 9 
5.1 
Study Procedures ................................................................................................... 9 
5.2 
Potential Risks and Benefits ................................................................................. 11 
5.2.1 
Potential Risks .......................................................................................... 11 
5.2.2 
Known Potential Benefits........................................................................... 13 
6 
Study Schedule ................................................................................................................ 14 
6.1 
Screening ............................................................................................................. 14 
6.2 
Day 1 through Day10 ............................................................................................ 14 
6.3 
Follow-up phone calls ........................................................................................... 14 
7 
Assessment of Outcome Measures .................................................................................. 15 
7.1 
Specification of the Appropriate Outcome Measures ............................................ 15 
7.1.1 
Primary Outcome Measures ...................................................................... 15 
8 
Safety assessment and reporting ..................................................................................... 17 
8.1 
Definition of Adverse Event (AE) and Serious Adverse Event (SAE) ..................... 17 
8.2 
Criteria for Discontinuation or Withdrawal of a Subject (or a Cohort), if applicable 20 
8.3 
Halting Rules ........................................................................................................ 20 
9 
Clinical Monitoring Structure ............................................................................................. 21 
9.1 
Data Safety and Monitoring Board – DSMB .......................................................... 21 
10 
Statistical Considerations ................................................................................................. 22 
10.1 
Study Outcome Measures .................................................................................... 22 
10.2 
Sample Size Considerations ................................................................................. 22 
10.3 
Analysis Plan ........................................................................................................ 22 
11 
Access to Source Data/Documents .................................................................................. 26 
12 
Ethics/Protection of Human Subjects ................................................................................ 27 
12.1 
Declaration of Helsinki .......................................................................................... 27 
12.2 
Institutional Review Board .................................................................................... 27 
12.3 
Informed Consent Process ................................................................................... 27 
12.4 
Subject Confidentiality .......................................................................................... 28 


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12.5 
Data Capture Methods .......................................................................................... 28 
12.6 
Study Records Retention ...................................................................................... 28 
13 
References ....................................................................................................................... 29 
14 
Appendices ...................................................................................................................... 30 
14.1 
Appendix A: Schedule of Assessments ................................................................. 30 
14.2 
Appendix B: Questionnaires .................................................................................. 31 
 
 


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Protocol Summary 
 
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v 
 
Title: 
Randomized controlled trial of Angiotensin 1-7/ TXA127 for the treatment 
of severe COVID-19 
 
Population: 
One hundred Male and Females aged 18-70, with COVID-19 positive 
status hospitalized in NYP/Columbia Hospital. 
 
Number of Sites: 
New York Presbyterian Hospital/ Columbia University Irving Medical 
Center 
 
Study Duration: 
1 year 
 
Subject Duration: 
Study duration is 10 days with 3 follow-up calls at 24-72hrs post hospital 
discharge, at day 28 and day 60 post enrollment date. 
 
Objectives: 
To determine if administration of angiotensin-(1-7) / TXA127 prevents 
acute kidney injury and deterioration into multi-organ failure in patients 
with severe COVID-19.  
 
 
 


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Schematic of Study Design: 
 
Randomized double-blinded placebo controlled clinical trial proof of concept. 
 
Prior to 
Enrollment 
 
 
 
Day 1 
 
 
 
 
Days 2-10 
 
 
 
Follow-up 
24-72hrs  
post hospital  
discharge 
 
 
Day 28 (+/-2)  
Follow-up call 
 
 
Day 60 (+/-2)  
Follow-up call 
 
 
 
Screen subjects by criteria; obtain medical history; obtain informed consent.  
Study Procedures: 
Drug Administration, Clinical blood work, research blood work, vitals, clinical x-
rays/CT scans, patient assessment questionnaires, oxygen administration information 
Assess for AE 
Assessment of Final Study 
Outcome Measures 
Assess for AE 
Assess for AE 
If patient remains hospitalized, the above study procedures will be collected except 
clinical X-rays/CT scans. Research blood-work collected only at Day 1, 5 and 10.  


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1 
KEY ROLES 
For questions regarding this protocol, contact:  
Individuals: Principal Investigator:  Jeanine D’Armiento, MD, PhD 
Columbia University Medical Center / NYP 
630 West 168th Street, P&S Box 46  
New York, NY 10032 
Tel# 212-305-3745 
Jmd12@cumc.columbia.edu 
 
 
     Investigator:  Gebhard Wagener, MD 
Columbia University Medical Center / NYP 
622 West 168th Street, P&S Box 46  
New York, NY 10032 
Tel# 212-305-3745 
Gw72@cumc.columbia.edu 
 
 
     Investigator:  Adam Gerber, MD, PhD 
Columbia University Medical Center / NYP 
630 West 168th Street, P&S Box 46  
New York, NY 10032 
Tel# 212-305-3745 
Amg2291@cumc.columbia.edu 
 
         Clinical Research Coordinator: Laura Fonseca 
Columbia University Medical Center / NYP 
630 West 168th Street, P&S Box 46  
New York, NY 10032 
Tel# 212-305-3745 
Lf2560@cumc.columbia.edu 
 
Institutions: New York Presbyterian Hospital / Columbia University Irving Medical Center  
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
 
TXA127 is a pharmaceutically-formulated angiotensin (1-7) [A(1-7)] heptapeptide, an 
endogenously produced, non-hypertensive derivative of angiotensin II (Ang II). TXA127 is 
currently in development to reduce progression of respiratory disease in COVID-19 patients. 
TXA127 has been shown to reduce inflammation and fibrosis and restore endothelial and 
epithelial barrier function in acute lung injury. The mechanism behind the beneficial effect of 
A(1-7) appears to be mediated via the Mas receptor. 
 
TXA127 or A(1-7) has been evaluated in several pre-clinical efficacy models of lung injury, 
including a bleomycin-induced acute lung injury model, a ventilator-induced acute lung injury 
model, an oleic acid-induced acute lung injury model and an ovalbumin model of asthma. 
A favorable safety profile was demonstrated with TXA127 in preclinical toxicology studies. 
Administration of TXA127 to rats and dogs by intravenous (IV) injection for 1 month at doses up 
to 1 mg/kg/day resulted in no adverse effects. Similarly, no adverse effects were found when 
TXA127 was administered by SC injection to rats and dogs at doses up to 10 mg/kg/day for 1 
month. In a 100-day toxicity study, the no observed adverse effects level (NOAEL) for systemic 
toxicity was 50 mg/kg/day in both the rat and dog. No hemodynamic changes were observed 
when TXA127 was administered to conscious rats by SC injection or IV infusion at doses up to 
1 mg/kg. No cardiovascular changes were noted in dogs treated for 4 weeks at doses up to 1 
mg/kg/day IV or 10 mg/kg/day SC. Functional assessment of the central nervous system (CNS) 
in the 100-day toxicity study in the rat showed no effects on functional observational battery 
(FOB) or locomotor activity after 95 days of treatment with up to 50 mg/kg/day. In the 100-day 
toxicity study in the dog at Day 94, electrocardiogram (ECG) assessment showed lower heart 
rate at all doses up to 50 mg/kg/day, a change that was treatment- but not dose-related,  
longer PR and RR intervals, and no changes in QRS, QT, or QT interval corrected according to 
the Van de Water formula (QTcV). Respiratory assessments in the same study showed no 
treatment-related changes in respiratory frequency, tidal volume, or minute volume doses up to 
50 mg/kg/day. TXA127 was not mutagenic in a battery of in vivo and in vitro tests. 
Ten clinical studies that have completed, terminated early, or are ongoing, have evaluated the 
safety and effectiveness of TXA127. Seven clinical studies that were either completed or 
terminated early have analyzed and reported final data on the safety and effectiveness of 
TXA127. A total of 108 subjects received TXA127 and 38 subjects received placebo or other 
drug in these studies. Two additional studies are ongoing; final data are being collected for one 
study that completed enrollment (n = 75, TXA127 or placebo, data are blinded) and for one 


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study that terminated early (n = 15, all TXA127-treated). One additional study, planned for 
pediatric patients and submitted under U.S. Investigational New Drug Application (IND) 58,561, 
was Institutional Review Board (IRB)-approved but was terminated before enrolling patients.  
All studies were conducted under U.S. IND 58,561 (oncology) with the exception of two studies 
that were conducted under different INDs: Study A17-002 (IND 60,159; renal) and Study 
TXA127-2008-001 (IND 101,736; infectious disease). The dose of TXA127 ranged from 0.0025 
to 1.0 mg/kg/day across a range of treatment regimens in the 9 studies that enrolled subjects. In 
the 7 completed and early terminated studies, TXA127 was found to be well-tolerated with no 
dose-limiting toxicities (DLTs) identified in any study. Of the 39 serious adverse events (SAEs) 
reported in these 7 studies, none were classified as definitely related or probably related to the 
study drug. Only one SAE, a case of anemia in Study A17-002 of patients with end-stage renal 
disease, was classified as possibly related to the study drug (TXA127). Of the SAEs reported for 
16 subjects in the 2 ongoing studies, one SAE of allergic reaction/hypersensitivity in Study 
TXA127-2010-001 was classified as possibly related to the study drug (TXA127).  
2.2 
Rationale 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus 
disease 2019 (COVID-19) that can be associated with severe respiratory and multi-organ 
failure. SARS-CoV-2 is thought to enter cells through angiotensin converting enzyme 2 (ACE-2) 
on the surface of cells resulting in endocytosis and then translocation. During this process ACE-
2 is also internalized and phagocytosed and thereby may become non-functional. ACE-2 
mediates the conversion of angiotensin II to angiotensin-(1-7), that opposes the effect of 
angiotensin II. It is likely that COVID-19 reduces levels of ACE-2 and therefore angiotensin-(1-
7). As a result, angiotensin II levels are going to be increased. This hypothesis explains many 
clinical observations in COVID-19 specifically the high incidence of acute kidney injury that may 
be due to profound intra-renal vasoconstriction caused by excessive levels of angiotensin II.  
The synthesized version of angiotensin-(1-7) is TXA127. Administration of TXA127 has been 
studied in multiple phase I and II studies such as   
• 
A phase I safety and biological activity study in patients with HIV 
• 
A phase II trial for the treatment of skeletal muscle fibrosis and reduced muscle strength 
in patients with Duchenne muscular dystrophy (DMD) to reduce or to prevent the 
disease progression 
• 
A phase I study in healthy volunteers 
• 
A Phase IIb Study Evaluating the Safety and Efficacy of TXA127 in the Reduction of 
Incidence and Severity of Thrombocytopenia in Patients Receiving Combination 
Gemcitabine and Platinum Therapy for Ovarian, Fallopian Tube, or Peritoneal 
Carcinoma 
• 
A Phase I/II Single-Blind, Randomized, Placebo-Controlled Trial of TXA127 alone and in 
combination with erythropoietin on optimization of hemoglobin in end-stage renal 
disease patients  


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Except for the last study, TXA127 has been administered subcutaneously with a dose range 
of 0.01 to 0.5 mg/kg per day with most studies using a dose of approximately 0.3 mg/kg/day.   
One study (“Effect of TXA127 alone and in combination with erythropoietin on optimization of 
hemoglobin in end-stage renal disease patients”) used a dose range of 0.01-0.05 mg/kg per day 
intravenously three times per week for 12 weeks.  
  
160 patients received TXA127 in dose ranges from 0.0025 to1.0 mg/kg/day. Only 1 of these 
patients were found to have a single serious adverse event (anemia) that was considered 
possibly related to the administration of TXA127.  
 
2.3 
Objective 
  
Primary endpoint  
• 
All-cause mortality (from start of experimental drug to day 28) with Acute Kidney Injury as a 
composite endpoint (two times serum creatinine above normal; this way we avoid potential 
noise with regard to small changes of serum creatinine). 
 
Secondary endpoints  
• 
Incidence of respiratory failure requiring intubation and ventilatory support  
o The proportion of patients alive and free of respiratory failure from start of 
experimental drug/randomization to day 28. With prolonged ventilation 
considered to be clinically equivalent to respiratory failure.  
 
• 
Renal failure requiring dialysis (either continuous or intermittent)  
o This will be measured by modality, duration and indications of dialysis from start 
of experimental drug/randomization to day 28.  
• 
Vasoplegic shock requiring vasopressors  
o Measured by proportion of participants experiencing this event from start of 
experimental drug/randomization to day 28.  
• 
Inflammatory markers, specifically IL-6 levels  
• 
Return to baseline oxygen requirement from start of experimental drug/randomization to 
day 28  
• 
ICU Length of stay 
• 
Hospital length of stay 
• 
Time of recovery to return to baseline oxygen requirement 


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• 
Clinical status  
o Measured with questionnaires of ordinal scale, NEWS scale and SOFA score. 
The subcomponents of these scales will be collected daily through Day 10 of 
patient hospitalization or until discharge, whichever comes first.  
• 
Proportion of patient improvement measured by return to room air and return to normal 
renal function 
• 
Time of improvement measured by return to room air scaled at days 5, 10, 28 and 60.  
• 
All-cause mortality at day 60 
 
 
 
 


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3 
STUDY DESIGN 
Description of Study Design 
This is a Prospective, double-blinded, randomized placebo-controlled trial with two groups: the 
study drug (treatment group) and the placebo group (control group). We will study severe 
COVID-19 patients admitted to the hospital with respiratory insufficiency and oxygen 
requirements.  
 
 
Approximate time to obtain data: 
 
 Data abstraction from EMR for clinical vitals, clinical blood work, clinical chest x-ray/CT 
chest imaging, COVID-19 history and symptoms: 25-30 minutes 
 Research Blood draw: 5 minutes 
 Nurse administration of study drug: 5 minutes  
 Completion of patient assessments: 10 minutes 
 
Expected duration of subject participation 
The participant is expected to complete study procedures during ten days of hospitalization – or 
until patient is discharged, whichever comes first. Afterwards a study member will call the 
participant for follow-up AEs at 24-72hrs post discharge, at day 28(+/- 2 days) and at day 60 (+/- 
2 days).  
 
 


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4 
STUDY POPULATION 
4.1 
Selection of the Study Population 
Sample size 
Target sample size is n=50.  
 
Recruitment pool: 
Subjects will be drawn from inpatient hospitalized patients at New York Presbyterian 
Hospital/Columbia University Irving Medical Center (including the Allen Hospital) via person-to-
person communication between physicians and review of electronic medical records for COVID-
19 admissions.  
 
 
Screened vs Enrolled: 
 Screened 
A participant is considered to be screened when their medical records have been 
reviewed by the investigators and eligibility criteria has been met. The CRC will keep 
record of the total number of eligible and ineligible screened participants.  
 
 Enrolled 
The participant is considered enrolled when the investigator has determined their 
eligibility based on the review of their EMR clinical chart and has signed the informed 
consent form. 
 
4.2 
Inclusion/Exclusion Criteria 
 
Inclusion criteria  
• 
Severe COVID-19: Adult patients admitted to the hospital through the ED requiring 
oxygen therapy (any level) to maintain SaO2 > 90%  
• 
COVID positive by PCR on hospital admission 
• 
Hospitalized patients aged 18 or greater 
• 
have a negative pregnancy test 
• 
willing to use highly effective methods of contraception 
  
Exclusion criteria  


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• 
Pre-existing chronic kidney disease  
• 
New use of or change in dose of ACE-inhibitors or ARB within the last 6 months   
• 
Acute kidney injury at the time of enrollment defined as either increase pf serum 
creatinine by more than 50% or 0.3 mg/dL above baseline or estimated creatinine 
clearance (by MDRD) of less than 60 ml/min (if no baseline serum creatinine available)  
• 
Pregnant and breastfeeding women  
• 
Contraindicated medications: new use or change of medications from start of trial 
o Start of an ACE inhibitor or ARB within 6 months of trial.  
 
 
Please Note: 
• 
Guidelines from the FDA and NIH for the definition of severe COPD were followed 
including: Positive testing by standard RT-PCR assay or an equivalent test; Symptoms 
suggestive of severe systemic illness with COVID-19, which could include any symptom 
of moderate illness or shortness of breath at rest, or respiratory distress; and Clinical 
signs indicative of severe systemic illness with COVID-19, such as respiratory rate ≥ 30 
per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air at sea level or 
PaO2/FiO2 < 300 
• 
Participants may receive investigational therapies that are used in the context of local 
standard of care for COVID-19, participation in other clinical studies may complicate the 
assessment and impact interpretation of efficacy and safety data in this study. Inclusion 
of other antiviral treatments consistent with standard of care is acceptable. 
• 
On May 1, 2020, FDA authorized use of the unapproved product remdesivir for 
treatment of suspected or laboratory confirmed COVID-19 in adults and children 
hospitalized with severe disease. Severe disease, for the purposes of the Emergency 
Use Authorization (EUA), was defined as patients with an oxygen saturation (SpO2) ≤ 
94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or 
requiring extracorporeal membrane oxygenation (ECMO). Therefore, incorporating 
remdesivir into clinical trials, as a component of standard of care for patients hospitalized 
with severe disease, in settings where remdesivir is available via the EUA mechanism is 
acceptable. 
 
 


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5 
STUDY PROCEDURES/EVALUATIONS 
5.1 
Study Procedures 
 
Methods for collecting Clinical data: 
 Medical History /Medications/Vitals/clinical blood-work/chest x-ray/CT 
imaging/COVID-19 symptoms and history/AE or SAE 
The clinical data will be abstracted daily from the NYP/Columbia’s EMR system called 
“EPIC.” Only individuals that have access to this system will abstract data; this includes 
the investigators and CRC.   
 
Methods for collecting Research data: 
 Research Blood-work Collection:  
Research blood-work will be collected on Days 1,5 and 10 only and if patient remains 
hospitalized. A study team member will ask phlebotomist to please assist in drawing 
blood for research purposes and will provide the proper tubes. If phlebotomist is 
unavailable, a study team member with certification in phlebotomy or MD degree will 
gown up wearing appropriate PPE and collect the labs needed.  
 
 
Procedures for study visits:  
 Registering participant: 
The participant needs to be registered in IBM CTMS system – a secure clinical trial 
website/tool used to validate research study participants so it may interface with EPIC.   
 
 Method of Randomization: 
SAS block randomization was used and disclosed to the research pharmacy for study 
drug randomization and dispensation.  
 
 Unblinded personnel: 
The Research Pharmacy will remain unblinded for safety purposes. If needed for safety 
concerns – the DSMB chair will be unblinded. In addition, the CRC is unblinded due to 
the creation of the SAS block randomization.  
 
 Ordering study drug / Scheduling study tests: 
Using the new electronic medical record system of EPIC, the PI and co-investigators will 
need to order and sign off on all study drug ordering.   


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Calculated dose (mg/kg) x Drug Factor (1.19mg) = Actual dose (mg). 
 
• 
Calculated Dose - The calculated dosage of the study drug per participant’s 
weight. For example: A participant weight is 75 kg and the dosage of the drug is 
0.5mg/kg. Therefore, 75kg x 0.5 mg/kg = 37.5 mg. This is the calculated dose. 
 
• 
Drug Factor - The drug substance of TXA127 acetate also contains moisture. In 
order to follow protocol of 0.5mg/kg, we have to weigh out more of the drug 
substance than corresponds to 0.5 mg/kg so we can end up dosing the patient 
with 0.5 mg/kg TXA127.  In other words, 1 mg of TXA127 would weight out 1.19 
mg of drug substance.  The Lead pharmacist and drug sponsor have agreed to 
add the drug factor to the calculated dosage as follows: 0.5 mg/kg x 1.19 = 0.595 
mg/kg. 
For example: If the calculated dose of a participant is 37.5mg, then we would multiply it 
by the drug factor as such: 37.5mp x 1.19 mg = 44.625 mg (round to 45 mg). Therefore, 
the actual dose would be 45 mg.  
Angiotensin (1-7) / TXA127: 0.5 mg/kg per day for ten days intravenously over 3 hours 
or Placebo.   
 
• 
The PI/Sub-Is/CRC will order the study drug order in EPIC. Within the order there 
will be an “order instruction” instructing the PI/Sub-I/CRC to include the “drug 
factor” of 1.19 to the calculation of the actual dose. Calculated dose x 1.19 = 
Actual dose.  The patient’s weight would be documented in the “administration 
instruction”. 
• 
To place the study drug order in EPIC, it must be as an “in-patient” order and 
linked to the research study.  
 
Type of Information gathered/collected/recorded Day1 through Day 10 (if patient remains 
hospitalized): 
 
Demographic Information 
Demographic information includes: Name, Address, DOB, Telephone number, email, gender, 
age, race and ethnicity. 
 
Medical History and Medications 


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Summary of medical history and main diagnosis. All medications currently taken will be 
collected. 
Vital Signs 
Clinical vitals will be collected including: heart rate, blood pressure, respiratory rate, 
temperature, and oxygen saturation. The time of vital collection will also be recorded. 
 
Drug Administration 
The drug dosage, maximum flow rate and time of administration will be recorded. 
 
Clinical Bloodwork 
Including time of collection, CBC. BMP, Hepatic Panel and other clinical markers (such as ESR, 
fibrinogen and CRP). 
 
Clinical Imaging 
Includes date of imaging and impression summary 
 
Clinical COVID-19 symptoms and history: 
Includes clinical review of physicians notes for symptom reporting and of the COVID-19 
diagnosis and date of recent positive COVID swab.  
 
 
Patient Assessments: 
The NEWS, Ordinal and Glasgow coma score will be completed by the CRC/Investigators 
based on the clinical information abstracted. No questions will be directly asked to the patient.  
 
Research Bloodwork 
Three tubes of blood collection on Days 1, 5 and 10 will be collected. Plasma, Buffy coat and 
serum will be abstracted stored in freezer -80 in the laboratory of Dr. D’Armiento.  
 
 
5.2 
Potential Risks and Benefits 
5.2.1 Potential Risks 
 
Immediate risks 
Extravasation, vasodilation, anemia 
 
 


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Rationale for the necessity of such risks 
Improvement in perfusion specifically renal perfusion, replacement of endogenous angiotensin 
1-7. 
 
Alternative data gathering procedures that have been considered or will be considered 
No alternatives as there are presently no treatment or prevention modalities of COVID-19 
associated AKI. 
 
Why alternative procedures may not be feasible 
There are presently no treatment or prevention modalities of COVID-19 associated AKI. 
 
Why the value of the information to be gained outweighs the risks involved. 
COVID-19 associated AKI has a very high mortality and preventing this AKI by administering 
angiotensin 1-7 at a dose that can be considered a replacement of physiologic levels and has 
no substantial adverse effects may improve mortality. 
 
For a list of adverse events previously reported in past human clinical trials, please refer to 
pages 78-85 of the Investigator Brochure. Below is a summarized list: 
 
Body System 
Adverse event 
Severity 
Relationship to 
TXA127 
General 
Injection Site Pain 
Mild 
Definitely Related 
Musculoskeletal 
Bone Pain 
Mild 
Probably Related 
Myalgia 
Mild 
Probably Related 
Fatigue 
Severe 
Possibly Related 
Influenza like illness 
Mild 
Possibly Related 
Gastrointestinal 
Abdominal distension 
Moderate 
Possibly Related 
Abdominal pain 
Moderate 
Possibly Related 
Constipation 
Moderate 
Possibly Related 
Dry mouth 
Mild 
Possibly Related 
Gingivitis 
Mild 
Possibly Related 
Nausea 
Moderate 
Possibly Related 
Vomiting 
Severe 
Possibly Related 
Oral pain 
Moderate 
Possibly Related 
Diarrhea 
Mild 
Possibly Related 
Bloated Feeling 
Mild 
Possibly Related 
Metabolism 
Thirst 
Mild 
Possibly Related 
Nervous system 
Tremors 
Mild 
Possibly Related 
Headache 
Moderate 
Possibly Related 


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Skin 
Rash 
Moderate 
Possibly Related 
Blood 
 
Neutropenia 
Life-threatening 
Possibly Related 
Anemia 
Severe 
Possibly Related 
5.2.2 Known Potential Benefits 
There are no direct benefits from participating in this study. However, this study will help 
the researchers determine if this study drug is safe and effectively treats severe 
COVID-19 patients. 
 
 


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6 
STUDY SCHEDULE 
Please refer to the Schedule of Assessments (Appendix A). 
6.1 
Screening 
 
 Screening will be done by the PI/Sub-Is on a weekday daily basis. Emails will be sent to 
the study group with list of new COVID-19 admissions and brief description of the 
potential participant’s medical history. Based on this the physicians would narrow which 
patients would be a good candidate for the study. Then a further in-depth review of their 
medical chart is done to ascertain the eligibility criteria.  
 The physicians or CRC will appropriately gown up in PPE and approach the patient for 
informed consent. 
6.2 
Day 1 through Day10 
 
 Day 1 through 10 procedures is listed in the Schedule of Assessments. These 
procedures will be done for 10 consecutive in-patient hospitalization day from date of 
consent or until patient is discharged (in the case patient is discharge prior to Day 10). 
6.3 
Follow-up phone calls 
 Assess for AE: Ask questions related to any possible adverse reaction to the drug and 
overall health status of the patient.  


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7 
ASSESSMENT OF OUTCOME MEASURES  
7.1 
Specification of the Appropriate Outcome Measures 
7.1.1 Primary Outcome Measures 
Table2: 
Outcome Measures 
Efficacy Endpoints 
All-cause mortality (from start of experimental drug to day 
28) including subcomponent of Acute Kidney Injury 
Primary 
Incidence of respiratory failure requiring intubation and 
ventilatory support; defined as the proportion of patients 
alive and free of respiratory failure from start of 
experimental drug to day 28.  
 
Secondary 
Renal failure requiring dialysis (either continuous or 
intermittent)  
Measured by modality, duration and indications of dialysis 
from start of experimental drug to day 28.  
 
Secondary 
Return to baseline oxygen requirement from start of 
experimental drug to day 28  
Secondary 
Vasoplegic shock requiring vasopressors  
Measured by proportion of participants experiencing this 
event from start of experimental drug to day 28.  
Secondary 
Inflammatory markers, specifically IL-6 levels  
Secondary 
ICU Length of stay 
Secondary 
Hospital length of stay 
Secondary 
Time of recovery to return to baseline oxygen requirement 
Secondary 
Clinical status measured on a ordinal scale of mechanical 
ventilation, requiring dialysis and death. 
Secondary 


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Proportion of patient improvement measured by return to 
room air and return to normal renal function 
Secondary 
Time of improvement scaled at days 5, 10, 28 and 60 
Secondary 
 
 


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8 
SAFETY ASSESSMENT AND REPORTING 
All AE and SAE will be captured and assessed at the end of each study visit and via AE phone 
calls done at 24-72hr post discharge and at Day 28 (+/- 2 days) and at Day 60 (+/- 2 days) post 
enrollment.  
8.1 
Definition of Adverse Event (AE) and Serious Adverse Event 
(SAE) 
 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a study subject. This may include 
symptom(s), illness, clinically significant abnormal laboratory value or change in value, or 
worsening in a subject during a clinical study.  
 
Procedures for Adverse Events 
During Day 1 through Day 10: 
AEs will be extracted from Standard Medical Treatment and clinical notes within EPIC. These 
will be reported in AE log within the regulatory binder. The PI/co-I will complete the Adverse 
Event Form within seven days of learning of the event (if life-threatening or death) and within 15 
days for all other SUSARs. The CRC will comply with local regulations and policies when 
notifying the institutional IRB.   
 
During follow-up phone calls: 
The CRC will record the AE within the CRF, as well as complete the AE log in the regulatory 
binder. Information recorded includes: name of event, date of onset, date of awareness, 
severity, duration, and relationship to study drug (if it can be determined). Severe adverse 
events will be followed until they are adequately resolved or stabilized during the study. The 
CRC will then notify the PI (or co-investigators if the PI is unavailable) and complete the Severe 
Adverse Event Form within seven days of learning of the event. 
The following general definitions for rating severity should be used for this study: 
Mild: Awareness of signs or symptoms, but easily tolerated and transient; causing no loss of 
time from normal activities; symptoms would not require medication or a medical treatment; 
signs and symptoms are transient. 
Moderate: Marked symptoms and discomfort severe enough to cause moderate interference 
with the subject’s usual activities. Symptomatic treatment is possible. 


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Severe: Incapacitating with inability to do work or usual activities; signs and symptoms may be 
of systemic nature or require medical intervention and/or treatment. Hospitalization may be 
required or prolonged. 
 
The relationship of an AE or SAE to the underlying disease or to the procedure will be attributed 
using the following definitions: 
Unrelated: There is no evidence that the event has a relationship to the drug(s). 
Unlikely: There is no evidence that the event has a relationship to the drug(s). However, the 
potential association to the drug cannot be totally eliminated.  
Possibly Related: The event has a timely relationship to the drug(s) used. However, a potential 
alternative etiology may be responsible for the adverse event. 
Probably Related: The event has a timely relationship to the drug(s) used and the causative 
relationship can clearly be established. No potential alternative etiology is apparent. 
Related: There is evidence that the event has a relationship to the drug(s). 
 
There is no standard scale for COVID patients, thus we will use the Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0  
• 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated.  
• 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL*.  
• 
Grade 3  
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL**.  
• 
Grade 4  
Life-threatening consequences; urgent intervention indicated.  
• 
Grade 5  
Death related to AE.  
Serious Adverse Events 
 
In accordance with 21 CFR Parts 803 and 812, an SAE is defined as any untoward medical 
occurrence that results in: 
o death,  


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o is life-threatening; any adverse experience that places the subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred (i.e., it does not 
include a reaction that, had it occurred in a more serious form, might have caused 
death),  
o requires inpatient hospitalization or prolongation of existing hospitalization,  
o results in persistent or significant disability/incapacity,  
o is a congenital anomaly/birth defect,  
o requires intervention to prevent permanent impairment or damage 
o Important medical events that do not result in death, are not life-threatening, or do not 
require hospitalization may be considered serious adverse events when, based upon 
appropriate medical judgment, they might jeopardize the subject and might require 
medical or surgical intervention to prevent one of the outcomes listed above. 
 
All SAE will be reported to the PI and co-investigators within 24 hours after knowledge of the 
occurrence. If a serious adverse event (SAE) occurs during an in-person study visit or by phone, 
the CRC will follow the same steps as with the AE reporting.  
The IND sponsor has the obligation to report all serious adverse events that are ‘Probably’ or 
‘Related’ and ‘Unexpected’ in relation to the study drug to the FDA. SAEs are reported to the 
IRB only if they meet the definition of a UP and these will be submitted by the PI. All events 
reported to the FDA by the IND sponsor are to be submitted utilizing the Form FDA 3500A 
(MedWatch Form), if applicable. 
 
Unanticipated Problem (UP) 
“Unanticipated problem”: any incident, experience or outcome involving risk to subjects or 
others in any human subjects’ research that meets all of the following criteria: 
 Unexpected (in terms of nature, severity or frequency) given (a) the research procedures 
that are described in the IRB approved protocol and informed consent document, and (b) 
the characteristics of the subject population being studied; 
 Related or possibly related to participation in such research (i.e., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the 
procedures involved in such research); and 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or 
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8.2 
Criteria for Discontinuation or Withdrawal of a Subject (or a 
Cohort), if applicable 
Withdrawal:  
The only reason for a patient being considered withdrawn should be withdrawal of consent. If 
this occurs. data collected up to the date of withdrawal may be used in data analysis. No further 
data collection will be done, and no follow-up calls will be made.  
Withdrawal will in no way affect the care management of the participant.  
Discontinuation: 
Treatment discontinuation from the study might occur if the participant experiences a serious 
adverse event per definition and the investigator decides to discontinue drug administration for 
the safety of the subject. However, patients who discontinue treatment will remain in the study 
and continue to be assessed for efficacy and safety.  
For example, for acute kidney injury: The study drug will be continued after development of 
acute kidney injury and we will continue to monitor the patient. However, if a patient starts 
dialysis, we will discontinue study drug but will still follow the patient clinically per protocol. 
Patients who become pregnant during the study will immediately discontinue the study drug but 
will continued to be followed per schedule of assessments. The outcome of pregnancy 
(spontaneous abortion, therapeutic abortion, live birth, fetal death in utero) will be recorded. 
Loss to Follow-up: 
To minimize loss to follow-up, we will continue to follow patients after discharge via phone calls 
post discharge date, at day 28 and day 60 and ascertain vital status in all patients.   
8.3 
Halting Rules 
 
The decision to halt the study will be left at the discretion of the DSMB, after the DSMB has had 
the opportunity at each DSMB meeting to review cumulative unblinded comparative safety 
results as well as cumulative unblinded comparative efficacy results.  


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9 
CLINICAL MONITORING STRUCTURE 
Study team (PI, co-investigators and CRC) research meetings will be held quarterly (less 
or more frequent depending on participant enrollment) to review the study status, any 
AEs or SAEs, primary and secondary outcome measures, among other topics. Any 
clinical safety modifications will be discussed and made during these meetings.  
The Anesthesiology department implemented a Compliance Research Coordinator 
whose responsibilities include quarterly reviews of the regulatory binder, consent and 
HIPAA forms and subject case histories. After the compliance coordinator reviews the 
study materials, a copy of the monitoring report is filed in the Regulatory Binder. Any 
revisions listed in the reporting are promptly addressed by the clinical research 
coordinator.  
9.1 
Data Safety and Monitoring Board – DSMB  
 
An independent Data Safety Monitoring Board (DSMB) composed of 4 individuals: 2 
pulmonary specialists, one regulatory/statistical clinical trial specialist and one kidney 
specialist  will be established to provide independent benefit/risk oversight during the 
conduct of the study. The DSMB will: 1) Review the protocol and consent form prior to 
study initiation, 2) Evaluate Serious Adverse Events on an “as needed” basis and all 
adverse events on a quarterly basis, 3) Recommend discontinuation of the study in the 
event of the occurrence of Serious or Unexpected Adverse Events that are determined by 
the DSMB to pose a significant safety concern. The Chairperson of the DSMB will notify 
the HRPO and Dr. D’Armiento who will in turn notify the FDA or other regulatory bodies of 
adverse safety outcome information sufficient to stop the study. This information will also 
be reported as part of required regulatory progress update reports. 
 


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10 
STATISTICAL CONSIDERATIONS 
10.1 Study Outcome Measures 
Severe COVID-19  
Primary endpoints  
• 
All-cause mortality (from start of experimental drug to day 28) including subcomponent 
of Acute Kidney Injury 
Secondary endpoints  
• 
Incidence of respiratory failure requiring intubation and ventilatory support  
• 
Renal failure requiring dialysis (either continuous or intermittent)  
• 
Vasoplegic shock requiring vasopressors  
• 
Inflammatory markers, specifically IL-6 levels  
• 
Reduction in supplemental oxygen requirements from start of experimental drug 
• 
ICU Length of stay 
• 
Hospital length of stay 
• 
Time of recovery to return to baseline oxygen requirement 
• 
Clinical status (mechanical ventilation, requiring dialysis and death) 
• 
Proportion of patient improvement measured by return to room air and return to normal 
renal function 
• 
Time of improvement scaled at days 5, 10, 28 and 60.  
10.2 Sample Size Considerations 
If we assume a proportion of 65% mortality in patients with severe COVID-19 and further 
assume that administration of angiotensin (1-7) / TXA127 will reduce the proportion of 
mortality to 15% we will require a total sample size of 50 subjects (25 in each group) to 
reach a power of 92% with a 95% confidence level. 
10.3 Analysis Plan 
 


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The definition of the primary efficacy endpoints: 
Primary endpoint of this study will be all-cause mortality (from start of experimental drug 
to day 28) including subcomponent of Acute Kidney Injury. 
Any cause mortality including palliative withdrawal or withholding of support from start of 
experimental drug to day 28.  For intercurrent events besides death, the main estimand 
for each key efficacy endpoint will follow the treatment policy strategy. Therefore, the 
analyses will include all observed on-study data regardless of patients’ use rescue 
medications, discontinuation of the investigational product, or other violations of the 
protocol. 
 
 
Secondary endpoints are defined as follows: 
 
Respiratory failure requiring intubation and ventilatory support  
Any endotracheal intubation for respiratory failure within 28 days after initiation of study 
drug/placebo; we will exclude intubations that are required for providing anesthesia for 
any surgeries or procedures. Patients who require intubation for the provision of 
anesthesia will remain in the study as prolonged ventilation is considered to be clinically 
equivalent to respiratory failure.  
 
Renal failure requiring dialysis (either continuous or intermittent) 
Any use of dialysis (continuous or intermittent hemodialysis or peritoneal dialysis) within 
28 days after initiation of study drug/placebo 
 
Vasoplegic shock requiring vasopressors 
Proportion of patient requiring any vasopressor drug such as phenylephrine, 
norepinephrine, vasopressin, epinephrine or dopamine for more than two hour within 28 
days after initiation of study drug/placebo. The time of possible procedures or operations 
are not included in this definition 
 
Inflammatory markers, specifically IL-6 levels 
Absolute levels of the following inflammatory markers (continuous variables): 
IL-6, IL-7, IL-8, C-reactive protein, erythrocyte sedimentation rate. We will determine the 
peak value within 28 days after start of experimental drug/placebo as a secondary 
endpoint 
 
Return to baseline oxygen requirement from start of experimental drug/placebo to day 
28  
Time to ability to maintain oxygen saturation (SaO2) >95% or above baseline in patients 
with baseline low sAo2 (for example due to COPD) with supplemental oxygen 
administration 
 
 


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The multiplicity control procedure to be used to control the family-wise type I 
error: 
 
We acknowledge that family-wise type errors are a concern considering that many of our 
primary and secondary endpoints are interdependent. For example, vasopressor use (a 
secondary endpoint) is frequently associated with AKI (our primary endpoint). We will 
attempt control for the multiplicity by 
1. Using all-cause mortality with a subcomponent of acute kidney injury to aligned with the 
type of study of a proof of concept study 
2. Use of a combined secondary endpoint; this endpoint is achieved if the patient either 
dies, requires intubation or renal replacement therapy within 28 of initial administration of 
study drug / placebo 
 
 
Main analysis for each of the key primary and secondary efficacy endpoints: 
 
Primary endpoint of all-cause mortality will be used as a binary variable and compared 
between patients receiving study drug and placebo using Chi-Square test. We will 
analyze all randomized patients in the main efficacy analysis for primary and secondary 
endpoints, regardless of whether they have missing data.  
 
Respiratory failure requiring intubation and ventilatory support, Renal failure requiring 
dialysis and vasoplegic shock requiring vasopressors will also be determined as binary 
variables. Peak Inflammatory markers within 28 days, specifically IL-6 level will be 
analyzed as a continuous variable. 
Intercurrent events are a concern and some of these patients may for example receive 
rescue medications or treatments. For intercurrent events besides death, the main 
estimand for each key efficacy endpoint will follow the treatment policy strategy. 
Therefore, the analyses will include all observed on-study data regardless of patients’ 
use rescue medications, discontinuation of the investigational product, or other violations 
of the protocol. 
 
We will use the appropriate statistical methods to analyze the primary and secondary 
endpoints such as Ch-Square for binary variables, t-test or Mann-Whitney test for 
continuous variables.  Significance will be determined at two-sided p <0.05. Variables 
that are significant in a univariate analysis will be included in a multi-variate analysis in 
addition to demographic variables such as sex, age or race, presence of co-morbidities 
and severity of COVID-19 as described below. 
More detailed statistical methods will be determined with the consultation of a statistician 
prior to unblinding and data analysis. 
 
Subgroup analyses 
 


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We will analyze the following subgroups separately 
- 
Age below and above 60 years 
- 
History of diabetes  
- 
History of hypertension 
- 
Race, sex 
- 
Severity of COVID-19 disease at enrollment 
o Mild COVID-19 
• 
No clinical signs indicative of Moderate, Severe, or Critical Severity 
o Moderate COVID-19 
• 
Respiratory rate ≥ 20 breaths per minute, saturation of oxygen (SpO2) > 93% on 
room air at sea level, heart rate ≥ 90 beats per minute 
o Severe COVID-19 
• 
Shortness of breath at rest, or respiratory distress and respiratory rate ≥ 30 per 
minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room air or PaO2/FiO2 < 
300 
 
Safety analyses 
 
Safety outcomes and adverse events that will be included in a safety analysis will 
include among others:  
- 
Anemia 
- 
Arrhythmia  
- 
Hypotension 
- 
Concurrent infections 
- 
Liver dysfunction 
 
Grading will occur as described by the FDA in the “Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0”  
Patients will be monitored closely for drug-drug interactions. Daily drug administration 
will be recorded and any potential drug-drug interaction reported to the DSMB that will 
then review these cases within 48 hours. Possible drug-drug interactions will include 
pharmacodynamic interactions with antihypertensives, specifically ACE inhibitors or 
Angiotensin receptor blocker and pharmacokinetic interactions.  
   


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11 
ACCESS TO SOURCE DATA/DOCUMENTS 
Any information collected during this study (coded or containing identifiers) will be kept 
confidential. Specimens will be assigned a code number, and separated from the 
participants’ name or any other information that could identify the participants. The 
research file that links the participants name to the code number will be kept in a locked 
file cabinet and only the investigator and study staff will have access to the file.  
 
 


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12 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 Declaration of Helsinki 
”The investigator will ensure that this study is conducted in full conformity with the 
current revision of the Declaration of Helsinki, or with the International Conference for 
Harmonisation Good Clinical Practice (ICH-GCP) regulations and guidelines, whichever 
affords the greater protection to the subject.” 
12.2 Institutional Review Board 
This protocol along with the associated informed consent documents and recruitment 
material will be reviewed by an appropriate independent ethics review committee (IEC) 
or Institutional Review Board (IRB) registered with OHRP.  Any amendments to the 
protocol or consent materials must be reviewed before they are placed into use. No 
study procedures will be conducted until the aforementioned is approved by the CUIMC 
IRB. 
12.3 Informed Consent Process 
“Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continuing throughout the individual’s study participation.  
Extensive discussion of risks and possible benefits of participation in this study will be 
provided to the subjects and their families.   
Consent forms describing in detail the study procedures and risks are given to the 
subject and written documentation of informed consent is required prior to enrolling in 
the study.  Consent forms will be IRB approved and the subject will be asked to read and 
review the document. Upon reviewing the document, the investigator will explain the 
research study to the subject and answer any questions that may arise.  The subjects 
will sign the informed consent document prior to being enrolled in the study.  The 
subjects should have the opportunity to discuss the study with their surrogates or think 
about it prior to agreeing to participate.  The subjects may withdraw consent at any time 
throughout the course of the study.  A copy of the informed consent document will be 
given to the subjects for their records.  The rights and welfare of the subjects 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.” 
Waiver of pre-screening consent 
 Initial Screening of Medical Records: 
Referrals of potential participant candidates will be provided by colleagues of the PI/Sub-
Is. Prior to approaching the potential patient, the CRC, PI and CO-I will review the 


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medical records in EMR system to determine further eligibility based on the 
Inclusion/Exclusion Criteria. 
 
 Signed Informed Consent Form 
The clinical research coordinator or PI or co-investigator will thoroughly go over the 
consent form and provides the participant ample time for them to read it and ask any 
questions or concerns they may have. After participant reviews the consent form, written 
consent is obtained by the participant. At that moment, the participant is considered to 
be enrolled in the study and an ID# is given. A copy of the consent and HIPAA forms are 
provided to the participant.  
12.4 Subject Confidentiality 
All subject identifiers will be removed after collection of the data and the data will receive 
a code that will allow us to link this data to the medical record number and will be stored 
in a locked and secured, encrypted computer. Access to any of the data will be restricted 
to the principal investigator, coinvestigators and CRC by assignment of a password.  
12.5 Data Capture Methods 
Study data is captured by paper and electronic forms. Any self-reported data by the 
patients will be captured and incorporated into CRF including timing of drug 
administration. Electronic data such as Medical Record abstraction will be extracted from 
EPIC. Excel tracking sheets are maintained by the CRC as internal electronic 
documents which will eventually be transferred to RedCap. Trained study staff will enter 
data from the paper CRFs into the excel file. This method, once implemented will serve 
as the source documents and may be printed for audit/review purposes if need be.  
12.6 Study Records Retention 
All source documents including but not limited to data collection, study materials, reports 
and internal documents will be retained within the CUIMC/NYP premise in a locked file 
cabinet, inside a locked office for the longest duration dictated by applicable regulations 
(6 years for HIPAA, 3 years for HHS, 2 years for FDA, contract with drug sponsor may 
require longer duration). 


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13 
REFERENCES 
Investigator Brochure Manual provided by the drug sponsor as well as the CUMC IRB 
Standard of Care policies. 
Stallard, N., Whitehead, J., Todd, S., & Whitehead, A. (2001). Stopping rules for phase II 
studies. British journal of clinical pharmacology, 51(6), 523–529. 
https://doi.org/10.1046/j.0306-5251.2001.01381.x 
Thabane, L., Mbuagbaw, L., Zhang, S. et al. A tutorial on sensitivity analyses in clinical 
trials: the what, why, when and how. BMC Med Res Methodol 13, 92 (2013). 
https://doi.org/10.1186/1471-2288-13-92 
Siew ED, Peterson JF, Eden SK, Moons KG, Ikizler TA, Matheny ME. Use of multiple 
imputation method to improve estimation of missing baseline serum creatinine in acute 
kidney injury research. Clin J Am Soc Nephrol. 2013;8(1):10-18. 
Aroda VR, Saugstrup T, Buse JB, Donsmark M, Zacho J, Davies MJ. Incorporating and 
interpreting regulatory guidance on estimands in diabetes clinical trials: The PIONEER 1 
randomized clinical trial as an example. Diabetes Obes Metab. 2019;21(10):2203-2210. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_5x7.pdf). Accessed 05/30/ 


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14 
APPENDICES 
14.1 Appendix A: Schedule of Assessments  
 
Event 
Scree
n 
Day 1 
+/- 2 
days of 
screen 
Day
2  
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
24-72 
hrs* 
Day 
28 
+/- 
2 
day
s 
Day 
60 
+/- 2 
days 
 
 
 
If patient remains hospitalized, the below assessments 
will be done 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Vitals1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Drug/Placebo 
Administration2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical Blood 
Work3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Research Blood 
Work 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Clinical Chest 
x-ray + Chest 
CT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical COVID-
19 symptoms 
and history 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical Patient 
Assessments4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Follow-up AE 
phone call 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
*Post hospital discharge date 
1-Vitals include: HR, RR, BP, O2Sat, Weight, Height 
2-Drug/Placebo Administration includes: Time drug was given, dosage, vitals within 3 hours of 
drug given 
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4-Patient Assessments include: collection of COVID-19 symptoms, SOFA, NEWS, Ordinal scale 
and Glasgow coma scale.  
14.2 Appendix B: Questionnaires 
 
Ordinal Scale:  
 
•  1.Death 
•  5.Hospitalized, not requiring 
supplemental oxygen 
•  2.Hospitalized, on invasive mechanical 
ventilation or ECMO 
•  6.Not Hospitalized, limitation on 
activities 
•  3.Hospitalized, on non-invasive ventilation or 
high flow oxygen devices 
•  7.Not Hospitalized, no limitation on 
activities 
•  4.Hospitalized, requiring supplemental 
oxygen 
 
 
 
NEWS Scale: 
     
 
 
Respiratory Rate 
Point Value 
•  <=8      
•  9-11 
•  12-20   
•  21-24   
•  >25 
+3 
+1 
0 
+2 
+3 
   Oxygen Sat % 
 
•  <91 
•  92-93 
•  94-95 
•  >=96 
+3 
+2 
+1 
0 
Any supplemental oxygen 
 
•  Yes 
•  No 
+2 
0 
Heart rate 
Point Value 
•  <=40 
•  41-50 
•  51-90 
•  91-110 
•  111-130 
•  >=131 
+3 
+1 
0 
+1 
+2 
+3 
Temperature in C 
Point Value 
•  <=35  
(95F) 
•  35.1-36  
(95.1-96.8) 
•  36.1-38.0  
(96.9-100.4 
•  38.1-39.0  
(100.5-102.2) 
•  >=39.1  
(>=102.3) 
+3 
 
+1 
 
0 
 
+1 
 
+2 
Systolic BP 
Point Value 
•  <=90 
•  91-100 
•  101-110 
•  111-219 
•  >=220 
+3 
+2 
1 
0 
+3 
Level of Consciousness 
Point Value 
•  Alert 
•  Not Alert (V, P or 
U) 
0 
3 
Total score