Conditions: COVID-19 Acute Respiratory Distress Syndrome (ARDS)
Keywords: COVID-19 ARDS Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 31
Healthy volunteers: no

Brief summary:
This was a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter, dose escalation and proof-of-concept study to evaluate the safety and efficacy of razuprotafib, administered 3 times daily (TID) (every 8 hours \[Q8H\]), in hospitalized subjects with moderate to severe Coronavirus disease 2019 (COVID-19) receiving standard of care therapy.

The study was planned to include 2 parts with Part 1 comprising the dose escalation period of the study and Part 2 comprising the proof-of-concept safety and efficacy period of the study.

Detailed description:
Part 1 was to be a 2-step dose escalation that included approximately 60 subjects. Part 1, Step 1 was to include 30 subjects, and Part 1, Step 2 was to include 30 subjects. Part 1 was designed to primarily focus on safety; however, efficacy data was to be collected and analyzed as well.

Despite the Data Review Committee (DRC) recommendation to continue the study, after completion of Part 1, Step 1, the Sponsor elected to discontinue the study due to business-related reasons. Recruitment challenges and slow site startup led to delays in completing the study in a practical timeframe, and were the primary reasons to discontinue the study. No further subjects were recruited after Part 1, Step 1 completion. A full analysis of the data from Part 1, Step 1 was conducted and is presented in this report.

Part 1, Step 2 and Part 2 was not conducted.

Arms:
arm 1: Active Comparator arm 2: Placebo Comparator arm 3: Active Comparator

Interventions: intervention 1: Razuprotafib Subcutaneous Solution intervention 2: Placebo Subcutaneous Solution
Intervention descriptions: intervention 1: Up to 3 daily dose levels of Razuprotafib Subcutaneous Solution will be evaluated. Doses will be administered subcutaneously three times daily (Q8H) for 7 days. intervention 2: Matched vehicle-controlled placebo solution will be administered subcutaneously three times daily (Q8H) for 7 days

Protocol document:
SAP_002.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Protocol Title: 
A Phase 2, Randomized, Double-Blind, Placebo- 
Controlled, Parallel-Group, Multicenter, Dose Escalation 
and Proof-of-Concept Study to Evaluate the Safety and 
Efficacy of Razuprotafib in Hospitalized Subjects With 
Moderate to Severe Coronavirus Disease 
2019 (COVID-19) (RESCUE Study) 
 
Protocol Number: 
AKB-9778-CI-6001 
Protocol Version/Date: 
Version 3.0 / 10 December 2020 
Investigational Product: 
AKB-9778 (razuprotafib) 
 
 
Sponsor: 
Aerpio Pharmaceuticals, Inc. 
9987 Carver Road, Suite 420 
Cincinnati, OH 45242 
United States 
Telephone: 513-985-1920 
Fax: 513-985-0999 
 
SAP Version/Date: 
Version 1.0 / 16 February 2021 
 
 
CONFIDENTIAL 
The information in this document is confidential and is not to be disclosed without the written 
consent of Aerpio Pharmaceuticals, Inc. except to the extent that disclosure would be required 
by law and for the purpose of evaluating and/or conducting a clinical study for Aerpio 
Pharmaceuticals, Inc. You are allowed to disclose the contents of this document only to your 
Institutional Review Board and study personnel directly involved with conducting this protocol. 
Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Aerpio Pharmaceuticals, Inc. and that it may not be further 
disclosed to third parties. 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 2 of 18 
 
 
 
 
SIGNATURE PAGE 
 
Protocol Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Multicenter, Dose Escalation and Proof-of- 
Concept Study to Evaluate the Safety and Efficacy of 
Razuprotafib in Hospitalized Subjects With Moderate to 
Severe Coronavirus Disease 
2019 (COVID-19) (RESCUE Study) 
 
Protocol Number: 
AKB-9778-CI-6001 
SAP Version/Date: 
Version 1.0 / 16 February 2021 
 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
 
 
Signature 
Date 
 
 
Electronically signed by: Ran Fu 
Reason: Approved 
Date: Feb 16, 2021 13:55 EST 
16-Feb-2021  
Ran Fu, PhD 
Biostatistician 
Medpace, Inc. 
 
 
Brian Murphy, MD 
Vice-President, Medical Department 
Medpace, Inc. 
 
 
Kevin Peters, MD 
CSO/CMO 
Aerpio Pharmaceuticals, Inc. 
 
Electronically signed by: Akshay Buch 
Reason: Approved 
Date: Feb 16, 2021 15:44 EST 
 
 
 
16-Feb-2021  
 
 
16-Feb-2021  
 
 
16-Feb-2021  
Akshay Buch, PhD 
Senior Director of Pharmacokinetics and Clinical 
Pharmacology 
Aerpio Pharmaceuticals, Inc. 
Electronically signed by: Brian Murphy 
Reason: Approved 
Date: Feb 16, 2021 13:57 EST 
Electronically signed by: Kevin Peters 
Reason: Approved 
Date: Feb 16, 2021 15:28 EST 
Ran Fu 
Akshay Buch 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 3 of 18 
 
 
 
 
VERSION HISTORY 
 
 
Version 
Version Date 
Description 
1.0 
16 February 2021 
Original version 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 4 of 18 
 
 
 
 
TABLE OF CONTENTS 
1 
Introduction .......................................................................................................................... 7 
2 
Study Overview .................................................................................................................... 7 
2.1 
Study Objectives ........................................................................................................... 7 
2.1.1 
Primary Objective ................................................................................................... 7 
2.1.2 
Secondary Objectives ............................................................................................ 7 
2.1.3 
Exploratory Objectives............................................................................................ 7 
2.2 
Study Design ................................................................................................................. 7 
2.2.1 
Overview ................................................................................................................ 7 
2.2.2 
Randomization and Blinding ................................................................................... 8 
2.2.3 
Study Drug ............................................................................................................. 9 
2.2.4 
Sample Size Determination .................................................................................... 9 
2.3 
Study Endpoints ............................................................................................................ 9 
2.3.1 
Efficacy Endpoints .................................................................................................. 9 
2.3.2 
Pharmacodynamic (PD) and Pharmacokinetic (PK) endpoints .............................. 10 
2.3.3 
Safety Endpoints .................................................................................................. 11 
3 
Statistical Methodology ........................................................................................................ 11 
3.1 
General Considerations ............................................................................................... 11 
3.1.1 
Analysis Day ........................................................................................................ 11 
3.1.2 
Definition of Baseline ............................................................................................ 11 
3.1.3 
Visit Windows ....................................................................................................... 11 
3.1.4 
Summary Statistics............................................................................................... 11 
3.1.5 
Hypothesis Testing ............................................................................................... 11 
3.1.6 
Handling of Dropouts and Missing Data ................................................................ 11 
3.2 
Analysis Populations ................................................................................................... 12 
3.2.1 
Intent-to-Treat (ITT) Population ............................................................................ 12 
3.2.2 
Full Analysis (FA) Population................................................................................ 12 
3.2.3 
Per-Protocol (PP) Population................................................................................ 12 
3.2.4 
Safety Population ................................................................................................. 12 
3.3 
Subject Data and Study Conduct ................................................................................. 12 
3.3.1 
Subject Disposition ............................................................................................... 12 
3.3.2 
Protocol Deviations .............................................................................................. 13 
3.3.3 
Analysis Populations ............................................................................................ 13 
3.3.4 
Demographic and Baseline Characteristics........................................................... 13 
3.3.5 
Medical History..................................................................................................... 13 
3.3.6 
Concomitant Medications ...................................................................................... 14 
3.3.7 
Study Drug Exposure and Compliance ................................................................. 14 
3.4 
Efficacy Assessment ................................................................................................... 14 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 5 of 18 
 
 
3.4.1 
Efficacy Endpoints ................................................................................................ 14 
3.5 
Pharmacodynamic and Pharmacokinetic Assessment ................................................. 16 
3.6 
Safety Assessment ....................................................................................................... 16 
3.6.1 
Adverse Events (AEs) .......................................................................................... 16 
3.6.2 
Clinical Laboratory Tests ...................................................................................... 17 
3.6.3 
Vital Signs ............................................................................................................ 17 
3.6.4 
Electrocardiograms............................................................................................... 17 
4 
Data review committee ....................................................................................................... 17 
5 
Interim Analysis .................................................................................................................. 18 
6 
Changes from Protocol-Specified Statistical Analyses ........................................................ 18 
7 
Programming Specifications ............................................................................................... 18 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 6 of 18 
 
 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ANOVA 
Analysis of Variance 
ATC 
Anatomical therapeutic chemical 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
DRC 
Data Review Committee 
FiO2 
Fractional inspired oxygen 
ECMO 
Extracorporeal membrane oxygenation 
FA 
Full Analysis 
GCP 
Good Clinical Practice 
HMGB-1 
High mobility group box 1 
ICH 
International Council for Harmonisation 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
NIAID 
National Institute of Allergy and Infectious Diseases 
PaO2 
Partial pressure of oxygen 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
Q8H 
Every 8 hours 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SpO2 
Peripheral capillary oxygen saturation 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
TID 
Three times daily 
TNFα 
Tumor necrosis factor alpha 
WHO 
World Health Organization 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 7 of 18 
 
 
 
 
1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number AKB- 
9778-CI-6001. The SAP will be finalized prior to database lock. Any deviations from the SAP 
after database lock will be documented in the final Clinical Study Report (CSR). 
 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objectives of this study are to assess the safety and efficacy of razuprotafib in 
subjects with moderate to severe COVID-19. 
2.1.2 Secondary Objectives 
The secondary objectives of this study are to examine the effects of razuprotafib on biomarkers 
of inflammation and coagulopathy (ie, C-reactive protein [CRP] and D-dimer) in the plasma of 
subjects with moderate to severe COVID-19 and to characterize exposure of razuprotafib based 
on plasma concentrations for the samples collected on Day 1 and Day 6. 
2.1.3 Exploratory Objectives 
The exploratory objective of this study is to examine the effects of razuprotafib on biomarkers of 
vascular leakage and inflammation (ie, Angpt-2, IL-6, IL-8, tumor necrosis factor alpha [TNFα], 
and high mobility group box 1 [HMGB-1]) in the plasma of subjects with moderate to severe 
COVID-19. 
2.2 Study Design 
2.2.1 Overview 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter, 
dose escalation and proof-of-concept study to evaluate the safety and efficacy of razuprotafib, 
administered three times daily (TID) (every 8 hours [Q8H]), in hospitalized subjects with 
moderate to severe COVID-19 receiving standard of care therapy. The study design is 
summarized in the figure below. 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 8 of 18 
 
 
 
 
 
 
2.2.2 Randomization and Blinding 
After eligibility is determined, 30 subjects (6 sentinel subjects) will be randomized in a 1:1:1 ratio 
to 1 of the treatment groups in Part 1, Step 1: 
• 
Razuprotafib 10 mg TID; 
• 
Razuprotafib 20 mg TID; or 
• 
Placebo TID. 
If the Data Review Committee (DRC) recommends that Part 1, Step 2 should proceed as 
planned, then another 30 subjects (6 sentinel subjects) will be randomized in a 1:1:1 ratio (or a 
2:1 ratio if only 1 razuprotafib dose level is chosen) to 1 of the treatment groups in Part 1, Step 
2: 
• 
Razuprotafib 20 mg TID; 
• 
Razuprotafib 30 mg TID; or 
• 
Placebo TID (the placebo volume will match the active volume for each treatment 
group). 
Note: The planned dosing for Part 1, Step 2 may be changed after the DRC reviews the safety 
and PK data from Part 1, Step 1. 
Based on the DRC’s review of the available safety and PK data from Part 1, Step 1 and Part 1, 
Step 2, the study will proceed to Part 2. In Part 2, 120 subjects will be randomized to 1 of the 
treatment groups (dose 1 razuprotafib TID, dose 2 razuprotafib TID [optional], or placebo TID) in 
a 1:1:1 ratio (or a 2:1 ratio [razuprotafib:placebo] if only 2 treatment groups). The dosage(s) for 
Part 1, Step 2 and Part 2 are contingent upon DRC recommendation. 
Subjects will be randomized using the centralized randomization system, according to a 
computer-generated randomization list, and stratified by disease severity. Sentinel subject 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 9 of 18 
 
 
 
 
randomization will not be stratified by disease severity. Treatment group assignment will be 
blinded to subjects, clinicians, Sponsor study team, Contract Research Organization (CRO) 
study team, and Investigators. Specific individuals from the bioanalytical CRO and Sponsor’s 
PK group will have access to the randomization code to allow for ongoing analysis of 
bioanalytical samples from the subjects treated with razuprotafib and to provide PK analysis 
results for the DRC reviews. 
2.2.3 Study Drug 
The drug product formulation contains AKB-9778-sodium salt ready to dose, preservative free, 
isotonic, sterile solution (20 mg/mL or 40 mg/mL) in a 3 mL borosilicate vial fitted with a 13 mm 
septum and aluminum flip top seal. Placebo for razuprotafib (sterile normal saline) will be 
sourced locally by the site as a parenteral formulation ready to dose. 
Razuprotafib will be provided in an open-label format that is compliant with International Council 
for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. The placebo will be sourced 
locally and provided with the commercially available product label. 
A volume of 0.50 mL or 0.75 mL of study drug will be administered TID (Q8H) by SC injection to 
the abdomen. Subjects will be dosed for 7 days or until discharge from the hospital (or death), 
whichever occurs first. The first study drug administration must occur within 12 hours after 
randomization. Study drug should be administered at the same nominal times (±1 hour) for each 
Q8H dose throughout the Treatment Period. Prior to the initiation of Part 2, the DRC may make 
a recommendation to increase the study drug dosing duration to up to 14 days. 
2.2.4 Sample Size Determination 
Part 1 will include approximately 60 subjects. In Part 1, Step 1, approximately 30 subjects 
(including the 6 sentinel subjects) will be enrolled. In Part 1, Step 2, approximately 30 subjects 
(including the 6 sentinel subjects) are planned to be enrolled. Part 2 will include approximately 
120 subjects. No formal statistical assessment for sample size determination has been 
performed for Part 1 or Part 2. The sample size is considered adequate to provide the 
necessary data to evaluate the objectives for Part 1 or Part 2. 
2.3 Study Endpoints 
2.3.1 Efficacy Endpoints 
The efficacy endpoints include the following: 
• 
Proportion of subjects alive and free of respiratory failure at Day 28; 
• 
Proportion of subjects alive and free of respiratory failure at Day 7; 
• 
Proportion of subjects alive and not requiring invasive mechanical ventilation at any time 
through Day 28; 
• 
Time to reach grade 6, 7 or 8 on the NIAID 8-point ordinal scale; 
• 
Change in PaO2:FiO2 ratio from baseline to Day 7 (or discharge) and baseline to Day 
28 (or discharge); 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 10 of 18 
 
 
 
 
• 
Length of hospitalization and not requiring invasive mechanical ventilation from baseline 
to Day 7 and baseline to Day 28 or death; 
• 
Length of hospitalization from baseline to Day 7 and baseline to Day 28 or death; 
• 
Proportion of subjects who improve by ≥2 categories on the National Institute of Allergy 
and Infectious Diseases (NIAID) 8-point ordinal scale from baseline to Day 7 and 
baseline to Day 28; 
• 
Proportion of subjects who worsen by ≥2 categories on the NIAID 8-point ordinal scale 
from baseline to Day 7 and baseline to Day 28; 
• 
All-cause mortality at Day 7 and Day 28; 
• 
Number of subjects in each category of the NIAID 8-point ordinal scale at Day 7 and Day 
28; 
• 
Time to return to prehospitalization oxygen requirement; and 
• 
Proportion of subjects who were discharged and remained free of respiratory failure prior 
to Day 7 and Day 28. 
The NIAID 8-point ordinal scale includes the following grades: 
1. Death; 
2. Hospitalized, on invasive mechanical ventilation or Extracorporeal membrane 
oxygenation (ECMO); 
3. Hospitalized, on noninvasive ventilation or high-flow oxygen devices; 
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplementation oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise); 
6. Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical 
care; 
7. Not hospitalized, limitation on activities and/or requiring home oxygen; and 
8. Not hospitalized, no limitations on activities. 
2.3.2 Pharmacodynamic (PD) and Pharmacokinetic (PK) endpoints 
The PD and PK endpoints include in the following: 
• 
Change from baseline in CRP and D-dimer; 
• 
Change from baseline in systemic biomarkers of vascular leakage and inflammation (ie, 
Angpt-2, IL-6, IL-8, TNFα, and HMGB-1); 
• 
Summary of plasma concentrations of biomarkers at each sampling time point for each 
treatment group; and 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 11 of 18 
 
 
 
 
• 
Summary of plasma razuprotafib concentrations for the samples collected on Day 1 and 
Day 6. 
2.3.3 Safety Endpoints 
The safety endpoints include the following: 
• 
Number of subjects with any serious adverse event (SAE); and 
• 
Number of subjects with any treatment-emergent AE. 
 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug. The day of the first 
dose of study drug will be Day 1, and the day immediately before Day 1 will be Day -1. There 
will be no Day 0. 
3.1.2 Definition of Baseline 
Baseline is defined as the last measurement prior to the first dose of study drug. 
3.1.3 Visit Windows 
No analysis visit windows will be defined for this study, i.e., the nominal visits /time-points will be 
used for all statistical summaries/analyses. 
3.1.4 Summary Statistics 
Categorical data will generally be summarized with counts and percentages of subjects. The 
denominator used for the percentage calculation will be clearly defined. Continuous data will 
generally be summarized with descriptive statistics including n (number of non-missing values), 
mean, median, standard deviation, minimum, and maximum. 
Summaries of change from baseline variables will include only patients who have both a 
baseline value and corresponding value at the post-baseline time point of interest. 
3.1.5 Hypothesis Testing 
All statistical comparisons will be made using two-sided tests at α = 0.05. All null hypotheses will 
be of no treatment difference, and all alternative hypotheses will be two-sided. Confidence 
intervals will be two-sided, unless stated otherwise. 
3.1.6 Handling of Dropouts and Missing Data 
For all efficacy endpoints that do not include death as a possible outcome, data from subjects 
who die prior to Day 28 will be imputed at Day 28 based on the worst outcome. Other missing 
data for selected endpoints will be imputed using the methods as described in Section 3.4. 
In cases of missing or incomplete dates (e.g. AE and concomitant medications), the missing 
component(s) will be assumed as the most conservative value possible. For example, AEs with 
missing start dates, but with stop dates either overlapping into the treatment period or missing, 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 12 of 18 
 
 
 
 
will be counted as treatment-emergent, taking the worst-case approach. When partial dates are 
present in the data, both a partial start date and/or a partial stop date will be evaluated to 
determine whether it can be conclusively established that the AE started prior to the start of 
study drug or ended prior to the start of study drug. If the above cannot be conclusively 
established based on the partial and/or present dates, then the AE will be considered as 
treatment-emergent. 
3.2 Analysis Populations 
3.2.1 Intent-to-Treat (ITT) Population 
The Intent-to-Treat (ITT) Population is defined as all subjects randomized. Subjects in this 
population will be analyzed according to the treatment group to which they were assigned at 
randomization. 
3.2.2 Full Analysis (FA) Population 
The Full Analysis (FA) Population is a subset of the ITT Population and will include subjects 
receive at least one dose of study drug and have at least 1 post-dose efficacy evaluation. 
3.2.3 Per-Protocol (PP) Population 
The Per-Protocol (PP) Population is a subset of the FA Population and will include subjects that 
have at least 1 post-dose efficacy evaluation and do not have major protocol deviations. 
3.2.4 Safety Population 
The Safety Population is defined as all randomized subjects who received at least 1 dose of 
study drug. Subjects in this population will be analyzed according to the study drug they actually 
received. 
3.2.5 Pharmacokinetic (PK) Population 
The Pharmacokinetic (PK) Population is defined as all randomized subjects who received at 
least one dose of study drug and had least one PK sample with plasma concentration. 
3.3 Subject Data and Study Conduct 
3.3.1 Subject Disposition 
The number and percentage of subjects in each of the following categories will be presented by 
the treatment group and overall for all screened subjects: 
• 
screened, 
• 
randomized, 
• 
treated, 
• 
randomized but not treated, 
• 
completed the Treatment Period, and 
• 
completed the study. 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 13 of 18 
 
 
 
 
Primary reasons for discontinuation of study treatment and primary reasons for early withdrawal 
from the study will be tabulated. 
3.3.2 Protocol Deviations 
Any major protocol deviation will be documented as described in the protocol deviation plan, 
and its impact on inclusion in each analysis population for any subject will be specified. The final 
list of protocol deviations impacting the analysis populations will be reviewed prior to database 
lock. Counts and percentages of subjects with major protocol deviations by deviation category 
will be summarized for all randomized subjects. 
3.3.3 Analysis Populations 
Counts and percentages of subjects in each analysis population will be summarized by 
treatment and in total based on all randomized subjects. 
3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
• 
Age (years) 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
COVID-19 severity (moderate or severe) 
• 
NIAID Assessment 
• 
PaO2:FiO2 ratio 
• 
Pre-hospitalization oxygen requirement (None, Low-flow or High-flow Nasal cannula or 
CPAP mask) 
• 
Concomitant medication to treat COVID-19 at baseline 
• 
Comorbid conditions (diabetes, obesity, hypertension, heart failure, chronic kidney 
disease) 
Demographic and baseline characteristics will be summarized with descriptive statistics or 
counts and percentages of subjects as appropriate by treatment group and overall for each 
Analysis Population. 
3.3.5 Medical History 
Medical history will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 23.1. Counts and percentages of 
subjects with medical history by system organ class and preferred term will be summarized by 
treatment group and overall. 
Counts and percentages of subjects with COVID-19 symptoms will be summarized by treatment 
group and overall. 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 14 of 18 
 
 
 
 
3.3.6 Concomitant Medications 
Concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and 
preferred term using the World Health Organization Drug Dictionary (WHO Drug Global B3, 
March 2020). 
Prior medications will include medications which started prior to the first dose of study drug. 
Concomitant medications will include medications taken on and after the first dose of study 
drug. 
Medications that started prior to the first dose of study drug but continued into treatment are 
considered as both prior and concomitant. 
Counts and percentages of subjects taking prior and concomitant medications by ATC class and 
preferred term will be summarized by treatment group and overall based on the ITT Population. 
Any novel therapies for COVID-19 will be summarized based on the ITT Population. 
3.3.7 Study Drug Exposure 
Exposure to study treatment will be described in terms of duration of treatment and number of 
doses administered. Days of exposure to study drug will be calculated as date of last dose of 
study drug – date of first dose of study drug + 1. The number of doses administered for each 
subject will be summarized with counts and percentages in total. 
3.4 Efficacy Assessment 
All efficacy analysis will be performed using the ITT Population. Selected endpoints will be 
repeated on the FA and PP Populations. In addition, the efficacy analyses will be analyzed for 
pooled razuprotafib doses and placebo. 
Additional analyses to understand safety and efficacy variables further may be carried out and 
will be labeled as post-hoc analyses. 
3.4.1 Efficacy Endpoints 
The following parameters will be analyzed using Cochran-Mantel-Haenszel (CMH) test stratified 
by disease severity: 
• 
Proportion of subjects alive and free of respiratory failure at Day 28; 
• 
Proportion of subjects alive and free of respiratory failure at Day 7; 
All results will be summarized descriptively by treatment arm and expressed as proportions, 
along with corresponding 95% CI of the difference between response rates, and p-values. The 
95% CI will be constructed using the normal approximation method. 
Additional Analysis may be considered by incorporating other covariate adjustments into the 
analysis. 
Respiratory failure will be defined as subjects who are on invasive mechanical ventilation; are 
receiving oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via 
reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) 
noninvasive positive pressure ventilation or extracorporeal membrane oxygenation; or have a 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 15 of 18 
 
 
 
 
clinical diagnosis of respiratory failure (ie, clinical need for 1 of the preceding therapies, but 
preceding therapies not able to be administered in setting of resource limitation).Subject who 
die prior to the study timepoint (Day 7 or Day 28) will be imputed based on the worst outcome. 
Other missing responses will be imputed using a multiple imputation (MI) method under the 
assumption of missing at random (MAR). 
Sensitivity Analysis 
• 
All missing responses will be considered as non-responders and which will be imputed 
taking the worst case approach. 
• 
The analysis will be repeated on FA and PP Populations. 
The following parameters will be analyzed using the CMH test as stated above: 
• 
Proportion of subjects alive and not requiring invasive mechanical ventilation at any time 
through Day 28; 
• 
Proportion of subjects who improve by ≥2 categories on the NIAID 8-point ordinal scale 
from baseline to Day 7 and baseline to Day 28; 
• 
Proportion of subjects who worsen by ≥2 categories on the NIAID 8-point ordinal scale 
from baseline to Day 7 and baseline to Day 28; 
• 
All-cause mortality at Day 7 and Day 28; and 
• 
Proportion of subjects who were discharged and remained free of respiratory failure prior 
to Day 7 and Day 28. 
The following parameters will be analyzed using an analysis of variance (ANOVA) model with 
effects for treatment, baseline value and disease severity as factors: 
• 
Change in PaO2:FiO2 ratio from baseline to Day 7 (or discharge) and baseline to Day 
28 (or discharge), 
• 
Length of hospitalization and not requiring invasive mechanical ventilation from baseline 
to Day 7 and baseline to Day 28 or death, 
• 
Length of hospitalization from baseline to Day 7 and baseline to Day 28 or death, 
Missing responses will be imputed using a multiple imputation (MI) method under the 
assumption of missing at random (MAR). 
All results will be summarized descriptively by treatment group, along with corresponding 95% 
CI of the difference between razuprotafib groups vs. placebo, and p-value. 
The length of hospitalization will include all days that the subject is admitted to the hospital. For 
subjects who are discharged and readmitted to the hospital, the length of hospitalization will 
include the days after readmission. 
Hospitalization days will be counted in 24-hour periods; any partial days will be counted as a 
whole day. 
Days that subjects are on the ventilator will be counted as days of respiratory failure. Days that 
subjects are of respiratory failure based on the definition will be counted as days of respiratory 
failure. For subjects receiving high flow oxygen by a nasal cannula or noninvasive positive 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 16 of 18 
 
 
 
 
pressure ventilation when enrolled, the length of respiratory failure will include all the days of 
respiratory failure from baseline. 
The time-to-event endpoint of time to reach grade 6, 7 or 8 on the NIAID 8-point ordinal scale 
will be summarized descriptively using the Kaplan-Meier method. The Kaplan-Meier estimate of 
the median time as well as the 2-sided 95% confidence interval will be presented by treatment 
group. 
The endpoint of number of subjects in each category of the NIAID 8-point ordinal scale at Day 7 
and Day 28 will be summarized by treatment group and timepoint using descriptive statistics. 
The endpoint of time to return to prehospitalization oxygen requirement will be summarized by 
treatment group using descriptive statistics. 
3.5 Pharmacodynamic and Pharmacokinetic Assessment 
The PD and PK endpoints include the following: 
• 
Change and percentage change from baseline in CRP and D-dimer; 
• 
Change and percentage change from baseline in systemic biomarkers of vascular 
leakage and inflammation (ie, Angpt-2, IL-6, IL-8, TNFα, and HMGB-1); 
• 
Summary of plasma concentrations of biomarkers at each sampling time point for each 
treatment group; and 
• 
Summary of plasma razuprotafib concentrations for the samples collected on Day 1 and 
Day 6. 
PD and PK endpoints will be summarized descriptively by treatment group using ITT population 
and PK population. 
3.6 Safety Assessment 
Safety data will be summarized based on the Safety Population. Safety will be determined by 
evaluating clinical laboratory findings (blood chemistry, hematology, and coagulation), vital signs 
(blood pressure, heart rate, SpO2 [for non-ventilated subjects only], and respiratory rate), 12- 
lead electrocardiograms, and AEs reported during the study. 
3.6.1 Adverse Events (AEs) 
AEs, which include clinical laboratory test variables, will be monitored and documented from the 
time of the first dose of study drug until Day 28. All AEs will be coded to system organ class and 
preferred term using MedDRA version 23.0. Treatment-emergent adverse events (TEAEs) will 
be defined as an event that occurs on or after the first dose of study drug. 
An overview of AEs will be provided including counts and percentages of subjects and event 
counts with the following: 
• 
Any TEAEs (Overall, by maximum severity) 
• 
Any study drug related TEAEs 
• 
Any treatment-emergent serious AEs (TESAEs) 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 17 of 18 
 
 
 
 
• 
Any TEAEs leading to discontinuation of study drug 
• 
Any TEAEs leading to death 
Counts and percentages of subjects and event counts will also be presented by system organ 
class and preferred term for each of the categories in the overview. 
All AEs will be displayed in listings. In addition, listings will be presented specifically for SAEs 
and TEAEs leading to discontinuation of study drug. 
3.6.2 Clinical Laboratory Tests 
Values and changes from baseline of clinical laboratory variables for blood chemistry, 
hematology, and coagulation will be summarized using descriptive statistics by treatment group 
and time point. The number of available observations and out-of-range values (absolute and in 
percentage) will also be presented by treatment group. Clinical Laboratory data will be listed. 
3.6.3 Vital Signs 
Vital signs will include blood pressure, heart rate, SpO2 (for non-ventilated subjects only), and 
respiratory rate. Temperature will be measured at Screening only. 
Values, changes from baseline, changes from pre-dose for each TID dose of vital signs will be 
summarized using descriptive statistics by treatment group and time point. Vital signs will be 
listed. 
3.6.4 Electrocardiograms 
Values and changes from baseline of electrocardiograms data will be summarized using 
descriptive statistics by treatment group and time point (baseline and Day 7). The overall 
interpretation will be summarized by counts and percentages by treatment group and total. 12- 
lead electrocardiograms data will be listed. 
 
4 DATA REVIEW COMMITTEE 
A DRC comprised of members with pertinent expertise will review emerging safety, efficacy, and 
PK data at appropriate times throughout the study, as described in this protocol and as set forth 
in the DRC Charter. 
The DRC will convene throughout the study to review safety and PK data to recommend if it is 
safe and appropriate to continue the study as planned. The DRC will convene to recommend if 
continuation of Part 1, Step 1 and Part 1, Step 2 as planned is acceptable or if dosing 
modifications are required once AE information through at least 8 hours following the first dose 
of study drug is available for all 6 sentinel subjects in both Step 1 and Step 2 of Part 1. Upon 
both reviews after Part 1, Step 1 and Part 1, Step 2, the DRC will recommend subsequent 
dosing regimen(s) to be tested in the study. Prior to the initiation of Part 2, the DRC may also 
make a recommendation to increase the study drug dosing duration to up to 14 days. The 
highest dose in this study will not exceed 30 mg TID. The DRC can request to unblind efficacy 
data at any point if deemed necessary to adequately complete their review. Additionally, the 
DRC may request to unblind efficacy data if an increase in the study drug dosing duration is 


Aerpio Pharmaceuticals, Inc. 
Protocol : AKB-9778-CI-6001 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 1.0, 16 February 2021 
Page 18 of 18 
 
 
 
 
under consideration. Further details regarding the role, responsibilities, and procedures of the 
DRC will be provided in the DRC Charter. 
In addition, ad hoc reviews of safety data will be performed throughout the study by appropriate 
study personnel and the Medical Monitor. 
 
5 INTERIM ANALYSIS 
No interim analysis is planned. 
 
6 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
The protocol does not include the following three endpoints: proportion of subjects alive and not 
requiring invasive mechanical ventilation at any time through Day 28, time to reach grade 6, 7 or 
8 on the NIAID 8-point ordinal scale, and length of hospitalization and not requiring invasive 
mechanical ventilation from baseline to Day 7 and baseline to Day 28 or death, these have been 
included in the SAP. The following two endpoints have been deleted from SAP: length of ICU 
stay from baseline to Day 28 or death has been deleted from SAP and length of hospitalized 
and free of respiratory failure from baseline to Day 7 and baseline to Day 28 or death. 
The protocol does not include percentage change for PD endpoints, this has been included in 
the SAP. 
 
7 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.4 or higher. All available data will be 
presented in subject data listings which will be sorted by subject and visit date as applicable. 
Detailed Programming Specifications will be provided in a separate document. 

Prot_001.pdf: 
      
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Multicenter, Dose Escalation and Proof-of-Concept 
Study to Evaluate the Safety and Efficacy of Razuprotafib in 
Hospitalized Subjects With Moderate to Severe Coronavirus Disease 
2019 (COVID-19) (RESCUE Study) 
Investigational Product: AKB-9778 (razuprotafib) 
Protocol Number: AKB-9778-CI-6001 
 
 
Sponsor: 
Aerpio Pharmaceuticals, Inc. 
9987 Carver Road, Suite 420 
Cincinnati, OH 45242 
United States 
Telephone: 513-985-1920 
Fax: 513-985-0999 
 
 
Version Number: 3.0 
Date: 10 December 2020 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Aerpio Pharmaceuticals, Inc. except to the extent that disclosure would be required by 
law and for the purpose of evaluating and/or conducting a clinical study for Aerpio 
Pharmaceuticals, Inc. You are allowed to disclose the contents of this document only to your 
Institutional Review Board and study personnel directly involved with conducting this protocol. 
Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Aerpio Pharmaceuticals, Inc. and that it may not be further 
disclosed to third parties. 


AerpiQ Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778,CI-600.J 
SIGNATURE PAGE 
STUDY TITLE: A Phase 2, .&:mdomized, 001.d:ile•Blind, Placebo...Cont.ro!led, 
Pa:raUel-Gtoup, Multi.center, Dose Escalation and Proof-of-Concept Study to .Evaluate the 
Safety and Efficacy of Razuprotafib in Hospitalized Subjects With Moderate to Severe 
Coronavirt111 Ditease 2019 (COVTD ... 19) (RESCUE Study) 
We, the undersigned, have 
this protocol and agree that it contains all necessary information 
required to conduct the study, 
Signature 
Date 
~:.---
\'2 /t\ /~en_~ 
Kevin Peters, MP 
Chit'lfScientific Officer, Chief Medical Officer, and Senior Vice President, Research and 
DeveleJ?ment 
Aerpio Phapnaceuticals, Inc. 
Akshay 
Senior Director, Clinical Pharn:iacokinetics 
Ae,plo P"""'aceofaa, 
Christopher· Ernst 
Vice President, GMCand Quality A:ssura.nee 
:Aerpio Pharmaceuticals, Inc. 
Barbara Withers, PhD 
Vice President, Clinical Operations 
A:erpio Pharmaceuticals, Inc. 
Stlnfidentia I &. Proprillh11-y 
'Ver,;kln 3,0, U> De1.-en1ber wio 
Page 2pf.$9 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 3 of 59 
Version 3.0, 10 December 2020 
INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Aerpio Pharmaceuticals, Inc. to study personnel under my supervision. I will discuss this 
material with them to ensure they are fully informed about the study product and study procedures. 
I will let them know that this information is confidential and proprietary to Aerpio 
Pharmaceuticals, Inc. and that it may not be further disclosed to third parties. I understand that the 
study may be terminated or enrollment suspended at any time by Aerpio Pharmaceuticals, Inc., 
with or without cause, or by me if it becomes necessary to protect the best interests of the study 
subjects. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations, and International Council for 
Harmonisation Guidelines for Good Clinical Practices. 
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 4 of 59 
Version 3.0, 10 December 2020 
SYNOPSIS 
TITLE:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Multicenter, Dose Escalation and Proof-of-Concept Study to Evaluate the Safety and Efficacy of 
Razuprotafib in Hospitalized Subjects With Moderate to Severe Coronavirus Disease 2019 
(COVID-19) (RESCUE Study) 
PROTOCOL NUMBER:  AKB-9778-CI-6001 
INVESTIGATIONAL PRODUCT:  AKB-9778 (razuprotafib) 
PHASE:  2 
INDICATION:  Moderate to severe coronavirus disease 2019 (COVID-19) 
OBJECTIVES: 
The primary objectives of this study are to assess the safety and efficacy of razuprotafib in subjects 
with moderate to severe COVID-19. 
The secondary objectives of this study are to examine the effects of razuprotafib on biomarkers of 
inflammation and coagulopathy (ie, C-reactive protein [CRP] and D-dimer) in the plasma of 
subjects with moderate to severe COVID-19 and to characterize exposure of razuprotafib based 
on plasma concentrations for the samples collected on Day 1 and Day 6. 
The exploratory objective of this study is to examine the effects of razuprotafib on biomarkers of 
vascular leakage and inflammation (ie, angiopoietin [Angpt]-2, interleukin [IL]-6, IL-8, tumor 
necrosis factor alpha [TNFα], and high mobility group box 1 [HMGB-1]) in the plasma of subjects 
with moderate to severe COVID-19. 
POPULATION: 
The population for this study is subjects ≥18 years of age with documented moderate to severe 
COVID-19 who are hospitalized and receiving standard of care therapy for COVID-19. The 
criteria for moderate and severe COVID-19 are as follows: 
Moderate COVID-19 (Note: Subjects with moderate COVID-19 will comprise a maximum of 
approximately 50% of the subjects enrolled in each of the following: Part 1, Step 1; Part 1, Step 2; 
and Part 2.)  
• Symptoms of moderate illness with COVID-19, which could include shortness of breath with 
exertion, fever, dry cough, headache, body aches, chills, loss of taste or smell, etc; and 
• Respiratory rate ≥20 breaths per minute, peripheral capillary oxygen saturation (SpO2) >93% 
on room air at sea level, or heart rate ≥90 beats per minute. 
Severe COVID-19 
• Symptoms suggestive of severe systemic illness with COVID-19, which could include 
shortness of breath at rest or respiratory distress; and 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 5 of 59 
Version 3.0, 10 December 2020 
• Respiratory rate ≥30 breaths per minute, heart rate ≥125 beats per minute, or SpO2 ≤93% on 
room air at sea level or partial pressure of oxygen (PaO2):fractional inspired oxygen (FiO2) 
<300. Note: Patients who are receiving high flow oxygen by a nasal cannula or noninvasive 
positive pressure ventilation are permitted. 
Respiratory failure will be defined as subjects who are on invasive mechanical ventilation; are 
receiving oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via 
reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) 
noninvasive positive pressure ventilation or extracorporeal membrane oxygenation; or have a 
clinical diagnosis of respiratory failure (ie, clinical need for 1 of the preceding therapies, but 
preceding therapies not able to be administered in setting of resource limitation). Subjects with 
respiratory failure, except those receiving high flow oxygen by a nasal cannula or noninvasive 
positive pressure ventilation, will not be eligible to enroll in the study. 
STUDY DESIGN AND DURATION: 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter, dose 
escalation and proof-of-concept study to evaluate the safety and efficacy of razuprotafib, 
administered three times daily (TID) (every 8 hours [Q8H]), in hospitalized subjects with 
moderate to severe COVID-19 receiving standard of care therapy. The study design is summarized 
in the figure below. 
Abbreviations: AE = adverse event; DRC = Data Review Committee; POC = proof-of-concept; TID = three times 
daily. 
The study is planned to include 2 parts as described below.  
Part 1 
Part 1 will be a 2-step dose escalation that includes approximately 60 subjects. Part 1, Step 1 will 
include approximately 30 subjects, and Part 1, Step 2 will include approximately 30 subjects. 
Part 1 will primarily focus on safety; however, efficacy data will be collected and analyzed as 
well. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 6 of 59 
Version 3.0, 10 December 2020 
Part 1, Step 1: For subjects enrolled in Part 1, Step 1, 6 sentinel subjects will be randomized to 
receive either razuprotafib 10 mg TID, razuprotafib 20 mg TID, or placebo TID (ie, 2 subjects 
will receive razuprotafib 10 mg TID, 2 subjects will receive razuprotafib 20 mg TID, and 
2 subjects will receive placebo TID). The DRC will convene to recommend if continuation of 
Part 1, Step 1 as planned is acceptable or if dosing modifications are required once adverse event 
(AE) information through at least 8 hours following the first dose of study drug is available for all 
6 sentinel subjects. 
If it is decided that Part 1, Step 1 should proceed as planned, then approximately 24 subjects will 
be randomized to 1 of 3 treatment groups (razuprotafib 10 mg TID, razuprotafib 20 mg TID, or 
placebo TID) in a 1:1:1 ratio according to a computer-generated randomization list and stratified 
by disease severity. Subjects with moderate COVID-19 will comprise a maximum of 
approximately 50% of the subjects enrolled in Part 1, Step 1. After the last subject enrolled in 
Part 1, Step 1 completes the Treatment Period, the Data Review Committee (DRC) will convene 
to review available safety and pharmacokinetic (PK) data as defined in the DRC Charter. 
Part 1, Step 2: The DRC will recommend if dose escalation to razuprotafib 30 mg TID is 
acceptable as planned, or if enrollment should continue with 1 or more lower doses. If the DRC 
recommends that Part 1, Step 2 should proceed as planned, then 6 sentinel subjects will be 
randomized to receive either razuprotafib 20 mg TID, razuprotafib 30 mg TID, or placebo TID 
(ie, 2 subjects will receive razuprotafib 20 mg TID, 2 subjects will receive razuprotafib 30 mg 
TID, and 2 subjects will receive placebo TID). The DRC will convene to recommend if 
continuation of Part 1, Step 2 as planned is acceptable or if dosing modifications are required once 
AE information through at least 8 hours following the first dose of study drug is available for all 
6 sentinel subjects. 
If it is decided that Part 1, Step 2 should proceed as planned, then approximately 24 subjects will 
be randomized to 1 of 3 treatment groups (razuprotafib 20 mg TID, razuprotafib 30 mg TID, or 
placebo TID) in a 1:1:1 ratio according to a computer-generated randomization list and stratified 
by disease severity. If it is decided that only 1 dose level will be evaluated in Part 1, Step 2, then 
subjects will be randomized to 1 of 2 treatment groups (razuprotafib or placebo) in a 2:1 ratio 
(razuprotafib:placebo). The placebo volume will match the active volume for each treatment 
group. Subjects with moderate COVID-19 will comprise a maximum of approximately 50% of 
the subjects enrolled in Part 1, Step 2. After the last subject enrolled in Part 1, Step 2 completes 
the Treatment Period, the DRC will convene to review all available safety and PK data from Part 1, 
Step 1 and Part 1, Step 2 as defined in the DRC Charter. 
Part 2 
Part 2 will be a proof-of-concept safety and efficacy study that will include approximately 
120 subjects. Based on the DRC’s review of the available safety and PK data from Part 1, Step 1 
and Part 1, Step 2, the study will proceed to Part 2, and the DRC will recommend either 1 or 
2 doses of razuprotafib to evaluate up to 30 mg TID. Subjects will be randomized to 1 of the 
treatment groups (dose 1 razuprotafib TID, dose 2 razuprotafib TID [optional], or placebo TID) 
in a 1:1:1 ratio (or a 2:1 ratio [razuprotafib:placebo] if only 2 treatment groups) according to a 
computer-generated randomization list and stratified by disease severity. The placebo volume will 
match the active volume for each treatment group. Subjects with moderate COVID-19 will 
comprise a maximum of approximately 50% of the subjects enrolled in Part 2. The DRC will 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 7 of 59 
Version 3.0, 10 December 2020 
convene at increments of approximately 25% enrollment in Part 2 to review all available safety 
and PK data as defined in the DRC Charter. 
After consent for study participation is obtained and eligibility is determined, subjects will be 
randomized to 1 of the treatment groups as described above. Treatment group assignment will be 
blinded to subjects, clinicians, Sponsor study team, Contract Research Organization study team, 
and Investigators. Subjects will be dosed subcutaneously (SC) in the abdomen TID for 7 days or 
until discharge from the hospital (or death), whichever occurs first. Prior to the initiation of Part 2, 
the DRC may make a recommendation to increase the study drug dosing duration to up to 14 days. 
Subjects will be followed for safety and efficacy through Day 28 at on-site visits if the subject has 
not been discharged or via telephone visits if the subject has been discharged. If a subject reports 
a decline in clinical status at a telephone visit, then per the discretion of the Investigator, the subject 
will be requested to return to the site for an Unscheduled Visit. 
In addition to the routine clinical monitoring that is part of standard of care, the following will be 
conducted: vital signs, blood chemistry, hematology, and coagulation will be assessed during the 
Treatment Period and until Day 28, unless discharged; 12-lead electrocardiograms will be 
performed at Screening, on Day 7 (or at discharge if subject is discharged prior to Day 7), and on 
the last day of dosing if the study drug dosing duration is increased to up to 14 days; data on the 
subject’s oxygen support requirements (ie, SpO2:FiO2 ratio or PaO2:FiO2 ratio if arterial blood gas 
is being performed per standard of care) will be collected during the Treatment Period and until 
Day 28, unless discharged; clinical status based on the National Institute of Allergy and Infectious 
Diseases (NIAID) 8-point ordinal scale and AEs will be assessed through Day 28; blood sampling 
for PK analysis will occur on Day 1 and Day 6 for Part 1 and may occur for Part 2; and blood 
sampling for biomarkers associated with coagulation, inflammation, and vascular leakage (CRP 
and D-dimer assessed at local laboratory; Angpt-2, IL-6, IL-8, TNFα, and HMGB-1 assessed at 
central laboratory) will occur at Screening and on Day 7 (or at discharge if subject is discharged 
prior to Day 7) for all subjects. If the study drug dosing duration is increased to up to 14 days, 
blood sampling for biomarkers will also occur on the last day of dosing. For all subjects remaining 
hospitalized on Day 14 or beyond, blood sampling for biomarkers will also occur on Day 28 or 
the day of hospital discharge, whichever occurs first.  
The duration of the study for each subject will be approximately 29 days: Screening 
(approximately 1 day), Treatment Period (7 days [or up to 14 days if recommended by the DRC]), 
and Post-Treatment Observation Period (approximately 21 days [or 14 to 20 days if Treatment 
Period is extended]). 
 REVIEW COMMITTEE: 
A DRC comprised of members with pertinent expertise will review emerging safety, efficacy, and 
PK data at appropriate times throughout the study, as described in this protocol and as set forth in 
the DRC Charter.  
The DRC will convene throughout the study to review safety and PK data to recommend if it is 
safe and appropriate to continue the study as planned. The DRC will convene to recommend if 
continuation of Part 1, Step 1 and Part 1, Step 2 as planned is acceptable or if dosing modifications 
are required once AE information through at least 8 hours following the first dose of study drug is 
available for all 6 sentinel subjects in both Step 1 and Step 2 of Part 1. Upon both reviews after 
Part 1, Step 1 and Part 1, Step 2, the DRC will recommend subsequent dosing regimen(s) to be 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 8 of 59 
Version 3.0, 10 December 2020 
tested in the study. Prior to the initiation of Part 2, the DRC may also make a recommendation to 
increase the study drug dosing duration to up to 14 days. The highest dose in this study will not 
exceed 30 mg TID. The DRC can request to unblind efficacy data at any point if deemed necessary 
to adequately complete their review. Additionally, the DRC may request to unblind efficacy data 
if an increase in the study drug dosing duration is under consideration. Further details regarding 
the role, responsibilities, and procedures of the DRC will be provided in the DRC Charter. 
In addition, ad hoc reviews of safety data will be performed throughout the study by appropriate 
study personnel and the Medical Monitor. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
The drug product formulation contains AKB-9778-sodium salt ready to dose, preservative free, 
isotonic, sterile solution (20 mg/mL or 40 mg/mL) in a 3 mL borosilicate vial fitted with a 13 mm 
septum and aluminum flip top seal. A dose volume of 0.50 mL of 20 mg/mL solution will deliver 
a dose of 10 mg, a dose volume of 0.75 mL of 20 mg/mL solution will deliver a dose of 15 mg, a 
dose volume of 0.50 mL of 40 mg/mL solution will deliver a dose of 20 mg, and a dose volume 
of 0.75 mL of 40 mg/mL solution will deliver a dose of 30 mg. The formulation also contains 15% 
hydroxypropyl-beta-cyclodextrin (Betadex), United States Pharmacopeia (USP), used as a 
solubilizer, and 1.2% mannitol, USP, for tonicity modification. The formulation is controlled to 
pH 4.0 to 8.6. 
Placebo for razuprotafib (sterile normal saline) will be sourced locally by the site as a parenteral 
formulation ready to dose. The volume of placebo will match the volume of razuprotafib based on 
the dose(s) of razuprotafib in each treatment group in Part 1 (Step 1 and Step 2) and in Part 2.  
A volume of 0.50 mL or 0.75 mL of study drug will be administered TID (Q8H) by SC injection 
to the abdomen. Subjects will be dosed for 7 days or until discharge from the hospital (or death), 
whichever occurs first. Prior to the initiation of Part 2, the DRC may make a recommendation to 
increase the study drug dosing duration to up to 14 days. 
ENDPOINTS:  
The efficacy endpoints include the following:  
• Proportion of subjects alive and free of respiratory failure at Day 28; 
• Proportion of subjects alive and free of respiratory failure at Day 7; 
• Change in PaO2:FiO2 ratio from baseline to Day 7 (or discharge) and baseline to Day 28 (or 
discharge); 
• Length hospitalized and free of respiratory failure from baseline to Day 7 and baseline to 
Day 28 or death; 
• Length of hospitalization from baseline to Day 7 and baseline to Day 28 or death; 
• Proportion of subjects who improve by ≥2 categories on the NIAID 8-point ordinal scale from 
baseline to Day 7 and baseline to Day 28; 
• Proportion of subjects who worsen by ≥2 categories on the NIAID 8-point ordinal scale from 
baseline to Day 7 and baseline to Day 28;  


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 9 of 59 
Version 3.0, 10 December 2020 
• All-cause mortality at Day 7 and Day 28; 
• Length of intensive care unit stay from baseline to Day 28 or death; 
• Number of subjects in each category of the NIAID 8-point ordinal scale at Day 7 and Day 28; 
• Time to return to prehospitalization oxygen requirement; and 
• Proportion of subjects who were discharged and remained free of respiratory failure prior to 
Day 7 and Day 28. 
The safety endpoints include the following: 
• Number of subjects with any serious AE (SAE); and  
• Number of subjects with any treatment-emergent AE. 
The pharmacodynamic and PK endpoints include the following: 
• Change from baseline in CRP and D-dimer; 
• Change from baseline in systemic biomarkers of vascular leakage and inflammation 
(ie, Angpt-2, IL-6, IL-8, TNFα, and HMGB-1); 
• Summary of plasma concentrations of biomarkers at each sampling time point for each 
treatment group; and 
• Summary of plasma razuprotafib concentrations for the samples collected on Day 1 and Day 6. 
SAFETY VARIABLES: 
Safety will be determined by evaluating clinical laboratory findings (blood chemistry, 
hematology, and coagulation), vital signs (blood pressure, heart rate, SpO2 [for non-ventilated 
subjects only], and respiratory rate), 12-lead electrocardiograms, and AEs reported during the 
study. 
STATISTICAL ANALYSES: 
Analysis Populations 
The Intent-to-Treat (ITT) Population is defined as all subjects randomized. Subjects in this 
population will be analyzed according to the treatment group to which they were assigned at 
randomization. The ITT Population will be used for efficacy analyses. 
The Per-Protocol (PP) Population is a subset of the ITT Population and will include subjects that 
have at least 1 post-dose efficacy evaluation and do not have major protocol deviations. 
The Safety Population is defined as all randomized subjects who received at least 1 dose of study 
drug. Subjects in this population will be analyzed according to the study drug they actually 
received. The Safety Population will be used for the analysis of safety endpoints. 
Additional details of the statistical analyses will be provided in the Statistical Analysis Plan, which 
will be finalized prior to database lock. 
Analysis of Efficacy 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 10 of 59 
Version 3.0, 10 December 2020 
Continuous efficacy endpoints will be analyzed using an analysis of variance model with effects 
for treatment and disease severity as factors. 
Binary efficacy endpoints will be analyzed using a Cochran-Mantel-Haenszel test stratified by 
disease severity. 
For all efficacy endpoints that do not include death as a possible outcome, data from subjects who 
die prior to Day 28 will be imputed at Day 28 based on the worst outcome. 
All efficacy analyses will be performed using the ITT Population. The efficacy analyses will be 
repeated on the PP Population. 
Analysis of Safety 
The safety endpoint data will be summarized for the Safety Population. AEs will be coded using 
the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). AEs and SAEs 
will be summarized by overall number of AEs, severity, and relationship to study drug per 
treatment group. Summaries will be presented by MedDRA system organ class and preferred term 
using frequency counts and percentages by treatment group and overall. 
SAMPLE SIZE DETERMINATION: 
Part 1 will include approximately 60 subjects. In Part 1, Step 1, approximately 30 subjects 
(including the 6 sentinel subjects) will be randomized to 1 of 3 treatment groups (razuprotafib 
10 mg TID, razuprotafib 20 mg TID, or placebo TID) in a 1:1:1 ratio. In Part 1, Step 2, 
approximately 30 subjects (including the 6 sentinel subjects) are planned to be randomized to 1 of 
3 treatment groups (razuprotafib 20 mg TID, razuprotafib 30 mg TID, or placebo TID) in a 1:1:1 
ratio. If it is decided that only 1 dose level will be evaluated in Part 1, Step 2, then subjects will 
be randomized to 1 of 2 treatment groups (razuprotafib or placebo) in a 2:1 ratio 
(razuprotafib:placebo). No formal statistical assessment for sample size determination has been 
performed for Part 1. The sample size is considered adequate to provide the necessary data to 
evaluate the objectives for Part 1. 
Part 2 will include approximately 120 subjects. Subjects will be randomized to 1 of the treatment 
groups (dose 1 razuprotafib TID, dose 2 razuprotafib TID [optional], or placebo TID) in a 1:1:1 
ratio (or a 2:1 ratio [razuprotafib:placebo] if only 2 treatment groups). No formal statistical 
assessment for sample size determination has been performed for Part 2. The sample size is 
considered adequate to provide the necessary data to evaluate the objectives for Part 2. 
SITES:  Approximately 20 sites in the United States 
SPONSOR: 
Aerpio Pharmaceuticals, Inc. 
9987 Carver Road, Suite 420 
Cincinnati, OH 45242 
United States 
Telephone: 513-985-1920 
Fax: 513-985-0999 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 11 of 59 
Version 3.0, 10 December 2020 
TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 11 
List of Figures ............................................................................................................................... 15 
List of Abbreviations and Definition of Terms............................................................................. 16 
1 Introduction and Background Information ............................................................................. 18 
1.1 
Razuprotafib and the Tie2 Pathway .............................................................................. 18 
1.2 
Clinical Development of Razuprotafib ......................................................................... 19 
1.3 
Study Rationale ............................................................................................................. 20 
1.4 
Risk/Benefit ................................................................................................................... 20 
1.5 
Intent to Benefit ............................................................................................................. 20 
2 Study Objectives ..................................................................................................................... 22 
2.1 
Primary Objectives ........................................................................................................ 22 
2.2 
Secondary Objectives .................................................................................................... 22 
2.3 
Exploratory Objective ................................................................................................... 22 
3 Study Description.................................................................................................................... 23 
3.1 
Summary of Study Design ............................................................................................ 23 
3.1.1 Overview of Study Schedule for All Subjects .................................................. 24 
3.2 
Data Review Committee ............................................................................................... 25 
3.3 
Study Indication ............................................................................................................ 26 
4 Selection and Withdrawal of Subjects .................................................................................... 27 
4.1 
Inclusion Criteria ........................................................................................................... 27 
4.2 
Exclusion Criteria .......................................................................................................... 28 
4.3 
Retesting ........................................................................................................................ 28 
4.4 
Stopping Criteria ........................................................................................................... 29 
4.4.1 Criteria for Discontinuation of Study Drug in Individual Subjects .................. 29 
4.4.2 Criteria for Study Termination .......................................................................... 29 
4.5 
Withdrawal and Discontinuation Criteria ..................................................................... 29 
5 Study Treatments .................................................................................................................... 31 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 12 of 59 
Version 3.0, 10 December 2020 
5.1 
Treatment Groups .......................................................................................................... 31 
5.2 
Rationale for Dosing ..................................................................................................... 31 
5.3 
Randomization and Blinding ......................................................................................... 32 
5.4 
Breaking the Blind ........................................................................................................ 32 
5.5 
Drug Supplies ................................................................................................................ 33 
5.5.1 Formulation and Packaging ............................................................................... 33 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 33 
5.5.3 Study Drug Administration ............................................................................... 33 
5.5.4 Treatment Compliance ...................................................................................... 34 
5.5.5 Storage and Accountability ............................................................................... 34 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 34 
5.6.1 Excluded Medications and/or Procedures ......................................................... 34 
5.6.2 Allowed Medications and/or Procedures .......................................................... 35 
5.6.3 Documentation of Prior and Concomitant Medication Use and/or Procedures 35 
6 Study Procedures .................................................................................................................... 36 
7 Efficacy, Pharmacodynamic, and Pharmacokinetic Assessments .......................................... 37 
7.1 
Hospitalization and Ventilator Data .............................................................................. 37 
7.2 
National Institute of Allergy and Infectious Diseases 8-Point Ordinal Scale ............... 38 
7.3 
Biomarker Analysis ....................................................................................................... 38 
7.4 
Pharmacokinetic Analysis ............................................................................................. 38 
8 Safety Assessments ................................................................................................................. 39 
8.1 
Adverse Events .............................................................................................................. 39 
8.1.1 Adverse Drug Reaction ..................................................................................... 39 
8.1.2 Unexpected Adverse Drug Reaction ................................................................. 40 
8.1.3 Assessment of Adverse Events by the Investigator .......................................... 40 
8.2 
Serious Adverse Events/Drug Reaction ........................................................................ 41 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 42 
8.4 
Pregnancy Reporting ..................................................................................................... 42 
8.5 
Expedited Reporting ...................................................................................................... 43 
8.6 
Special Situation Reports .............................................................................................. 43 
8.7 
Safety Assessments ....................................................................................................... 44 
8.8 
Clinical Laboratory Evaluations .................................................................................... 44 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 13 of 59 
Version 3.0, 10 December 2020 
8.9 
Vital Signs ..................................................................................................................... 45 
8.10 12-lead Electrocardiogram ............................................................................................ 45 
9 Statistics .................................................................................................................................. 46 
9.1 
Analysis Populations ..................................................................................................... 46 
9.2 
Statistical Methods ........................................................................................................ 46 
9.2.1 Analysis of Efficacy .......................................................................................... 46 
9.2.2 Pharmacodynamic Analysis .............................................................................. 46 
9.2.3 Pharmacokinetic Analysis ................................................................................. 46 
9.2.4 Analysis of Safety ............................................................................................. 46 
9.2.5 Sample Size Determination ............................................................................... 47 
10 Data Management and Record Keeping ................................................................................. 48 
10.1 Data Management ......................................................................................................... 48 
10.1.1 Data Handling ................................................................................................... 48 
10.1.2 Computer Systems ............................................................................................. 48 
10.1.3 Data Entry ......................................................................................................... 48 
10.1.4 Medical Information Coding ............................................................................. 48 
10.1.5 Data Validation ................................................................................................. 48 
10.2 Record Keeping ............................................................................................................. 48 
10.3 End of Study .................................................................................................................. 49 
11 Investigator Requirements and Quality Control ..................................................................... 50 
11.1 Ethical Conduct of the Study ........................................................................................ 50 
11.2 Institutional Review Board ............................................................................................ 50 
11.3 Informed Consent .......................................................................................................... 50 
11.4 Study Monitoring Requirements ................................................................................... 50 
11.5 Disclosure of Data ......................................................................................................... 51 
11.6 Retention of Records ..................................................................................................... 51 
11.7 Publication Policy ......................................................................................................... 51 
11.8 Financial Disclosure ...................................................................................................... 52 
12 Study Administrative Information .......................................................................................... 53 
12.1 Protocol Amendments ................................................................................................... 53 
13 References ............................................................................................................................... 54 
Appendix A:  Schedule of Procedures .......................................................................................... 56 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 14 of 59 
Version 3.0, 10 December 2020 
Appendix B:  Clinical Laboratory Analytes ................................................................................. 58 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 15 of 59 
Version 3.0, 10 December 2020 
 LIST OF FIGURES 
Figure 1. Study Design Schematic ............................................................................................. 23 
 
 
 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 16 of 59 
Version 3.0, 10 December 2020 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
Angpt 
Angiopoietin 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
COVID-19 
Coronavirus disease 2019 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DIC 
Disseminated intravascular coagulation 
DRC 
Data Review Committee 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure In Utero 
eNOS 
Endothelial nitric oxide synthase 
FDA 
Food and Drug Administration 
FiO2 
Fractional inspired oxygen 
GCP 
Good Clinical Practice 
HMGB-1 
High mobility group box 1 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IL 
Interleukin 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LAR 
Legally Authorized Representative 
LPS 
Lipopolysaccharide 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIAID 
National Institute of Allergy and Infectious Diseases 
NO 
Nitric oxide 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 17 of 59 
Version 3.0, 10 December 2020 
Abbreviation 
Definition 
PaO2 
Partial pressure of oxygen 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
Q8H 
Every 8 hours 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous(ly) 
SOP 
Standard operating procedure 
SpO2 
Peripheral capillary oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T½ 
Elimination half-life 
TID 
Three times daily 
TNFα 
Tumor necrosis factor alpha 
UACR 
Urine albumin/creatinine ratio 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
VEGF 
Vascular endothelial growth factor 
VE-PTP 
Vascular endothelial protein tyrosine phosphatase 
 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 18 of 59 
Version 3.0, 10 December 2020 
1 
INTRODUCTION AND BACKGROUND INFORMATION \ 
Coronavirus disease 2019 (COVID-19) is a rapidly progressive respiratory tract infection that 
quickly leads to respiratory failure, mortality, and overwhelmed healthcare systems (ie, limited 
intensive care unit [ICU] and ventilatory capacity). Approximately 14% of patients with 
COVID-19 develop severe disease that requires hospitalization and oxygen support, and 5% 
require admission to the ICU.1 
In addition to pulmonary pathology, cardiovascular, renal, and neurologic complications are 
emerging as important factors in COVID-19 outcomes, potentially due to endothelial cell 
dysfunction and vascular destabilization, including abnormal coagulation (ie, disseminated 
intravascular coagulation [DIC]).2,3,4 Notably, angiotensin converting enzyme 2, a functional 
receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes 
COVID-19, is broadly expressed in vascular endothelium, including pulmonary endothelium, 
indicating that the vasculature is a direct target in the development of COVID-19 pathology.5,6,7 
In fact, in patients with COVID-19, endothelial cell involvement has been shown across vascular 
beds of various organs, including the kidney, heart, small intestine, liver, and lung, with evidence 
of direct viral infection of the endothelial cell and diffuse endothelial inflammation.2 An effective 
host-targeted intervention to ameliorate progression of pulmonary and vascular pathology in 
COVID-19 is urgently needed.  
1.1 
Razuprotafib and the Tie2 Pathway 
Tie2 is the receptor for the angiopoietin (Angpt) family of secreted proteins and is expressed on 
vascular endothelial cells throughout the adult vasculature, including pulmonary endothelial cells. 
Tie2 activation is required for maintaining normal endothelial function and the overall stability of 
the quiescent, adult vasculature.8,9 Over the past decade, endothelial dysfunction and vascular 
destabilization due to reduced Tie2 activation have been implicated in the pathophysiology of a 
variety of acute and chronic conditions characterized by endothelial dysfunction, vascular injury, 
DIC, and inflammation, including acute respiratory distress syndrome (ARDS) and now 
COVID-19.8,10,11,12,13 Providing a clinical correlate and biomarker of reduced Tie2 activation, 
multiple studies have shown that circulating Angpt-2, a Tie2 conditional antagonist ligand, is 
increased in patients with either sepsis and/or ARDS and correlates with clinical severity and 
mortality.14,15,16,17,18 Thus, restoring Tie2 activation could be an effective host-targeted 
intervention to ameliorate progression of pulmonary and vascular pathology in COVID-19. 
Vascular endothelial protein tyrosine phosphatase (VE-PTP), the molecular target for razuprotafib, 
is a receptor tyrosine phosphatase expressed on vascular endothelial cells that blocks Tie2 
signaling by dephosphorylating phosphotyrosine residues on Tie2 required for signal 
transduction.19,20 
Razuprotafib is a novel small molecule that restores Tie2 activation by inhibiting the catalytic 
domain of VE-PTP. Notably, inhibition of VE-PTP with razuprotafib increased Tie2 
phosphorylation in cultured endothelial cells even in the absence of Angpt-1 or Angpt-2 and 
enhanced the agonist properties of both ligands.19 
Importantly, preclinical data show that razuprotafib, via Tie2 pathway activation, has pleiotropic 
actions to improve endothelial function and stabilize the vasculature. For example, razuprotafib 
stabilized endothelial junctions, via Tie2-mediated activation of Rap1, leading to dissolution of 
radial stress fibers via Rac1 and suppression of nonmuscle myosin II.21 In addition, treatment of 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 19 of 59 
Version 3.0, 10 December 2020 
endothelial cells with razuprotafib dose-dependently increased the phosphorylation of endothelial 
nitric oxide synthase (eNOS) on serine 1177, a marker of eNOS activation.19 Nitric oxide (NO), 
generated by activation of eNOS, is a crucial mediator of normal endothelial vasodilatory, 
anti-thrombotic, and anti-inflammatory functions.22,23 In addition, local generation of NO could 
have direct inhibitory effects on coronavirus replication.24 Furthermore, disruption of the 
endothelial Tie2 axis has also been demonstrated to be a critical event in septic DIC,12 making 
razuprotafib a strong candidate for addressing such conditions now shown to be associated with 
poor COVID-19 outcomes. 
In vivo, subcutaneous (SC) administration of razuprotafib restores Tie2 activation and reduces 
lipopolysaccharide (LPS)/endotoxin-mediated vascular leakage and leukocyte transmigration 
(neutrophil and lymphocyte) in the lung, two key components of COVID-19 and ARDS pulmonary 
pathology that contribute to respiratory failure.21 Razuprotafib also reduced lung toxicity and 
improved survival in mouse models of interleukin (IL)-2-induced cytokine storm, possibly 
relevant to the cytokine storm that is associated with poor outcomes in COVID-19.25,26,27 
Consistent with potential benefits in other vascular beds commonly affected in COVID-19, 
razuprotafib restored Tie2 activation and improved outcomes in an LPS-induced acute renal injury 
model (AKB-9778-NC-0084). In addition, VE-PTP inhibition with AKB-9785, a close chemical 
congener of razuprotafib, showed improved outcomes in a transient middle cerebral artery 
occlusion stroke model.28 
Importantly, in conditions associated with chronic endothelial dysfunction and vascular injury 
such as diabetes and hypertension, VE-PTP expression is increased and Tie2 activation is 
decreased, possibly explaining the predisposition of patients with these conditions for increased 
severity of COVID-19.29,30,31,32 Moreover, VE-PTP is highly expressed in the lung, and VE-PTP 
expression is increased and Tie2 activation is decreased by hypoxia, perhaps contributing to the 
rapid deterioration and multiorgan failure that occurs in COVID-19 patients with severe 
respiratory failure.19,29 
1.2 
Clinical Development of Razuprotafib 
The efficacy of razuprotafib in humans has not been tested in clinical studies for the treatment of 
COVID-19. However, SC administration of razuprotafib has been assessed in patients with 
clinically significant diabetic eye disease. In early human SC injection studies, razuprotafib 
absorption was demonstrated to be very rapid, with maximum plasma concentration (Cmax) 
achieved within 15 to 30 minutes after dosing, followed by a rapid decline in concentrations with 
an elimination half-life (T½) of approximately 1 hour across a wide dose range (5 to 80 mg single 
doses [AKB-9778-CI-2001]). The short T½ supported no significant accumulation when multiple 
doses were administered using a twice daily (BID) regimen for a dose range of 5 to 30 mg BID 
(AKB-9778-CI-2002). As an indicator of target engagement consistent with eNOS activation 
downstream of Tie2, there was a dose-dependent reduction in blood pressure in a 1-month 
Phase 1b study, TIME1 (AKB-9778-CI-2002), which corresponded with the plasma concentration 
profile. In a 3-month Phase 2 study, TIME2 (AKB-9778-CI-2003), the bulk of the reduction in 
blood pressure occurred in patients with baseline systolic blood pressures >140 mmHg versus very 
little reduction in patients with baseline systolic blood pressures <140 mmHg, consistent with 
enhanced endothelial function in the hypertensive, diabetic patients. 
Other end-organ readouts of vascular stability in the context of diabetes are also improved by 
razuprotafib. In a Phase 2 study in patients with diabetic macular edema (AKB-9778-CI-2003), 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 20 of 59 
Version 3.0, 10 December 2020 
SC razuprotafib 15 mg BID combined with monthly intravitreal injections of the anti-vascular 
endothelial growth factor (VEGF) compound ranibizumab (Lucentis®) resulted in a highly 
statistically significant reduction in retinal thickness compared to either agent alone. This was the 
first demonstration of a clinical benefit in a randomized, placebo-controlled study of any therapy 
in combination with anti-VEGF in diabetic macular edema.33 Furthermore, among patients with 
evidence of diabetic nephropathy (urine albumin/creatinine ratio [UACR] ≥30 mg/g), razuprotafib 
reduced UACR by approximately 20% compared to an increase in UACR among patients treated 
with Lucentis alone, indicative of a potential beneficial effect on renal function.  
In a Phase 2 study, TIME2b (AKB-9778-CI-5001), in patients with non-proliferative diabetic 
retinopathy, SC razuprotafib 15 mg BID for 48 weeks in patients with significant albuminuria 
(UACR >30 mg/g) again reduced UACR by approximately 20% compared to an increase in 
patients receiving placebo. Thus, the evidence of target engagement indicated by the blood 
pressure effect and evidence of efficacy suggested by the beneficial effects in the diabetic retina 
and kidney, together with data from multiple preclinical models, support further evaluation of 
razuprotafib in patients with COVID-19. 
 
1.3 
Study Rationale 
Razuprotafib represents a unique, first-in-class, host-targeted intervention to ameliorate 
progression of pulmonary and vascular pathology in COVID-19, potentially meeting an urgent 
unmet medical need. A Phase 2 clinical study (RESCUE) has been designed to test the safety and 
efficacy of SC administration of razuprotafib to reduce the severity of pulmonary and vascular 
pathology in patients with moderate to severe COVID-19. This would likely result in earlier 
recovery, fewer patients requiring mechanical ventilation, decreased time in the ICU on ventilator 
support, and concomitant reduction in morbidity and mortality. Additionally, razuprotafib together 
with emerging antiviral drugs and other therapeutics could provide the optimal combination of 
host and virus targeted therapy for the treatment of COVID-19. 
1.4 
Risk/Benefit 
In the completed clinical studies AKB-9778-CI-2003 and AKB-9778-CI-5001, the frequency and 
other characteristics of serious adverse events (SAEs) and events leading to discontinuations were 
generally consistent with those anticipated in the primarily diabetic population evaluated in these 
studies and were generally similar between the razuprotafib and control groups. All SAEs to date 
have been reported as unrelated, and no serious adverse reactions have been reported. Based on all 
available safety information from nonclinical and clinical studies, the overall benefit-risk profile 
of razuprotafib appears favorable. Given the potential beneficial effect of razuprotafib in patients 
with endothelial dysfunction and vascular injury, evaluation of razuprotafib in clinical studies for 
the treatment of moderate to severe COVID-19 is considered justified. 
1.5 
Intent to Benefit 
All study participants will receive additional safety monitoring as required per the research 
protocol which they are participating, in addition to the standard of care they would receive and 
would still receive, if they did not participate in the trial. While standard of care varies by 
institution, the additional safety monitoring all study participants will receive per the AKB-9778-
CI-6001 protocol includes but is not limited to: increased vital signs monitoring (blood pressure, 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 21 of 59 
Version 3.0, 10 December 2020 
heart rate, oxygen saturation); additional blood chemistry, hematology, and coagulation testing; 
electrocardiograms; additional oversight from local study physician(s), nurses, and research staff 
as well as physicians and medical personnel at the Sponsor and the CRO; and continued follow up 
and monitoring after hospital discharge.  
Standard of care varies per institution and even more so under resource limitations brought on by 
COVID-19. Due to this, participation in this clinical trial provides every subject with a more 
personalized and thorough hospital experience provided for by the designated study clinical team 
in addition to the standard of care team, with continued oversight following discharge through Day 
28. Patients or LARs who do not participate in this trial are likely not able to easily connect with 
the same physician(s) who managed their care while hospitalized or connect with a physician at 
all. It may also be that these patients are unsure of when/how to reach out to their treating 
physician. With a clear mechanism of follow up defined in the study protocol, these patients or 
LARs can discuss post-hospitalization status with their study physician allowing early 
identification of any lingering COVID-19-related sequelae. This post-hospitalization follow up, 
and even continued follow up if still hospitalized, will lead to better outcomes for all participants.  
. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 22 of 59 
Version 3.0, 10 December 2020 
2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of this study are to assess the safety and efficacy of razuprotafib in subjects 
with moderate to severe COVID-19. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to examine the effects of razuprotafib on biomarkers of 
inflammation and coagulopathy (ie, C-reactive protein [CRP] and D-dimer) in the plasma of 
subjects with moderate to severe COVID-19 and to characterize exposure of razuprotafib based 
on plasma concentrations for the samples collected on Day 1 and Day 6. 
2.3 
Exploratory Objective 
The exploratory objective of this study is to examine the effects of razuprotafib on biomarkers of 
vascular leakage and inflammation (ie, Angpt-2, IL-6, IL-8, tumor necrosis factor alpha [TNFα], 
and high mobility group box 1 [HMGB-1]) in the plasma of subjects with moderate to severe 
COVID-19.  


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 23 of 59 
Version 3.0, 10 December 2020 
3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter, dose 
escalation and proof-of-concept study to evaluate the safety and efficacy of razuprotafib, 
administered three times daily (TID) (every 8 hours [Q8H]), in hospitalized subjects with moderate 
to severe COVID-19 receiving standard of care therapy. The study design is summarized in 
Figure 1. 
Figure 1. Study Design Schematic 
 
Abbreviations: AE = adverse event; DRC = Data Review Committee; POC = proof-of-concept; TID = three times 
daily. 
The study is planned to include 2 parts as described below.  
Part 1 
Part 1 will be a 2-step dose escalation that includes approximately 60 subjects. Part 1, Step 1 will 
include approximately 30 subjects, and Part 1, Step 2 will include approximately 30 subjects. 
Part 1 will primarily focus on safety; however, efficacy data will be collected and analyzed as well. 
Part 1, Step 1: For subjects enrolled in Part 1, Step 1, 6 sentinel subjects will be randomized to 
receive either razuprotafib 10 mg TID, razuprotafib 20 mg TID, or placebo TID (ie, 2 subjects will 
receive razuprotafib 10 mg TID, 2 subjects will receive razuprotafib 20 mg TID, and 2 subjects 
will receive placebo TID). The DRC will convene to recommend if continuation of Part 1, Step 1 
as planned is acceptable or if dosing modifications are required once adverse event (AE) 
information through at least 8 hours following the first dose of study drug is available for all 
6 sentinel subjects. 
If it is decided that Part 1, Step 1 should proceed as planned, then approximately 24 subjects will 
be randomized to 1 of 3 treatment groups (razuprotafib 10 mg TID, razuprotafib 20 mg TID, or 
placebo TID) in a 1:1:1 ratio according to a computer-generated randomization list and stratified 
by disease severity. Subjects with moderate COVID-19 will comprise a maximum of 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 24 of 59 
Version 3.0, 10 December 2020 
approximately 50% of the subjects enrolled in Part 1, Step 1. After the last subject enrolled in 
Part 1, Step 1 completes the Treatment Period, the Data Review Committee (DRC) will convene 
to review available safety and pharmacokinetic (PK) data as defined in the DRC Charter. 
Part 1, Step 2: The DRC will recommend if dose escalation to razuprotafib 30 mg TID is 
acceptable as planned, or if enrollment should continue with 1 or more lower doses. If the DRC 
recommends that Part 1, Step 2 should proceed as planned, then 6 sentinel subjects will be 
randomized to receive either razuprotafib 20 mg TID, razuprotafib 30 mg TID, or placebo TID 
(ie, 2 subjects will receive razuprotafib 20 mg TID, 2 subjects will receive razuprotafib 30 mg 
TID, and 2 subjects will receive placebo TID). The DRC will convene to recommend if 
continuation of Part 1, Step 2 as planned is acceptable or if dosing modifications are required once 
AE information through at least 8 hours following the first dose of study drug is available for all 
6 sentinel subjects. 
If it is decided that Part 1, Step 2 should proceed as planned, then approximately 24 subjects will 
be randomized to 1 of 3 treatment groups (razuprotafib 20 mg TID, razuprotafib 30 mg TID, or 
placebo TID) in a 1:1:1 ratio according to a computer-generated randomization list and stratified 
by disease severity. If it is decided that only 1 dose level will be evaluated in Part 1, Step 2, then 
subjects will be randomized to 1 of 2 treatment groups (razuprotafib or placebo) in a 2:1 ratio 
(razuprotafib:placebo). The placebo volume will match the active volume for each treatment 
group. Subjects with moderate COVID-19 will comprise a maximum of approximately 50% of the 
subjects enrolled in Part 1, Step 2. After the last subject enrolled in Part 1, Step 2 completes the 
Treatment Period, the DRC will convene to review all available safety and PK data from Part 1, 
Step 1 and Part 1, Step 2 as defined in the DRC Charter. 
Part 2 
Part 2 will be a proof-of-concept safety and efficacy study that will include approximately 
120 subjects. Based on the DRC’s review of the available safety and PK data from Part 1, Step 1 
and Part 1, Step 2, the study will proceed to Part 2, and the DRC will recommend either 1 or 
2 doses of razuprotafib to evaluate up to 30 mg TID. Subjects will be randomized to 1 of the 
treatment groups (dose 1 razuprotafib TID, dose 2 razuprotafib TID [optional], or placebo TID) in 
a 1:1:1 ratio (or a 2:1 ratio [razuprotafib:placebo] if only 2 treatment groups) according to a 
computer-generated randomization list and stratified by disease severity. The placebo volume will 
match the active volume for each treatment group. Subjects with moderate COVID-19 will 
comprise a maximum of approximately 50% of the subjects enrolled in Part 2. The DRC will 
convene at increments of approximately 25% enrollment in Part 2 to review all available safety 
and PK data as defined in the DRC Charter. 
3.1.1 
Overview of Study Schedule for All Subjects 
After consent for study participation is obtained and eligibility is determined, subjects will be 
randomized to 1 of the treatment groups as described above. Treatment group assignment will be 
blinded to subjects, clinicians, Sponsor study team, Contract Research Organization (CRO) study 
team, and Investigators. Subjects will be dosed SC in the abdomen TID for 7 days or until 
discharge from the hospital (or death), whichever occurs first. Prior to the initiation of Part 2, the 
DRC may make a recommendation to increase the study drug dosing duration to up to 14 days. 
Subjects will be followed for safety and efficacy through Day 28 at on-site visits if the subject has 
not been discharged or via telephone visits if the subject has been discharged. If a subject reports 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 25 of 59 
Version 3.0, 10 December 2020 
a decline in clinical status at a telephone visit, then per the discretion of the Investigator, the subject 
will be requested to return to the site for an Unscheduled Visit. See Appendix A for a list of 
assessments to be performed at the Unscheduled Visit. 
In addition to the routine clinical monitoring that is part of standard of care, the following will be 
conducted: vital signs, blood chemistry, hematology, and coagulation will be assessed during the 
Treatment Period and until Day 28, unless discharged; 12-lead electrocardiograms will be 
performed at Screening, on Day 7 (or at discharge if subject is discharged prior to Day 7), and on 
the last day of dosing if the study drug dosing duration is increased to up to 14 days; data on the 
subject’s 
oxygen 
support 
requirements 
(ie, 
peripheral 
capillary 
oxygen 
saturation 
[SpO2]:fractional inspired oxygen [FiO2] ratio or partial pressure of oxygen [PaO2]:FiO2 ratio if 
arterial blood gas is being performed per standard of care) will be collected during the Treatment 
Period and until Day 28, unless discharged; clinical status based on the National Institute of 
Allergy and Infectious Diseases (NIAID) 8-point ordinal scale and AEs will be assessed through 
Day 28; blood sampling for PK analysis will occur on Day 1 and Day 6 for Part 1 and may occur 
for Part 2; and blood sampling for biomarkers associated with coagulation, inflammation, and 
vascular leakage (CRP and D-dimer assessed at local laboratory; Angpt-2, IL-6, IL-8, TNFα, and 
HMGB-1 assessed at central laboratory) will occur at Screening and on Day 7 (or at discharge if 
subject is discharged prior to Day 7) for all subjects. If the study drug dosing duration is increased 
to up to 14 days, blood sampling for biomarkers will also occur on the last day of dosing. For all 
subjects remaining hospitalized on Day 14 or beyond, blood sampling for biomarkers will also 
occur on Day 28 or the day of hospital discharge, whichever occurs first.  
The duration of the study for each subject will be approximately 29 days: Screening 
(approximately 1 day), Treatment Period (7 days [or up to 14 days if recommended by the DRC]), 
and Post-Treatment Observation Period (approximately 21 days [or 14 to 20 days if Treatment 
Period is extended]). 
The study will take place at approximately 20 sites in the United States. 
3.2 
Data Review Committee 
A DRC comprised of members with pertinent expertise will review emerging safety, efficacy, and 
PK data at appropriate times throughout the study, as described in this protocol and as set forth in 
the DRC Charter.  
The DRC will convene throughout the study to review safety and PK data to recommend if it is 
safe and appropriate to continue the study as planned. The DRC will convene to recommend if 
continuation of Part 1, Step 1 and Part 1, Step 2 as planned is acceptable or if dosing modifications 
are required once AE information through at least 8 hours following the first dose of study drug is 
available for all 6 sentinel subjects in both Step 1 and Step 2 of Part 1. Upon both reviews after 
Part 1, Step 1 and Part 1, Step 2, the DRC will recommend subsequent dosing regimen(s) to be 
tested in the study. Prior to the initiation of Part 2, the DRC may also make a recommendation to 
increase the study drug dosing duration to up to 14 days. The highest dose in this study will not 
exceed 30 mg TID. The DRC can request to unblind efficacy data at any point if deemed necessary 
to adequately complete their review. Additionally, the DRC may request to unblind efficacy data 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 26 of 59 
Version 3.0, 10 December 2020 
if an increase in the study drug dosing duration is under consideration. Further details regarding 
the role, responsibilities, and procedures of the DRC will be provided in the DRC Charter. 
In addition, ad hoc reviews of safety data will be performed throughout the study by appropriate 
study personnel and the Medical Monitor. 
3.3 
Study Indication 
The indication for this study is moderate to severe COVID-19. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 27 of 59 
Version 3.0, 10 December 2020 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria will be eligible to participate in the study: 
1. Ability to understand and provide informed consent; 
Note: where permitted by local regulations, in cases where a prospective subject’s diminished 
mental capacity affects his or her capability to provide informed consent, consent provided by 
a legally authorized representative (LAR) is allowed. If the subject regains decision-making 
mental capacity during conduct of the study, the subject will be reconsented at the earliest 
opportunity.   
2. Males and non-pregnant females ≥18 years of age at the time of Screening; 
3. Laboratory-confirmed active SARS-CoV-2 infection as determined by polymerase chain 
reaction (PCR) or other commercial or public health assay in any specimen, as documented by 
either of the following: 
o SARS-CoV-2 PCR positive in sample collected <72 hours prior to randomization; OR 
o SARS-CoV-2 PCR positive in sample collected ≥72 hours prior to randomization, 
documented inability to obtain a repeat sample (eg, due to lack of testing supplies, limited 
testing capacity, results taking >24 hours to obtain, etc), AND progressive disease 
suggestive of ongoing SARS-CoV-2 infection; 
4. Females of childbearing potential must be willing to completely abstain or agree to use a highly 
effective method of contraception (ie, less than 1% failure rate) from the time of signing the 
ICF and for the duration of study participation (through Day 28); and 
o Note: Females of childbearing potential must have a negative urine pregnancy test during 
Screening. A female of childbearing potential is any female, regardless of sexual 
orientation, who meets the following criteria: has not undergone a hysterectomy or bilateral 
oophorectomy or has not been naturally postmenopausal for at least 12 consecutive months 
(ie, has had menses at any time in the preceding 12 consecutive months). 
5. Currently hospitalized, receiving standard of care therapy for COVID-19, and meets the 
criteria for moderate or severe COVID-19 as follows: 
Moderate COVID-19 (Note: Subjects with moderate COVID-19 will comprise a maximum of 
approximately 50% of the subjects enrolled in each of the following: Part 1, Step 1; Part 1, 
Step 2; and Part 2.) 
o Symptoms of moderate illness with COVID-19, which could include shortness of breath 
with exertion, fever, dry cough, headache, body aches, chills, loss of taste or smell, etc; 
and 
o Respiratory rate ≥20 breaths per minute, SpO2 >93% on room air at sea level, or heart rate 
≥90 beats per minute. 
OR 
Severe COVID-19 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 28 of 59 
Version 3.0, 10 December 2020 
o Symptoms suggestive of severe systemic illness with COVID-19, which could include 
shortness of breath at rest or respiratory distress; and 
o Respiratory rate ≥30 breaths per minute, heart rate ≥125 beats per minute, or SpO2 ≤93% 
on room air at sea level or PaO2:FiO2 <300. 
Note: Patients receiving high flow oxygen by a nasal cannula or noninvasive positive 
pressure ventilation are permitted. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Inability to initiate study drug within 12 hours after randomization; 
2. Female of childbearing potential who is unable or unwilling to forego breastfeeding through 
Day 28; 
3. Systolic blood pressure <100 mmHg; 
4. In shock or requiring pressor support; 
5. Subjects who are on invasive mechanical ventilation; are receiving oxygen delivered by  
extracorporeal membrane oxygenation (ECMO); or have clinical need for 1 of the preceding 
therapies, but preceding therapies not able to be administered in setting of resource limitation; 
6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit of 
normal (ULN); 
7. Total bilirubin >2 × ULN; 
8. Estimated glomerular filtration rate <30 mL/min or receiving hemodialysis or hemofiltration; 
9. Moribund subject not expected to survive 24 hours in the opinion of the treating clinical team; 
10. Any concurrent serious medical condition (eg, active malignancies on chemotherapy, 
post-organ transplant, end stage congestive heart failure) or not likely to respond to treatment; 
11. Decision to withhold life-sustaining treatment; 
Note: In the event of cardiac arrest, the decision to withhold cardiopulmonary resuscitation 
only does not fulfill this exclusion criterion. 
12. Use of sensitive substrates of cytochrome P450 (CYP) 2C8 (eg, repaglinide, paclitaxel, or 
cerivastatin); 
13. Use of CYP2C8 inhibitors (eg, gemfibrozil, fluvoxamine, or ketoconazole); 
14. Participation in another investigational study during the present study through the last visit 
(Day 28); or 
15. Previous randomization in this study. 
4.3 
Retesting 
If laboratory abnormalities during Screening are considered by the Investigator to be transient, 
then the laboratory tests may be repeated once within the Screening window. The Investigator’s 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 29 of 59 
Version 3.0, 10 December 2020 
rationale for retesting should be documented. If the retest result is no longer exclusionary, the 
subject may be randomized. 
4.4 
Stopping Criteria 
4.4.1 
Criteria for Discontinuation of Study Drug in Individual Subjects 
Subjects will be discontinued from study drug, but will continue to be followed in the study, if 
they experience any of the following: 
• ≥Grade 3 (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) AE or 
clinically significant laboratory abnormality considered related to study drug; 
• ≥Grade 3 (CTCAE version 5.0) injection reaction in the first 24 hours post-injection; 
• Significant drop in the subject’s blood pressure such that medical intervention is necessary 
(ie, ≥Grade 3 [CTCAE version 5.0] AE), a blood pressure <80/60 that is considered related to 
study drug, or lack of response to simple measures such as postural change (eg, supine with 
legs raised) or oral or intravenous bolus; and/or 
• Anaphylactic reaction that is moderate or severe, or any anaphylactic reaction that requires 
emergency medical management. 
For any subject who prematurely discontinues from study drug, the reason and date of 
discontinuation will be documented in the source and electronic case report forms (eCRFs). The 
subject should continue to complete all safety assessments at subsequent study visits up to and 
including Day 28. 
4.4.2 
Criteria for Study Termination 
In the event that any of the following is encountered, the DRC will convene to determine status of 
study enrollment: 
• ≥2 subjects are discontinued from treatment for study drug-related safety reasons; and/or 
• ≥2 subjects experience similar SAEs or Grade 3 (CTCAE version 5.0) AEs regardless of 
relatedness to study drug. 
The following will not be considered as criteria for study termination: 
• Grade 3 to 4 fever if present at study entry; 
• Grade 3 nausea if resolves to ≤Grade 1 within 72 hours; and/or 
• Grade 3 fatigue, malaise, or insomnia if resolves to ≤Grade 1 within 72 hours. 
4.5 
Withdrawal and Discontinuation Criteria 
Subjects may be withdrawn from the study for the following reasons: 
• Withdrawn consent by subject or LAR; or 
• Loss to follow-up. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 30 of 59 
Version 3.0, 10 December 2020 
In addition to the criteria listed in Section 4.4.1, subjects may be discontinued from study drug 
(but will continue to be followed in the study) for any of the following reasons: 
• Occurrence of any medical condition or circumstance that exposes the subject to substantial 
risk and/or does not allow the subject to adhere to the requirements of the protocol; 
• Any SAE, clinically significant AE, severe laboratory abnormality (eg, worsening renal or 
hepatic impairment), intercurrent illness, or other medical condition which indicates to the 
Investigator that continued participation is not in the best interest of the subject; 
• Pregnancy; 
• Requirement of prohibited concomitant medication; 
• Subject failure to comply with protocol requirements or study-related procedures; or 
• Termination of the study by the Sponsor or the regulatory authority. 
Prior to subject discontinuation from study drug, the site should notify the Sponsor or Medical 
Monitor, unless the subject is in a life-threatening situation.  
If a subject discontinues from study drug prematurely due to the above criteria or any other reason, 
site staff should make every effort to complete the full panel of assessments scheduled for the 
Day 7 visit (except study drug administration). Subjects who discontinue study drug should 
continue to complete all safety assessments at subsequent study visits up to and including Day 28, 
unless the subject or LAR withdraws consent or is lost to follow-up. The reason for subject 
discontinuation from study drug or study withdrawal must be documented in the source and 
eCRFs. 
If, after a subject is discharged, the subject is lost to follow-up, attempts to contact the subject must 
be made and documented in the source. 
Randomized subjects who have received a dose of study drug will not be replaced.  


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 31 of 59 
Version 3.0, 10 December 2020 
5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Subjects will be randomized to 1 of the following treatment groups in Part 1, Step 1: 
• Razuprotafib 10 mg TID; 
• Razuprotafib 20 mg TID; or 
• Placebo TID. 
Subjects will be randomized to 1 of the following treatment groups in Part 1, Step 2: 
• Razuprotafib 20 mg TID; 
• Razuprotafib 30 mg TID; or 
• Placebo TID (the placebo volume will match the active volume for each treatment group). 
Note: The planned dosing for Part 1, Step 2 may be changed after the DRC reviews the safety and 
PK data from Part 1, Step 1. 
Subjects will be randomized to 1 of the following treatment groups in Part 2: 
• Dose 1 razuprotafib TID (dose may be recommended by the DRC up to 20 mg TID); 
• Dose 2 razuprotafib TID (optional; dose may be recommended by the DRC up to 30 mg TID); 
or 
• Placebo TID (the placebo volume will match the active volume for each treatment group). 
The dosage(s) for Part 1, Step 2 and Part 2 are contingent upon DRC recommendation. If 
2 razuprotafib dose levels are chosen, subjects will be randomized 1:1:1 to dose 1, dose 2, or 
placebo. If 1 razuprotafib dose level is chosen, subjects will be randomized 2:1 
(razuprotafib:placebo). 
5.2 
Rationale for Dosing 
Previous clinical studies with razuprotafib have evaluated 15 mg and 30 mg BID dosing regimens, 
administered by SC injection, in diabetic patients with eye diseases. In all of the studies conducted, 
razuprotafib has exhibited a predictable, dose-dependent PK profile. Also, the results have clearly 
confirmed target engagement of razuprotafib as evidenced by a dose-dependent decrease in blood 
pressure, the effect that has been associated with a downstream effect of razuprotafib on Tie2 
activation resulting in an increase in eNOS. The effect on blood pressure has been transient in 
duration and is a function of the Cmax value for the razuprotafib dose. In human studies, the PK 
profile exhibited a rapid increase in plasma concentration after SC dose administration with time 
to Cmax values achieved within 15 to 30 minutes, followed by a rapid decline with a T½ of 
approximately 1 hour. Due to the short T½, no significant razuprotafib accumulation is expected 
when administered on a TID regimen in this study. 
Based on the unknown pharmacologic effects of razuprotafib in patients with COVID-19, this 
study is designed as a 2-part, placebo-controlled, parallel-group study with appropriate safety 
monitoring and PK assessments (see Figure 1). Part 1 will be a 2-step dose escalation conducted 
in approximately 60 subjects assessing doses of up to 30 mg TID, and Part 2 will be a 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 32 of 59 
Version 3.0, 10 December 2020 
proof-of-concept safety and efficacy study conducted in approximately 120 subjects. In this study, 
administering study drug on a TID frequency in the hospital setting is feasible and provides 
additional safety mitigation by dividing a total daily dose into smaller individual doses. In 
particular, the TID regimen would mitigate the Cmax-related blood pressure effects. In addition, the 
initial doses of 10 mg and 20 mg TID proposed in Part 1, Step 1 do not exceed the highest daily 
dose that was evaluated in previous clinical studies in diabetic patients. In addition to standard of 
care blood pressure monitoring, following each dose of the TID regimen, timed blood pressure 
assessments will be conducted to monitor safety. The proposed design ensures that a full safety 
and PK review of the 10 mg and 20 mg TID doses (Part 1, Step 1) is conducted by the DRC prior 
to dose escalating to up to 30 mg TID (Part 1, Step 2). In addition, following dose escalation, a 
second safety evaluation will be conducted to assess the safety and PK of the doses evaluated in 
Part 1, Step 2 and to select doses for the larger proof-of-concept evaluation in approximately 
120 subjects (Part 2). The doses selected for this study are supported by the preclinical toxicology 
data generated for razuprotafib. The study design includes PK sampling, appropriate safety 
monitoring, periodic formal review of the safety data for dose escalation and continued safety of 
the subjects, individual stopping rules, and interim safety analyses. Moreover, multiple biomarkers 
are planned to be analyzed to evaluate the effect of razuprotafib dosing and changes in 
COVID-19-related effects. 
5.3 
Randomization and Blinding 
After eligibility is determined, subjects will be randomized to 1 of the treatment groups as 
described in Sections 3.1 and 5.1. Subjects will be randomized using the centralized randomization 
system, according to a computer-generated randomization list, and stratified by disease severity. 
Sentinel subject randomization will not be stratified by disease severity. Treatment group 
assignment will be blinded to subjects, clinicians, Sponsor study team, CRO study team, and 
Investigators. Specific individuals from the bioanalytical CRO and Sponsor’s PK group will have 
access to the randomization code to allow for ongoing analysis of bioanalytical samples from the 
subjects treated with razuprotafib and to provide PK analysis results for the DRC reviews. 
5.4 
Breaking the Blind 
Unblinding by request of an Investigator should occur only in the event of an emergency or AE 
for which it is necessary to know the study drug to determine an appropriate course of therapy for 
the subject. If the Investigator must identify the treatment assignment of an individual subject, the 
Investigator or qualified designee should request the treatment assignment from the centralized 
randomization system. They should not attempt to get this information from the site’s unblinded 
pharmacist or qualified designee. The Investigator is advised not to reveal the study drug 
assignment to other site or Sponsor personnel.  
Prior to unblinding, and if the situation allows, the Investigator should consult with the Sponsor’s 
Medical Monitor. If this is impractical, the Investigator must notify the Sponsor’s Medical Monitor 
as soon as possible, without revealing the treatment assignment of the unblinded subject. The 
Investigator must document the subject identification and the date and time for breaking the blind 
and must clearly explain the reasons for breaking the blind.  
Medically necessary care should not be delayed for unblinding information (ie, the Investigator 
should treat the subject based on the subject’s signs/symptoms without waiting for the unblinding 
process to be completed).  


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 33 of 59 
Version 3.0, 10 December 2020 
Subjects who are unblinded and discontinue study drug should continue to complete all safety 
assessments at subsequent study visits up to and including Day 28, unless the subject or LAR 
withdraws consent or is lost to follow-up.  
5.5 
Drug Supplies 
5.5.1 
Formulation and Packaging 
The drug product formulation contains AKB-9778-sodium salt ready to dose, preservative free, 
isotonic, sterile solution (20 mg/mL or 40 mg/mL) in a 3 mL borosilicate vial fitted with a 13 mm 
septum and aluminum flip top seal. A dose volume of 0.50 mL of 20 mg/mL solution will deliver 
a dose of 10 mg, a dose volume of 0.75 mL of 20 mg/mL solution will deliver a dose of 15 mg, a 
dose volume of 0.50 mL of 40 mg/mL solution will deliver a dose of 20 mg, and a dose volume of 
0.75 mL of 40 mg/mL solution will deliver a dose of 30 mg. The formulation also contains 15% 
hydroxypropyl-beta-cyclodextrin (Betadex), United States Pharmacopeia (USP), used as a 
solubilizer, and 1.2% mannitol, USP, for tonicity modification. The formulation is controlled to 
pH 4.0 to 8.6. 
Placebo for razuprotafib (sterile normal saline) will be sourced locally by the site as a parenteral 
formulation ready to dose. The volume of placebo will match the volume of razuprotafib based on 
the dose(s) of razuprotafib in each treatment group in Part 1 (Step 1 and Step 2) and in Part 2. 
Refer to the Pharmacy Manual for specific requirements of sterile normal saline. 
Razuprotafib will be provided in an open-label format that is compliant with International Council 
for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. The placebo will be sourced 
locally and provided with the commercially available product label.  
5.5.2 
Study Drug Preparation and Dispensing 
Study drug will be prepared locally by an unblinded pharmacist. Syringes will be prepared using 
aseptic technique prior to administration and stored for no more than 24 hours. One vial of 
razuprotafib (20 mg/mL or 40 mg/mL) contains sufficient quantity to prepare 3 doses for TID 
administration per subject per day. Prepared syringes will be labeled as required per local standard 
operating procedures (SOPs) to ensure proper identification and to protect the study blinding. 
Refer to the Pharmacy Manual for specific study drug preparation instructions and specifications 
for the disposable sterile syringe. 
5.5.3 
Study Drug Administration 
A volume of 0.50 mL or 0.75 mL of study drug will be administered TID (Q8H) by SC injection 
to the abdomen. Subjects will be dosed for 7 days or until discharge from the hospital (or death), 
whichever occurs first. Subjects will be in the supine position during dosing, and they must remain 
supine with their head no higher than 45° until the vital sign assessment is completed 90 minutes 
following dosing. The first study drug administration must occur within 12 hours after 
randomization. Study drug should be administered at the same nominal times (±1 hour) for each 
Q8H dose throughout the Treatment Period. Prior to the initiation of Part 2, the DRC may make a 
recommendation to increase the study drug dosing duration to up to 14 days. Refer to the Pharmacy 
Manual for specific study drug administration instructions. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 34 of 59 
Version 3.0, 10 December 2020 
5.5.4 
Treatment Compliance 
To ensure treatment compliance, all doses will be administered by the site staff.  
The exact time of study drug administration and the volume of study drug administered will be 
recorded in the eCRF. 
5.5.5 
Storage and Accountability 
At the investigational site, study drug will be stored in a secure area with access limited to 
authorized personnel. Active drug product vials will be stored and maintained at USP controlled 
room temperature, 15°C to 25°C (59°F to 77°F), with transient excursions of up to 30°C permitted. 
Prepared syringes can be stored for no more than 24 hours at USP controlled room temperature, 
15°C to 25°C (59°F to 77°F), with excursions of up to 30°C permitted. 
The responsible pharmacist at the investigational site must keep an ongoing and accurate inventory 
of study drug shipments received and the number of unused and used vials per subject. A full 
reconciliation of study drug inventory will be performed at the end of the study, and the results of 
the inventory will be recorded in the Drug Accountability Form. 
Used vials will be retained for the duration of the study or until verified by the Clinical Research 
Associate (CRA) as outlined below. All administered syringes and/or prepared syringes that are 
beyond the defined 24-hour holding period will be discarded locally in a sharps container as per 
local SOPs and/or as biohazardous exposure control plans require. 
At the conclusion of the study, the CRA will account for all used and unused study drug. After 
completion of the study, or if it is prematurely terminated, all unused materials will be returned to 
the Sponsor or a delegate or destroyed locally at the site following an approved SOP and/or vendor. 
Additional information can be found in the Pharmacy Manual. 
5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
During the period of hospitalization prior to randomization, the following medications and/or 
procedures are prohibited: 
• Invasive mechanical ventilation; or oxygen delivered by ECMO; 
• Pressor support; and 
• Sensitive CYP2C8 substrates (eg, repaglinide, paclitaxel, or cerivastatin) and CYP2C8 
inhibitors (eg, gemfibrozil, fluvoxamine, or ketoconazole). 
After randomization, the following medications and/or procedures are prohibited: 
• Sensitive CYP2C8 substrates (eg, repaglinide, paclitaxel, or cerivastatin) and CYP2C8 
inhibitors (eg, gemfibrozil, fluvoxamine, or ketoconazole). 
Note: CYP2C8 substrates or inhibitors should be withheld if possible. However, any 
medications that are CYP2C8 substrates or inhibitors that are required for standard of care can 
be provided if deemed necessary for management of the patient by the Investigator. Subjects 
that receive these medications, as standard of care for COVID-19, should not be withdrawn. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 35 of 59 
Version 3.0, 10 December 2020 
5.6.2 
Allowed Medications and/or Procedures 
Use of medications for COVID-19, such as remdesivir, antivirals, and dexamethasone, are 
permitted for the management of COVID-19.  
5.6.3 
Documentation of Prior and Concomitant Medication Use and/or Procedures 
Any therapies that are being used for other non-COVID-19 indications but may have an impact on 
SARS-CoV-2 and COVID-19 (eg, IL-6 inhibitors or hydroxychloroquine for rheumatological 
conditions) should be listed as concomitant medication along with the time, dose, and duration of 
their administration. 
Any treatment given in addition to the study drug during the study is regarded as a concomitant 
medication and must be recorded on the appropriate eCRF. 
Any relevant medications received in the 14 days prior to study drug administration must be 
recorded on the appropriate eCRF, along with the reason for use, dates of administration, and 
dosages. 
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the subject’s welfare, are unlikely to interfere with the study drug, and 
not specifically excluded, then they may be given at the discretion of the Investigator and recorded 
in the subject’s source documents and the eCRF. Investigators are encouraged to discuss specific 
medications with the Medical Monitor or Sponsor when in question. 
Any care decisions that are made due to resource limitation (eg, ventilation not available) must be 
documented.  
Data surrounding major changes in background therapy will be collected. The standard of care that 
is followed for each subject and site must be recorded. If standard of care therapies are not able to 
be delivered due to resource limitations, this should also be recorded. 
Any reasons for discontinuation of ventilation must be recorded on the appropriate eCRF, 
including all data related to clinical decision making that guides removal from mechanical 
ventilation in relation to clinical deterioration or lack of clinical response. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 36 of 59 
Version 3.0, 10 December 2020 
6 
STUDY PROCEDURES 
Study procedures will follow the Schedule of Procedures (Appendix A). 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 37 of 59 
Version 3.0, 10 December 2020 
7 
EFFICACY, PHARMACODYNAMIC, AND PHARMACOKINETIC 
ASSESSMENTS 
The efficacy endpoints include the following: 
• Proportion of subjects alive and free of respiratory failure at Day 28; 
• Proportion of subjects alive and free of respiratory failure at Day 7; 
• Change in PaO2:FiO2 ratio from baseline to Day 7 (or discharge) and baseline to Day 28 (or 
discharge); 
• Length hospitalized and free of respiratory failure from baseline to Day 7 and baseline to 
Day 28 or death; 
• Length of hospitalization from baseline to Day 7 and baseline to Day 28 or death; 
• Proportion of subjects who improve by ≥2 categories on the NIAID 8-point ordinal scale from 
baseline to Day 7 and baseline to Day 28; 
• Proportion of subjects who worsen by ≥2 categories on the NIAID 8-point ordinal scale from 
baseline to Day 7 and baseline to Day 28;  
• All-cause mortality at Day 7 and Day 28; 
• Length of ICU stay from baseline to Day 28 or death; 
• Number of subjects in each category of the NIAID 8-point ordinal scale at Day 7 and Day 28; 
• Time to return to prehospitalization oxygen requirement; and 
• Proportion of subjects who were discharged and remained free of respiratory failure prior to 
Day 7 and Day 28. 
The pharmacodynamic and PK endpoints include the following: 
• Change from baseline in CRP and D-dimer; 
• Change from baseline in systemic biomarkers of vascular leakage and inflammation 
(ie, Angpt-2, IL-6, IL-8, TNFα, and HMGB-1); 
• Summary of plasma concentrations of biomarkers at each sampling time point for each 
treatment group; and 
• Summary of plasma razuprotafib concentrations for the samples collected on Day 1 and Day 6. 
7.1 
Hospitalization and Ventilator Data 
The length of hospitalization will include all days that the subject is admitted to the hospital. For 
subjects who are discharged and readmitted to the hospital, the length of hospitalization will 
include the days after readmission.  
Hospitalization days will be counted in 24-hour periods; any partial days will be counted as a 
whole day. 
Days that subjects are weaning off and on the ventilator will be counted as days of respiratory 
failure. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 38 of 59 
Version 3.0, 10 December 2020 
7.2 
National Institute of Allergy and Infectious Diseases 8-Point Ordinal Scale 
The NIAID 8-point ordinal scale includes the following grades:  
1. Death; 
2. Hospitalized, on invasive mechanical ventilation or ECMO; 
3. Hospitalized, on noninvasive ventilation or high-flow oxygen devices; 
4. Hospitalized, requiring supplemental oxygen; 
5. Hospitalized, not requiring supplementation oxygen – requiring ongoing medical care 
(COVID-19 related or otherwise); 
6. Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care; 
7. Not hospitalized, limitation on activities and/or requiring home oxygen; and 
8. Not hospitalized, no limitations on activities. 
7.3 
Biomarker Analysis 
Blood sampling for biomarkers associated with coagulation, inflammation, and vascular leakage 
(CRP, D-dimer, Angpt-2, IL-6, IL-8, TNFα, and HMGB-1) will occur at Screening and on Day 7 
(or at discharge if subject is discharged prior to Day 7) for all subjects. If the study drug dosing 
duration is increased to up to 14 days, blood sampling for biomarkers will also occur on the last 
day of dosing. For all subjects remaining hospitalized on Day 14 or beyond, blood sampling for 
biomarkers will also occur on Day 28 or the day of hospital discharge, whichever occurs first. CRP 
and D-dimer biomarker analysis will be performed at the local laboratory. Vascular leakage and 
inflammation biomarker (Angpt-2, IL-6, IL-8, TNFα, and HMGB-1) analysis will be performed 
at a central laboratory. 
Blood samples for vascular leakage and inflammation biomarker analysis will be stored at a central 
laboratory for reanalysis if needed and will be destroyed no later than 6 months after the final 
clinical study report has been submitted to the relevant regulatory authority(ies).  
All blood samples for biomarker analysis will be de-identified at the time of sample collection. 
7.4 
Pharmacokinetic Analysis 
Blood samples for PK analysis will be collected on Day 1 and Day 6 at 30 (±15) minutes and 
90 (±15) minutes after the first study drug dose of the day. The exact time of study drug 
administration and the exact time of blood sample for PK analysis collection will be recorded on 
the eCRF. PK analysis will be performed at a central laboratory. Blood samples for PK analysis 
will be collected for all subjects; however, samples for subjects randomized to placebo will not be 
analyzed. Blood samples for PK analysis will be collected for all subjects in Part 1; blood samples 
for PK analysis may be collected for subjects in Part 2, after review of the PK data in Part 1. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 39 of 59 
Version 3.0, 10 December 2020 
8 
SAFETY ASSESSMENTS 
8.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product, whether or not related to the investigational medicinal product. 
All AEs, including observed or volunteered problems, complaints, or symptoms, are to be recorded 
on the appropriate eCRF. 
AEs, which include clinical laboratory test variables, will be monitored and documented from the 
time of the first dose of study drug until Day 28. Subjects should be instructed to report any AE 
that they experience to the Investigator, whether or not they think the event is due to study 
treatment. Beginning at the date of the first dose of study drug, Investigators should make an 
assessment for AEs at each visit and record the event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure itself.  
Any medical condition already present at the date of the first dose of study drug should be recorded 
as medical history and not be reported as an AE unless the medical condition or signs or symptoms 
present at baseline changes in severity, frequency, or seriousness at any time during the study. In 
this case, it should be reported as an AE. 
Clinically significant abnormal laboratory or other examination findings that are detected during 
the study or are present at the date of the first dose of study drug and significantly worsen during 
the study should be reported as AEs, as described below. The Investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other 
abnormal assessment is clinically significant. Clinically significant abnormal laboratory values 
occurring during the clinical study will be followed until repeat tests return to normal, stabilize, or 
are no longer clinically significant. Abnormal test results that are determined to be an error should 
not be reported as an AE. Laboratory abnormalities or other abnormal clinical findings should be 
reported as an AE if any of the following are applicable: 
• If an intervention is required as a result of the abnormality; 
• If action taken with the study drug is required as a result of the abnormality; or 
• Based on the clinical judgment of the Investigator. 
8.1.1 
Adverse Drug Reaction 
All noxious and unintended responses to study drug related to any dose should be considered an 
adverse drug reaction (ADR).  


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 40 of 59 
Version 3.0, 10 December 2020 
The phrase “responses to study drug” means that a causal relationship between study drug and an 
AE is at least a reasonable possibility, ie, the relationship cannot be ruled out. All AEs judged by 
the reporting Investigator or the Sponsor as having a reasonable causal relationship to study drug 
qualify as ADRs. 
8.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For razuprotafib, the reference 
safety information is included in the Investigator’s Brochure currently in force. The reference 
safety information will be reviewed yearly. 
8.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator is responsible for the detection and documentation of events meeting the criteria 
and definitions of an AE or SAE as described in this protocol. The Investigator will assess the 
severity (intensity) of each AE according to the CTCAE version 5.0, and will also categorize each 
AE as to its potential relationship to study drug using the categories of yes or no. 
Assessment of Severity 
The severity of all AEs should be graded according to the CTCAE version 5.0. For those AE terms 
not listed in the CTCAE, the following grading system should be used: 
• CTCAE Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; 
• CTCAE Grade 2: Moderate; minimal local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living; 
• CTCAE Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living; 
• CTCAE Grade 4: Life-threatening consequences; urgent intervention indicated; and 
• CTCAE Grade 5: Death related to the AE. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity, 
whereas an SAE is an AE that meets serious criteria, as described in Section 8.2. 
Causality Assessment 
The relationship of an AE to the administration of the study drug is to be assessed according to the 
following definitions: 
No (unrelated, not related, unlikely to be related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE rules out a causal relationship and another 
cause (concomitant drugs, therapies, complications, etc) is suspected. 
Yes (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the AE is consistent with a causal relationship and 
no other cause (concomitant drugs, therapies, complications, etc) can be identified. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 41 of 59 
Version 3.0, 10 December 2020 
The definition implies a reasonable possibility of a causal relationship between an AE or SAE and 
the study drug. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
The following factors should also be considered: 
• The temporal sequence from study drug administration; 
The event should occur after the study drug is given. The length of time from study drug 
exposure to event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases; 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the subject may have. 
• Concomitant drug; 
The other drugs the subject is taking or the treatment the subject receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
• Known response pattern for this class of study drug; 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses; and 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
• The pharmacology and PK of the study drug. 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
the study drug should be considered. 
8.2 
Serious Adverse Events/Drug Reaction 
An AE or adverse reaction is considered serious if, in the view of either the Investigator or Sponsor, 
it results in any of the following outcomes: 
• Death; 
• Is life-threatening; 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at immediate risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalizations; 
Note: Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as an SAE under this criterion, nor will hospitalization for a procedure scheduled 
or planned before signing of informed consent, or elective treatment of a pre-existing condition 
that did not worsen from baseline. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AEs and assessed for 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 42 of 59 
Version 3.0, 10 December 2020 
seriousness. Admission to the hospital for social or situational reasons (ie, no place to stay, live 
too far away to come for hospital visits, respite care) will not be considered inpatient 
hospitalizations.  
• Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions; 
• Is a congenital anomaly/birth defect; or 
• Is an important medical event. 
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent 1 of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency. 
8.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time of the first dose of study drug until Day 28 must be reported to 
Medpace Clinical Safety within 24 hours of knowledge of the occurrence. After the reporting 
window, any SAE that the Investigator considers related to study drug must be reported to 
Medpace Clinical Safety or the Sponsor/designee. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, Medpace Safety personnel will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to Medpace Safety at 
medpace-safetynotification@medpace.com or call the Medpace SAE hotline (telephone number 
listed below), and fax/email the completed paper SAE form to Medpace (contact information listed 
in Section 8.6) within 24 hours of awareness. When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available. 
Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the subject 
dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the SAE form 
electronically in the EDC system for the study and submit any supporting documentation 
(eg, subject discharge summary or autopsy reports) to Medpace Clinical Safety via fax or email. 
If it is not possible to access the EDC system, refer to the procedures outlined above for initial 
reporting of SAEs. 
8.4 
Pregnancy Reporting 
If a subject becomes pregnant during the study or within the safety follow-up period defined in the 
protocol, the Investigator is to stop dosing with study drug immediately. The subject should 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 43 of 59 
Version 3.0, 10 December 2020 
discontinue study drug but continue to complete all safety assessments at subsequent study visits 
up to and including Day 28, unless the subject or LAR withdraws consent or is lost to follow-up. 
A pregnancy is not considered to be an AE or SAE; however, it must be reported to Medpace 
Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical Safety will then 
provide the Investigator/site the Exposure In Utero (EIU) form for completion. The 
Investigator/site must complete the EIU form and fax/email it back to Medpace Clinical Safety.  
If the female partner of a male subject becomes pregnant while the subject is receiving study drug 
or within the safety follow-up period defined in the protocol, the Investigator should notify 
Medpace Clinical Safety as described above.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the EIU form should be completed and faxed/emailed to 
Medpace Clinical Safety. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
8.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about Suspected Unexpected Serious 
Adverse Reactions (SUSARs) that are fatal or life-threatening as soon as possible to the Food and 
Drug Administration (FDA), and in any case no later than 7 days after knowledge by the 
Sponsor/designee of such a case. Relevant follow-up information will subsequently be 
communicated within an additional 8 days.  
All other SUSARs will be reported to the FDA as soon as possible but within a maximum of 
15 days of first knowledge by the Sponsor/designee.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation.  
The Sponsor/designee will also inform all Investigators as required per local regulation. 
The requirements above refer to the requirements relating to investigational medicinal product. 
8.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
• Overdose: Refers to the administration of a quantity of study drug given per administration or 
cumulatively (accidentally or intentionally), which is above the maximum recommended dose 
according to the protocol. Clinical judgment should always be applied. In cases of a 
discrepancy in the drug accountability, overdose will be established only when it is clear that 
the subject has taken additional dose(s) or the Investigator has reason to suspect that the subject 
has taken additional dose(s).  
• Misuse: Refers to situations where study drug is intentionally and inappropriately used in a 
way that is not in accordance with the protocol instructions or local prescribing information 
and may be accompanied by harmful physical and/or psychological effects.  


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 44 of 59 
Version 3.0, 10 December 2020 
• Abuse: Is defined as persistent or sporadic, intentional excessive use of study drug, which is 
accompanied by harmful physical or psychological effects. 
• Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of study drug by a healthcare professional, subject, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors. Cases of subjects missing doses of study 
drug are not considered reportable as medication errors. 
• Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A Special Situations Report 
form will only be completed if a complaint is associated with an ADR.  
All special situation events as described above must be reported on the Special Situations Report 
form and faxed/emailed to Medpace Clinical Safety (contact information listed below) within 
24 hours of knowledge of the event. All AEs associated with these special situation reports 
should be reported as AEs or SAEs as well as recorded on the AE eCRF and/or the SAE report 
form. Details of the symptoms and signs, clinical management, and outcome should be provided, 
when available. 
Safety Contact Information:  
Medpace Clinical Safety 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, dial 3 or +1-513-579-9911, dial 3 
Fax: +1-866-336-5320 or +1-513-570-5196 
Email: medpace-safetynotification@medpace.com 
8.7 
Safety Assessments 
The safety endpoints include the following: 
• Number of subjects with any SAE; and  
• Number of subjects with any treatment-emergent AE. 
Safety will be determined by evaluating clinical laboratory findings (blood chemistry, hematology, 
and coagulation), vital signs (blood pressure, heart rate, SpO2 [for non-ventilated subjects only], 
and respiratory rate), 12-lead electrocardiograms, and AEs reported during the study. 
8.8 
Clinical Laboratory Evaluations 
Samples for blood chemistry, hematology, and coagulation will be obtained as indicated in 
Appendix A. See Appendix B for a complete list of analytes. If a blood chemistry, hematology, or 
coagulation assessment was performed within 24 hours prior to the first dose of study drug, it is 
not necessary to repeat the assessment on Day 1. Effort should be made to obtain blood chemistry, 
hematology, and coagulation at approximately the same time on each day indicated in Appendix A; 
however, it should not be considered a protocol deviation if this is not possible. After the Treatment 
Period, blood chemistry, hematology, and coagulation will be assessed weekly until Day 28, unless 
discharged. All safety clinical laboratory evaluations will be performed at the local laboratory as 
indicated in Appendix A.  


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 45 of 59 
Version 3.0, 10 December 2020 
A local urine pregnancy test will be performed for females of childbearing potential only at 
Screening. 
Arterial blood gas should be obtained locally only if clinically indicated. If arterial blood gas is 
obtained, the subject’s current oxygen requirement should also be recorded. 
8.9 
Vital Signs 
Vital signs will be collected as indicated in Appendix A. Vital signs will include blood pressure, 
heart rate, SpO2 (for non-ventilated subjects only), and respiratory rate. If vital signs are to be 
assessed at the same time point as a blood draw, vital signs should be assessed prior to blood draw. 
Vital signs will be assessed within 1 hour prior to each dose of study drug and 30 (±15) minutes, 
60 (±15) minutes, and 90 (±15) minutes following each dose of study drug. Additionally, after the 
first dose of study drug, supine blood pressure will be assessed every 5 (±1) minutes for the first 
15 minutes, and then every 15 (±5) minutes for the first hour. Subjects will be in the supine position 
during dosing, and they must remain supine with their head no higher than 45° until the vital sign 
assessment is completed 90 minutes following dosing. After the Treatment Period, vital signs will 
be assessed daily until Day 28, unless discharged. 
Temperature will be measured at Screening only. 
8.10 
12-lead Electrocardiogram 
12-lead electrocardiograms will be performed as indicated in Appendix A. If a 12-lead 
electrocardiogram was performed within 24 hours prior to informed consent, it is not necessary to 
repeat the 12-lead electrocardiogram at Screening. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 46 of 59 
Version 3.0, 10 December 2020 
9 
STATISTICS 
9.1 
Analysis Populations 
The Intent-to-Treat (ITT) Population is defined as all subjects randomized. Subjects in this 
population will be analyzed according to the treatment group to which they were assigned at 
randomization. The ITT Population will be used for efficacy analyses. 
The Per-Protocol (PP) Population is a subset of the ITT Population and will include subjects that 
have at least 1 post-dose efficacy evaluation and do not have major protocol deviations. 
The Safety Population is defined as all randomized subjects who received at least 1 dose of study 
drug. Subjects in this population will be analyzed according to the study drug they actually 
received. The Safety Population will be used for the analysis of safety endpoints. 
9.2 
Statistical Methods 
Additional details of the statistical analyses will be provided in the Statistical Analysis Plan, which 
will be finalized prior to database lock. 
9.2.1 
Analysis of Efficacy 
Continuous efficacy endpoints will be analyzed using an analysis of variance model with effects 
for treatment and disease severity as factors. 
Binary efficacy endpoints will be analyzed using a Cochran-Mantel-Haenszel test stratified by 
disease severity. 
For all efficacy endpoints that do not include death as a possible outcome, data from subjects who 
die prior to Day 28 will be imputed at Day 28 based on the worst outcome. 
All efficacy analyses will be performed using the ITT Population. The efficacy analyses will be 
repeated on the PP Population. 
9.2.2 
Pharmacodynamic Analysis 
Pharmacodynamic endpoints will be summarized descriptively. 
9.2.3 
Pharmacokinetic Analysis 
PK concentrations will be summarized descriptively by treatment group and by day and time of 
sample collection post dose. 
9.2.4 
Analysis of Safety 
The safety endpoint data will be summarized for the Safety Population. AEs will be coded using 
the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). AEs and SAEs 
will be summarized by overall number of AEs, severity, and relationship to study drug per 
treatment group. Summaries will be presented by MedDRA system organ class and preferred term 
using frequency counts and percentages by treatment group and overall. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 47 of 59 
Version 3.0, 10 December 2020 
9.2.5 
Sample Size Determination 
Part 1 will include approximately 60 subjects. In Part 1, Step 1, approximately 30 subjects 
(including the 6 sentinel subjects) will be randomized to 1 of 3 treatment groups (razuprotafib 
10 mg TID, razuprotafib 20 mg TID, or placebo TID) in a 1:1:1 ratio. In Part 1, Step 2, 
approximately 30 subjects (including the 6 sentinel subjects) are planned to be randomized to 1 of 
3 treatment groups (razuprotafib 20 mg TID, razuprotafib 30 mg TID, or placebo TID) in a 1:1:1 
ratio. If it is decided that only 1 dose level will be evaluated in Part 1, Step 2, then subjects will be 
randomized to 1 of 2 treatment groups (razuprotafib or placebo) in a 2:1 ratio 
(razuprotafib:placebo). No formal statistical assessment for sample size determination has been 
performed for Part 1. The sample size is considered adequate to provide the necessary data to 
evaluate the objectives for Part 1. 
Part 2 will include approximately 120 subjects. Subjects will be randomized to 1 of the treatment 
groups (dose 1 razuprotafib TID, dose 2 razuprotafib TID [optional], or placebo TID) in a 1:1:1 
ratio (or a 2:1 ratio [razuprotafib:placebo] if only 2 treatment groups). No formal statistical 
assessment for sample size determination has been performed for Part 2. The sample size is 
considered adequate to provide the necessary data to evaluate the objectives for Part 2. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 48 of 59 
Version 3.0, 10 December 2020 
10 
DATA MANAGEMENT AND RECORD KEEPING 
10.1 
Data Management 
10.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data have 
been accounted for. 
10.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
10.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure username and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
10.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• MedDRA (latest) for medical history and AEs; and 
• World Health Organization Drug Dictionary for prior and concomitant medications. 
10.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
10.2 
Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data are defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 49 of 59 
Version 3.0, 10 December 2020 
10.3 
End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study.  
 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 50 of 59 
Version 3.0, 10 December 2020 
11 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
11.1 
Ethical Conduct of the Study 
GCP is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting studies that involve human subjects. Compliance with this standard provides public 
assurance that the rights, safety, and wellbeing of study subjects are protected, consistent with the 
principles that have their origin in the Declaration of Helsinki, and that the clinical study data are 
credible. 
11.2 
Institutional Review Board 
The Institutional Review Board (IRB) will review all appropriate study documentation in order to 
safeguard the rights, safety, and wellbeing of subjects. The study will only be conducted at sites 
where IRB approval has been obtained. The protocol, Investigator’s Brochure, ICF, advertisements 
(if applicable), written information given to the subjects, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB by the Investigator. 
Federal regulations and ICH Guidelines require that approval be obtained from an IRB prior to 
participation of subjects in research studies. Prior to study onset, the protocol, any protocol 
amendments, ICFs, advertisements to be used for subject recruitment, and any other written 
information regarding this study to be provided to a subject must be approved by the IRB. 
No drug will be released to the site for dosing until written IRB authorization has been received 
by the Sponsor. 
11.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and approved by the IRB prior to its use and must be in compliance with all 
ICH GCP, local regulatory requirements, and legal requirements. 
The Investigator must ensure that each study subject or their LAR is fully informed about the 
nature and objectives of the study and possible risks associated with participation and must ensure 
that the subject has been informed of his/her rights to privacy. The Investigator will obtain written 
informed consent from each subject or LAR before any study-specific activity is performed and 
should document in the source documentation that consent was obtained prior to enrollment in the 
study. The original signed copy of the ICF must be maintained by the Investigator and is subject 
to inspection by a representative of the Sponsor, their representatives, auditors, the IRB, and/or 
regulatory agencies. A copy of the signed ICF will be given to the subject or LAR. Subjects 
consented via a LAR will be re-consented at the earliest opportunity they are able to provide 
consent.  
11.4 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, Declaration of Helsinki, ICH GCP, and applicable regulatory requirements, and that 
valid data are entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized, and easily retrievable data. 
Before the enrollment of any subject in this study, the Sponsor or their designee will review with 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 51 of 59 
Version 3.0, 10 December 2020 
the Investigator and site personnel the following documents: protocol, Investigator’s Brochure, 
eCRFs and procedures for their completion, informed consent process, and the procedure for 
reporting SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents and requests for clarification or correction may be made. After the eCRF data are 
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
Investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
11.5 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Subjects may request 
their medical information be given to their personal physician or other appropriate medical 
personnel responsible for their welfare. 
Subject medical information obtained during the study is confidential and disclosure to third 
parties other than those noted above is prohibited. 
11.6 
Retention of Records 
To enable evaluations and/or audits from and permit access for regulatory authorities or the 
Sponsor, the Investigator will keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, eCRFs and hospital records), all original signed ICFs, 
copies of all eCRFs, SAE forms, source documents, and detailed records of treatment disposition. 
The records should be retained by the Investigator according to specifications in the ICH 
guidelines, local regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
The Investigator must obtain written permission from the Sponsor before disposing of any records, 
even if retention requirements have been met. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or to the Sponsor. 
11.7 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 52 of 59 
Version 3.0, 10 December 2020 
11.8 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, Investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 53 of 59 
Version 3.0, 10 December 2020 
12 
STUDY ADMINISTRATIVE INFORMATION 
12.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by Medpace or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB, unless immediate implementation of the change is necessary for subject safety. In this case, 
the situation must be documented and reported to the IRB within 5 working days. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 54 of 59 
Version 3.0, 10 December 2020 
13 
REFERENCES 
 
1. 
Team NCPERE. Vital surveillances: the epidemiological characteristics of an outbreak of 
2019 novel coronavirus diseases (COVID-19) – China. China CDC Weekly. 
2020;2(8):113-22. 
2. 
Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in 
COVID-19. Lancet. 2020;395(10234):1417‐1418. 
3. 
Tang N, Li D, Wang X, et al. Abnormal coagulation parameters are associated with poor 
prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 
2020;18(4):844‐847. 
4. 
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients 
with 
COVID-19 
in 
Wuhan, 
China: 
a 
retrospective 
cohort 
study. 
Lancet. 
2020;395(10229):1054-1062. 
5. 
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on 
ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 
2020;181(2):271‐280.e8. 
6. 
Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) 
in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875‐879. 
7. 
Shenoy V, Qi Y, Katovich MJ, et al. ACE2, a promising therapeutic target for pulmonary 
hypertension. Curr Opin Pharmacol. 2011;11(2):150‐155.  
8. 
Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. 
Nat Rev Drug Discov. 2017;16(9):635-661. 
9. 
Peters KG, Kontos CD, Lin PC, et al. Functional significance of Tie2 signaling in the adult 
vasculature. Recent Prog Horm Res. 2004;59:51‐71. 
10. 
Sack KD, Kellum JA, Parikh SM. The angiopoietin-Tie2 pathway in critical illness. Crit 
Care Clin. 2020;36(2):201‐216. 
11. 
Parikh SM. The angiopoietin-Tie2 signaling axis in systemic inflammation. J Am Soc 
Nephrol. 2017;28(7):1973‐1982. 
12. 
Higgins SJ, De Ceunynck K, Kellum JA, et al. Tie2 protects the vasculature against 
thrombus formation in systemic inflammation. J Clin Invest. 2018;128(4):1471‐1484. 
13. 
Leligdowicz A, Richard-Greenblatt M, Wright J, et al. Endothelial activation: the Ang/Tie 
axis in sepsis. Front Immunol. 2018;9:838. 
14. 
Statz S, Sabal G, Walborn A, et al. Angiopoietin 2 levels in the risk stratification and 
mortality outcome prediction of sepsis-associated coagulopathy. Clin Appl Thromb 
Hemost. 2018;24(8):1223‐1233. 
15. 
Giuliano JS Jr, Lahni PM, Harmon K, et al. Admission angiopoietin levels in children with 
septic shock. Shock. 2007;28(6):650‐654. 
16. 
Kümpers P, van Meurs M, David S, et al. Time course of angiopoietin-2 release during 
experimental human endotoxemia and sepsis. Crit Care. 2009;13(3):R64. 
17. 
Calfee CS, Gallagher D, Abbott J, et al. Plasma angiopoietin-2 in clinical acute lung injury: 
prognostic and pathogenetic significance. Crit Care Med. 2012;40(6):1731‐1737. 
18. 
Agrawal A, Matthay MA, Kangelaris KN, et al. Plasma angiopoietin-2 predicts the onset 
of acute lung injury in critically ill patients. Am J Respir Crit Care Med. 
2013;187(7):736-742. 
19. 
Shen J, Frye M, Lee BL, et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular 
vasculature. J Clin Invest. 2014;124(10):4564‐4576. 
 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 55 of 59 
Version 3.0, 10 December 2020 
 
20. 
Souma T, Thomson BR, Heinen S, et al. Context-dependent functions of angiopoietin 2 
are determined by the endothelial phosphatase VEPTP. Proc Natl Acad Sci USA. 
2018;115(6):1298‐1303. 
21. 
Frye M, Dierkes M, Küppers V, et al. Interfering with VE-PTP stabilizes endothelial 
junctions in vivo via Tie-2 in the absence of VE-cadherin. J Exp Med. 
2015;212(13):2267-2287. 
22. 
Michel T, Vanhoutte PM. Cellular signaling and NO production. Pflugers Arch. 
2010;459(6):807‐816. 
23. 
Farah C, Michel LYM, Balligand JL. Nitric oxide signalling in cardiovascular health and 
disease. Nat Rev Cardiol. 2018;15(5):292‐316. 
24. 
Akerström S, Mousavi-Jazi M, Klingström J, et al. Nitric oxide inhibits the replication 
cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005;79(3):1966‐1969. 
25. 
Cao M, Linder D, Peters K, et al. VE-PTP inhibitor AKB 9778 mitigates vascular leak 
syndrome induced by IL-2 and augments anti-tumor action of the cytokine in mice. 2011. 
Unpublished manuscript. 
26. 
Li G, Nottebaum AF, Brigell M, et al. A small molecule Tie2 activator, AKB-9778, reduces 
intraocular pressure by targeting VE-PTP in Schlemm’s Canal. Manuscript submitted to 
Nature Medicine. 2020. 
27. 
Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes 
and immunosuppression. Lancet. 2020;395(10229):1033‐1034. 
28. 
Gurnik S, Devraj K, Macas J, et al. Angiopoietin-2-induced blood-brain barrier 
compromise and increased stroke size are rescued by VE-PTP-dependent restoration of 
Tie2 signaling. Acta Neuropathol. 2016;131(5):753‐773. 
29. 
Carota IA, Kenig-Kozlovsky Y, Onay T, et al. Targeting VE-PTP phosphatase protects the 
kidney from diabetic injury. J Exp Med. 2019;216(4):936‐949. 
30. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 
coronavirus 
in 
Wuhan, 
China 
[published 
correction 
appears 
in 
Lancet. 
2020;395(10223):496]. Lancet. 2020;395(10223):497‐506. 
31. 
Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, 
health care workers, and health systems during the COVID-19 pandemic. J Am Coll 
Cardiol. 2020;75(18):2352‐2371. 
32. 
Clerkin KJ, Fried JA, Raikhelkar J, et al. COVID-19 and cardiovascular disease. 
Circulation. 2020;141(20):1648‐1655. 
33. 
Campochiaro PA, Khanani A, Singer M, et al. Enhanced benefit in diabetic macular edema 
from AKB-9778 Tie2 activation combined with vascular endothelial growth factor 
suppression. Ophthalmology. 2016;123(8):1722‐1730. 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 56 of 59 
Version 3.0, 10 December 2020 
APPENDIX A:  SCHEDULE OF PROCEDURES 
 
Screeninga 
Treatment Period 
Post-Treatment Observation 
Periodb 
Unscheduled 
Visitb 
Day (± Visit Window) 
See 
Footnotea 
1 
2 
3 
4 
5 
6 
7c  
14 (±2 d) 
21 (±2 d) 
28 (±3 d) 
Unscheduled 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy teste,f 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood chemistry, hematology, 
and coagulationf,g 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
SARS-CoV-2 testf,h 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for PKi 
 
X 
 
 
 
 
X 
 
 
 
 
 
12-lead electrocardiogramj 
X 
 
 
 
 
 
 
X 
 
 
 
 
Temperature 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximeter for SpO2:FiO2 or 
ABGf,l for PaO2:FiO2m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical statusn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for CRP and 
D-dimer biomarkersf,o 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Blood sampling for vascular 
leakage and inflammation 
biomarkersp,o 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Randomizationq 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administrationr 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Note: This Schedule of Procedures does not include assessments that are part of standard of care.  
a. 
Unless otherwise specified, all Screening assessments must be performed within 24 hours prior to randomization. The Screening and Day 1 procedures may be performed on 
the same calendar day. Study Days may not correspond exactly with calendar days. 
b. 
During the Post-Treatment Observation Period, the site will perform weekly telephone visits for subjects who have been discharged to assess concomitant medications, clinical 
status, and adverse events. If a subject reports a decline in clinical status at a telephone visit, then per the discretion of the Investigator, the subject will be requested to return to 
the site for an Unscheduled Visit. For subjects who remain in the hospital during the Post-Treatment Observation Period, assessments will be performed at the site as indicated. 
c. 
For subjects who are discharged prior to Day 7, all of the Day 7 procedures will be performed on the day of discharge. For subjects who are discharged on Days 1 through 4, 
concomitant medications, clinical status, and adverse events will be assessed by a telephone visit on Day 7 (±2 d). If a subject discontinues from study drug prematurely, site 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 57 of 59 
Version 3.0, 10 December 2020 
staff should make every effort to complete the full panel of assessments scheduled for the Day 7 visit (except study drug administration). Subjects who discontinue study drug 
should continue to complete all safety assessments at subsequent study visits up to and including Day 28, unless the subject or LAR withdraws consent or is lost to follow-up. 
The reason for subject discontinuation from study drug or study withdrawal must be documented in the source and eCRFs. 
d. 
Signed informed consent must be obtained before any study-related procedures are performed. 
e. 
For females of childbearing potential only. 
f. 
Assessment will be performed at the local laboratory. 
g. 
If a blood chemistry, hematology, or coagulation assessment was performed within 24 hours prior to the first dose of study drug, it is not necessary to repeat the assessment on 
Day 1. Effort should be made to obtain blood chemistry, hematology, and coagulation at approximately the same time on each day indicated; however, it should not be considered 
a protocol deviation if this is not possible. After the Treatment Period, blood chemistry, hematology, and coagulation will be assessed weekly until Day 28, unless discharged.  
h. 
Laboratory-confirmed active SARS-CoV-2 infection must be determined by PCR or other commercial or public health assay in any specimen, as documented by either of the 
following: SARS-CoV-2 PCR positive in sample collected <72 hours prior to randomization; OR SARS-CoV-2 PCR positive in sample collected ≥72 hours prior to 
randomization, documented inability to obtain a repeat sample (eg, due to lack of testing supplies, limited testing capacity, results taking >24 hours to obtain, etc), AND 
progressive disease suggestive of ongoing SARS-CoV-2 infection. 
i. 
Blood samples for PK analysis will be collected on Day 1 and Day 6 at 30 (±15) minutes and 90 (±15) minutes after the first study drug dose of the day. The exact time of study 
drug administration and the exact time of blood sample for PK analysis collection will be recorded on the eCRF. PK analysis will be performed at a central laboratory. Blood 
samples for PK analysis will be collected for all subjects; however, samples for subjects randomized to placebo will not be analyzed. Blood samples for PK analysis will be 
collected for all subjects in Part 1; blood samples for PK analysis may be collected for subjects in Part 2, after review of the PK data in Part 1. 
j. 
If a 12-lead electrocardiogram was performed within 24 hours prior to informed consent, it is not necessary to repeat the 12-lead electrocardiogram at Screening. 
k. 
Vital signs will include blood pressure, heart rate, SpO2 (for non-ventilated subjects only), and respiratory rate. If vital signs are to be assessed at the same time point as a blood 
draw, vital signs should be assessed prior to blood draw. Vital signs will be assessed within 1 hour prior to each dose of study drug and 30 (±15) minutes, 60 (±15) minutes, and 
90 (±15) minutes following each dose of study drug. Additionally, after the first dose of study drug, supine blood pressure will be assessed every 5 (±1) minutes for the first 
15 minutes, and then every 15 (±5) minutes for the first hour. Subjects will be in the supine position during dosing, and they must remain supine with their head no higher than 
45° until the vital sign assessment is completed 90 minutes following dosing. After the Treatment Period, vital signs will be assessed daily until Day 28, unless discharged.  
l. 
ABG should be obtained only if clinically indicated. If ABG is obtained, the subject’s current oxygen requirement should also be recorded. 
m. During the Treatment Period, SpO2:FiO2 or PaO2:FiO2 (if ABG is being performed per standard of care) will be assessed TID, within 1 hour prior to each dose of study drug. 
After the Treatment Period, SpO2:FiO2 or PaO2:FiO2 (if ABG is being performed per standard of care) will be assessed daily until Day 28, unless discharged. 
n. 
During the Treatment Period, clinical status will be assessed TID, within 1 hour prior to each dose of study drug, using the NIAID 8-point ordinal scale. After the Treatment 
Period, clinical status will be assessed once daily until Day 28, unless discharged. If the subject is discharged alive prior to Day 28, clinical status will be assessed at the 
Post-Treatment Observation Period telephone visits only. 
o. 
For all subjects remaining hospitalized on Day 14 or beyond, blood sampling for biomarkers will also occur on Day 28 or the day of hospital discharge, whichever occurs first. 
p. 
Vascular leakage and inflammation biomarker (Angpt-2, IL-6, IL-8, TNFα, and HMGB-1) analysis will be performed at a central laboratory. 
q. 
After it is determined that all eligibility criteria have been met, the subject will be randomized.  
r. 
A volume of 0.50 mL or 0.75 mL of study drug will be administered TID (Q8H) by SC injection to the abdomen. Subjects will be dosed for 7 days (21 doses) or until discharge 
from the hospital (or death), whichever occurs first. Subjects will be in the supine position during dosing, and they must remain supine with their head no higher than 45° until 
the vital sign assessment is completed 90 minutes following dosing. The first study drug administration must occur within 12 hours after randomization. Study drug should be 
administered at the same nominal times (±1 hour) for each Q8H dose throughout the Treatment Period. Prior to the initiation of Part 2, the DRC may make a recommendation 
to increase the study drug dosing duration to up to 14 days. If the study drug dosing duration is increased, the Day 5 procedures will be performed on Day 8 through the day 
before the last day of dosing, and the Day 7 procedures will be performed on the last day of dosing. 
 
Abbreviations: ABG = arterial blood gas; Angpt = angiopoietin; CRP = C-reactive protein; d = days; DRC = Data Review Committee; eCRF = electronic case report form; 
FiO2 = fractional inspired oxygen; HMGB-1 = high mobility group box 1; IL = interleukin; NIAID = National Institute of Allergy and Infectious Diseases; PaO2 = partial pressure 
of oxygen; PCR = polymerase chain reaction; PK = pharmacokinetic(s); Q8H = every 8 hours; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SC = subcutaneous; 
SpO2 = peripheral capillary oxygen saturation; TID = three times daily; TNFα = tumor necrosis factor alpha.


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 58 of 59 
Version 3.0, 10 December 2020 
APPENDIX B:  CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Chloride 
Creatine kinase 
Creatinine 
Estimated glomerular filtration rate 
Gamma glutamyltransferase 
Glucose 
Lactate dehydrogenase 
Potassium 
Sodium 
Total bilirubin 
Total protein 
 
 
Additional Chemistry Parameters 
Arterial blood gas [1] 
 
1. 
Only if clinically indicated. 
 
Coagulation 
International normalized ratio 
Partial thromboplastin time 
Prothrombin time 
 
 
Endocrinology 
Beta human chorionic gonadotropin [1] 
1. 
Urine pregnancy tests will be performed for females of childbearing potential only. 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cells 
White blood cell count and differential [1] 
 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of 
reference range. 
 
Biomarkers/Pharmacodynamic Parameters 
Angiopoietin-2 
C-reactive protein 
D-dimer 
High mobility group box 1 
Interleukin-6 
Interleukin-8 
Tumor necrosis factor alpha 
 
 
 
 
 


Aerpio Pharmaceuticals, Inc. 
Clinical Study Protocol AKB-9778-CI-6001 
Confidential & Proprietary 
Page 59 of 59 
Version 3.0, 10 December 2020 
Additional Tests 
Severe acute respiratory syndrome 
coronavirus 2 [1] 
 
1. 
Tests performed using polymerase chain reaction or other commercial or public health assay in any specimen.