Conditions: COVID-19
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 81
Healthy volunteers: no

Brief summary:
Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway, a trigger of the inflammatory cascade. The study team hypothesizes that aldose reductase inhibition with AT-001 (caficrestat) might represent a novel therapeutic approach to reduce inflammation and risk of adverse outcomes in diabetic patients with COVID-19.

An open-label pilot study to assess safety, tolerability and efficacy of AT-001 in hospitalized COVID-19 patients with history of diabetes mellitus and heart disease will be conducted. Eligible participants will be treated with AT-001 1500 mg twice daily for up to 14 days. Safety, tolerability, survival and length of hospital stay data were compared with matched controls from a contemporaneous registry of COVID-19 patients.

Detailed description:

Arms:
arm 1: AT-001 1500 mg (3 capsules) were administered by mouth twice daily for up to 14 days arm 2: Matched control from a contemporaneous de-identified registry of hospitalized patients with clinical COVID-19 diagnosis at the same institution was selected. The first matching approach selected all subjects with diabetes mellitus and hypertension, and available data to match participants who received AT-001 for gender, age group (in bins of 5 years), weight, and C-reactive protein (CRP) value at the time of hospital admission. arm 3: Matched control from a contemporaneous de-identified registry of hospitalized patients with clinical COVID-19 diagnosis at the same institution was selected. The second matching approach selected all subjects in the registry with diabetes mellitus and available data to match participants who received AT-001 for gender, age group (in bings of 5 years), and weight (+/- 0.5 kgs).

Interventions: intervention 1: AT-001
Intervention descriptions: intervention 1: Investigational novel Aldose Reductase Inhibitor (ARI) Product: AT-001 500mg capsule for oral administration Dosage: 1,500mg (3X500mg capsules) twice daily Mode of Administration: Oral Up to 14 days per discretion of the investigators and treatment team

Protocol document:
Prot_SAP_001.pdf: 
 
 
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A single-center registry and embedded interventional study of the effects of 
COVID-19 with and without treatment with AT-001 on cardiac structure and 
function in patients hospitalized for management of COVID-19 infection 
 
Principal Investigator: 
 
Stuart Katz, MD 
Additional Investigators: 
 
See table below 
NYULMC Study Number: 
s20-00416 
Funding Sponsor:  
Applied Therapeutics, Inc. 
545 Fifth Avenue, Suite 1400 New York, NY 10017 212.220.9319  
www.appliedtherapeutics.com 
IND/IDE Number: 
IND number 136043 held by Sponsor 
Study Product: 
AT-001 
Study Product Provider:  
Applied Therapeutics, Inc. 
545 Fifth Avenue, Suite 1400 New York, NY 10017 212.220.9319  
www.appliedtherapeutics.com 
ClinicalTrials.gov Number    NCT04365699 
 
Protocol Revision History: 
 
Version Number 
Version Date 
Summary of Revisions Made 
1.0 
22 MARCH 
2020 
Initial Draft 
1.1 
24 MARCH 
2020 
Updated With AT-001 intervention 
1.2 
26 MARCH 
2020 
Revisions to study procedures 
1.3 
13 APRIL 2020 
Addition of NYU Winthrop for AT001 intervention 
1.4 
03 MAY 2020 
Revisions to entry criteria and analysis related to co-
enrollment and EUA of remdesivir 
 


Study number: s20-00416 
 
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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes 
referred to as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and 
DHHS regulations. The Principal Investigator will assure that no deviation from, or changes to the 
protocol will take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human Subjects 
Protection Training. 
 
 


Study number: s20-00416 
 
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Table of Contents 
 
STATEMENT OF COMPLIANCE .................................................................................................................. II 
LIST OF ABBREVIATIONS ........................................................................................................................ VI 
PROTOCOL SUMMARY ............................................................................................................................... 1 
SCHEMATIC OF STUDY DESIGN ............................................................................................................... 4 
1 
KEY ROLES .......................................................................................................................................... 5 
2 
, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ................................................... 5 
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE ................................................................ 5 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT ............................................................... 7 
2.2.1 
Preclinical Data ........................................................................................................................ 7 
2.2.2 
Clinical Data to Date ................................................................................................................ 8 
2.2.3 
Dose Rationale (if applicable) .................................................................................................. 9 
2.3 
RATIONALE ..................................................................................................................................... 9 
2.4 
POTENTIAL RISKS & BENEFITS ........................................................................................................ 9 
2.4.1 
Known Potential Risks ............................................................................................................. 9 
2.4.2 
Known Potential Benefits ....................................................................................................... 10 
3 
OBJECTIVES AND PURPOSE .......................................................................................................... 10 
3.1 
PRIMARY OBJECTIVE ..................................................................................................................... 10 
3.2 
SECONDARY OBJECTIVES (IF APPLICABLE) ..................................................................................... 10 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................................. 10 
4.1 
DESCRIPTION OF STUDY DESIGN ................................................................................................... 10 
4.2 
STUDY ENDPOINTS ....................................................................................................................... 11 
4.2.1 
Primary Study Endpoints........................................................................................................ 11 
4.2.2 
Secondary Endpoints ............................................................................................................. 11 
5 
STUDY ENROLLMENT AND WITHDRAWAL ................................................................................... 11 
5.1 
INCLUSION CRITERIA ..................................................................................................................... 11 
5.2 
EXCLUSION CRITERIA .................................................................................................................... 12 
5.3 
VULNERABLE SUBJECTS ................................................................................................................ 12 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 13 
5.4.1 
Use of DataCore/Epic Information for Recruitment Purposes ............................................... 13 
5.5 
DURATION OF STUDY PARTICIPATION ............................................................................................. 13 
5.6 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 13 
5.7 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 13 
5.7.1 
Reasons for Withdrawal or Termination ................................................................................ 13 
5.7.2 
Handling of Participant Withdrawals or Termination .............................................................. 14 
5.8 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 14 
6 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE ETC.) AND/OR PROCEDURAL 
INTERVENTION .......................................................................................................................................... 14 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .............................................................................. 14 
6.1.1 
Acquisition .............................................................................................................................. 14 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................................. 15 
6.1.3 
Product Storage and Stability ................................................................................................ 15 
6.1.4 
Preparation ............................................................................................................................. 15 
6.1.5 
Dosing and Administration ..................................................................................................... 15 
6.1.6 
Route of Administration .......................................................................................................... 15 
6.1.7 
Duration of Therapy ............................................................................................................... 15 
6.1.8 
Tracking of Dose .................................................................................................................... 15 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES .............................................................................. 15 


Study number: s20-00416 
 
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7 
STUDY PROCEDURES AND SCHEDULE ........................................................................................ 15 
7.1 
STUDY PROCEDURES/EVALUATIONS .............................................................................................. 15 
7.1.1 
Study Specific Procedures ..................................................................................................... 15 
7.1.2 
Standard of Care Study Procedures ...................................................................................... 16 
7.2 
LABORATORY PROCEDURES/EVALUATIONS .................................................................................... 16 
7.2.1 
Clinical Laboratory Evaluations .............................................................................................. 16 
7.3 
STUDY SCHEDULE ........................................................................................................................ 16 
7.3.1 
Enrollment/Baseline ............................................................................................................... 16 
7.3.2 
Daily Interventional Study Visits (up to 14 days) ................................................................... 16 
7.3.3 
Final Study Visit ..................................................................................................................... 17 
7.3.4 
Withdrawal/Early Termination Visit ........................................................................................ 17 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .................................................... 17 
7.4.1 
Precautionary Medications, Treatments, and Procedures ..................................................... 17 
7.5 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ........................................................ 17 
7.6 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................... 17 
7.7 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES .............................................................. 17 
7.8 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE......................................................... 17 
8 
ASSESSMENT OF SAFETY .............................................................................................................. 17 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 17 
8.1.1 
Definition of Adverse Events (AE).......................................................................................... 17 
8.1.2 
Definition of Serious Adverse Events (SAE) .......................................................................... 18 
8.1.3 
Definition of Unanticipated Problems (UP) ............................................................................ 18 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT........................................................................................ 19 
8.2.1 
Severity of Event .................................................................................................................... 19 
8.2.2 
Relationship to Study Agent ................................................................................................... 19 
8.2.3 
Expectedness ......................................................................................................................... 19 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................................... 19 
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB ........................................................................... 20 
8.4.1 
Adverse Event Reporting ....................................................................................................... 20 
8.4.2 
Serious Adverse Event Reporting .......................................................................................... 20 
8.4.3 
Unanticipated Problem Reporting .......................................................................................... 21 
8.4.4 
Reporting of Pregnancy ......................................................................................................... 21 
8.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SPONSOR ....................................................... 22 
8.6 
STUDY HALTING RULES................................................................................................................. 22 
8.7 
SAFETY OVERSIGHT ...................................................................................................................... 22 
9 
CLINICAL MONITORING ................................................................................................................... 23 
10 
STATISTICAL CONSIDERATIONS ................................................................................................... 23 
10.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) .................................................................................. 23 
10.2 
STATISTICAL HYPOTHESES ............................................................................................................ 23 
10.3 
ANALYSIS DATASETS..................................................................................................................... 23 
10.4 
DESCRIPTION OF STATISTICAL METHODS ....................................................................................... 23 
10.4.1 
General Approach .............................................................................................................. 23 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ..................................................................... 23 
10.4.3 
Analysis of the Secondary Endpoint(s).............................................................................. 24 
10.4.4 
Safety Analyses ................................................................................................................. 24 
10.4.5 
Adherence and Retention Analyses .................................................................................. 24 
10.4.6 
Baseline Descriptive Statistics ........................................................................................... 24 
10.5 
SAMPLE SIZE ................................................................................................................................ 24 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 24 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ........................................................................ 25 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 25 
13.1 
ETHICAL STANDARD ...................................................................................................................... 25 


Study number: s20-00416 
 
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13.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 26 
13.3 
INFORMED CONSENT PROCESS ..................................................................................................... 26 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ............... 26 
13.3.2 
Consent Procedures and Documentation ......................................................................... 26 
13.4 
POSTING OF CLINICAL TRIAL CONSENT FORM ................................................................................ 27 
13.5 
PARTICIPANT AND DATA CONFIDENTIALITY ..................................................................................... 27 
14 
DATA HANDLING AND RECORD KEEPING ................................................................................... 27 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 27 
14.2 
STUDY RECORDS RETENTION........................................................................................................ 28 
14.3 
PROTOCOL DEVIATIONS ................................................................................................................ 28 
14.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 29 
15 
STUDY FINANCES ............................................................................................................................. 30 
15.1 
FUNDING SOURCE ........................................................................................................................ 30 
15.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 30 
15.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................. 30 
16 
STUDY ADMINISTRATION ................................................................................................................ 30 
16.1 
STUDY LEADERSHIP ...................................................................................................................... 30 
17 
CONFLICT OF INTEREST POLICY ................................................................................................... 30 
18 
REFERENCES .................................................................................................................................... 31 
19 
ATTACHMENTS ................................................................................................................................. 32 
20 
SCHEDULE OF EVENTS ................................................................................................................... 33 
 
 
 
 


Study number: s20-00416 
 
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List of Abbreviations 
 
AE 
Adverse Event/Adverse Experience 
ARDS 
Adult Respiratory Distress Syndrome 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
FWA 
Federal-wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IL-6 
Interleukin-6 
IRB 
Institutional Review Board 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SARS-CoV-2 
Severe Adult Respiratory Syndrome Coronavirus2 
SOP 
Standard Operating Procedure 
US 
United States 
 
 


Study number:  
 
Page 1 
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Protocol Summary 
Title 
A multi-center registry and embedded interventional study of the 
effects of COVID-19 with and without treatment with AT-001 on 
cardiac structure and function in patients hospitalized for management 
of COVID-19 infection 
Short Title 
Cardiovascular effects of COVID-19 
Brief Summary 
This is a prospective multicenter registry with an embedded open-label 
randomized clinical trial to determine the effects of standard of care 
treatment vs. standard of care plus AT-001 on cardiac structure and 
function and in-hospital survival in patients hospitalized for 
management of COVID-19 infection. Eligible subjects with COVID-19 
infection will be identified at the time of hospital admission based on 
existing infection control surveillance protocols, and will have clinical 
data extracted from the electronic medical record to determine clinical 
characteristics associated with cardiac structure and function and in-
hospital survival. A subset of patients with history of diabetes mellitus 
and/or acute hyperglycemia (any glucose measurement >200 mg/dl) 
and evidence of acute or chronic heart disease will be treated in an 
open-label fashion to receive an investigational aldose reductase 
inhibitor, AT-001 plus standard of care. The primary objective of the 
interventional study is provide emergency access to open-label 
treatment to COVID-19 patients with acute cardiopulmonary 
symptoms.  
Phase 
Phase II 
Objectives 
• 
To characterize serial measures cardiac structure and function and 
in-hospital survival in hospitalized patients with COVID-19 infection 
• 
To develop predictive models of cardiac risk in hospitalized COVID-
19 infection patients 
• 
To assess safety of treatment with AT-001 plus standard of care on 
in-hospital survival in patients with COVID-19 
• 
To characterize the effects of treatment with AT-001 plus standard of 
care on in-hospital mortality, progression of acute lung injury 
requiring mechanical ventilation, and serial measures of cardiac 
structure and function 
 
Methodology 
Prospective, open-label registry with embedded open-label study 


Study number: s20-00416 
 
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Endpoint 
Primary Endpoint for Registry Study: Proportion of subjects with 
decreased left ventricular ejection fraction ≥10% from baseline at time 
of hospitalization 
 
Primary Endpoint for Embedded Clinical Trial: Safety of AT-001 
 
Secondary Endpoints (for registry and clinical trial): 
• 
Change in left ventricular ejection fraction 
• 
Change in left ventricular end-diastolic diameter 
• 
Change in left ventricular end-systolic diameter 
• 
Change in biomarkers of cardiac injury 
• 
Frequency of atrial fibrillation 
• 
Frequency of heart block 
• 
Frequency of non-sustained ventricular tachycardia 
• 
Frequency of sustained ventricular tachycardia 
• 
Frequency of ventricular fibrillation 
 
Secondary Endpoints (for clinical trial): 
• 
Proportion of subjects requiring mechanical ventilation 
• 
Proportion of subjects with decrease in left ventricular ejection 
fraction ≥10% from baseline at time of hospitalization 
 
Study Duration 
One year 
Participant Duration 
Up to 30 days after hospital discharge 
Duration of IP 
administration 
1-14 days per treatment physician discretion 
Population 
All subjects hospitalized with COVID-19 infection hospitalized will be 
enrolled in the registry; a subgroup meeting specific entry criteria 
listed below will be enrolled in the open-label interventional trial 
Study Sites 
NYU Langone Tisch Hospital (registry and embedded clinical trial) 
NYU Langone Brooklyn Hospital (registry only) 
NYU Langone Winthrop Hospital (registry and embedded clinical 
trial) 
Bellevue Hospital Center (registry only) 
Number of 
participants 
500 registry subjects enrolled at all sites 
20 interventional trial subjects at NYU Tisch Hospital and NYU 
Winthrop 
Description of Study 
Agent/Procedure 
AT-001 is an investigational novel Aldose Reductase Inhibitor (ARI) in 
Phase 2/3 development in the US, Canada and Europe for treatment of 
Diabetic Cardiomyopathy.  The US IND# is 136043. A full 
Investigational Brochure is for the ongoing Diabetic Cardiomyopathy 
program is attached to this protocol. 
Reference Therapy 
Standard of care 
Key Procedures 
Data extraction from electronic medical record 
Administration of AT-001 1500 mg twice daily for up to 14 days 


Study number: s20-00416 
 
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Statistical Analysis 
Registry Study 
 
• 
Multivariable logistic regression models and Cox Proportional Hazard 
models will be used to estimate the association between clinical 
variables at time of hospital admission and ICU admission with 
proportion of patients with decreased left ventricular ejection fraction 
≥10% and secondary endpoints cardiac structure and function. 
 
• 
Multivariable mixed models will be used to estimate the association 
between serial measures of cardiac structure and function and in-
hospital mortality. 
 
Interventional Study 
 
• 
Safety assessment of AT-001 based on reported adverse events 
• 
Exploratory analyses with descriptive statistics to describe clinical 
outcomes in patients treated with AT-001 plus standard of care 
 
 
 
 


Study number: s20-00416 
 
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Schematic of Study Design 
 
 
 
 
 
 
Hospitalized Patients With 
COVID-19 infection
Clinical Data Collection For 30 
Days or Until Hospital Discharge
Registry Enrollment for Clinical 
Data Collection
No
Yes
Consent, Study Drug 
Administration
Clinical and Safety Data 
Collection for up to 30 Days After 
Hospital Discharge
Meets Trial 
Entry Criteria


Study number: s20-00416 
 
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1 Key Roles 
 
Name 
Role 
Appointment 
Department 
Site 
Stuart Katz 
Principal 
Investigator 
NYU Grossman 
SOM 
Department of 
Medicine 
NYU Tisch 
Judith Hochman 
Co-Investigator 
NYU Grossman 
SOM 
Department of 
Medicine 
NYU Tisch 
Harmony 
Reynolds 
Co-Investigator 
NYU Grossman 
SOM 
Department of 
Medicine 
NYU Tisch 
Glenn Fishman 
Co-Investigator 
NYU Grossman 
SOM 
Department of 
Medicine 
NYU Tisch 
Alex 
Reyentovich 
Co-Investigator 
NYU Grossman 
SOM 
Department of 
Medicine 
NYU Tisch 
Claudia Gidea 
Co-Investigator 
NYU Grossman 
SOM 
Department of 
Medicine 
NYU Tisch 
Juan Gaztanaga 
Co-Investigator 
NYU Grossman 
SOM 
Department of 
Medicine 
NYU 
Winthrop 
 
2 Background Information and Scientific Rationale 
2.1 Background Information and Relevant Literature 
An outbreak of viral pneumonia in Hubei province China in December 2019 led to the 
identification of a novel coronavirus (SARS-CoV-2, subsequently renamed as COVID-19) as the 
etiologic agent.1, 2 COVID-19 infection rapidly spread through China and then globally to all 
continents except Antarctica. Based on reported observations from the initial epidemic in China, 
hypertension and underlying cardiac diseases, as well as diabetes and treatment with 
immunosuppressants, may be associated with increased risk of death in patients with COVID-19. 
Like related coronaviruses, COVID-19 infects host cells via interaction with membrane-bound 
angiotensin converting enzyme-isoform 2 (ACE2) on respiratory epithelium. ACE2 is part of the 
renin-angiotensin-aldosterone (RAAS) neurohormonal pathway, a neuroendocrine, paracrine, 
and autocrine system that regulates cardiac structure and function, vasomotor tone, sodium 
metabolism, and blood pressure homeostasis. COVID-19 infection is also associated with 
activation of inflammatory cytokines that induce myocardial contractile dysfunction, myocyte 
cell injury, cardiac arrhythmias, and vascular endothelial cell and smooth cell dysfunction. 
Initial reports from China in 41 patients indicated that severe COVID-19 infection in 
hospitalized patients is associated with approximately 10-20% risk of cardiac complications 
include increased biomarkers of myocardial injury, decreased left ventricular contractile 
function, cardiac arrhythmias, chest pain, hypotension, and fatal circulatory collapse.3 There are 
also reported anectodal cases of sudden cardiac arrest occurring in young patients recovering 
from COVID-19 induced acute respiratory failure. 
The current study is being undertaken to create increase knowledge of the cardiovascular 
complications of COVID-19 infection at NYU Langone Health and Bellevue Hospital Center. A 
prospective registry is proposed to characterize the cardiovascular manifestations of COVID-19 


Study number: s20-00416 
 
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infection in US patients. The prospective registry also provides a platform for execution of a 
clinical trial of an investigational agent for treatment of COVID-19 infection. 
Aldose reductase (AR), the first and rate-limiting step in the polyol pathway, is activated by 
hyperglycemic and ischemic conditions. AR initiates this pathway by catalyzing the NADPH-
dependent reduction of the aldehyde form of glucose to produce sorbitol as an intermediate. 
Sorbitol is then oxidized using NAD to form fructose, catalyzed by the enzyme sorbitol 
dehydrogenase. Excess intracellular sorbitol produced by AR accumulates in cells, resulting in 
osmotic damage and ultimately cell death (figure 1).4, 5 
 
 
 
Aldose Reductase plays a critical role in mediation of oxidative tissue damage in setting of 
inflammation induced by infection or ischemia.6 A potent Aldose Reductase Inhibitor (ARI) with 
a favorable safety profile may be an important tool for short-term use in the clinical setting to 
prevent lung inflammatory damage and cardiomyopathy in patients with COVID-19 infection.7, 8 
 
Aldose Reductase Inhibitors (ARIs), including the first-generation ARI zopolrestat, and the next 
generation ARI, AT-001 prevent oxidative-induced cardiac and lung injury in vivo and in vitro 
by preventing AR-induced downstream accumulation of reactive oxygen species and advanced 
glycation end-products. AT-001 has been shown to prevent oxidative damage to cardiomyocytes 
in oxidative-induced cardiomyopathies. AT-001 prevents ischemic/oxidative damage to 
cardiomyocytes in an ex-vivo system and decreases CK and other markers of cardiac damage In 
a Phase 1/2 clinical trial, AT-001 treatment in patients with Diabetic Cardiomyopathy decreased 
NTproBNP levels, a biomarker of cardiac stress or damage. 
 
AT-001 demonstrates approximately 1,000-fold increased activity or potency vs. prior ARIs with 
excellent safety and tolerability profile. (see attach Investigator Brochure and Reference: Perfetti 
et al Overcoming the Safety Challenges of Aldose Reductase Inhibition: Development of AT-
001 for Diabetic Cardiomyopathy; poster presented at WCIR Dec 2019; 
https://www.appliedtherapeutics.com/wp-
content/uploads/2020/01/2019_WCIRDC_Poster_Final_1.pdf) 
 


Study number: s20-00416 
 
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This interventional trial is intended to allow open-label emergency use of AT-001 for COVID-19 
infected patients experiencing acute cardiopulmonary sequelae of disease. 
2.2 Name and Description of the Investigational Agent  
AT-001 is a small molecule with a molecular weight of 421 g/mol. Its chemical structure is 
provided below. 
 
Chemical Structure of AT-001 
 
 
AT-001 drug product is provided as AT-001 powder in a capsule in a 500 mg strength, packaged 
in blister cards. There are no excipients used in the manufacture of AT-001 powder in capsule, 
and no materials of human or animal origin are present. The white, opaque capsule shells contain 
hypromellose and titanium dioxide. AT-001 is currently in Phase 2/3 development for Diabetic 
Cardiomyopathy under IND 136043. Based on pre-clinical and clinical data presented in the 
Investigator Brochure, a dose of 1,500mg BID (3 X 500mg capsules twice daily) will be used. 
 
AT-001 is an inhibitor of aldose reductase (AR), the first and rate-controlling enzyme of the 
polyol pathway which converts glucose to sorbitol and then to fructose. Hyperactivation of this 
pathway in patients with diabetes is thought to play a critical role in the pathogenesis of diabetic 
complications, including damage to peripheral nerves and blood vessels. Excess intracellular 
sorbitol produced by AR accumulates in cells, resulting in osmotic damage and ultimately cell 
death (Miki 2013). This pathological effect of excess sorbitol in cardiac cells can be seen in 
ventricular myocardial biopsies from diabetic patients which show significantly higher necrotic 
cardiomyocytes compared to biopsies from non-diabetic patients (Frustaci 2000). 
 
In vitro assays demonstrate that AT-001 binds to AR with high affinity and specificity, and with 
no evidence of off-target effects. In in vivo animal studies, AT-001 normalized sorbitol levels in 
diabetic rats, prevented cardiac ischemic injury in diabetic mice, prevented acute cardiac 
ischemic injury in non-diabetic rats, and treated acute cardiac ischemic injury in non- diabetic 
rats. 
2.2.1 Preclinical Data 
A comprehensive program to evaluate the preclinical profile of AT-001 has been conducted to 
support the clinical development program. In vivo Good Laboratory Practice (GLP) safety 
pharmacology studies showed no effect of AT-001 on gross behavioral, physiological, or 
neurological function in rats (Irwin Test), and no cardiovascular or respiratory effects in dogs at 
doses up to 2000 mg/kg/day, the highest dose studied. The AT-001 oral toxicology program to 
date consists of two single-dose studies in rats, one single-dose study in dogs, a dose range 
finding study in rats, a dose range finding study in dogs, two definitive 28-day GLP studies (rats, 
dogs); and two chronic GLP toxicity studies conducted in rats (26 weeks) and dogs (39 weeks). 
In vitro and in vivo genotoxicity testing has been performed. Doses up to 2000 mg/kg/day have 


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been orally administered to rats and dogs for up to 39 weeks. In the single-dose studies, the MTD 
was considered to be 2000 mg/kg/day, since there were no findings in these studies. In the 28-
day toxicology studies, the no adverse effect level (NOAEL) was determined to be 2000 
mg/kg/day in both rats and dogs. Four reproductive studies of the effects of AT-001 have been 
conducted: 2 studies in rats (GLP) and 2 studies in rabbits (one non-GLP, one GLP). Based on 
these findings, the NOAEL for maternal and embryo/fetal developmental toxicity was 1000 
mg/kg/day (the highest dosage level tested) in rats and 200 mg/kg/day in rabbits. AT-001 was 
shown to be negative for mutagenic activity in the reverse mutation assay, negative in the in vitro 
micronucleus assay, and negative in the in vivo micronucleus assay. 
2.2.2 Clinical Data to Date 
To date, one clinical study (AT-001.1001) has been conducted with AT-001. Full details are 
provided in the attached Investigator Brochure. 
 
StudyAT-001-1001, the first in human study of AT-001, was a Phase 1-2, three-part, 
randomized, placebo-controlled study designed to assess the safety, tolerability, PK, and PD 
(effect on sorbitol) of AT-001 in adults with Type 2 Diabetes Mellitus (T2DM). Since AR 
converts glucose to sorbitol, and AR activity is elevated in diabetic patients, sorbitol 
normalization was examined as a PD biomarker of target engagement. The study had 3 parts: 
single ascending dose (SAD) (Part A), 7-day multiple ascending dose (MAD) (Part B), and a 28-
day MAD extension part (Part C). A thorough safety review of each dose cohort was conducted 
prior to escalation to the next higher dose. 
 
All doses and dosing regimens were well-tolerated with no safety issues identified. There were 
no serious adverse events (SAEs) considered treatment-related and no AEs causing 
discontinuation of study treatment. No clinically relevant changes in vital signs, ECG or clinical 
safety laboratory values were noted. AT-001 did not cause an increase in glucose levels and was 
not associated with adverse interactions with any concomitant diabetes medications used by 
patients during the study. 
Mean AT-001 Tmax was between 1.5 to 3 hours, and mean half-life ranged between 1.2 to 3.4 
hours across all SAD and MAD cohorts. The maximal and systemic exposure in terms of Cmax 
and AUC0-inf appear to increase with increasing dose in a dose proportional manner in SAD 
cohorts, as well as in MAD cohorts on Days 1, Day 7, and day 28. AT-001 did not accumulate in 
plasma following administration of daily doses for up to 28 days. 
 
No clinical drug interaction studies have been conducted with AT-001 to date. The potential of 
AT-001 to inhibit the catalytic activities of key CYP isoforms was evaluated in an in vitro 
metabolism study using recombinant human CYP isoforms, while its potential to induce the 
catalytic activities of key CYP isoforms was evaluated in an ex vivo metabolism study using 
human hepatocytes. AT-001 over the concentration range tested (0.00545 to 50.0 μM) did not 
significantly inhibit human CYP450 isozymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 
(midazolam and testosterone substrates). The induction of human CYP1A2, 2B6, and 3A4 by 
AT-001 at the highest concentration tested (100 μM), observed in one of the three lots of 
hepatocytes, was lower than that with the control inducers which produced effects in all lots of 
hepatocytes. 


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2.2.3 Dose Rationale (if applicable)  
The 1500 mg twice daily dose is based on safety observations from the 28-day multiple 
ascending dose extension study. 
2.3 Rationale 
COVID-19 and previous coronaviruses associated with acute respiratory syndrome have high 
mortality rates, primarily attributable to respiratory failure and a substantial minority with 
cardiovascular complications. The proposed study will provide novel data in US patients to 
enhance cardiovascular risk prediction and identify potential novel therapies for therapy. 
 
2.4 Potential Risks & Benefits 
2.4.1 Known Potential Risks 
 
In subjects enrolled in the prospective registry, the only risk is potential breach of confidentiality.  
 
In subjects enrolled in the interventional trial, additional risk is associated with investigational 
agent. In the completed first in human study (Study AT-001.1001) AT-001 was generally well 
tolerated with no safety issues identified. There were no SAEs considered treatment-related and 
no AEs causing discontinuation of study treatment. No clinically relevant changes in vital signs, 
ECG or clinical safety laboratory values were noted. 
 
Potential risks of AT-001 based on non-clinical data and previous experience with other aldose 
reductase inhibitors include: 
 
• 
Acute hypersensitivity reactions 
• 
Hepatic toxicity, including fatal hepatic necrosis 
• 
Renal toxicity: Nephrolithiasis (calculi and pelvic dilation suggestive of an obstructive mechanism 
leading to development of pyelonephritis were reported in female rats in a 6-month chronic 
toxicology study. These renal findings were not reproduced in dogs in a 9-month chronic 
toxicology study) 
• 
Gastrointestinal events, including nausea, vomiting, diarrhea, flatulence, abdominal pain 
• 
Ocular effects (two cases of non-adverse, reversible multifocal pinpoint corneal opacities in a 28-
day toxicology study in dogs, which was not reproduced in a 9- month chronic toxicology study) 
• 
Hypotension and dizziness 
• 
Skin rash/eczema 
• 
Decreases in hemoglobin, erythrocyte count, and lymphocyte count 
• 
Reduction in total protein in blood 
 
The incidence of these side effects for short-term exposure to AT-001 in COVID-19 patients is 
unknown. We anticipate that patients with COVID-19 infection will receive concomitant 
treatments including off-label use of FDA-approved drugs, anti-viral therapy with remdesivir 
under expanded access or emergency use access, and treatment with hydroxychloroquine, 
convalescent sera, and/or IL-6 inhibitors within the context of clinical trials. Based on 
knowledge of the pathophysiology of COVID-19 infection and the pharmacology of AT-001, we 
do not anticipate that these concomitant medications will increase risk associated with AT-001. 
Patients with COVID-19 infection are known to be a high risk of complications including 


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multisystem organ failure (liver, kidney, heart, lung, hematological system, nervous system with 
associated laboratory abnormalities) and septic shock (hypotension with metabolic 
abnormalities). We will collect daily clinical information to monitor evidence of organ 
dysfunction and septic shock in the electronic CRF. We will identify potential AE related to 
study drug based upon temporal relationship with study drug administration, AE in the above list 
of potential AE associated with aldose reductase inhibition, or suspicion that the magnitude 
and/or duration of organ dysfunction and associated laboratory abnormalities is different from 
that expected due to COVID-19 infection alone. If treatment related AE are identified, the study 
drug may be discontinued per the discretion of the PI, Sponsor, and treating physician. 
2.4.2 Known Potential Benefits 
There is no direct benefit to subjects enrolled in the prospective registry. 
 
Based on its known mechanism of action and observations in the first in human study, there is 
possible benefit to subjects who receive AT-001 in the interventional study.  
 
 
3 Objectives and Purpose 
3.1 Primary Objective 
• 
Registry Study: To characterize serial measures cardiac structure and function and in-hospital 
survival in hospitalized patients with COVID-19 infection 
• 
Interventional Trial: To characterize safety of AT-001 in hospitalized patients with COVID-19 
infection 
3.2 Secondary Objectives (if applicable) 
• 
To develop predictive models of cardiac risk in hospitalized COVID-19 infection patients 
• 
To assess safety of treatment with AT-001 plus standard of care on in-hospital survival in patients 
with COVID-19 
• 
To characterize the effects of treatment with AT-001 plus standard of care on in-hospital mortality, 
progression of acute lung injury requiring mechanical ventilation, and serial measures of cardiac 
structure and function 
4 Study Design and Endpoints 
4.1 Description of Study Design 
The proposed study is a prospective registry of patients hospitalized with COVID-19 infections 
at participating sites (NYU Tisch, NYU Brooklyn, NYU Winthrop, Bellevue Hospital Center). 
Clinical data related to the COVID-19 infection will be extracted from the electronic medical 
record as described below in patients who meet study entry criteria. To maintain confidentiality, 
all subjects will be assigned a unique study identifier number. De-identified data will be recorded 
in an electronic database (REDCap). 
 
A subset of patients enrolled in the registry study may be eligible to participate in an open-label 
interventional trial of AT-001. For the substudy, informed consent will be obtained at the time of 
study entry, and clinical data will be extracted from the medical record using the same protocol 


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as the registry study. Additional safety and tolerability data will be collected for patients 
participating in the interventional trial.  
 
4.2 Study Endpoints 
4.2.1 Primary Study Endpoints 
 
Primary Endpoint for Registry Study: Proportion of subjects with decreased left ventricular 
ejection fraction ≥10% from baseline at time of hospitalization 
 
Primary Endpoint for Embedded Clinical Trial: Safety of AT-001 based on adverse events 
reporting 
 
4.2.2 Secondary Endpoints 
 
Secondary Endpoints (for registry and clinical trial): 
• 
Change in left ventricular ejection fraction 
• 
Change in left ventricular end-diastolic diameter 
• 
Change in left ventricular end-systolic diameter 
• 
Change in biomarkers of cardiac injury 
• 
Frequency of atrial fibrillation 
• 
Frequency of heart block 
• 
Frequency of non-sustained ventricular tachycardia 
• 
Frequency of sustained ventricular tachycardia 
• 
Frequency of ventricular fibrillation 
 
Secondary Endpoints (for clinical trial): 
• 
Proportion of subjects requiring mechanical ventilation 
• 
Proportion of subjects with decrease in left ventricular ejection fraction ≥10% from baseline at 
time of hospitalization 
 
5 Study Enrollment and Withdrawal 
5.1 Inclusion Criteria 
Registry Study: In order to be eligible to participate in the registry study, an individual must 
meet all of the following criteria: 
1. Age ≥18 years of age 
2. Hospitalized at one of the participating NYULH locations 
3. Confirmed COVID-19 infection 
 
Interventional Study: In order to be eligible to participate in the registry study, and individual must meet all 
of the inclusion criteria of the registry study plus the following critieria: 
 
1. Hospitalized at NYU Tisch or NYU Winthrop 
2. History of diabetes mellitus or blood glucose measurement >126 mg/dl 
AND  
EITHER 


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3. History of hypertension and/or ischemic heart disease and/or heart failure 
OR 
4. Other co-morbid condition that in the opinion of the PI increases risk of heart or lung injury related 
to the aldose reductase pathway 
 
5.2 Exclusion Criteria 
Registry Study: An individual who meets any of the following criteria will be excluded from 
participation in the registry study: 
1. Persons who have opted out of research participation at NYU 
2. Pregnancy 
 
 
Interventional study: An individual who meets any of the following criteria will be excluded 
from participation in the interventional study: 
1. Persons who have opted out of research participation at NYU 
2. Pregnancy 
3. Women of childbearing potential 
4. Breast-feeding women 
5. Participation in another FDA-regulated investigational drug placebo-controlled clinical trial within 
previous 30 days 
6. Hospital length of stay at time of study entry >14 days 
7. Inability to comply with oral or nasogastric tube administration of study drug 
 
Co-enrollment in other interventional studies in the COVID-19 population will be permitted if in 
the judgement of the PI and Sponsor, there is no anticipated increase in risk of exposure to AT-
001 based on the known pathophysiology of COVID-19 infection and pharmacology of AT-001, 
and co-enrollment is permitted in the other protocol(s). Co-enrollment will be tracked at reported 
to the IRB and Sponsor. 
5.3 Vulnerable Subjects 
Critically-ill patients with COVID-19 may not have capacity to provide consent. The registry 
research is minimal risk without direct benefit. Waiver of consent and authorization are 
requested as is not feasible to obtain informed consent and HIPAA authorization from 500 
subjects in order to conduct the prospective chart review for the registry component of the study. 
Although we will need access to the subjects’ medical record for the duration of the study, an 
individual’s PHI will be destroyed once they complete the study. 
 
The primary treatment team, which consists of critical care physicians will determine subject 
capacity based on their interactions with the patient, presence of neurological complications, and 
use of sedative agents. These critical care physicians are qualified to assess capacity for consent 
as part of their clinical management of the patient. Subjects will be regularly assessed by the 
primary critical care team throughout the study to determine whether or not they have regained 
or lost the capacity to consent. If subjects who have the capacity to consent at the onset of the 
study lose capacity during the study, their legally authorized representative will be identified and 
consent sought for the subject's continued participation in the study. If subjects regain the 
capacity to consent during the study and decline to continue participation, state they will be 
asked if previously collected data can still be used. If they decline, this data will be discarded. 


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If the potential participant lacks capacity, the legally authorized representative (identified in 
accordance with NYS as the highest in priority of the following: court appointed LAR, health 
care proxy, spouse or domestic partner, adult son or daughter, parent, grandparent, adult 
grandchild who maintains regular contact with subject as to be familiar with subject’s activities, 
health, or beliefs) will provide consent for the interventional study. 
 
5.4 Strategies for Recruitment and Retention 
Existing infection surveillance procedures identify all patients with COVID-19 admitted to the 
participating sites. These daily surveillance lists will be used to identify patients for the registry. 
Subjects potentially eligible for the interventional study will be identified by the intensivist in 
charge of patient care. The primary treatment team of critical care physicians will approach the 
patient and/or LAR regarding interest in participation in the study. 
 
5.4.1 Use of DataCore/Epic Information for Recruitment Purposes 
 
The study will use DataCore and EPIC for recruitment purposes. All subjects with COVID-19 
infectoins are tracked to specific hospital floors for infection control purposes. Patients who meet 
entry criteria on COVID-19 positive hospital floors will be identified by electronic chart review. 
The primary care team will be contacted to confirm that the patient is appropriate for the study 
and willing to be approached for research. 
 
5.5 Duration of Study Participation 
Duration of study participation for the registry study is until hospital discharge, or up to 30 days, 
whichever is shorter. 
 
Duration of study participation for the interventional study is up to 30 days after last dose of AT-
001. 
 
5.6 Total Number of Participants and Sites  
Recruitment will end when approximately 500 participants are enrolled in the registry, and 
approximately 20 participants in the interventional study. 
 
5.7 Participant Withdrawal or Termination 
5.7.1 Reasons for Withdrawal or Termination 
 
Participants are free to withdraw from participation in the study at any time upon request. An 
investigator may terminate participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 


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• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
 
5.7.2 Handling of Participant Withdrawals or Termination 
If a participant requests withdrawal from the study, all data collection will stop and all previously 
collected data will be deleted from the research database. Any analyses already completed at the 
time of the withdrawal request will remain unchanged. 
 
5.8 Premature Termination or Suspension of Study 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to investigator, IND/IDE 
sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the PI 
will promptly inform the IRB and will provide the reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
• 
Sponsor determination 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed 
and satisfy the sponsor, IRB and/or FDA. 
 
6 Study Agent (Study drug, device, biologic, vaccine etc.) and/or 
Procedural Intervention  
6.1 Study Agent(s) Description 
Product: AT-001 500mg capsule for oral administration 
Dosage: 1,500mg (3X500mg capsules) twice daily 
Mode of Administration: Oral  
Compound: 
 
 
Please see attached Sponsor pharmacy manual for additional details. 
6.1.1 Acquisition 
Investigational product will be shipped by the Sponsor and IND holder Applied Therapeutics Inc 
 


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6.1.2 Formulation, Appearance, Packaging, and Labeling 
AT-001 drug product is provided as AT-001 powder in a capsule in a 500 mg strength, packaged 
in blister cards. There are no excipients used in the manufacture of AT-001 powder in capsule, 
and no materials of human or animal origin are present. The white, opaque capsule shells contain 
hypromellose and titanium dioxide. 
6.1.3 Product Storage and Stability 
The product is stable at room temperature 
 
6.1.4 Preparation 
None 
 
6.1.5 Dosing and Administration 
Three 500 mg capsules (1500 mg) twice daily 
 
6.1.6 Route of Administration 
Oral. For subjects unable to swallow capsules, the capsules will be opened to allow mixing with 
soft foods, or mixed with water for nasogastric tube administration. 
 
6.1.7 Duration of Therapy 
Up to 14 days per discretion of the investigators and treatment team 
 
6.1.8 Tracking of Dose 
Dosing will be tracked in EPIC per hospital nursing and pharmacy protocol 
 
6.2 Study Agent Accountability Procedures 
The investigational pharmacy will track Investigational product 
 
7 Study Procedures and Schedule 
7.1 Study Procedures/Evaluations 
7.1.1 Study Specific Procedures 
Study procedures include data collection from the electronic medical record. The data collection 
will be performed by automated data extraction and chart review, and will be recorded on de-
identified electronic case report forms (see Appendix for eCRF). 
 


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7.1.2 Standard of Care Study Procedures 
All participants will receive standard of care for COVID-19 infection. This includes supportive 
measures for symptomatic relief, assisted ventilation including use of sedatives, pharmacological 
management of shock, organ injury, co-morbid bacterial infections, and co-morbid conditions. 
 
7.2 Laboratory Procedures/Evaluations 
7.2.1 Clinical Laboratory Evaluations 
Standard of care laboratory procedures will be performed; results will be recorded in the research 
database There are no study-related laboratory evaluations. 
 
• 
Hematology: hemoglobin, hematocrit, white blood cells (WBC) with differential count, platelet 
count. 
• 
Biochemistry: serum electrolytes, blood urine nitrogen, creatinine, total bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total protein, calcium, 
magnesium, phosphate, troponin-I, brain natriuretic peptide, ferritin, CRP, ESR, IL-6, . 
• 
Urinalysis: dipstick urinalysis, including protein, hemoglobin and glucose; if dipstick is abnormal, 
complete urinalysis with microscopic evaluation is required. 
• 
Pregnancy test, usually to be done within 24 hours prior to study intervention and results must 
be available prior to administration of study product. 
 
7.3 Study Schedule 
Registry Study: All clinically-derived data on the attached eCRF will be collected on a daily 
basis until hospital discharge, or first 30 days of hospitalization (whichever is shorter). 
 
Interventional study: All clinically-derived data on the attached eCRF will be collected on a daily 
basis during IP administration, with safety monitoring continuing 30 days after last dose of IP. In 
additional the following study procedures will be performed: 
 
7.3.1 Enrollment/Baseline 
Enrollment/Baseline Visit (Visit 1, Day 0) 
• 
Obtain informed consent for potential participant (or their LAR) verified by signature on study 
informed consent form. 
• 
Verify inclusion/exclusion criteria. 
• 
See electronic case report form. These data will be collected at baseline. 
• 
Start study drug administration 
• 
Safety monitoring 
 
7.3.2 Daily Interventional Study Visits (up to 14 days) 
• 
See electronic case report form. These data will be collected daily. 
• 
Study drug administration 
• 
Safety monitoring 
 


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7.3.3 Final Study Visit 
• 
Safety monitoring for 30 days after last dose of IP 
 
7.3.4 Withdrawal/Early Termination Visit 
See electronic case report form 
 
7.4 Concomitant Medications, Treatments, and Procedures 
 
All concomitant prescription medications taken during study participation will be recorded on 
the case report forms (CRFs). For this protocol, a prescription medication is defined as a 
medication that can be prescribed only by a properly authorized/licensed clinician. Medications 
to be reported in the CRF are concomitant prescription medications, over-the-counter 
medications and non-prescription medications. 
 
7.4.1 Precautionary Medications, Treatments, and Procedures 
None 
 
7.5 Prohibited Medications, Treatments, and Procedures 
Other investigational medications 
7.6 Prophylactic Medications, Treatments, and Procedures 
None 
 
7.7 Rescue Medications, Treatments, and Procedures 
None 
 
7.8 Participant Access to Study Agent at Study Closure 
None 
 
8 Assessment of Safety 
8.1 Specification of Safety Parameters  
All subjects in the interventional study will be observed daily by the treatment team for detection 
of adverse events. 
 
8.1.1 Definition of Adverse Events (AE) 
 


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An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
 
8.1.2 Definition of Serious Adverse Events (SAE) 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
8.1.3 Definition of Unanticipated Problems (UP) 
 
 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators brochure, 
etc) 
• Related or possibly related to participation in the research (i.e. 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) 


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• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
8.2 Classification of an Adverse Event 
8.2.1 Severity of Event 
 
For AEs not included in the protocol defined grading system, the following guidelines will be 
used to describe severity. 
 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
 
8.2.2 Relationship to Study Agent 
 
The clinician’s assessment of an AE's relationship to study agent (drug, biologic, device) is part 
of the documentation process, but it is not a factor in determining what is or is not reported in 
the study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. All AEs must have their relationship to study agent assessed. In a clinical trial, the 
study product must always be suspect. To help assess, the following guidelines are used. 
 
• Related – The AE is known to occur with the study agent, there is a reasonable possibility that the 
study agent caused the AE, or there is a temporal relationship between the study agent and event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the 
study agent and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study agent 
caused the event, there is no temporal relationship between the study agent and event onset, or 
an alternate etiology has been established. 
 
8.2.3 Expectedness 
 
The PI 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. 
 
8.3 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, or upon review by a 
study monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs 


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will be captured on the appropriate RF. 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 data collection system 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 will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 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.  
 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study.  
 
8.4 Reporting Procedures – Notifying the IRB  
8.4.1 Adverse Event Reporting 
Adverse events that do not meet criteria for serious adverse event or unanticipated event will be 
submitted at the time of study continuation or termination, whichever occurs first. 
 
8.4.2 Serious Adverse Event Reporting 
 
According to CFR 21 CFR 312.32(c)(1), “the sponsor must notify FDA and all participating 
investigators in an IND safety report of potential serious risks, from clinical trials or any other 
source, as soon as possible, but in no case later than 15 calendar days after the sponsor 
determines that the information qualifies reporting. In each IND safety report, the sponsor must 
identify all IND safety reports previously submitted to FDA concerning a similar suspected 


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adverse reaction, and must analyze the significance of the suspected adverse reaction in light of 
previous, similar reports or any other relevant information. The sponsor must report any 
suspected adverse reaction that is both serious and unexpected. The sponsor must report an 
adverse event as a suspected adverse reaction only if there is evidence to suggest a causal 
relationship between the drug and the adverse event, such as: 
 
(A) A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); 
(B) One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
(C) An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those events 
occur more frequently in the drug treatment group than in a concurrent or historical ̮control 
group.” 
 
Furthermore, according to 21 CFR 312.32(̮c)(2), “the sponsor must also notify FDA of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case 
later than 7 calendar days after the sponsor’s initial receipt of the information.” 
 
8.4.3 Unanticipated Problem Reporting 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of 
an UP report form. It is the site investigator’s responsibility to report UPs to their IRB and to the 
DCC/study sponsor. 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: 
 
• UPs that are SAEs will be reported to the IRB and to the study sponsor within 24 hours of the 
investigator becoming aware of the event. 
• Any other UP will be reported to the IRB and to the study sponsor within 72 hours of the 
investigator becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures) within 72 hours of the IR’s receipt of the report of the problem from 
the investigator. 
 
8.4.4 Reporting of Pregnancy 
Pregnancy will be considered an unanticipated event and will be reported to the IRB and Sponsor 
within 24 hours. 


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8.5 Reporting Procedures – Notifying the Study Sponsor 
 
The study clinician will complete a SAE Form within the following timelines: 
 
• All deaths and immediately life-threatening events, whether related or unrelated, will be recorded 
on the SAE Form and submitted to the DCC/study sponsor within 24 hours of site awareness. See 
Section 1, Key Roles for contact information. 
• Other SAEs regardless of relationship will be submitted to the DCC/study sponsor within 72 hours 
of site awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the 
event to be chronic or the adherence to be stable. Other supporting documentation of the event 
may be requested by the DCC/study sponsor and should be provided as soon as possible.  
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the 
investigator shall provide further information, as applicable, on the unanticipated event or the 
unanticipated problem in the form of a written narrative.  This should include a copy of the 
completed Unanticipated Problem form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing unanticipated adverse 
effects shall be provided promptly to the study sponsor. 
 
8.6 Study Halting Rules 
 
Administration of study agent will be halted when three grade 3 AEs determined to be “probably 
related” are reported to the Sponsor.  
 
8.7 Safety Oversight 
 
It is the responsibility of the Principal Investigator and Sponsor to oversee the safety of the study 
at his/her site.  This safety monitoring will include careful assessment and appropriate reporting 
of adverse events as noted above, as well as the construction and implementation of a site data 
and safety-monitoring plan. The data safety monitoring plan will consist of daily review of the 
clinical and laboratory data recorded in the attached electronic CRF. Medical monitoring will 
include a regular assessment of the number and type of serious adverse events with complete 
review of the clinical course of each subject after 7 and 14 days of treatment. Due to the nature 
of COVID-19 infection, many events related to organ dysfunction and septic shock are 
anticipated in this population. Only suspected treatment related adverse events, based on 
temporal relationship, biological plausibility of relation to aldose reductase inhibition, or 
magnitude/duration greater than anticipated from COVID-19 alone will be reported. A summary 
of the outcomes of these reviews will be submitted to the IRB at the time of continuation 
application, or sooner if protocol modifications are required for subject safety. 
 


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9 Clinical Monitoring 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are 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). 
 
• The PI will oversee the monitoring for data integrity for this study. 
• Independent audits will not be conducted to ensure monitoring practices are performed 
consistently across all participating sites. 
• Each clinical site will perform internal quality management of study conduct, data collection, 
documentation and completion. An individualized quality management plan will be developed to 
describe a site’s quality management. 
 
10 Statistical Considerations 
10.1 Statistical and Analytical Plans (SAP) 
Due to the urgent COVID-19 crisis, there is no formal SAP.  
 
10.2 Statistical Hypotheses 
The null hypothesis for the registry study is that there are no significant associations between 
clinical characteristics at study entry and subsequent occurrence of cardiac dysfunction, lung 
dysfunction or death in hospitalized patients with COVID-19 infection. 
 
There will be no hypothesis testing for the interventional trial. The primary endpoint is safety of 
AT-001 based on descriptive statistics and qualitative evaluation of adverse event monitoring. 
Descriptive statistics will be used to assess frequency of secondary endpoints without hypothesis 
testing. 
 
10.3 Analysis Datasets 
The registry dataset consists of all subjects with any entered data. 
The interventional safety data set will be all subjects who received at least one dose of AT-001 
 
10.4 Description of Statistical Methods 
10.4.1 General Approach 
Descriptive statistics will be used to define data missingness, data distributions. 
 
10.4.2 Analysis of the Primary Efficacy Endpoint(s) 
Registry Study 
 


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• 
Multivariable logistic regression models and Cox Proportional Hazard models will be used to 
estimate the association between clinical variables at time of hospital admission and ICU 
admission with proportion of patients with decreased left ventricular ejection fraction ≥10% and 
secondary endpoints cardiac structure and function. 
 
• 
Multivariable mixed models will be used to estimate the association between serial measures of 
cardiac structure and function, need for mechanical ventilation, and in-hospital mortality. 
 
Interventional Study 
 
• 
Safety assessment of AT-001 based on reported adverse events 
• 
Exploratory analyses with descriptive statistics to estimate effects of co-enrollment on safety 
outcomes 
• 
Exploratory analyses with descriptive statistics to describe clinical outcomes in patients treated 
10.4.3 Analysis of the Secondary Endpoint(s) 
The same analyses will be used for secondary endpoints. 
10.4.4 Safety Analyses 
Adverse events will be analyzed as summary statistics and coded by MedDRA. 
 
10.4.5 Adherence and Retention Analyses 
Data missingness will be assessed with descriptive statistics. 
 
10.4.6 Baseline Descriptive Statistics 
Baseline characteristics will be summarized with non-parametric statistics 
 
10.5 Sample Size 
The estimated sample size for the registry (500 participants) and the interventional trial (20 
participants) are convenience samples based on the anticipated number of patients at NYU with 
COVID-19 infection. These numbers should provide sufficient power to conduct the regression 
analyses for the registry (up to 50 predictor variables), and for safety assessment of AT-001. 
11 Source Documents and Access to Source Data/Documents 
 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. It is acceptable to use CRFs as source documents. If this is the case, it should 


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be stated in this section what data will be collected on CRFs and what data will be collected from 
other sources. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
 
Access to study records will be limited to IRB-approved members of the study team. The 
investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
 
12 Quality Assurance and Quality Control 
 
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 
communicated to the site(s) for clarification/resolution. 
 
Following written SOPs, the monitors 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), Good Manufacturing 
Practices (GMP)). 
 
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 the sponsor, and inspection by local 
and regulatory authorities. 
 
13 Ethics/Protection of Human Subjects 
13.1 Ethical Standard 
 


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The investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
CFR Part 56, and/or the ICH E6. 
 
13.2 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 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. 
 
13.3 Informed Consent Process 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product.  
 
In the event that the participant is critically ill and unable to provide consent, a study team 
member may conduct the informed consent process via telephone or video (webex) with use of 
e-consent through REDCap to obtain and document informed consent from the subject/LAR. 
 
13.3.2 Consent Procedures and Documentation 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families. 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
document. The investigator will explain the research study to the participant and/or LAR and 
answer any questions that may arise. All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to 
participate. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the signed informed consent document will be given 
to the participants for their records. 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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A copy of the signed informed consent document will be stored in the subject’s research record. 
The consent process, including the name of the individual obtaining consent, will be thoroughly 
documented in the subject’s research record. Any alteration to the standard consent process (e.g. 
use of a translator, consent from a legally authorized representative, consent document presented 
orally, etc.) and the justification for such alteration will likewise be documented.  
 
In the event that the participant is not able to provide consent due to temporary loss of capacity 
during critical illness, the LAR will provide consent. 
 
13.4 Posting of Clinical Trial Consent Form 
The  informed consent form will be posted on the Federal website after the clinical trial is closed 
to recruitment, and no later than 60 days after the last study visit by any subject, as required by 
the protocol.  
 
13.5 Participant and Data Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. The research record data will be securely stored on the 
NYU REDCap database with password controlled access limited to authorized study personnel. 
The research record will not contain any identifiers. Each subject will be assigned a random 
study ID number. The link between the subject PHI and the study ID number will be maintained 
by the PI on encrypted shared drives maintained NYU and in the study binder which is kept in a 
locked cabinet in a locked room. 
 
14 Data Handling and Record Keeping 
14.1 Data Collection and Management Responsibilities 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 


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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. DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON 
THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and 
maintained for recording data for each participant enrolled in the study. Data reported in the 
eCRF 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 <specify name of data capture system>, a 21 CFR 
Part 11-compliant data capture system provided by the <specify DCC>. 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. 
 
14.2 Study Records Retention 
 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, or 2 years after the last approval of a marketing application is approved for 
the drug for the indication for which it is being investigated or 2 years after the investigation is 
discontinued and FDA is notified if no application is to be filed or if the application has not been 
approved for such indication. No records will be destroyed without the written consent of the 
sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
 
14.3 Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 


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It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working 
days of the scheduled protocol-required activity. 
 
All protocol deviations must be addressed in study source documents, reported to the Sponsor 
and IRB. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff 
is responsible for knowing and adhering to their IRB requirements. Further details about the 
handling of protocol deviations will be included in the MOP. 
 
14.4 Publication and Data Sharing Policy 
 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical 
trial as any research project that prospectively assigns human subjects to intervention or 
concurrent comparison or control groups to study the cause-and-effect relationship between a 
medical intervention and a health outcome. Medical interventions include drugs, surgical 
procedures, devices, behavioral treatments, process-of-care changes, and the like. Health 
outcomes include any biomedical or health-related measures obtained in patients or participants, 
including pharmacokinetic measures and adverse events. The ICMJE policy, and the Section 801 
of the Food and Drug Administration Amendments Act of 2007, requires that all clinical trials be 
registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine. Other biomedical journals are considering adopting similar 
policies. For interventional clinical trials performed under NIH IC grants and cooperative 
agreements, it is the grantee’s responsibility to register the trial in an acceptable registry, so the 
research results may be considered for publication in ICMJE member journals. The ICMJE does 
not review specific studies to determine whether registration is necessary; instead, the committee 
recommends that researchers who have questions about the need to register err on the side of 
registration or consult the editorial office of the journal in which they wish to publish. 
 
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal 
investigator) register and report results of certain "applicable clinical trials": 
 
• Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations 
of a product subject to FDA regulation; 
• Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric postmarket surveillance studies. 
• NIH grantees must take specific steps to ensure compliance with NIH implementation of FDAAA. 
 


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15 Study Finances 
15.1 Funding Source 
Applied Therapeutics, Inc. 
 
 
15.2 Costs to the Participant 
None 
 
15.3 Participant Reimbursements or Payments 
None 
16 Study Administration 
16.1 Study Leadership 
 
The Sponsor and PI will lead the study at NYU. 
 
17 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. The 
study leadership in conjunction with the <specify NIH IC> has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the NYU Langone Conflict of Interest Management Unit (CIMU) with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study sponsor prior to participation in this study. All NYULMC investigators will follow the 
applicable conflict of interest policies. 
 
 
 


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18 References 
 
1. 
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao 
Y, Li Y, Wang X and Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 
Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020. 
2. 
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei 
Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H and Cao B. Clinical course and risk factors for 
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 
Lancet. 2020. 
3. 
Zheng YY, Ma YT, Zhang JY and Xie X. COVID-19 and the cardiovascular system. Nat 
Rev Cardiol. 2020. 
4. 
Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B and 
Anversa P. Myocardial cell death in human diabetes. Circ Res. 2000;87:1123-32. 
5. 
Kaneko M, Bucciarelli L, Hwang YC, Lee L, Yan SF, Schmidt AM and Ramasamy R. 
Aldose reductase and AGE-RAGE pathways: key players in myocardial ischemic injury. Ann N 
Y Acad Sci. 2005;1043:702-9. 
6. 
Miki T, Yuda S, Kouzu H and Miura T. Diabetic cardiomyopathy: pathophysiology and 
clinical features. Heart Fail Rev. 2013;18:149-66. 
7. 
Ravindranath TM, Mong PY, Ananthakrishnan R, Li Q, Quadri N, Schmidt AM, 
Ramasamy R and Wang Q. Novel role for aldose reductase in mediating acute inflammatory 
responses in the lung. J Immunol. 2009;183:8128-37. 
8. 
Son NH, Ananthakrishnan R, Yu S, Khan RS, Jiang H, Ji R, Akashi H, Li Q, O'Shea K, 
Homma S, Goldberg IJ and Ramasamy R. Cardiomyocyte aldose reductase causes heart 
failure and impairs recovery from ischemia. PLoS One. 2012;7:e46549. 
 
 
 


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19 Attachments 
These documents are relevant to the protocol, but they are not considered part of the protocol.  
They are stored and modified separately. As such, modifications to these documents do not 
require protocol amendments. 
 
• Sponsor Investigator Brochure 
• Sponsor Emergency use IND protocol 
• Sponsor Pharmacy Manual 
• eCRF for data collection 
 


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Interventional Template Version: 11 JAN 2019 
 
20 Schedule of Events 
 
 
Activity 
Daily Data 
Collection during 
hospitalization 
 
Interventional 
Trial Entry 
 
Interventional 
Trial Daily 
Procedures (up 
to 14 days) 
Study team procedures 
  
  
 
Consent 
 
X 
 
eCRF completion 
X 
X 
X 
Study drug/device dispensation 
 
X 
X 
Safety Monitoring (until 30 days after last 
dose of IP) 
 
X 
X