A Randomized, Double-Blinded, Placebo Controlled Phase II Study to Evaluate the Safety and Efficacy of IV Ampion in Adult COVID-19 Patients Requiring Oxygen Supplementation
Phase: PHASE2
Conditions: COVID-19
Sponsor: Ampio Pharmaceuticals. Inc.

 
 
 
 
A RANDOMIZED, DOUBLE‐BLINDED, 
PLACEBO‐CONTROLLED PHASE II STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF 
INTRAVENOUS AMPION IN ADULT COVID‐
19 PATIENTS REQUIRING OXYGEN 
SUPPLEMENTATION 
 
STUDY PROTOCOL 
 
STUDY NUMBER: AP‐017 
 
NCT04839965 
 
21 JANUARY 2022 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
CONFIDENTIAL 
Page 1 
 
CLINICAL STUDY PROTOCOL TITLE PAGE 
Protocol Title: 
A Randomized, Double-Blinded, Placebo-Controlled 
Phase II Study to Evaluate the Safety and Efficacy of 
Intravenous Ampion in Adult COVID-19 Patients 
Requiring Oxygen Supplementation 
Study Number: 
AP-017 
Investigational Product: 
Ampion 
Drug Development Phase: 
Phase II  
Indication: 
Adult COVID-19 patients on supplemental oxygen 
Route of Administration: 
Intravenous (IV) infusion 
Regulatory Agency Identifier: 
IND 22628 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
373 Inverness Parkway 
Englewood, CO 80112 
Date: 
21 January 2022 
 
 
Study Conduct:  The study is conducted in accordance with the ethical principles that originate from 
the Declaration of Helsinki and that are consistent with International Conference on Harmonization 
(ICH) guidelines on Good Clinical Practice (GCP) and regulatory requirements as applicable. 
 
 
Confidential Information: The information contained in this document is confidential and is 
intended for clinical investigator use. It is the property of Ampio Pharmaceuticals, Inc. This 
document and any and all information contained herein has to be considered and treated as 
confidential. No disclosure or publication shall be made without the prior written consent of 
Ampio Pharmaceuticals, Inc. 
 
 
 
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
CONFIDENTIAL 
Page 2 
 
 
 
PROTOCOL ATTESTATION 
I have read and understand the contents of this clinical protocol for Study Number AP-017 
dated 21January 2022 and agree to meet all obligations of Ampio Pharmaceuticals Inc. as 
detailed in all applicable regulations and guidelines. 
 
Signed By: 
 
<Study personnel signature> 
 
<Enter date> 
 
 
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
CONFIDENTIAL 
Page 3 
1 
PROTOCOL SUMMARY 
1.1 
Protocol Synopsis 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Title of Study:   
A Randomized, Double-Blinded, Placebo-Controlled Phase II Study to Evaluate the Safety and 
Efficacy of Intravenous Ampion in Adult COVID-19 Patients Requiring Oxygen 
Supplementation 
Rationale: 
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the 
pandemic spread of coronavirus disease 2019 (COVID-19), which has a high rate of infection, 
has a high rate of hospitalization, has overwhelmed healthcare systems, and can be fatal.  
Ampion is the low molecular weight filtrate of human serum albumin with the in vitro ability to 
modulate inflammatory cytokine levels. Ampion has the potential to improve clinical outcomes 
for COVID-19 patients by reducing inflammatory cytokines correlated with the disease. 
This study aims to evaluate Ampion and clinical outcomes in patients with COVID-19 who 
require supplemental oxygen. The data from this study will inform decisions for the Ampion 
clinical development. 
Lead Investigators:   
Michael Roshon, MD, PhD, USA 
Number of Sites:   
Approximately 10 sites 
Indication:   
Adult COVID-19 patients on supplemental oxygen 
Number of Participants: 
Sample size is approximately 200 patients, randomized 1:1 for Ampion or control.  
An interim analysis will be conducted at 30 participants, randomized 1:1 for Ampion or control 
to allow for sample size re-estimation as needed.  
Treatment Groups:  
There are two planned treatment arms: 
Treatment Arm 
Investigational Treatment 
Active 
IV Ampion for 5-days 
Control 
IV Placebo for 5-days 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
CONFIDENTIAL 
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Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Objectives and Endpoints:  
Objective 
Endpoint 
Primary 
Assess the effect of Ampion compared to 
placebo on prevention of need for 
mechanical ventilation or death 
• Occurrence of mechanical ventilation or death by Day 28.  
Secondary 
Assess the effect of Ampion compared to 
placebo on safety 
• Incidence of adverse events (AEs) and serious adverse events 
(SAEs) from baseline to Day 60. 
Assess the effect of Ampion compared to 
placebo on hospital stay  
• Hospital length of stay (LOS) from admission to discharge. 
Assess the effect of Ampion compared to 
placebo on oxygen use 
• Change from baseline in oxygen use, blood oxygen saturation, 
and oxygen flow rate from baseline through Day 5. 
Assess the effect of Ampion compared to 
placebo on duration of respiratory failure 
to ventilator-free days 
• Percentage of participants who progress to respiratory failure 
(i.e., need for mechanical ventilation, ECMO, non-invasive 
ventilation) by Day 28. 
Assess the effect of Ampion compared to 
placebo on intensive care  
• Percentage of participants who require Intensive Care Unit 
(ICU) admission by Day 28. 
• ICU-free days through Day 28. 
• ICU LOS from ICU admission to discharge. 
Assess the effect of Ampion compared to 
placebo on clinical improvement 
• Change in ordinal scale from baseline through Day 7. 
• Change in ordinal scale from baseline to hospital discharge or 
Day 14 (whichever occurs first). 
• Change in ordinal scale from baseline to hospital discharge or 
Day 28 (whichever occurs first). 
Assess the effect of Ampion compared to 
placebo on clinical health 
• Change in NEWS2 score from baseline through Day 5. 
• Change in NEWS2 score from baseline to hospital discharge. 
Assess the effect of Ampion compared to 
placebo on cytokine profile 
• Modulation of cytokine levels from baseline to Day 5 
 
 

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Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
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Study Design:   
Overall Design 
This is a Phase II randomized, double-blinded, placebo-controlled study in adult participants 
with COVID-19 who require supplemental oxygen. 
Screening 
Interested participants will sign the appropriate informed consent document(s) prior to 
completion of any study procedures. The investigator will review symptoms, risk factors and 
other non-invasive inclusion, including COVID testing, and exclusion criteria prior to any study 
procedures. If the participant is eligible after this review, then the site will perform the necessary, 
if any, study procedures to confirm eligibility. 
Treatment and Assessment 
Participants will be randomized to active treatment or control, following an equal allocation to 
treatment arms. Given the changing nature of the pandemic, periodic adjustments to the 
allocation ratio may be made in an effort to achieve equal allocation across the treatment arms 
at the end of the enrollment. There are two planned treatment arms:  
 Treatment Arm 
Investigational Treatment 
Active 
IV Ampion for 5-days 
Control 
IV Placebo for 5-days 
The general sequence of events during the treatment and assessment period: 
• Complete baseline procedures and sample collection 
• Participants are randomized to receive either Ampion or a placebo. 
• Participants receive study intervention (active or placebo) as an IV infusion for 5 days.  
• Complete safety monitoring and post-infusion sample collection. 
 
The Schedule of Assessments is shown in Section 1.2. Visit types are described as follows: 
Study Day 
Visit Description 
Visit Type 
0-5 
Treatment 
Site 
28, 60 
Follow-up 
Telephone  
Early discontinuation  
ED 
May be conducted at site or via telephone 
 
Post-Treatment Follow-up 
Post-treatment follow-up will occur after Day 5 to assess clinical status and for adverse events.  
 
Disclosure Statement 
Assigned treatment, active or placebo, will be blinded to the patients, clinicians, and the 
investigators conducting the study. 
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
CONFIDENTIAL 
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Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
 
Data Safety Monitoring Board 
There will be a Data Safety Monitoring Board (DSMB). Safety, including incidence of 
AEs/SAEs will be evaluated by a DSMB throughout the study.  
 
Diagnosis and Main Criteria for Inclusion:  
1. Male or female, ≥ 18 years old 
2. Diagnosed with COVID-19, as evaluated by laboratory diagnostic test or diagnosis based on 
radiological clinical findings.  
3. Baseline severity categorization of severe or critical COVID-19 infection per FDA Guidance 
for developing drugs and biological products for COVID-19 (February 2021): 
a) Severe COVID-19: 
• Symptoms suggestive of severe systemic illness with COVID-19, which could include 
shortness of breath or respiratory distress 
• Clinical signs indicative of severe systemic illness with COVID-19, such as 
respiratory rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room 
air at sea level (SpO2 ≤ 90% at altitude) or PaO2/FiO2 < 300 
b) Critical COVID-19: 
• Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered 
via reinforced cannula at flow rates > 20 L/min with fraction of oxygen ≥ 0.5) or 
• Non-invasive mechanical or endotracheal mechanical ventilation 
4. Informed consent obtained from the patient or the patient's legal representative. 
Main Criteria for Exclusion: 
1. As a result of the medical review and screening investigation, the Principal Investigator 
considers the patient unfit for the study and/or progression to death is imminent and 
inevitable irrespective of the provision of treatments. 
2. Clinical diagnosis of respiratory failure (therapy not able to be administered in setting of 
resource limitation)  
3. Shock defined by systolic blood pressure <90 mm Hg, or diastolic blood pressure <60 mm 
Hg or requiring vasopressors. Vasopressor therapy is exclusionary if used to treat shock. 
Subjects receiving low dose vasopressors to maintain renal perfusion are eligible. 
4. Multi-organ dysfunction/failure  
5. Patient has severe chronic obstructive or restrictive pulmonary disease (COPD) (as defined 
by prior pulmonary function tests), chronic renal failure (only exclusionary if subject is 
currently on renal replacement therapy, i.e., subjects receiving peritoneal dialysis, 
hemodialysis, ultrafiltration are ineligible), or significant liver abnormality (e.g., cirrhosis, 
transplant, etc.). 

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Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
CONFIDENTIAL 
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Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
6. Patient has chronic conditions requiring chemotherapy or immunosuppressive medication 
(only exclusionary if subject is currently receiving a high dose or therapy for transplantation, 
e.g., subjects receiving low dose inhaled or oral steroids for asthma are eligible). 
7. A history of allergic reactions to human albumin (reaction to non-human albumin such as 
egg albumin is not an exclusion criterion) or ingredients in 5% human albumin (N-
acetyltryptophan, sodium caprylate). 
8. Prolonged QT interval. 
9. Patient has known pregnancy or is currently breastfeeding. 
10. Patient planning to become pregnant, or father a child, during the treatment and follow-up 
period and/or is not willing to remain abstinent or use contraception.  
11. Participation in another clinical trial (not including treatments for COVID-19 as approved 
by the FDA through expanded access, emergency, or compassionate use), or participation in 
a trial such that enrollment in this study would fall within the time frame of the half-life of 
the other investigational product(s). 
Test Product, Dose, and Mode of Administration: 
Participants in the active arm will receive a 250cc daily dose of Ampion as an IV infusion for 5 
days. The daily dose of Ampion will be delivered by IV twice daily (125cc/dose), every 12 
hours, for 5 days.  
All subjects receiving test product will also receive the standard of care (SOC) for COVID-19, 
which includes: 
• Oxygen administration to maintain oxygen saturation of 90% or greater. 
• Nursing physical that may include review of neurological, pulmonary, cardiac 
gastrointestinal, and urinary assessment at least daily. 
• Vital monitoring (heart rate, blood pressure, temperature, respiratory rate, SpO2) daily 
• Telemetry monitoring to evaluate heart rhythm and rate.  
• Diet as tolerated to satisfy nutritional needs. 
• Treatments for COVID-19 symptoms including antibiotics, cough suppressants/ 
expectorants, anti-coagulants, fever reducers/pain killers, anti-nausea drugs, and/or 
bronchodilators.  
• Treatments for COVID-19 as approved by the FDA including expanded access, 
emergency, or compassionate use (i.e., remdesivir, dexamethasone, convalescent plasma). 
Medications will be recorded as concomitant medication, tabulated, and compared among 
groups.  
Reference Therapy, Dose and Mode of Administration: 

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Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-017 
 
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Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Participants in the control arm will receive a 250cc daily dose of Placebo as an IV infusion for 
5 days. The daily dose of Placebo will be delivered by IV twice daily (125cc/dose), every 12 
hours, for 5 days.  
All subjects receiving placebo will also receive the SOC for COVID-19 as described previously. 
Study Duration:   
Treatment: 5 days 
Follow-up: 60 days 
 
 

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Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
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1.2 
Schedule of Assessments (SoA) 
Visits will be conducted as described:  
 
Screen 
Treatment 
Hospitalization/ 
Continued Care 
Follow-Up 
Study Day 
-3 to 0 
0 
1 
2 
3 
4 
5 
Every day until 
Day 7 
28 
60 
Visit Window (± days) 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
3 
3 
COVID-19 diagnosis 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history and pre-
existing conditions 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test 1 
 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
IV treatment 
 
 
X 
X 
X 
X 
X 
 
 
 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood oxygen saturation 
 
X 
X 
X 
X 
X 
X 
X 
 
 
ECG monitoring (telemetry)2 
 
X 
X 
X 
X 
X 
X 
X 2 
 
 
Hematology3 
 
X 
 
X 
 
X 
X 
X 3 
 
 
Biochemistry2 
 
X 
 
X 
 
X 
X 
X 3 
 
 
Cytokine/chemokine assay4 
 
X 
 
 
 
 
X 
X 4 
 
 
Mortality 
 
 
 
 
 
 
 
X 
X 
X 
Ordinal scale for clinical status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NEWS2 score for clinical 
status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hospital LOS and ICU LOS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Date of intubation/ extubation, 
days on ventilation 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 
As applicable 
2 
Telemetry monitored as needed for patients who have events or abnormal readings requiring measurements. 
3 
Hematology and biochemistry tests are performed at baseline and every other day through treatment and inpatient 
stay unless an abnormal value is observed. In the case of an abnormal lab result, continue to collect and test those 
samples to follow subject through resolution. 
4 
Cytokine and chemokine assays are collected at baseline before treatment, at Day 5 after treatment, and at discharge.  
 

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Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
 
1 
PROTOCOL SUMMARY ............................................................................................ 3 
1.1 
Protocol Synopsis.................................................................................................... 3 
1.2 
Schedule of Assessments (SoA) ............................................................................. 9 
2 
INTRODUCTION ...................................................................................................... 14 
2.1 
Study Drug ............................................................................................................ 14 
2.2 
Background to the Disease .................................................................................... 14 
2.3 
Previous Human Experience ................................................................................. 15 
2.4 
Study Rationale ..................................................................................................... 16 
2.4.1 
Study Background ........................................................................................... 16 
2.4.2 
Preclinical Data ............................................................................................... 16 
2.4.3 
Dosing Rationale ............................................................................................. 17 
2.5 
Benefit and Risk Assessment ................................................................................ 18 
3 
STUDY DESIGN........................................................................................................ 19 
3.1 
Study Design Overview ........................................................................................ 19 
3.2 
Study Objectives ................................................................................................... 20 
3.2.1 
Primary Objective ........................................................................................... 20 
3.2.2 
Secondary Objectives...................................................................................... 20 
3.3 
Study Endpoints .................................................................................................... 20 
3.3.1 
Primary Endpoint ............................................................................................ 20 
3.3.2 
Secondary Endpoints ...................................................................................... 20 
3.4 
Blinding and Randomization ................................................................................ 21 
3.5 
Data Safety Monitoring Board .............................................................................. 21 
3.6 
Stopping rules ....................................................................................................... 21 
4 
SELECTION OF PARTICIPANTS ........................................................................... 22 
4.1 
Number of Participants ......................................................................................... 22 
4.2 
Recruitment Methods ............................................................................................ 22 
4.3 
Participant Characteristics .................................................................................... 22 
4.4 
Inclusion Criteria .................................................................................................. 23 
4.5 
Exclusion Criteria ................................................................................................. 23 
4.6 
Inclusion of Patients Incapable of Giving Informed Consent ............................... 24 
5 
STUDY PLAN, PROCEDURES, AND ASSESSMENTS ........................................ 25 
5.1 
Description of Study Visits ................................................................................... 25 
5.1.1 
Screening (-3 Days to Day 0) .......................................................................... 25 
5.1.2 
Baseline (Day 0) ............................................................................................. 25 
5.1.3 
Treatment Period (Day 1 to Day 5)................................................................. 25 
5.1.4 
Hospitalization Period, as applicable (Day 6 through hospital discharge) ..... 26 
5.1.5 
Post-Treatment Follow-Up (Days 28, 60) ...................................................... 26 
5.2 
Assessment Methods ............................................................................................. 27 

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6 
DISCONTINUATION CRITERIA ............................................................................ 30 
6.1 
Early Discontinuation of the Study ....................................................................... 30 
6.2 
Early Discontinuation of Individual Participants .................................................. 30 
7 
TREATMENT ............................................................................................................ 31 
7.1 
Dosing and Administration of Study Medication ................................................. 31 
7.2 
Study Medication Storage and Accountability ..................................................... 32 
7.3 
Concomitant Treatments ....................................................................................... 32 
7.4 
Treatment Compliance .......................................................................................... 32 
8 
ADVERSE EVENTS .................................................................................................. 33 
8.1 
Definition of an Adverse Event ............................................................................ 33 
8.2 
Definition of a Serious Adverse Event ................................................................. 33 
8.3 
Recording of Adverse Events and Serious Adverse Events ................................. 34 
8.3.1 
AE Follow up .................................................................................................. 34 
8.3.2 
Overdose ......................................................................................................... 34 
8.4 
Serious Adverse Event Reporting ......................................................................... 35 
8.4.1 
Reporting Requirements ................................................................................. 35 
8.4.2 
SAE Contact Information ............................................................................... 35 
9 
STATISTICAL METHODS ....................................................................................... 36 
9.1 
General Considerations ......................................................................................... 36 
9.2 
Analysis Populations ............................................................................................. 36 
9.2.1 
Safety Analysis Population: ............................................................................ 36 
9.2.2 
Intent-to-treat Population: ............................................................................... 36 
9.2.3 
Interim Analysis .............................................................................................. 36 
9.3 
Data presentation .................................................................................................. 37 
9.4 
Study Endpoints .................................................................................................... 38 
9.4.1 
Primary Endpoint ............................................................................................ 38 
9.4.2 
Secondary Endpoints ...................................................................................... 38 
9.5 
Missing and Spurious Data ................................................................................... 39 
10 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ................................... 40 
10.1 
Declaration of Helsinki ......................................................................................... 40 
10.2 
Good Clinical Practice .......................................................................................... 40 
10.3 
Institutional Review Boards/Ethics Committees .................................................. 40 
10.4 
Regulatory Authority Approval ............................................................................ 40 
10.5 
Informed Consent.................................................................................................. 40 
10.6 
Patient Confidentiality and Disclosure ................................................................. 40 
10.7 
Collection, Monitoring and Auditing Study Documentation, and Data Storage .. 41 
10.7.1 
Collection of Data and Monitoring Procedures .............................................. 41 
10.7.2 
Auditing Procedure ......................................................................................... 42 
10.7.3 
Retention of Documents ................................................................................. 42 
10.8 
Disclosure of Information ..................................................................................... 42 
10.9 
Discontinuation of the Study ................................................................................ 42 

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Clinical Study Protocol: AP-017 
 
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10.10 
Study Report, Publication Policy and Archiving of Study Documentation .......... 42 
10.10.1 
Study Report and Publication Policy .............................................................. 42 
10.10.2 
Study Documents ............................................................................................ 43 
10.10.3 
Archiving of Documents ................................................................................. 43 
11 
REFERENCES ........................................................................................................... 44 
 
 
 
 

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Clinical Study Protocol: AP-017 
 
Version 3.0, 21 January 2022 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse event 
ALI 
Acute lung injury 
ARDS 
Acute respiratory distress syndrome 
BP 
Blood pressure 
CDC 
Centers for Disease Control and Prevention 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 19  
CRO 
Contract research organization 
DSMB 
Data and safety monitoring board 
EC 
Ethics committee 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EMR 
Electronic medical record 
EUA 
Emergency use authorization 
HSA 
Human serum albumin 
ICH 
International conference on harmonization 
ICU 
Intensive care unit 
IRB 
Investigational review board 
ITT 
Intent to treat 
IV 
Intravenous 
LAR 
Legally authorized representative 
LOS 
Length of Stay 
NEWS 
National Early Warning Score 
q12 
Every 12 hours 
RCT 
Randomized controlled trial 
SAE 
Serious adverse event 
SOP 
Standard operating procedure 
SpO2 
Blood oxygen saturation 
TNFα 
Tumor necrosis factor alpha 
WHO 
World Health Organization 
 
 
 
 

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2 
INTRODUCTION 
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic 
spread of coronavirus disease 2019 (COVID-19). The COVID-19 virus has a high rate of 
infection and complications due to the virus has resulted in a high rate of hospitalization, has 
overwhelmed healthcare systems, and can be fatal. Approximately 20% of patients with 
COVID-19 will progress to severe disease (CDC.gov). Identifying drugs and therapies that 
address the full spectrum of symptoms related to COVID-19 infection is critical.  
This is a phase II randomized controlled trial (RCT) to evaluate intravenous (IV) Ampion for 
adults with COVID-19 who require supplemental oxygen. Ampion is being developed as an 
immunomodulatory therapy with anti-inflammatory effects that could provide a beneficial 
treatment for COVID-19 patients with symptoms, like difficulties breathing and the need for 
supplemental oxygen. This study aims to investigate the safety and the clinical outcomes in 
these patients with COVID-19 on supplemental oxygen when treated with IV Ampion. 
2.1 
Study Drug 
Ampion is the low molecular weight filtrate of 5% Human Serum Albumin (HSA), USP, 
derived from human blood. It is a homogenous solution containing three main active 
components: Aspartyl-Alanyl Diketopiperazine (DA-DKP), N-Acetyl-Tryptophan (NAT), and 
Sodium Caprylate (Caprylate). These ingredients have the in vitro ability to decrease 
inflammatory cytokine levels. The modulation of these inflammatory cytokines is expected to 
mitigate respiratory complications in patients with COVID-19 as these cytokines are correlated 
with the respiratory symptoms and disease severity. Ampion is packaged as a sterile solution 
(125cc) ready for IV infusion. 
The study control arm will use a saline placebo solution packaged in the same configuration 
as Ampion to protect blinding. 
Ampion or placebo will be delivered intravenously as a 125cc dose, delivered twice a day, for 
a 250cc daily dose administered for five days. Ampion or placebo will be administered using 
an infusion pump through an existing intravenous access (central line, PICC, peripheral, or 
saline lock). Ampion will be administered as an intravenous piggyback/secondary if the patient 
at the time of the administration of Ampion has an existing primary infusion. If there are no 
intravenous fluids being administered at the time of the Ampion infusion, Ampion treatment 
will be infused as an intermittent intravenous infusion. Ampion will be administered undiluted 
at a flow rate of 100cc/hour. 
2.2 
Background to the Disease 
COVID-19 infection is a respiratory illness caused by a novel coronavirus (SARS-COV-2) and 
has been classified as a pandemic with no known cure to date. COVID-19 is detected and 
diagnosed with a laboratory test. The primary symptoms of COVID-19 infection include mild 
symptoms such as fever, cough, chills, muscle pain, headache, gastrointestinal symptoms, and 
the loss of taste or smell. Once infected, the virus moves down a patient’s respiratory tract, 

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where the lungs may become inflamed, making breathing difficult and requiring supplemental 
oxygen, resulting in more severe cases of the disease.  
Inflammation associated with COVID-19 may trigger even more severe complications 
including pneumonia, acute lung injury (ALI) and/or acute respiratory distress syndrome 
(ARDS), which is a leading cause of mortality in COVID-19 (Zhou 2020). ALI/ARDS is a 
rapidly progressive disease characterized by widespread inflammation in the lungs. Under 
normal circumstances, there is approximately a 40% mortality rate for patients with 
ALI/ARDS (Bellani 2016). However, ARDS secondary to COVID-19 infection might prove 
to be more lethal than ARDS due to other causes. A study of 191 patients in Wuhan, China 
reported an 85% (50/59) case mortality rate of ARDS secondary to COVID-19 infection (Zhou 
2020).  
Inflammation is initiated when a patient experiences moderate to severe COVID-19 symptoms 
(Gandhi 2020) and the continuing destructive cycle of inflammation impact the clinical course 
of COVID-19 patients in several significant and potentially fatal ways. Patients with severe 
COVID-19 require supplemental oxygen and careful monitoring as inflammation continues. 
Remdesivir and dexamethasone have demonstrated benefits in hospitalized patients with 
severe COVID-19, but in patients with moderate disease, dexamethasone is not efficacious 
(and may be harmful) and data are insufficient to recommend for or against routine use of 
remdesivir (Gandhi 2020). There is a continued need for a treatment that can interrupt and/or 
prevent this inflammatory cascade to address the severe and critical COVID-19 patient 
population who require oxygen supplementation. 
As an immunomodulatory agent, Ampion may be effective in interrupting the inflammation 
associated with COVID-19 and improving the clinical course and outcome of patients. 
2.3 
Previous Human Experience 
Human serum albumin (HSA, 5%) is a human blood product approved by FDA for intravenous 
(IV) infusion to treat hypovolemia and other serious conditions, including ARDS (Polito 2013, 
Farag, 2016). Albumin and large molecules are removed to manufacture Ampion, the low 
molecular weight (< 5 kDa) ultrafiltrate of 5% HSA.   
Ampion has been investigated for clinical use as an IV treatment compared to standard of care 
for adults with COVID-19 infection requiring supplemental oxygen in a Phase 1, randomized, 
open label study in 10 adults with severe COVID-19. The study met its primary endpoint for 
the safety and tolerability of IV Ampion treatment, with no remarkable difference in the 
incidence, frequency, and severity of adverse events between IV Ampion and standard of care. 
At hospital discharge, Ampion-treated patients showed greater clinical improvement than 
standard of care alone using the WHO ordinal scale and NEWS2 scale for clinical health.  
Ampion is also in human clinical development for a separate inflammatory indication 
(arthritis). In that program more than 1,000 patients have been exposed to a localized 4cc 
injection of Ampion with no treatment-related adverse events. 

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2.4 
Study Rationale  
This study aims to evaluate the impact of IV Ampion on the occurrence of mechanical 
ventilation or death and clinical outcomes in adults with COVID-19 who require supplemental 
oxygen. The data from this study will inform decisions for the clinical development of Ampion. 
2.4.1 
Study Background 
COVID-19 infection is associated with pathological findings including pneumonia and 
inflammation of lung tissue. The triggering insult to the tissue has been associated with a hyper 
innate inflammatory response in which cytokines and related proteins, such as tumor necrosis 
factor alpha (TNFα), are excessively increased with the severity of COVID-19 and respiratory 
failure. This inflammatory response commonly results in ALI or its more severe form, ARDS, 
in which leads to pulmonary edema and fibrosis with poor prognosis. ALI/ARDS is believed 
to be a major cause of mortality in COVID-19 patients. 
In vitro nonclinical studies show Ampion modulates cytokine levels in various immune cell 
models where it decreases the levels of inflammatory cytokines, including TNFα. Due to its 
mode of action, Ampion may be a viable treatment option for those infected with COVID-19 
in effort to improve clinical outcomes, slow the progression and severity with associated 
critical COVID-19 inflammatory conditions (e.g., progression to respiratory failure, the need 
for assisted breathing, and ultimately mortality) (Thomas, 2020). This study evaluates the 
safety and tolerability of IV Ampion treatment for COVID-19 patients who require 
supplemental oxygen before they progress to these critical cases. 
2.4.2 
Preclinical Data  
Ampion is a filtrate of a human blood product, 5% human serum albumin (HSA), approved by 
FDA for IV infusion to treat critically ill patients including patients with compromised 
respiration with ALI and ARDS (HSA prescribing information; Farag, 2016; Polito 2013). The 
IV administration of HSA has exposed humans, including the indicated population with 
respiratory inflammation, to the components in Ampion with no remarkable safety concerns.  
The Ampion preclinical testing program is designed to support clinical development for the 
treatment of inflammatory diseases and the dysregulation of proteins responsible for 
modulating the immune response. COVID-19 infection is associated with a hyper innate 
inflammatory response, where increased levels of cytokines and related proteins (e.g., TNFα) 
are correlated with the severity of COVID-19 illness (Channappanavar 2017, Feldman 2020). 
Preclinical pharmacology studies of Ampion using human in vitro models of immunology 
(e.g., peripheral blood mononuclear cells and macrophages) indicate that Ampion reduces 
inflammatory cytokines (e.g., TNFα) responsible for the inflammation and tissue damage 
initiated by viral diseases like COVID-19 (Channappanavar, 2017) and in respiratory distress 
syndromes (Yang, 2017), while promoting the production of prostaglandins responsible for 
resolving inflammation in respiratory disease (Loynes 2018).   

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2.4.3 
Dosing Rationale  
Human serum albumin, including 5% HSA, has been administered safely via IV for many years 
at volumes exceeding 500cc in a day (5% HSA prescribing information). A comparison of the 
active components in Ampion against those in the starting material HSA demonstrates that the 
proposed daily dose (250cc) of Ampion can be safely administered via IV.   
  
The proposed daily dose of 250cc is based on Ampion’s in vitro biological activity and the 
amount of Ampion required to achieve its in vitro anti-inflammatory effect. The biological 
activity of Ampion is measured using a bioassay which tests the release of pro-inflammatory 
cytokine (TNFα) in activated immune cells. In the bioassay, human peripheral blood 
mononuclear cells (PBMC) are stimulated to release TNFα. The cells are treated with either 
Ampion or saline, and Ampion activity is reported as inhibition (%) of TNFα in cells treated 
with Ampion compared to the cells treated with saline. In the bioassay, the treatment effect is 
achieved by adding 50 µL of Ampion to 100,000 cells. A dose-dependent effect is observed (a 
representative dose curve is shown in Figure 1).  
 
Figure 1: TNFα Inhibition and Dose Response in Human Immune Cells Treated with Ampion 
 
 
To model efficacy of an in vivo clinical dose of Ampion, the number blood monocytes in the 
bloodstream provides a means of estimating the concentration of immune cells in circulation. 
Based on the average monocyte density in an adult human bloodstream (Sharma, 2018, 
Healthline.com), and the ratio of cells used in the Ampion TNFα bioassay, a therapeutic dose 
range of Ampion (250 – 1187cc) would be required to achieve the anti-inflammatory effect.  
The proposed dose for this study is the lowest possible effective dose of 250cc a day and is 
the dose used in a previous phase I study.  
 
10%
20%
30%
40%
0
10
20
30
40
TNFα Inhibition (%)
Drug Dilution Factor
Ampion Treatment

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2.5 
Benefit and Risk Assessment 
Patients with COVID-19 may be at a high risk of progressing to life-threatening, critical 
disease. Ampion may provide a safe and effective treatment option for these patients.  
 
The anticipated risks of IV Ampion treatment are considered low and are based on IV use in 
COVID-19 patients, decades of use of IV HSA in severely ill patients, and other indications 
(arthritis). Theoretical risks come from historical use of IV HSA, including rare allergic 
reactions and facial flushing. The product is a derivative of human plasma, however based on 
effective donor screening and product manufacturing processes, it carries an extremely remote 
risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob 
Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases 
or CJD have been identified for 5% HSA or Ampion.  
 
Given the well-describe safety profile of 5% HSA and the lack of therapeutic options targeted 
for severe and critical COVID-19 patients, the overall benefit-risk assessment of this study is 
considered favorable. As an immunomodulatory drug, Ampion may interrupt the inflammatory 
cascade for COVID-19 patients with respiratory distress which could improve clinical 
outcomes. 

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3 
STUDY DESIGN 
3.1 
Study Design Overview 
This is a Phase II randomized, double-blinded, placebo-controlled study to evaluate the safety 
and efficacy of IV Ampion in participants with COVID-19 who require supplemental oxygen. 
Interested COVID-19 patients will sign the appropriate informed consent document(s) prior to 
completion of any procedures. The investigator will review inclusion and exclusion criteria 
prior to any invasive procedures. If the patient is eligible after this review, the site will perform 
the necessary, if any, study procedures to confirm eligibility.  
Participants will be randomized 1:1 to active or placebo using a random allocation sequence 
stratified by disease severity. The general sequence of events during the treatment and 
assessment period: 
• Complete baseline procedures and sample collection. 
• Participants are randomized to Ampion or placebo. 
• Participants receive study intervention (active or placebo) through IV infusion for 5 days. 
• Complete safety monitoring, study procedures, and sample collection through Day 60. 
All subjects receiving test product will also receive the standard of care (SOC) for COVID-19, 
which includes:  
• Oxygen administration to maintain oxygen saturation of 90% or greater. 
• Nursing physical that may include review of neurological; pulmonary; cardiac; 
gastrointestinal; and urinary assessment at least daily during treatment. 
• Vital monitoring (heart rate, blood pressure, temperature, respiratory rate, SpO2) at least 
daily during treatment. 
• Telemetry monitoring to evaluate heart rhythm and rate.  
• Diet as tolerated to satisfy nutritional needs. 
• Treatments for COVID-19 symptoms including antibiotics, cough suppressants/ 
expectorants, anti-coagulants, fever reducers/pain killers, anti-nausea drugs, and/or 
bronchodilators.  
• Treatments for COVID-19 as approved by the FDA including expanded access, 
emergency, or compassionate use (i.e., remdesivir, dexamethasone, convalescent 
plasma). 
• Medications will be recorded as concomitant medication, tabulated, and compared 
among groups.  
The clinical effects, safety, and tolerability of treatment will be evaluated from baseline 
through Day 60. Evaluations at screening and during the 5-day treatment occur in person. 
Evaluations after the 5-day treatment to the end of the study (days 7 to 60) will typically occur 
via telephone contact unless the patient is in an inpatient setting.  

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3.2 
Study Objectives 
3.2.1 
Primary Objective 
The primary trial objective is to evaluate the effect of Ampion on the prevention of need for 
mechanical ventilation or death in adult participants with respiratory distress due to COVID-
19. 
3.2.2 
Secondary Objectives 
The secondary trial objectives evaluate the efficacy of IV Ampion versus control in improving 
the clinical course and outcomes of participants with COVID-19 who require supplemental 
oxygen. 
3.3 
Study Endpoints 
3.3.1 
Primary Endpoint 
The primary endpoint assesses the effect of Ampion compared to placebo on the prevention of 
need for mechanical ventilation or death. This is measured as the occurrence of participants on 
mechanical ventilation or death by Day 28. 
3.3.2 
Secondary Endpoints 
Secondary efficacy endpoints assess the effect of IV Ampion compared to SOC on the clinical 
outcomes for participants with COVID-19 who require supplemental oxygen as follows: 
 
Objective 
Endpoint 
Secondary Endpoints 
Assess the effect of Ampion compared to 
placebo on safety 
• Incidence of adverse events (AEs) and serious adverse events 
(SAEs) from baseline to Day 60. 
Assess the effect of Ampion compared to 
placebo on hospital stay  
• Hospital length of stay (LOS) from admission to discharge. 
Assess the effect of Ampion compared to 
placebo on oxygen use 
• Duration of oxygen use, blood oxygen saturation, and 
oxygen flow rate from baseline through Day 5. 
Assess the effect of Ampion compared to 
placebo on duration of respiratory failure 
to ventilator-free days 
• Percentage of participants who progress to respiratory failure 
(i.e., need for mechanical ventilation, ECMO, non-invasive 
ventilation) by Day 28. 
Assess the effect of Ampion compared to 
placebo on intensive care  
• Percentage of participants who require Intensive Care Unit 
(ICU) admission by Day 28. 
• ICU-free days through Day 28. 
• ICU LOS from ICU admission to discharge. 
Assess the effect of Ampion compared to 
placebo on clinical improvement 
• Change in ordinal scale from baseline through Day 7. 
• Change in ordinal scale from baseline to hospital discharge 
or Day 14 (whichever occurs first). 

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Objective 
Endpoint 
• Change in ordinal scale from baseline to hospital discharge 
or Day 28 (whichever occurs first). 
Assess the effect of Ampion compared to 
placebo on clinical health 
• Change in NEWS2 score from baseline through Day 5. 
• Change in NEWS2 score from baseline to hospital discharge. 
Assess the effect of Ampion compared to 
placebo on oxygen use 
• Duration of oxygen use, blood oxygen saturation, and 
oxygen flow rate from baseline through Day 5. 
3.4 
Blinding and Randomization 
The treatment in this study will be blinded to the subjects, investigators, any individual 
conducting the study (e.g., nursing and pharmacy staff) and clinical study personnel. 
Participants will be assigned to treatment by a randomization schedule developed and 
maintained by an independent statistician. 
Participants are randomized to active or control, following an equal allocation to treatment 
arms, stratified by COVID-19 disease severity (severe or critical as defined in Section 4.4). 
Study drug and placebo will be provided as blinded investigational product (IP) with 
appropriate labeling to link to the randomization code. Where required, safety personnel and/or 
investigator may be unblinded to a particular subject’s treatment assignment to meet reporting 
requirements to Regulators. 
A data management plan and statistical analysis plan will be approved by the sponsor prior to 
unblinding study data. 
3.5 
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be established to review the safety of IV 
Ampion as the study progresses. The DSMB will be primarily responsible for reviewing any 
serious Adverse Event (SAE) and other clinically important safety findings (e.g., 
discontinuations due to AEs) that may occur during the study.  
3.6 
Stopping rules 
The entire study may be stopped under defined circumstances as outlined in Section 6. 

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4 
SELECTION OF PARTICIPANTS 
4.1 
Number of Participants 
The trial is designed to enroll up to approximately 200 patients across two treatment arms 
(active or control), with a 100 subjects per arm, randomized 1:1 using a random allocation 
sequence stratified by COVID-19 disease severity (severe or critical). An interim analysis of 
the data is planned after 30 subjects (n=15 subjects per arm) to evaluate the relative effect. At 
the interim analysis, the sample size may be re-estimated to determine the additional number 
of patients for adequate power up to the 200 subjects. 
 
The number of participants is selected based on the effects observed for the primary endpoint. 
A study recently reported in Lancet Respiratory Medicine with 243 hospitalized patients 
receiving the placebo for COVID-19 found 22% did not achieve day 28 ventilation-free 
survival (Lancet Respir Med 2021; https://doi.org/10.1016/S2213-2600(21)00494-X). In the 
AP-014 study, a lower rate (8%) was observed for subjects receiving inhaled Ampion. 
Assuming the same proportions  (8% for Ampion and 22% for control) by Day 28, with 100 
subjects per group, a two-sided 5% significance level, and using a z-test with unpooled 
variances, then under binomial enumeration the power to detect this difference is about 81.3%.  
 
4.2 
Recruitment Methods 
Subjects will be recruited from the population being seen by Investigators at the clinical sites 
participating in the study. 
4.3 
Participant Characteristics 
The participant population are those infected with SARS-CoV-2 that have developed severe or 
critical symptoms consistent with COVID-19 and require supplemental oxygen to maintain 
blood oxygen saturation levels. Treatment of COVID-19 depends on the stage and severity of 
disease with a hyperinflammatory state observed in the moderate to severe stages that are 
thought to lead to clinical respiratory complications and critical COVID-19 (Gandhi 2020). 
Treatment with immunomodulators at this point in the disease may be more effective than anti-
viral treatments.  
The population of participants with COVID-19 who require supplemental oxygen were 
selected for this study to evaluate the efficacy of Ampion as an immunomodulatory therapy 
that may improve the clinical outcome of the disease and may reduce mortality. 

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4.4 
Inclusion Criteria 
Patients should fulfill all the following inclusion criteria:  
1. Male or female, ≥ 18 years old. 
2. Diagnosed with COVID-19, as evaluated by laboratory diagnostic test or diagnosis based 
on radiological clinical findings.  
3. Baseline severity categorization of severe or critical COVID-19 infection per FDA 
Guidance for developing drugs and biological products for COVID-19 (February 2021): 
a) Severe COVID-19: 
• Symptoms suggestive of severe systemic illness with COVID-19, which could 
include shortness of breath or respiratory distress 
• Clinical signs indicative of severe systemic illness with COVID-19, such as 
respiratory rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room 
air at sea level (SpO2 ≤ 90% at altitude) or PaO2/FiO2 < 300 
b) Critical COVID-19: 
• Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered 
via reinforced cannula at flow rates > 20 L/min with fraction of oxygen ≥ 0.5) or 
• Non-invasive mechanical or endotracheal mechanical ventilation 
4. Informed consent obtained from the patient or the patient’s legal representative. 
4.5 
Exclusion Criteria 
Patients fulfilling one or more of the following criteria may not be enrolled in the study: 
1. As a result of the medical review and screening investigation, the Principal Investigator 
considers the patient unfit for the study and/or progression to death is imminent and 
inevitable irrespective of the provision of treatments. 
2. Clinical diagnosis of respiratory failure (therapy not able to be administered in setting 
of resource limitation).  
3. Shock defined by systolic blood pressure <90 mm Hg, or diastolic blood pressure <60 
mm Hg or requiring vasopressors. Vasopressor therapy is exclusionary if used to treat 
shock. Subjects receiving low dose vasopressors to maintain renal perfusion are 
eligible. 
4. Multi-organ dysfunction/failure.  
5. Patient has severe chronic obstructive or restrictive pulmonary disease (COPD) (as 
defined by prior pulmonary function tests), chronic renal failure (only exclusionary if 
subject is currently on renal replacement therapy, i.e., subjects receiving peritoneal 
dialysis, hemodialysis, ultrafiltration are ineligible), or significant liver abnormality 
(e.g., cirrhosis, transplant, etc.). 
6. Patient has chronic conditions requiring chemotherapy or immunosuppressive 
medication (only exclusionary if subject is currently receiving a high dose or therapy 
for transplantation, e.g., subjects receiving low dose inhaled or oral steroids for asthma 
are eligible). 

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7. A history of allergic reactions to human albumin (reaction to non-human albumin such 
as egg albumin is not an exclusion criterion) or ingredients in 5% human albumin (N-
acetyltryptophan, sodium caprylate). 
8. Prolonged QT interval. 
9. Patient has known pregnancy or is currently breastfeeding. 
10. Patient planning to become pregnant, or father a child, during the treatment and follow-
up period and/or is not willing to remain abstinent or use contraception.  
11. Participation in another clinical trial (not including treatments for COVID-19 as 
approved by the FDA through expanded access, emergency, or compassionate use), or 
participation in a trial such that enrollment in this study would fall within the time 
frame of the half-life of the other investigational product(s). 
4.6 
Inclusion of Patients Incapable of Giving Informed Consent 
Patients who are not sedated or otherwise cognitively impaired may be capable of giving 
informed consent. In the remaining cases, patients will be enrolled in the study via their legally 
authorized representative (LAR) by telephone or in person. Enrolled via LAR by telephone 
requires confirmation of enrollment by two clinicians (e.g., registered nurse or physician).    

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5 
STUDY PLAN, PROCEDURES, AND ASSESSMENTS 
5.1 
Description of Study Visits 
The mortality, clinical effects, safety, and tolerability of treatment will be evaluated from 
baseline through Day 60. Evaluations at screening and during the 5-day treatment occur in 
person. Evaluations after the 5-day treatment to the end of the study (days 6 to 60) will typically 
occur via telephone. The Schedule of Assessments is shown in Section 1.2.  
5.1.1 
Screening (-3 Days to Day 0) 
The following procedures will be performed at Screening: 
• Evaluate all inclusion and exclusion criteria to ensure that patients meet all inclusion 
criteria and none of the exclusion criteria. 
• Medical history, pre-existing conditions, and comorbidities. Include the symptom onset 
date for COVID-19 symptoms and date of COVID-19 test. 
• Diphenhydramine, hydroxychloroquine, and azithromycin all prolong the cardiac QT 
interval, increasing risk of fatal cardiac arrhythmia. Therefore, severely-ill subjects 
receiving multiple drugs that prolong QT intervals will be reviewed carefully by the P.I. 
on a case-by-case adjudication for benefit-risk ratio and close cardiovascular monitoring. 
Note, subjects who have baseline QT prolongation are excluded from this study. 
• Obtain informed consent before the starting any study specific procedures, including 
COVID testing. 
5.1.2 
Baseline (Day 0)  
The following procedures will be performed at Baseline (first assessment prior to treatment): 
• Confirm eligibility (review inclusion/exclusion criteria). 
• Randomize patient to study arm.  
• Demographics (age, sex, race, height and weight) 
• Concomitant medications/therapies 
• Vital signs: heart rate, systolic and diastolic BP, body temperature, respiratory rate 
• SpO2 and supplementation oxygen mode/flow rate 
• ECG monitoring (telemetry) or 12-lead ECG: record aberrant changes in waves/ intervals  
• Hematology, biochemistry tests  
• Cytokine and chemokine assays  
• Ordinal scale and NEWS2 assessments 
• AEs 
5.1.3 
Treatment Period (Day 1 to Day 5) 
The following procedures will be performed during the Treatment Period (Day 1 to Day 5): 
• Administer Ampion or placebo as a daily IV infusion. Begin treatment within 6 hours of 
randomization. 
• Concomitant medications/therapies 

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• Vital signs: heart rate, systolic and diastolic BP, body temperature, respiratory rate – vital 
signs are collected shortly after (within 30 minutes) treatment.  
• SpO2 and supplementation oxygen mode/flow rate 
• ECG monitoring (telemetry) or 12-lead ECG: record aberrant changes in waves/ intervals 
– monitored as needed for patients who have abnormal readings or events requiring 
measurements. 
• Hematology, biochemistry tests – these tests are performed at baseline and every other 
day through treatment and through hospital stay unless an abnormal value is observed. 
In the case of an abnormal lab result, continue to collect and test those samples to follow 
subject through resolution. 
• Cytokine and chemokine assays – these tests are performed at baseline and at Day 5. 
• Ordinal and NEWS2 assessments 
• AEs 
5.1.4 
Hospitalization Period, as applicable (Day 6 through Day 7) 
Hospitalization refers to hospital and/or in-patient settings. The following procedures will be 
performed for the remainder of the hospitalization, as applicable: 
• Concomitant medications/therapies 
• Vital signs: heart rate, systolic and diastolic BP, body temperature, respiratory rate 
• SpO2 and supplementation oxygen mode/flow rate 
• ECG monitoring (telemetry) or 12-lead ECG: record aberrant changes in waves/ intervals 
– monitored as needed for patients who have abnormal readings or events requiring 
measurements. 
• Hematology, biochemistry tests – these tests are performed at baseline and every other 
day through treatment and through hospital stay unless an abnormal value is observed. 
In the case of an abnormal lab result, continue to collect and test those samples to follow 
subject through resolution. 
• Cytokine and chemokine assays – these tests are performed at hospital discharge. 
• Ordinal scale and NEWS2 assessments 
• AEs 
5.1.5 
Post-Treatment Follow-Up (Days 28, 60)  
The following procedures will be performed at all follow-up visits (Days 28, 60): 
• Mortality 
• Concomitant medications/therapies 
• Hospital LOS 
• ICU LOS 
• Ordinal scale and NEWS2 assessments  
• AEs 

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5.2 
Assessment Methods 
Demographic Data 
Demographic data will be collected from medical records: age, gender, race, height and weight, 
comorbidities. 
Medical History 
Medical history and pre-existing conditions will be collected from medical records. 
Concomitant Medications 
Concomitant medications will be collected from the medical records: prior (pre-
hospitalization) concomitant medications, in-patient concomitant medications. 
Mortality 
All-cause mortality will be recorded at hospital discharge, Days 28 and 60, as applicable. Cause 
of mortality will be assessed and documented. All-cause mortality is calculated for the primary 
endpoint as the percentage of participants with a successful outcome (life) or unsuccessful 
outcome (death). 
Length of Stay (LOS) 
Due to the COVID-19 health emergency, the Centers for Medicare and Medicaid is temporarily 
allowing long-term care facilities not normally used as a resident’s room to accommodate beds 
and residents for care in emergencies/situations needed to help with surge capacity. Therefore, 
hospitalization refers to hospital and/or inpatient care during the COVID-19 health emergency. 
Inpatient care may include hospitals treating COVID-19 patients; dedicated COVID-19 
treatment facilities with 24/7 care; and/or dedicated research facilities with 24/7 care. 
 
Dates of hospitalization and ICU admission as well as discharge dates will be recorded at 
hospital discharge, Days 28 and 60, as applicable. The hospital LOS and ICU LOS will be 
calculated as follows: 
• ICU admission: defined (in days) as the first study day when ICU status is changed to 
“yes” minus baseline date + 1 
• Hospital LOS: is defined (in days) as the date of hospital discharge minus date of 
hospital admission + 1 
• ICU LOS: defined (in days) as the date moved out of ICU minus first study date when 
ICU admission changed to “yes” + 1 
Oxygen Use 
Oxygen use measured as blood oxygen saturation (SpO2) and oxygen flow rate (liters per 
minute, lpm) will be recorded at every visit from baseline to Day 5.  

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Intubation/Extubation 
Date and time of intubation/extubation and days on ventilator will be recorded at hospital 
discharge, Days 28 and 60, as applicable. Proportion of participants who progress to respiratory 
failure (i.e., need for mechanical ventilation, ECMO, non-invasive ventilation, or high-flow 
nasal cannula oxygen) will be evaluated. 
Vital Signs 
Vital signs will be collected daily during the treatment period and at follow-up visits from 
medical records as follows: heart rate (or pulse rate), systolic BP, diastolic BP, body 
temperature (⁰F in the US, ⁰C out of the US), respiratory rate. Vital signs are collected shortly 
after (within 30 minutes) treatment. 
Hematology 
Hematology lab tests will be collected from the medical records at baseline and every other 
day through treatment and hospital stay (as applicable) unless an abnormal value is observed. 
In the case of an abnormal lab result, continue to collect and test those samples to follow subject 
through resolution. 
The follow hematology labs are tested: white cell count, red blood cell count, hemoglobin, 
hematocrit, mean cell volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin 
concentration (MCHC), platelets, neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils. 
Serum Biochemistry 
Biochemistry lab tests will be collected from the medical records at baseline and every other 
day through treatment and hospital stay (as applicable) unless an abnormal value is observed. 
In the case of an abnormal lab result, continue to collect and test those samples to follow subject 
through resolution. 
The following biochemistry lab tests are tested: sodium, potassium, chloride, bicarbonate, urea, 
creatinine, glucose, total calcium, phosphate, ferritin, high-sensitivity C-reactive protein (hs-
CRP), protein, albumin, globulins, total bilirubin, alkaline phosphatase (ALP), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). 
Cytokine and Chemokine Assays 
Cytokine and chemokine assay lab test results will be collected and recorded before and after 
treatment (at baseline and again at Day 5 and at hospital discharge). A cytokine panel is tested 
to include, but not limited to: Tumor Necrosis Factor alpha (TNFα), interferon gamma (IFNγ), 
Interleukin 1 beta (IL-1β), interleukins (IL-6, IL-8, IL-10, IL-12). Data is reported for research 
purposes, and the sample is destroyed after data is collected.  
Ordinal Scale for Clinical Improvement 
The clinical status will be recorded at every visit from baseline to Day 60 using the World 
Health Organization (WHO) “Ordinal Scale for Clinical Improvement”. This 8-point ordinal 

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scale was created to be responsive to the eligible patient population, intervention, and course 
of illness of COVID-19. The following is scores are collected: 
Score 
Descriptor 
0 
No clinical or virological evidence of infection 
1 
No limitation of activities 
2 
Limitation of activities 
3 
Hospitalized, no oxygen 
4 
Hospitalized, oxygen by mask or nasal prongs 
5 
Hospitalized, non-invasive ventilation or high-flow oxygen 
6 
Hospitalized, mechanical ventilation 
7 
Hospitalized, ventilation + additional organ support – pressors, RRT, ECMO 
8 
Death 
NEWS2 Score for Determining the Degree of Illness 
The NEWS2 will be calculated using the oxygenation requirement (room air or supplemental 
oxygen), SpO2 level, and vitals (body temperature, respiratory rate, heart rate and blood 
pressure) collected during study visits. The NEWS2 score is recommended by the National 
Institute for Health and Care Excellence (“NICE”) for managing COVID-19 patients.  
Adverse Events 
Any documented adverse event. These include but are not limited to the following: cardiac 
injury, arrhythmia, septic shock, liver dysfunction, acute kidney injury, and multi-organ 
failure. 

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6 
DISCONTINUATION CRITERIA 
6.1 
Early Discontinuation of the Study 
Discontinuation or temporary suspension is allowed for any reason. The Sponsor may suspend or 
terminate the study due to the development of any new or unexpected life threatening or adverse 
events, prolonged hospitalization, or other potential grounds for stopping the study. The number 
of subjects, as well as the types and the grade severity of the adverse events (according to Common 
Terminology Criteria for Adverse Events (CTCAE)) may trigger the temporary suspension of 
study product administration pending a safety investigation as follows: 
If any infusion reactions of grade 3 and above (as defined using the CTCAE grading scale version 
5.0 or newer) are observed in any patient within 24 hours of product administration, a safety 
investigation will occur, which may trigger the temporary suspension of study product 
administration. 
It is agreed that for reasonable cause, either the investigator or the Sponsor may terminate this 
study, provided written notice is submitted at a reasonable time in advance of intended termination; 
if by the investigator notice is to be submitted to Ampio Pharmaceuticals, Inc., and if by the 
Sponsor, notice will be provided to each investigator. 
If a severe local reaction or drug-related SAE occurs at any time during the study, the DSMB will 
review the case immediately. 
The study will be immediately suspended and no additional Ampion treatments administered 
pending review and discussion of all appropriate study data by the DSMB if one or more 
participants develop any of the following adverse events deemed to be possibly, probably, or 
definitely related to Ampion by the Investigator and/or Medical Monitor, based upon close 
temporal relationship or other factors: 
• Death 
• Respiratory deterioration requiring extracorporeal membrane oxygenation (ECMO) 
• Anaphylaxis 
• Acute adverse reaction at administration of treatment (i.e., sudden change in vital signs)  
The study will not be restarted until all parties have agreed to the course of action to be taken and 
the IRB/EC has been notified. 
6.2 
Early Discontinuation of Individual Participants 
Discontinuation of individual participants is allowed for any reason. Evaluations of participants 
who discontinue the study early are described in the Schedule of Assessments in Section 1.2. 

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7 
TREATMENT 
All participants will receive the standard of care for COVID-19. Participants randomized to the 
active arm will receive Ampion as an IV infusion daily for five days. Participants randomized to 
the control arm will receive placebo as an IV infusion daily for 5 days. 
Patients will be allocated to a sequentially numbered treatment in accordance with the 
randomization schedule following confirmation of eligibility and before treatment. 
7.1 
Dosing and Administration of Study Medication 
Ampion treatment will be provided as a solution in IV bags ready for human use and treatment 
administration. Appropriately trained site personnel will administer the study treatment. Treatment 
should start within 6 hours of randomization and should terminate on the 5-day treatment period.   
Participants will receive a daily dose (250cc/day) of study intervention (active or placebo) through 
IV delivered in two equally divided doses of 125cc, every 12 hours, for 5 days. Treatment should 
commence within 6 hours of randomization. Treatment should terminate at the end of the 5-day 
treatment period, or when a patient is discharged, whichever comes first.  
 
Treatment (active or control) will be administered on an infusion pump through an existing 
intravenous access (central line, PICC, peripheral, or saline lock). Treatment may be administered 
as an intravenous piggy-back/secondary if the subject has an existing primary infusion. If there are 
no IV fluids being administered at the time of the treatment infusion, Treatment will be infused as 
an intermittent intravenous infusion. Ampion will be administered undiluted at an infusion rate of 
100cc/hour. 
 
Participants will be monitored for any respiratory and/or cardiac distress via vital sign monitoring 
including respiratory rate, heart rate, and blood pressure shortly after (defined as within 30 minutes 
from the end of the infusion) study product administration. 
 
Product administration may be temporarily suspended until resolution of any of the following 
criteria: acute change in vital signs that require intervention and/or support; sudden decrease in 
oxygen until stabilization occurs and/or consideration of mechanical ventilation depending on 
severity; and/or infusion reaction. The nature of the event will be evaluated (i.e., allergic; localized; 
systemic or otherwise) and appropriate measures applied, which may include symptomatic 
treatment with antihistamines and antiallergic measures, paracetamol (acetaminophen), 
corticosteroids, pressor, and/or removal and replacement of IV to another location to manage 
reactions if clinically indicated.  
 
As described in Section 6.1, if any infusion reactions of grade 3 and above (as defined using the 
CTCAE grading scale version 5.0 or newer) are observed in any patient within 24 hours of product 
administration, a safety investigation will occur, which may trigger the temporary suspension of 
study product administration. 
 

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7.2 
Study Medication Storage and Accountability 
Investigational product should be stored at room temperature (59º – 77ºF or 15º – 25ºC) in a secure 
area with restricted access. The Investigator, the clinical site pharmacist, or other personnel 
authorized to store and dispense investigational product is responsible for ensuring that the 
investigational product used in the clinical study is securely maintained as specified by the Sponsor 
and in accordance with the applicable regulatory requirements. 
All investigational product is to be dispensed in accordance with the Investigator’s prescription. 
It is the Investigator’s responsibility to ensure that an accurate record is maintained of 
investigational product issued. All investigational product not used during the study must be 
returned to Ampio Pharmaceuticals Inc., or designated representative after study completion. 
If any quality issue is noticed upon the receipt or use of an investigational product (i.e., deficiencies 
in condition, packaging, appearance, associated documentation, labeling, expiry date, etc.), Ampio 
Pharmaceuticals, Inc. must be promptly notified. 
Under no circumstances may the Investigator supply investigational product to a third party, allow 
the investigational product to be used other than as directed by this clinical study protocol, or 
dispose of investigational product in any other manner. 
7.3 
Concomitant Treatments  
Any medication used during the study should be recorded. The start and stop dates, total daily 
dose, route of administration, and indication for all concomitant medications should be recorded.  
7.4 
Treatment Compliance 
Compliance with the investigational product use will be documented. 

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8 
ADVERSE EVENTS 
8.1 
Definition of an Adverse Event 
An adverse event (AE) is defined as any undesired medical occurrence in a patient or clinical 
investigation patient receiving a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable sign and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporarily associated with the 
use of a study drug, whether or not related to the study drug. 
Assessment of severity of an AE will be rated according to the following categories: 
Grade 1 (MILD): 
The symptom is barely noticeable to the study patient and does not influence performance or functioning.  
Concomitant medication is not ordinarily indicated for relief of mild AEs. 
Grade 2 (MODERATE): 
The symptom is of sufficient severity to make the study patient uncomfortable and to influence performance of 
daily activities.  Concomitant medication may be indicated for relief of moderate AEs. 
Grade 3 (SEVERE): 
The symptom causes severe discomfort, sometimes of such severity that the study patient cannot continue in the 
study.  Daily activities are significantly impaired or prevented by the symptom. Concomitant medication may be 
indicated for relief of severe AEs. 
 
Determination of the relationship between the AE and the study drug will be made using the 
following guidelines: 
Unrelated 
The adverse event is unlikely to have been caused by study drug. 
Possibly related 
It is unclear whether the adverse event may have been caused by the study drug.  
Related 
The adverse event is likely to have been caused by study drug.  
 
8.2 
Definition of a Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence that occurs at any dose that: 
• Results in death 
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in any congenital anomaly/birth defect 
 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment or blood dyscrasias or convulsions that do not result in in-patient 
hospitalization. 

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Hospitalizations for elective surgery or other medical procedures that are not related to a treatment-
emergent AE are not considered SAEs. 
8.3 
Recording of Adverse Events and Serious Adverse Events 
Recording and reporting of adverse events should be in accordance with the FDA's final “Guidance 
for Industry and Investigators Safety Reporting Requirements for INDs and BA/BE Studies” of 
December 2012. 
Any AE is to be recorded in the eCRF.  In order to avoid vague, ambiguous, or colloquial 
expressions, the AE should be recorded in standard medical terminology rather than the patient’s 
own words.  Whenever possible, the investigator should combine signs and symptoms that 
constitute a single diagnosis. 
The existence of an AE may be concluded from a spontaneous report of the patient; from the 
physical examination; or from special tests e.g., laboratory assessments, where applicable, or other 
study-specified tests (source of AE). 
The reporting period begins from the time that the patient is randomized through index 
hospitalization until discharge or death, whichever should occur first. Any events continuing at 
study exit will be followed for 30 days or to resolution, or until no improvement is expected, 
whichever comes first. Any SAE occurring after the reporting period must be promptly reported if 
a causal relationship to the investigational drug is suspected.  If the patient begins a new therapy, 
the safety reporting period ends at the time the new treatment is started, however, death must 
always be reported when it occurs during the study period irrespective of intervening treatment. 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug.  The action taken and the outcome must also be recorded. 
8.3.1 
AE Follow up 
All AEs occurring during the study are to be followed up in accordance with good medical practice 
until they are resolved, stabilized or judged no longer clinically significant or, if a chronic 
condition, until fully characterized.  Any AEs that are considered drug-related (possibly related, 
definitely related) must be followed for 30 days, or to resolution, or until no improvement is 
expected, whichever occurs first. 
8.3.2 
Overdose 
No information on treatment of overdose of Ampion is currently available.  In the case of 
overdose the patient should be followed as for an AE and appropriate supportive medical 
treatment instigated. 

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8.4 
Serious Adverse Event Reporting 
8.4.1 
Reporting Requirements 
Unexpected serious suspected adverse reactions are subject to expedited reporting to FDA. All 
SAEs must be entered into the eCRF within 24 hours of first knowledge of the event by study 
personnel.  The investigator must provide his/her assessment of the relationship to study drug at 
the time of the initial report.  The entry of an SAE into the eCRF triggers an automatic alert to the 
clinical research organization (CRO) safety team.  The following information must be reported: 
• Protocol number 
• Site and/or Investigator number 
• Patient number 
• Demographic data 
• Brief description of the event 
• Onset date and time 
• Resolution date and time, if the event resolved 
• Current status, if event not yet resolved 
• Any concomitant treatment and medication 
• Investigator’s assessment of whether the SAE was related to Investigative product or not. 
 
The CRO Safety Associate will contact the site for clarification of data entered onto the eCRF, or 
to obtain missing information.  In the event of questions regarding SAE reporting, the site may 
contact the appropriate individual as in Section 8.4.2. 
8.4.2 
SAE Contact Information 
Ampio Pharmaceuticals Inc, or their designee CRO, is responsible for submitting reports of AEs 
associated with the use of the drug that are both serious and unexpected to FDA according to 21 
CFR 312.32 and the final guidance (2012). All investigators participating in ongoing clinical 
studies with the study medication will receive copies of these reports for prompt submission to 
their Institutional Review Board (IRB) or Ethics committee (EC). 

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9 
STATISTICAL METHODS 
9.1 
General Considerations 
This section describes the rules and conventions to be used in the presentation and analysis of the 
data. The details of all these analyses will be presented in the Statistical Analysis Plan. 
This trial is designed for approximately 200 patients across two treatment arms (active or control), 
with a 100 subjects per arm, randomized 1:1 using a random allocation sequence equally stratified 
by COVID-19 disease severity.  
The number of participants is selected based on the effects observed for the primary endpoint, 
need for mechanical ventilation or death prior to day 28. A study recently reported in Lancet 
Respiratory Medicine with 243 hospitalized patients receiving the placebo for COVID-19 found 
22% did not achieve day 28 ventilation-free survival (Lancet Respir Med 2021; 
https://doi.org/10.1016/S2213-2600(21)00494-X). In the AP-014 study, a lower rate (8%) was 
observed for subjects receiving inhaled Ampion. Assuming the same proportions (8% for 
Ampion and 22% for control) by Day 28, with 100 subjects per group, a two-sided 5% 
significance level, and using a z-test with unpooled variances, then under binomial enumeration 
the power to detect this difference is about 81.3%. 
9.2 
Analysis Populations 
9.2.1 
Safety Analysis Population: 
The safety analysis population is defined as all patients who are randomized. Participants will be 
analyzed as treated. 
9.2.2 
Intent-to-treat Population: 
The intent-to-treat (ITT) analysis population is defined as all randomized patients. All efficacy 
analyses will be performed in the ITT population. Patients will be analyzed as randomized. 
9.2.3 
Interim Analysis 
This trial is designed to enroll up to approximately 200 subjects, randomized to active or control, 
following an equal allocation to treatment arms. An interim analysis of the data is planned after 30 
subjects (n=15 subjects per arm) to evaluate the relative effect. At the interim analysis, the sample 
size may be re-estimated to include additional subjects to attain adequate power up to a 200 total 
subjects. This will be conducted at an alpha level of 0.001 and thus the overall alpha level for the 
final test will be performed at α=0.047 instead of α=0.05. The sponsor also reserves the right to 
alter the final sample size if the assumptions of the death rates are not satisfied at this interim 
analysis.   
 
 

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9.3 
Data presentation 
9.3.1.1 
Demographic and Baseline Characteristics: 
Demographic (e.g., age, sex, race, ethnicity) and baseline characteristics (e.g., weight, height, 
comorbidities) summarized using descriptive statistics, overall and by treatment group for the ITT 
and safety analysis population. 
9.3.1.2 
Medical History and Physical Examination: 
The number and percent of participants with past and current medical disorders at the time of 
randomization will be presented overall and by treatment group for the ITT and safety analysis 
population. 
9.3.1.3 
Concomitant Medications or Treatments: 
The number and percent of subjects receiving concomitant medications or therapies prior to and 
during the study and at the final visit will be tabulated and presented overall and by treatment 
group for the ITT analysis population.  
Concomitant medications/treatments will be summarized using descriptive statistics and will be 
presented by type of drug (WHO DRUG classification) overall and by treatment group for the 
safety and ITT analysis populations. There should be no significant differences in the use of 
concomitant treatments between groups. All concomitant therapies will be recorded to be able to 
compare any inadvertent imbalances between the groups. 
9.3.1.4 
Safety Data: 
Safety data will be presented by treatment arm. Safety data will be evaluated by changes in vital 
sign measurements, laboratory assessments, and the frequency and severity of AEs. Concomitant 
medication will be recorded for safety. AEs will be collected from baseline to Day 60. The severity 
of AEs (mild, moderate, severe), relatedness (related, possibly related, unrelated) along with the 
duration, action taken, and outcome (e.g., study withdrawal) will also be recorded.   
All data collected under this study protocol will be included in the assessment of patient safety.  
Missing or incomplete AE data will assume greatest relationship to study drug and/or severity. 
Remaining safety data will be collected from enrollment though index hospitalization until hospital 
discharge (or in-hospital death). Safety data will be tabulated and presented overall and by 
treatment group for the safety analysis population. 
9.3.1.5 
Efficacy Data:  
The efficacy of treatment on the clinical course and outcome of COVID-19 will be evaluated by 
treatment arm. Summaries will be performed by severity (severe or critical), individually, and 
combined. 

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Unless otherwise specified, continuous variables will be summarized with the number of non-
missing observations, mean, standard deviation, median, minimum, maximum, and 95% 
confidence intervals displayed. Categorical data will be summarized as counts, percentages, and 
95% confidence intervals.  
9.4 
Study Endpoints 
9.4.1 
Primary Endpoint 
The primary endpoint assesses the effect of Ampion compared to placebo on the prevention of 
need for mechanical ventilation or death. This is measured as the occurrence of mechanical 
ventilation or death by Day 28. 
 
Let πA and πS represent the rate of this outcome for Ampion and control during the first 28 days 
after randomization. Then it is desired to demonstrate that the mechanical ventilation and death 
rate for Ampion is different than the corresponding rate for the control. Formally, this is presented 
as:  
H0: πA = πS versus HA: πA ≠ πS  
 
This will be tested utilizing the appropriate chi-square test or Fisher’s exact test utilizing PROC 
FREQ with the EXACT option, if necessary.  
9.4.2 
Secondary Endpoints  
Secondary efficacy endpoints assess the effect of IV Ampion compared to SOC on the clinical 
outcomes for participants with COVID-19 on supplemental oxygen. The secondary endpoints will 
be tested in a hierarchical manner in the order presented, and thus no adjustment to the alpha level 
is necessary: 
 
Objective 
Endpoint 
Secondary Endpoints 
Assess the effect of Ampion compared to 
placebo on safety 
• Incidence of adverse events (AEs) and serious adverse 
events (SAEs) from baseline to Day 60. 
Assess the effect of Ampion compared to 
placebo on clinical improvement 
• Change in ordinal scale from baseline through Day 7. 
• Change in ordinal scale from baseline to hospital 
discharge or day 14 (whichever occurs first). 
• Change in ordinal scale from baseline to hospital 
discharge or day 28 (whichever occurs first). 
• Change in NEWS2 score from baseline through Day 5. 
• Change in NEWS2 score from baseline to hospital 
discharge. 
• Modulation of cytokine levels from baseline to Day 5. 
Assess the effect of Ampion compared to 
placebo on duration of respiratory failure to 
ventilator-free days. 
• Percentage of participants who progress to respiratory 
failure (i.e., need for mechanical ventilation, ECMO, 
non-invasive ventilation) by Day 28. 

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Objective 
Endpoint 
Assess the effect of Ampion compared to 
placebo on intensive care  
• Percentage of participants who require Intensive Care 
Unit (ICU) admission by Day 28. 
• ICU-free days through Day 28. 
• ICU LOS from ICU admission to discharge. 
Assess the effect of Ampion compared to 
placebo on hospital stay  
• Hospital length of stay (LOS) from admission to 
discharge. 
• Hospital-free days through Day 28. 
Assess the effect of Ampion compared to 
placebo on oxygen use 
• Duration of oxygen use, blood oxygen saturation, and 
oxygen flow rate from baseline through Day 5. 
 
The efficacy endpoints will be evaluated to estimate the treatment effect and use descriptive 
statistics including mean, standard deviation, percentages, minimum/maximum, and 95% 
confidence intervals. All endpoints will be tabulated and presented by treatment arm, cohort 
(severe and critical), and timepoint. Where appropriate, data will be tabulated and presented 
cumulatively across cohorts and/or timepoints. 
 
All binary outcomes are single incident percentages and thus the differences between the treatment 
groups will be tested using Fisher’s exact test. The length of stay endpoints are also single incident 
endpoints the differences between the treatment groups will be tested using two sample t-test. All 
the other change from baseline variables are repeated assessments and will be analyzed utilizing a 
repeated measures analysis of variance. 
 
9.5 
Missing and Spurious Data 
All data collected under this study protocol will be included in the assessment of patient safety.  
Missing or incomplete AE data will assume greatest relationship to study drug and/or severity. 
For the effectiveness endpoint analysis of all-cause mortality at Day 28 and 60 a sensitivity 
analysis will be performed for all participants that have been discharged from the hospital, cannot 
be reached via telephone contact, and their death status is not known. The sensitivity analysis will 
be performed where missing mortality status at Day 28 and 60 will be replaced as having died. 

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10 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
10.1 Declaration of Helsinki 
The Principal Investigator will ensure that this Study is conducted in accordance with the most 
recent revision of the Declaration of Helsinki. 
10.2 Good Clinical Practice 
The Study will be conducted according to the study protocol and to Standard Operating Procedures 
(SOPs) that meet the guidelines provided by the International Conference on Harmonization (ICH) 
for Good Clinical Practice in clinical studies. 
10.3 Institutional Review Boards/Ethics Committees 
Before implementing this study, the protocol, the proposed patient informed consent forms and 
other information for the patients must be reviewed by a properly constituted committee or 
committees responsible for approving clinical studies. The IRB/IEC written signed approval 
letter/form must contain approval of the designated investigator, the protocol (identifying protocol 
title, date, and version number), and of the patient informed consent form (date, version). 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the Sponsor, the IRB/IEC, and the Health Authorities. 
10.4 Regulatory Authority Approval 
Before this study is implemented, the protocol must be approved by the relevant regulatory 
authority. 
10.5 Informed Consent 
The investigator must fully inform the patient or patient’s legally authorized representative of all 
pertinent aspects of the trial including the written information approved/favorably assessed by the 
IRB/IEC. 
Prior to the start of the pre-study examination, the written informed consent form must be signed 
and personally dated by the patient, or the patient’s legally authorized representative, and by the 
physician who conducted the informed consent discussion. One copy of the written information 
and signed consent form must be given to each patient or the patient’s legally authorized 
representative, and one (1) copy must be retained in the investigator's study records. 
10.6 Patient Confidentiality and Disclosure 
Data on patients collected on eCRFs during the trial will be documented in an anonymous fashion 
and the patient will only be identified by the patient number, and by his/her initials. If, as an 
exception, it is necessary for safety or regulatory reasons to identify the patient, all parties are 
bound to keep this information confidential. 

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The investigator will guarantee that all persons involved will respect the confidentiality of any 
information concerning the trial patients. All parties involved in the study will maintain strict 
confidentiality to assure that neither the person nor the family privacy of a patient participating in 
the trial is violated. Likewise, the appropriate measures shall be taken to prevent access of non-
authorized persons to the trial data. 
10.7 Collection, Monitoring and Auditing Study Documentation, and Data Storage 
10.7.1 
Collection of Data and Monitoring Procedures 
This study will use a 21 CFR Part 11 compliant electronic data capture system (EDC). An 
electronic case report form (eCRF) is used for data recording.  All data requested on the eCRF 
must be entered and all missing data must be accounted for. 
The data will be checked for completeness and correctness as it is entered by the real-time online 
checks applied by the EDC system. Off-line checks will also be run to perform any additional data 
review required.  Discrepancy reports will be generated accordingly and transferred to the study 
center for resolution by the investigator or his/her designee. 
Accurate and reliable data collection will be assured by verification and cross–check of the eCRF 
against the investigator’s records by the study monitor (source document verification), and the 
maintenance of a study drug–dispensing log by the investigator. 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Sponsor 
representative will review the protocol and case report forms with the investigators and their staff.  
During the study a monitor will visit the site regularly to check the completeness of patient records, 
the accuracy of entries on the case report forms, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment.  The monitor will ensure during on-site visits that study 
medication is being stored, dispensed and accounted for according to specifications.  Key trial 
personnel must be available to assist the monitors during these visits. 
The investigator must give the monitor access to relevant hospital or clinical records, to confirm 
their consistency with the case report form entries. No information in these records about the 
identity of the patients will leave the study center. Monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation 
of SAEs and the recording of primary efficacy and safety variables. Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. 
 
 

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10.7.2 
Auditing Procedure 
In addition to the routine monitoring procedures, the Sponsor or the regulatory authority can 
conduct an audit or an inspection (during the study or after its completion) to evaluate compliance 
with the protocol and the principles of Good Clinical Practice. 
The investigator agrees that representatives of the Sponsor and Regulatory Authorities will have 
direct access, both during and after the course of this study, to audit and review all study-relevant 
medical records. 
10.7.3 
Retention of Documents 
The investigator must maintain source documents for each patient in the study, consisting of all 
demographic and medical information, including laboratory data, and keep a copy of the signed 
informed consent form.  All information on case report forms must be traceable to these source 
documents in the patient's file.  Data without a written or electronic record will be defined before 
trial start and will be recorded directly on the case report forms, which will be documented as 
being the source data. 
10.8 Disclosure of Information 
All information provided to the investigator by Ampio Pharmaceuticals, Inc. or their designee, will 
be kept strictly confidential. No disclosure shall be made except in accordance with a right of 
publication granted to the investigator. 
No information about this study or its progress will be provided to anyone not involved in the 
study other than to Ampio Pharmaceuticals, Inc or its authorized representatives, or in confidence 
to the IRB, or similar committee, except if required by law. 
10.9 Discontinuation of the Study 
Ampio Pharmaceuticals, Inc., may terminate the study at any time upon immediate notice from 
the Sponsor to all investigators for any reason, including the Sponsor’s belief that discontinuation 
of the study is necessary for the safety of patients. 
10.10 Study Report, Publication Policy and Archiving of Study Documentation 
10.10.1 Study Report and Publication Policy 
Depending on the outcome of the study, an ICH-compliant integrated clinical and statistical report 
may be prepared upon completion of the study and data analysis. The results of the study may also 
be published in a relevant peer-reviewed journal, with authorship status and ranking designated 
according to the acknowledged contributions of participating investigators, institutions and the 
Sponsor. 

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10.10.2 Study Documents 
The investigator must maintain source documents for each patient in the study, consisting of all 
demographic and medical information, questionnaires, including laboratory data, etc., and keep a 
copy of the signed informed consent form. All information on the e-case report forms must be 
traceable to these source documents in the patient's file. Data without a written or electronic record 
will be defined before trial start and will be recorded directly on the e-case report forms, which 
will be documented as being the source data. 
10.10.3 Archiving of Documents 
Essential documents, as listed below, must be retained by the investigator for as long as needed to 
comply with national and international regulations. The Sponsor will notify the 
investigator(s)/institution(s) when the study-related records are no longer required. The 
investigator agrees to adhere to the document retention procedures by signing the protocol.  
Essential documents include: 
• IRB/IEC/REB approvals for the study protocol and all amendments 
• All source documents and laboratory records 
• CRF copies (electronic copies on a CDROM) 
• Patients' informed consent forms (with study number and title of trial) 
• FDA form 1572 
• Any other pertinent study document. 
 

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