A Randomized, Double-Blinded, Placebo-Controlled Phase I Study to Evaluate the Safety and Efficacy of Ampion in Patients With Prolonged Respiratory Symptoms Due to COVID-19 (Long COVID)
Phase: PHASE1
Conditions: Covid19
Sponsor: Ampio Pharmaceuticals. Inc.

 
 
 
 
A RANDOMIZED, DOUBLE‐BLINDED, 
PLACEBO‐CONTROLLED PHASE I STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF 
AMPION IN PATIENTS WITH PROLONGED 
RESPIRATORY SYMPTOMS DUE TO COVID‐
19 (LONG‐COVID) 
 
STUDY PROTOCOL 
 
STUDY NUMBER: AP‐018 
 
NCT04880161 
 
15 May 2021 

Ampion™ 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
Version 1.2, 15 May 2021 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL TITLE PAGE 
Protocol Title: 
A Randomized, Double-Blinded, Placebo-Controlled 
Phase I Study to Evaluate the Safety and Efficacy of 
Ampion in Patients with Prolonged Respiratory 
Symptoms due to COVID-19 (Long-COVID) 
Study Number: 
AP-018 
Investigational Product: 
Ampion 
Drug Development Phase: 
Phase I 
Indication: 
Prolonged Respiratory Symptoms due to COVID-19 
(Long-COVID) 
Route of Administration: 
Inhalation 
Regulatory Agency Identifier: 
IND 19828 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
373 Inverness Parkway 
Englewood, CO 80112 
Date: 
15 May 2021 
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-018 
Version 1.2, 15 May 2021 
CONFIDENTIAL 
Page 2 
PROTOCOL ATTESTATION 
I have read and understand the contents of this clinical protocol for Study Number AP-018 
dated 15 May 2021 and agree to meet all obligations of Ampio Pharmaceuticals Inc. as 
detailed in all applicable regulations and guidelines. 
Signed By: 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
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 I Study to Evaluate the Safety and 
Efficacy of Ampion in Patients with Prolonged Respiratory Symptoms due to COVID-19 (Long-
COVID) 
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, and has overwhelmed healthcare systems. Increasing numbers 
of people with COVID-19 are experiencing the lingering effects of COVID-19 and continue to 
have prolonged respiratory complications months after the onset of the disease, also known as 
Post-Acute Sequelae of SARS-CoV-2 (PASC), long-COVID, and/or long-hauler patients.  
The SARS-CoV-2 virus is transmitted through the respiratory system, which can cause a severe 
dysregulation of the immune response and damage in the lungs. Chronic, prolonged 
inflammation of the lungs maybe responsible for a myriad of continuing respiratory signs and 
symptoms post-infection, including cough, shortness of breath, chest discomfort, low exercise 
tolerance and low blood oxygen saturation.  
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 long-COVID patients. 
This study aims to evaluate the safety of Ampion and the clinical outcomes in patients with long-
COVID. This is the first study for at-home use of Ampion inhaled treatment for long-COVID 
patients and will be used to inform decisions for the clinical development of Ampion. 
Lead Investigator(s):   
Dr. Michael Barber MD 
Indication:   
Prolonged Respiratory Symptoms due to COVID-19 (Long-COVID) 
Number of Sites: 
Up to 5 sites 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
CONFIDENTIAL 
Page 4 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Number of Patients: 
Sample size is approximately 15 participants per treatment arm 
Treatment Groups:  
There are two planned treatment arms randomized 1:1, active to control: 
Treatment Arm 
Investigational Treatment 
Active 
Ampion Inhalation for 5-days 
Control 
Placebo Inhalation for 5-days 
 
Objectives and Endpoints:  
Objective 
Endpoint 
Primary 
Assess the effect of Ampion 
compared to placebo on safety 
• Incidence and severity of adverse events (AEs) and serious adverse 
events (SAEs) from baseline to Day 28  
Exploratory 
 
Assess the effect of Ampion 
compared to placebo on 
symptom improvement 
• Change in FDA Assessment of 14 Common COVID-19-Related 
Symptoms questionnaire from baseline to Day 7; Day 28; Day 60 
• Change in Borg Dyspnoea Scale (mBDS) from baseline to Day 7; Day 
28; Day 60  
• Change in all-cause mortality  
Assess the effect of Ampion 
compared to placebo on 
pulmonary function 
• Change in blood oxygen saturation from baseline to Day 7; Day 28; Day 
60 
• Change in six-minute walk test (6MWT) score from baseline to Day 7; 
Day 28; Day 60 
Assess the effect of Ampion 
compared to placebo on global 
impression 
• Change in Quality-of-Life Assessment using SF-36 from baseline to Day 
7; Day 28; Day 60  
• Change in Fatigue questionnaire from baseline to Day 7; Day 28; Day 60  
• Change in Sleep Disturbance questionnaire from baseline to Day 7; Day 
28; Day 60  
Assess the effect of Ampion 
compared to placebo on 
radiographic findings 
• Change in chest imaging on ground-glass opacity, local patchy 
shadowing, bilateral patchy shadowing, and/or interictal abnormalities 
from baseline to Day 60 
 
 
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
CONFIDENTIAL 
Page 5 
Study Design:   
Overall Design 
This is a Phase I randomized, double-blinded, placebo-controlled study in adult participants with 
prolonged respiratory symptoms due to COVID-19 (long-COVID). 
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 
inclusion/exclusion criteria prior to any study procedures. If the participant is eligible and 
interested after this review, the participant will sign the appropriate informed consent 
document(s) prior to completion of any study procedures. 
Double-Blind Treatment and Assessment 
Participants will be randomized 1:1 to active treatment or placebo control using a random 
allocation sequence. 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 
Ampion Inhalation for 5-day 
Control 
Placebo Inhalation for 5-days 
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) repeated daily for 5 days  
• Complete safety monitoring and data collection 
• Study visit types are described in the tables below: 
 
Study Day 
Visit Description 
Visit Type 
1 
Baseline safety/efficacy measures 
Conducted in outpatient clinic 
1-5 
Ampion inhalation treatment, safety measures 
Conducted at home 
7, 28, 60 
Post-treatment safety/efficacy measures 
Conducted in outpatient clinic 
Post-Treatment Follow-up 
Post-treatment follow-up will occur after Day 5 to assess clinical status and adverse events.  
Disclosure Statement 
This treatment study will be blinded to the investigator(s) and subject(s) 
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.  
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
CONFIDENTIAL 
Page 6 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Diagnosis and Main Criteria for Inclusion:  
1. Male or female adults: ≥ 18 years. 
2. Must have a clinical diagnosis of COVID-19 at least 4 weeks prior to the screening date, 
with at least one of clinical symptoms (e.g., fever ≥ 38°C, fatigue, cough) and a positive 
result by the reverse-transcription polymerase chain reaction (RT-PCR) testing or equivalent. 
3. Experiencing at least two COVID-19 respiratory symptoms with a score of two or higher 
using the FDA Assessment of 14 Common COVID-19-Related Symptoms questionnaire for 
at least 4 weeks (28 days) after initial positive COVID-19 diagnosis: cough, sore throat, 
runny/stuffy nose, shortness of breath (difficulties breathing), tightness of chest, low exercise 
tolerance. 
4. Able to bear weight and ambulate a minimum of 10 meters distance. 
5. Women of childbearing potential and their partner must agree to use at least one highly 
effective method of contraception (e.g., hormonal contraceptives [implants, injectables, 
combination oral contraceptives, transdermal patches, or contraceptive rings], intrauterine 
devices, bilateral tubal occlusion, or sexual abstinence) for the duration of the study. 
6. Informed consent obtained from the patient. 
Main Criteria for Exclusion: 
1. Subjects who require hospitalization. 
2. Patient has severe chronic obstructive or restrictive pulmonary disease (COPD) as defined 
by prior pulmonary function tests, chronic renal failure, or significant liver abnormality (e.g., 
cirrhosis, transplant, etc.). 
3. History of Chronic Fatigue Syndrome prior to COVID-19 infection. 
4. Patient is on chronic immunosuppressive medication. 
5. Patient requires surgery that could be life-threatening within the study window. 
6. 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-acetyl 
tryptophan, sodium caprylate). 
7. Patient has known pregnancy or is currently breastfeeding. 
8. 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). 
9. Clinically significant findings via electrocardiogram (ECG), including acute myocardial 
infarction, acute ischemic changes, atrial fibrillation, atrial flutter, paced rhythms in 
individuals who have undergone permanent pacemaker placement, evidence of prior 
infarction, unchanged stable conduction abnormalities e.g., right bundle branch block, or any 
other finding which does not significantly impact mortality. 
10. Pre-existing co-morbid condition(s) preventing outcome assessments, e.g. disease or 
condition that would prevent ability to transfer and walk for 6 minutes, prior to confirmed 
COVID-19 diagnosis (assisted walking devices are acceptable) 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
CONFIDENTIAL 
Page 7 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
11. As a result of the medical review and screening investigation, the Principal Investigator 
considers the patient unfit for the study. 
Test Product, Dose, and Mode of Administration: 
Participants in the active arm will inhale nebulized Ampion (8 mL) administered four times 
daily, every four to six hours, for 5 days. Nebulized drug will be delivered using the Aerogen 
Solo Nebulizer System with the Aerogen Solo Adaptor (FDA 510K K133360) manufactured by 
Aerogen Limited, Galway, Ireland. The Aerogen Solo Adaptor is a vibrating mesh nebulizer 
with a drug reservoir used for delivery of respiratory therapy, including the hand-held Aerogen 
Ultra. 
Medications will be recorded as concomitant medication, tabulated, and compared among 
groups. 
 
Reference Therapy, Dose and Mode of Administration: 
Participants in the control arm will inhale nebulized placebo (8 mL) administered four times 
daily for 5 days. Nebulized placebo will be delivered using the Aerogen Solo Nebulizer System 
with the Aerogen Solo Adaptor (FDA 510K K133360) manufactured by Aerogen Limited, 
Galway, Ireland. The Aerogen Solo Adaptor is a vibrating mesh nebulizer with a drug reservoir 
used for delivery of respiratory therapy, including the hand-held Aerogen Ultra. 
Medications will be recorded as concomitant medication, tabulated, and compared among 
groups. 
 
Study Duration:   
Treatment: 5 days 
Follow-up: 60 days 
 
 
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
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1.2 
Schedule of Assessments 
Visits will be conducted as described: 
 
Screening 
Treatment 
Post-Treatment Follow Up 
Study Day1 
-3 to 1 
12 
2 
3 2 
4 
5 2 
7 
 
28 
 
 
60 
 
Visit Window (+/- # days) 
-- 
-- 
-- 
-- 
-- 
-- 
3 
3 
3 
COVID-19 tests 
X 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history and pre-
existing conditions 
X 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Treatment1, 2 
 
X 
X 
X 
X 
X 
 
 
 
Health check1, 2 
 
X 
 
X 
 
X 
 
 
 
Blood oxygen saturation 
 
X 
 
 
 
 
X 
X 
X 
Assessment of 14 Common 
COVID-19-related symptoms 
questionnaire  
 
X 
 
 
 
 
X 
X 
X 
Borg Dyspnoea Scale 
(mBDS) 
 
X 
 
 
 
 
X 
X 
X 
Walk test 
 
X 
 
 
 
 
X 
X 
X 
Chest x-ray imaging 
 
X 3 
 
 
 
 
 
 
X 
Concomitant medications2 
 
X 
X 
X 
X 
X 
X 
X 
X 
Quality-of-Life Assessment 
SF-36 
 
X 
 
 
 
 
X 
X 
X 
PROMIS Fatigue 
questionnaire  
 
X 
 
 
 
 
X 
X 
X 
PROMIS Sleep Disturbance 
questionnaire  
 
X 
 
 
 
 
X 
X 
X 
Adverse events2 
 
X 
X 
X 
X 
X 
X 
X 
X 
1 Day 1, baseline assessments (health check, blood oxygen saturation, assessment of symptoms/questionnaires, mBDS, 
walk test, and chest x-ray) should occur before the first dose of treatment. These tests and the first dose of treatment 
will occur at the clinic. Treatment for the remainder of Day 1 and Days 2, 3, 4, 5 will occur at home.  
2 Day 1 post-first dose, Day 3 and Day 5 health check, concomitant medications and adverse event collection will occur 
via telephone visit. 
3 Baseline chest x-ray may be performed after Screening, up to 3 days prior to Day 1. 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
CONFIDENTIAL 
Page 9 
 
TABLE OF CONTENTS 
 
1 
PROTOCOL SUMMARY ............................................................................................ 3 
1.1 
Protocol Synopsis.................................................................................................... 3 
1.2 
Schedule of Assessments ........................................................................................ 8 
2 
INTRODUCTION ...................................................................................................... 13 
2.1 
Study Drug ............................................................................................................ 13 
2.2 
Background to the Disease.................................................................................... 14 
2.3 
Previous Human Experience ................................................................................. 14 
2.4 
Study Rationale ..................................................................................................... 15 
2.4.1 
Study Design ................................................................................................... 15 
2.4.2 
Study Background ........................................................................................... 15 
2.4.3 
Preclinical Data ............................................................................................... 16 
2.4.4 
Dosing Rationale ............................................................................................. 17 
2.5 
Benefit and Risk Assessment ................................................................................ 17 
3 
STUDY DESIGN........................................................................................................ 18 
3.1 
Study Design Overview ........................................................................................ 18 
3.2 
Study Objectives ................................................................................................... 18 
3.2.1 
Primary Objective ........................................................................................... 18 
3.2.2 
Secondary Objectives ...................................................................................... 18 
3.3 
Study Endpoints .................................................................................................... 18 
3.3.1 
Primary Endpoint ............................................................................................ 18 
3.3.2 
Exploratory Endpoints .................................................................................... 18 
3.4 
Blinding and Randomization ................................................................................ 19 
3.5 
Data Safety Monitoring Board .............................................................................. 20 
3.6 
Stopping rules ....................................................................................................... 20 
4 
SELECTION OF PARTICIPANTS ........................................................................... 21 
4.1 
Number of Participants ......................................................................................... 21 
4.2 
Recruitment Methods ............................................................................................ 21 
4.3 
Participant Characteristics .................................................................................... 21 
4.4 
Inclusion Criteria .................................................................................................. 21 
4.5 
Exclusion Criteria ................................................................................................. 22 
5 
STUDY PLAN, PROCEDURES, AND ASSESSMENTS ........................................ 23 
5.1 
Study Plan ............................................................................................................. 23 
5.2 
Description of Study Visits ................................................................................... 24 
5.2.1 
Screening (-3 Days to Day 1) .......................................................................... 24 
5.2.2 
Baseline (Day 1) ............................................................................................. 24 
5.2.3 
Treatment Period (Day 1 to Day 5) ................................................................. 24 
5.2.4 
Post Treatment Follow Up (Day 7) ................................................................. 25 
5.2.5 
Post-Treatment Follow-Up (Day 28) .............................................................. 25 

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Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
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5.2.6 
Post-Treatment Follow-Up (Day 60) .............................................................. 25 
5.3 
Assessment Methods ............................................................................................. 26 
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 ..................................................... 31 
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 .................................................................................................. 36 
9.4 
Study Endpoints .................................................................................................... 37 
9.4.1 
Primary Endpoint ............................................................................................ 37 
9.4.2 
Exploratory Endpoints .................................................................................... 37 
9.5 
Missing and Spurious Data ................................................................................... 38 
10 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ................................... 39 
10.1 
Declaration of Helsinki ......................................................................................... 39 
10.2 
Good Clinical Practice .......................................................................................... 39 
10.3 
Institutional Review Boards/Ethics Committees .................................................. 39 
10.4 
Regulatory Authority Approval ............................................................................ 39 
10.5 
Informed Consent.................................................................................................. 39 
10.6 
Patient Confidentiality and Disclosure ................................................................. 39 
10.7 
Collection, Monitoring and Auditing Study Documentation, and Data Storage .. 40 
10.7.1 
Collection of Data and Monitoring Procedures .............................................. 40 
10.7.2 
Auditing Procedure ......................................................................................... 41 
10.7.3 
Retention of Documents ................................................................................. 41 

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Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
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10.8 
Disclosure of Information ..................................................................................... 41 
10.9 
Discontinuation of the Study ................................................................................ 41 
10.10 
Study Report, Publication Policy and Archiving of Study Documentation ......... 41 
10.10.1 
Study Report and Publication Policy .............................................................. 41 
10.10.2 
Study Documents ............................................................................................ 42 
10.10.3 
Archiving of Documents ................................................................................. 42 
11 
REFERENCES ........................................................................................................... 43 
 
 
 
 

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Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
6MWT 
Six-Minute Walk Test 
AE 
Adverse event 
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 
HSA 
Human serum albumin 
ICH 
International conference on harmonization 
IRB 
Investigational review board 
ITT 
Intent to treat 
IV 
Intravenous 
mBDS 
Modified Borg Dyspnoea Scale 
PASC 
Post Acute Sequelae SARS-CoV-2 
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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Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
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2 
INTRODUCTION 
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, and has overwhelmed healthcare systems. Increasing numbers of people 
with COVID-19 are experiencing the lingering effects of COVID-19 and continue to have 
prolonged respiratory complications months after the onset of the disease, now clinically known 
as Post-Acute Sequelae SARS-CoV-2 (PASC), long-COVID, and/or long-hauler patients. 
Identifying drugs and therapies that address the prolonged respiratory complications related to 
COVID-19 infection is critical for patients to resolve the symptoms. 
This is a Phase I randomized, double-blinded, placebo-controlled trial to evaluate inhaled Ampion 
for adults with long-COVID. Ampion is being developed as an immunomodulatory therapy with 
anti-inflammatory effects that could provide a beneficial treatment for COVID-19 patients with 
these symptoms, including cough, shortness of breath, chest discomfort, low exercise tolerance 
and low blood oxygen saturation.  
This study aims to investigate the safety and the clinical outcomes in these patients with long-
COVID after a COVID-19 infection when treated with Ampion. The data from this study will 
inform decisions for the clinical development of 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 the 
continuing, chronic, low level inflammation observed in patients with long-COVID respiratory 
symptoms. 
The study control arm will use a saline placebo solution packaged in the same configuration as 
Ampion to protect blinding. 
Ampion or placebo (saline) will be delivered by inhalation using a nebulizer as a 32mL daily dose 
administered four times daily (8mL per treatment) every four to six hours for five days. Ampion 
or placebo is presented as a sterile liquid in a glass vial. For each use, the contents of are transferred 
to the drug reservoir in the nebulizer and nebulized continuously until the drug is fully 
administered.  
Ampion is aerosolized for inhalation using the Aerogen Ultra handheld nebulizer (Aerogen 
Limited, Galway, Ireland, FDA 510K K133360), which consists of the Aerogen Pro-X Controller 
and the Aerogen Ultra handheld unit. The system is a portable medical device for single patient 
use indicated for aerosolization of physician-prescribed solutions for inhalation. Ampion is 
nebulized using the continuous setting on the Aerogen controller, and the study drug is nebulized 
until it is fully aerosolized.  

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Version 1.2, 15 May 2021 
 
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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, where the lungs may 
become inflamed, making breathing difficult and sometimes requiring supplemental oxygen in the 
more severe cases of the disease.  
SARS-CoV-2 is transmitted through the respiratory system and can cause severe dysregulation of 
the immune response, particularly involving molecular pathways in inflammation (Coperchini 
2020). Chronic or prolonged inflammation of the lungs maybe responsible for a myriad of 
respiratory signs and symptoms experienced by patients after a COVID-19 infection. Chest x-rays 
and computerized tomography (CT) scans reveal disturbing patterns of perhaps extensive fibrosis 
and potential loss of elasticity and oxygen diffusion capacity (Alhiyari 2020, Lechowicz 2020, 
Vasarmidi 2020).  
 
A review of over 3000 patients recovering from COVID-19 found that many still suffered from 
respiratory complications due to COVID-19, including dyspnoea, cough, and persistent low 
oxygen (Nalbandian 2021). Furthermore, these complications were accompanied by a decline in 
quality of life, fatigue, and loss of sleep. 
 
Respiratory symptoms after a COVID-19 infection include shortness of breath, cough, chest 
discomfort, low exercise tolerance and low oxygen saturation, all of which point to potential 
inflammation related complication sequalae. Infiltrating or resident cells in the immune system 
(e.g., macrophages, peripheral blood mononuclear cells, etc.) maybe responsible for the 
development of these respiratory long-term consequences. 
 
Some treatments (remdesivir, dexamethasone, bamlanivimab) are being used in patients with 
immediate, short-term COVID-19 symptoms, but no treatments have been indicated for patients 
with long-COVID. There is a continued need to identify treatments that can interrupt chronic 
inflammation to address the needs of patients with long-COVID. 
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 
Ampion has been administered via inhalation to humans with severe COVID-19 in a Phase I 
clinical trial utilizing inhaled Ampion in treating respiratory distress in patients as a result of 
COVID-19 (AP-014). The results from this study to date (n=27 subjects) indicate inhaled Ampion 
may be safe and well-tolerated with no differences in the incidence, frequency, and severity of 
adverse events for patients treated with Ampion compared to control. Preliminary results from the 
AP-014 Phase I trial of inhaled Ampion indicate: 

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Clinical Study Protocol: AP-018 
 
Version 1.2, 15 May 2021 
 
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• 
Ampion demonstrated an improvement in all-cause mortality in COVID-19 
patients compared to standard of care (SOC). A lower all-cause mortality rate of 
8% is observed for the Ampion treatment group, compared to 21% in standard of care 
alone. 
• 
Patients who received Ampion required less hospitalization time. The average 
hospital length of stay was 7 days for the Ampion group compared to 11 days for 
standard of care patients. 
• 
Patients who received Ampion required less oxygen than standard of care alone, and 
86% of Ampion patients were stable or had improvement compared to 75% of SOC 
patients. 
• 
More patients who received Ampion were stable or had improvement on a scale 
of clinical improvement compared to standard of care alone. By day 5, 86% of patients 
who received Ampion were stable or had improvement compared to 75% of standard 
of care patients. This trend in improvement with Ampion treatment is noted as early as 
day 2 and continues to day 5. 
• 
Adverse events were the same between Ampion and standard of care, and no drug-
related serious adverse events have been reported. 
Ampion has also been administered via intravenous (IV) infusion to humans with severe COVID-
19 in a Phase I safety study (AP-016). The final results from this study (n=10 subjects) found 
Ampion to be safe and well-tolerated with no differences in the incidence, frequency, and severity 
of adverse events for patients treated with Ampion compared to control. 
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 noted to date. 
Additionally, Ampion is derived from pharmaceutical grade 5% human serum albumin (HSA), a 
human blood product approved by FDA for IV infusion, that has a safety profile including more 
than 50 years of use in many settings of perioperative medicine including hypovolemia, shock, 
burns, surgical blood loss, sepsis, and ARDS (Farag, 2016).   
2.4 
Study Rationale  
2.4.1 
Study Design  
This protocol has been designed to evaluate the safety and efficacy of inhaled Ampion in adults 
with prolonged respiratory complications after COVID-19 infection. The data from this study will 
inform decisions for the clinical development of Ampion. 
2.4.2 
Study Background 
COVID-19 infection is associated with respiratory findings which may be related to inflammation 
of the 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 complications.  

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This study focuses on the patients who have long-term symptoms and clinical signs related to 
continued respiratory illness after the viral infection is cleared. The SARS-Cov-2 virus is 
transmitted through the respiratory system, which can cause a severe dysregulation of the immune 
response and damage in the lungs (Coperchini 2020). Chronic, prolonged inflammation of the 
lungs maybe responsible for a myriad of continuing respiratory signs and symptoms post-infection, 
including cough, shortness of breath, chest discomfort, low exercise tolerance and low blood 
oxygen saturation.  
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 of patients with continuing symptoms (Thomas 2020). This study 
evaluates the safety and tolerability of IV Ampion treatment for patients with prolonged respiratory 
symptoms which continue after the COVID-19 infection has cleared. 
2.4.3 
Preclinical Data  
The proposed treatment regimen uses the smallest amount of Ampion that may provide a positive 
clinical outcome while minimizing safety risks. The safety of exposure is leveraged using the 
systemic exposure to Ampion’s active ingredients in 5% HSA, which has been given to patients 
with ARDS and other critical indications (Polito 2013). Ampion is derived from the low-molecular 
weight filtrate of pharmaceutical grade 5% HSA and consists of small molecules that can move 
freely between the lung and bloodstream.  
 
The potential for local toxicity of Ampion has been evaluated in an in vivo preclinical study using 
the inhaled route of administration. In the in vivo toxicity study, there were no clinical signs 
observed that were considered related to treatment with Ampion. There were no treatment-related 
effects on body weight or food consumption during the treatment period. There were no treatment-
related changes in hematology, clinical biochemistry or respiratory tract histopathology that could 
be attributed to treatment with Ampion. The inhalation exposure of Ampion at the highest dose for 
5 days was well tolerated and produced no apparent changes in any of the parameters evaluated. 
The maximum feasible dose achieved in the study was established as the no observable adverse 
effect level (NOAEL), which corresponded to approximately 15 times the proposed clinical dose 
of Ampion in this study. 
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 (Del Valle 2020, Yang 2017, Channappanavar 2017). 
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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2.4.4 
Dosing Rationale  
The proposed daily dose of 32mL of Ampion delivered via inhalation is based on Ampion’s in 
vitro effect to reduce cytokine (TNFα) combined with results from vivo safety study and 
experience from the Phase I study AP-014.  Nebulized Ampion will be administered as an 
individual 8mL dose four times daily (q.i.d.) every 4-6 hours (q4-q6), which is a daily dose of 
32mL. This treatment regimen is repeated for 5 days. This dosing uses a dose of Ampion that may 
provide a positive clinical outcome while minimizing safety risks. 
2.5 
Benefit and Risk Assessment 
Patients with prolonged respiratory complications after a COVID-19 infection 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 inhaled Ampion treatment are considered low and are based preclinical 
safety studies, inhalation use in COVID-19 patients, IV use in COVID-19 patients, intra-articular 
use for another indication (osteoarthritis), and decades of use of the sole starting material of the 
product, IV HSA, in severely ill patients. 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 
patients with prolonged respiratory complications after a COVID-19 infection, the overall benefit-
risk assessment of this study is considered favorable. As an immunomodulatory drug, Ampion 
may interrupt the inflammatory cascade for patients with prolonged respiratory complications after 
a COVID-19 infection which could improve clinical outcomes. 

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3 
STUDY DESIGN 
3.1 
Study Design Overview 
This is a randomized, double-blinded, placebo-controlled Phase I trial to evaluate the safety and 
efficacy of a 5-day Ampion inhalation treatment in participants with prolonged respiratory 
complications after a COVID-19 infection. 
Participants with COVID-19 infection will be screened for eligibility and consented. Participants 
(n=30) will be randomized in one of two groups, active (n=15) or placebo control (n=15) and 
randomized 1:1 following an equal allocation. The treatment arm will receive Ampion inhalation 
treatment, and the control arms will receive saline inhalation treatment. Participants will be 
followed for 60 days.  
3.2 
Study Objectives 
3.2.1 
Primary Objective 
The primary trial objective is to evaluate the safety and tolerability of inhaled Ampion versus 
placebo control in adult participants with prolonged respiratory complications after COVID-19 
infection. 
3.2.2 
Secondary Objectives 
The secondary trial objectives evaluate the efficacy of inhaled Ampion versus placebo control in 
improving the clinical course and outcomes of participants with prolonged respiratory 
complications after a COVID-19 infection. 
3.3 
Study Endpoints 
3.3.1 
Primary Endpoint 
Adverse events (AEs) will be evaluated from baseline through Day 60. The primary endpoint is 
incidence and severity of adverse events (AEs) and serious adverse events (SAEs) from baseline 
to Day 28 and Day 60.  
3.3.2 
Exploratory Endpoints 
Exploratory efficacy endpoints assess the effect of inhaled Ampion compared to placebo on the 
clinical outcomes for participants with prolonged respiratory complications after a COVID-19 
infection as follows: 

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Objective 
Endpoint 
Exploratory 
 
Assess the effect of Ampion 
compared to placebo on 
symptom improvement 
• Change in FDA Assessment of 14 Common COVID-19-Related 
Symptoms questionnaire from baseline to Day 7; Day 28; Day 60 
• Change in Borg Dyspnoea Scale (mBDS) from baseline to Day 7; Day 
28; Day 60  
• Change in all-cause mortality  
Assess the effect of Ampion 
compared to placebo on 
pulmonary function 
• Change in blood oxygen saturation from baseline to Day 7; Day 28; Day 
60 
• Change in six-minute walk test (6MWT) score from baseline to Day 7; 
Day 28; Day 60 
Assess the effect of Ampion 
compared to placebo on global 
impression 
• Change in Quality-of-Life Assessment using SF-36 from baseline to Day 
7; Day 28; Day 60  
• Change in Fatigue questionnaire from baseline to Day 7; Day 28; Day 60  
• Change in Sleep Disturbance questionnaire from baseline to Day 7; Day 
28; Day 60  
Assess the effect of Ampion 
compared to placebo on 
radiographic findings 
• Change in chest imaging on ground-glass opacity, local patchy 
shadowing, bilateral patchy shadowing, and/or interictal abnormalities 
from baseline to Day 60 
 
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 1:1 to active treatment or placebo control, following an equal 
allocation to treatment arms as follows:  
Treatment Arm 
Investigational Treatment 
Active 
Ampion Inhalation for 5-days 
Control 
Placebo Inhalation for 5-days 
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. 
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. 

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3.5 
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be established to review the safety, as the study 
progresses, of IV Ampion. 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 
This is a Phase I study and is not intended to be powered for the primary endpoint. This trial is 
designed to enroll up to 30 subjects, randomized to active treatment or placebo control, following 
an equal allocation to treatment arms (n=15 subjects per arm). 
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 prolonged 
respiratory symptoms consistent with COVID-19. Treatment of COVID-19 depends on the stage 
of disease with a continued hyperinflammatory state observed that are thought to lead to prolonged 
clinical complications. Treatment with immunomodulators at this point in the disease would be 
more effective than anti-viral treatments.  
The population of participants with prolonged respiratory complications after an initial COVID-
19 infection were selected for this study to evaluate the efficacy of Ampion as an 
immunomodulatory therapy that may improve the clinical outcome by addressing the chronic, 
prolonged inflammation in the lungs that maybe responsible for a myriad of continuing respiratory 
issues, including cough, shortness of breath, chest discomfort, low exercise tolerance and low 
blood oxygen saturation. 
4.4 
Inclusion Criteria 
Patients should fulfill all the following inclusion criteria:  
1. Male or female adults: ≥ 18 years. 
2. Must have a clinical diagnosis of COVID-19 at least 4 weeks prior to the screening date, 
with at least one of clinical symptoms (e.g., fever ≥ 38°C, fatigue, cough) and a positive 
result by the reverse-transcription polymerase chain reaction (RT-PCR) testing or 
equivalent. 
3. Experiencing at least two COVID-19 respiratory symptoms with a score of two or higher 
using the FDA Assessment of 14 Common COVID-19-Related Symptoms questionnaire 
for at least 4 weeks (28 days) after initial positive COVID-19 diagnosis: cough, sore throat, 
runny/stuffy nose, shortness of breath (difficulties breathing), tightness of chest, low 
exercise tolerance. 
4. Able to bear weight and ambulate a minimum of 10 meters distance. 
5. Women of childbearing potential and their partner must agree to use at least one highly 
effective method of contraception (e.g., hormonal contraceptives [implants, injectables, 

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combination oral contraceptives, transdermal patches, or contraceptive rings], intrauterine 
devices, bilateral tubal occlusion, or sexual abstinence) for the duration of the study. 
6. Informed consent obtained from the patient. 
4.5 
Exclusion Criteria 
Patients fulfilling one or more of the following criteria may not be enrolled in the study: 
1. Subjects who require hospitalization. 
2. Patient has severe chronic obstructive or restrictive pulmonary disease (COPD) as defined 
by prior pulmonary function tests, chronic renal failure, or significant liver abnormality 
(e.g., cirrhosis, transplant, etc.). 
3. History of Chronic Fatigue Syndrome prior to COVID-19 infection. 
4. Patient is on chronic immunosuppressive medication. 
5. Patient requires surgery that could be life-threatening within the study window. 
6. 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-acetyl 
tryptophan, sodium caprylate). 
7. Patient has known pregnancy or is currently breastfeeding. 
8. 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). 
9. Clinically significant findings via electrocardiogram (ECG), including acute myocardial 
infarction, acute ischemic changes, atrial fibrillation, atrial flutter, paced rhythms in 
individuals who have undergone permanent pacemaker placement, evidence of prior 
infarction, unchanged stable conduction abnormalities e.g., right bundle branch block, or 
any other finding which does not significantly impact mortality. 
10. Pre-existing co-morbid condition(s) preventing outcome assessments, e.g., disease or 
condition that would prevent ability to transfer and walk for 6 minutes, prior to confirmed 
COVID-19 diagnosis (assisted walking devices are acceptable) 
11. As a result of the medical review and screening investigation, the Principal Investigator 
considers the patient unfit for the study. 

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5 
STUDY PLAN, PROCEDURES, AND ASSESSMENTS 
5.1 
Study Plan 
Patients with confirmed COVID-19 infection will be screened for up to 72 hours from referral to 
an outpatient clinic. Patients meeting the selection criteria will be approached for consent in the 
study. If consented, participants will be randomized in one of two groups, active or control. Within 
each group, participants are randomized 1:1 following an equal allocation to treatment arms to 
either active or control arms of the study as follows: 
Treatment Arm 
Investigational Treatment 
Active 
Ampion Inhalation for 5-days 
Control 
Placebo Inhalation for 5-days 
Participants who have been randomized into the control arm will receive a daily dose (32mL/day) 
of placebo (saline) inhalation treatment. Participants who have been randomized into the active 
treatment arm will receive a daily dose (32mL/day) of inhaled Ampion. Inhaled treatment (Ampion 
or placebo) will be delivered four times daily, every four to six hours using the nebulizer in equally 
divided doses of 8mL. This treatment regimen is repeated for 5 days.  
The health check vital signs and baseline assessments for blood oxygen saturation, assessment of 
symptoms/questionnaires, mBDS, walk test, and chest x-ray should occur before the first dose of 
treatment. These tests and the first dose of treatment will occur at the clinic. Treatment for the 
remainder of Day 1 and Days 2, 3, 4, 5 will occur at home. Health checks, concomitant 
medications, and adverse events for Day 1 post-first dose and Days 3 and 5 will be collected via 
telephone visit. 
 
Safety will be assessed by recording adverse events and with a health check during treatment. 
Safety is assessed by recording adverse events for the length of the study (60 days). 
 
Efficacy will be assessed by recording the effects of inhalation Ampion compared to placebo on 
the clinical outcomes for participants with prolonged respiratory complications after a COVID-19 
infection using the following clinical outcomes: time to symptom improvement, percentage of 
participants demonstrating improvement, change in Borg Dyspnoea Scale, time to sustained 
recovery, blood oxygen saturation, a walk test, and chest x-ray. Assessments for clinical outcomes 
are performed from baseline to Day 7, Day 28, and Day 60.  
 
Exploratory will be assessed by recording the effects of inhalation Ampion compared to placebo 
on the clinical outcomes for participants with prolonged respiratory complications after a COVID-
19 infection using the following clinical outcomes: Quality of life assessment using SF-36, 
PROMIS fatigue questionnaire and PROMIS sleep disturbance questionnaire. Assessments for 
clinical outcomes are performed from baseline to Day 7, Day 28, Day 60.  

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5.2 
Description of Study Visits 
The Schedule of Assessments is shown in Section 1.2. Visit types are described as follows: 
Study Day 
Visit Description 
Visit Type 
1 
Baseline safety/efficacy measures 
Conducted in outpatient clinic 
1-5 
Ampion inhalation treatment, safety measures 
Conducted at home 
7, 28, 60 
Post-treatment safety/efficacy measures 
Conducted in outpatient clinic 
5.2.1 
Screening (-3 Days to Day 1) 
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. 
• Confirm date of initial positive COVID-19 test.  
• Medical history, pre-existing conditions, ECG, and comorbidities. Include the symptom 
onset date for COVID-19 symptoms. 
• Obtain informed consent before the starting any study specific procedures, including COVID 
testing. 
• Demographics (age, sex, race, height and weight) 
• Pregnancy test for women of childbearing age. 
5.2.2 
Baseline (Day 1)  
The following procedures will be performed at Baseline (first assessment prior to treatment): 
• Confirm eligibility (review inclusion/exclusion criteria) 
• Randomize patient to study arm. Start inhalation treatment within 24 hours. 
• Vital signs 
• Blood oxygen saturation 
• Assessment of 14 Common COVID-19-related symptoms questionnaire 
• Borg Dyspnoea Scale and walk test 
• Chest x-ray imaging 
• Record concomitant medications/therapies 
• Quality-of-life assessment SF-36 
• PROMIS fatigue and PROMIS sleep disturbance questionnaires  
• Record adverse events 
5.2.3 
Treatment Period (Day 1 to Day 5) 
The following procedures will be performed during the Treatment Period (Day 1 to Day 5): 
• Begin inhalation treatment of study intervention (active or placebo) daily within 24 hours of 
randomization. Subjects will administer inhaled treatment (active or placebo) through 
nebulization daily as described in Section 2.1. 

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• Subjects will have a general health check conducted via telephone or text message on Day 1, 
3, 5. 
• Record concomitant medications/therapies 
• Record adverse events 
5.2.4 
Post Treatment Follow Up (Day 7) 
The following procedures will be performed at Day 7 (endpoint): 
• Blood oxygen saturation 
• Assessment of 14 Common COVID-19-related symptoms questionnaire  
• Borg Dyspnoea Scale and walk test. 
• Record concomitant medications/therapies 
• Quality-of-life assessment SF-36 
• PROMIS fatigue and PROMIS sleep disturbance questionnaires  
• Record adverse events 
5.2.5 
Post-Treatment Follow-Up (Day 28)  
The following procedures will be performed at follow-up visits (Day 28): 
• Blood oxygen saturation  
• Assessment of 14 Common COVID-19-related symptoms questionnaire  
• Borg Dyspnoea Scale and walk test 
• Concomitant medications/therapies 
• Quality-of-life assessment SF-36 
• PROMIS fatigue and PROMIS sleep disturbance questionnaires  
• Record adverse events 
 
5.2.6 
 Post-Treatment Follow-Up (Day 60)  
The following procedures will be performed at follow-up visits (Day 60) end of study: 
• Blood oxygen saturation  
• Assessment of 14 Common COVID-19-related symptoms questionnaire 
• Borg Dyspnoea Scale and walk test 
• Chest x-ray imaging 
• Record Concomitant medications/therapies. 
• Quality-of-life assessment SF-36 
• PROMIS fatigue and PROMIS sleep disturbance questionnaires  
• Record adverse events 

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5.3 
Assessment Methods 
Demographic Data 
Demographic data will be collected: age, gender, race, height and weight, comorbidities. 
Health Check 
A health check will be conducted at the clinic at baseline to include the measurement of vital signs 
(i.e., heart rate, blood pressure, respiratory rate, temperature). A general health check will be 
conducted Day 1 post-first dose, Day 3, and Day 5 via telephone visit.  
Blood Oxygen Saturation (SpO2) 
SpO2 will be collected at baseline and Days 7, 28, and 60 using a pulse-oxygen measuring device. 
Assessment of 14 Common COVID-19-related symptoms questionnaire  
The FDA assessment of 14 Common COVID-19- related symptoms questionnaire will be 
conducted at baseline, Day 7, Day 28, and Day 60 as follows: 

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Time to Sustained Recovery 
The time to sustained recovery will be evaluated using the FDA Assessment of 14 Common 
COVID-19-Related Symptoms questionnaire. Time to sustained recovery is defined as the first 
day on which the patient achieves a state of ‘none’ or ‘0’ using the FDA assessment.  
Borg Dyspnoea Scale  
Borg Dyspnoea Scale will be conducted at baseline, Day 7, Day 28, and Day 60. This scale asks 
you to rate the difficulty of your breathing it starts at number 0 where you are breathing is causing 
you no difficulty at all and progresses through to number 10 where your breathing difficulty is 
maximal.  
Walk Test 
A six-minute walk test will be conducted at baseline, Day 7, Day 28, and Day 60. The walk test is 
conducted as follows: 
 Flat, straight corridor 30 m (100 feet) in length 
 Turnaround points marked with a cone 
 Patient should wear comfortable clothes and shoes 
 Patient rests in chair for at least 10 minutes prior to test (ie, no warm-up period) 

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 Heart rate and pulse oxygen saturation (SpO2) should be monitored throughout the test  
 If the patient is using supplemental oxygen, record the flow rate and type of device 
 Have patient stand and rate baseline dyspnea and overall fatigue using Borg scale*[1] 
 Set lap counter to zero and timer to six minutes 
 Instruct the patient: Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or 
jog. Pivot briskly around the cone. 
 Standardized encouragement statements should be provided at one-minute intervals, such as "You are doing well. 
You have _ minutes to go" and "Keep up the good work. You have _ minutes to go." 
 At the end of the test, mark the spot where the patient stopped on the floor 
 If using a pulse oximeter, measure the pulse rate and SpO2 and record 
 After the test record the Borg*[1] dyspnea and fatigue levels 
 Ask, "What, if anything, kept you from walking farther?" 
 Calculate the distance walked and record 
1. 
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14:377. 
2. 
American Thoracic Society. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 
166:111. 
3. 
Holland AE, Spruit MA, Troosters T, et al. An official European Respiratory Society/American Thoracic Society technical 
standard: field walking tests in chronic respiratory disease. Eur Respir J 2014; 44:1428. 
Chest X-Ray Imaging 
Chest x-ray images will be taken at baseline and Day 60. The standard chest examination consists 
of a PA (posterior anterior) and lateral chest x-ray.  
Concomitant Medications 
Concomitant medications will be collected: prior concomitant medications, concomitant 
medications through study exit. 
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. 
Quality-of-Life Assessment SF-36 
Quality of life assessment SF-36 questionnaire with 36 questions health survey for subject’s 
general health will be conducted at baseline, Day 7, Day 28, and Day 60. 
PROMIS Fatigue and Sleep Questionnaires  
PROMIS fatigue and PROMIS sleep questionnaires will be conducted at baseline, Day 7, Day 28, 
and Day 60. 

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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 nebulization 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 
Participants randomized to the active arm will receive inhaled Ampion through nebulization daily 
for 5 days. Participants randomized to the control arm will receive placebo through nebulized 
inhalation 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 
Study treatment (Ampion or placebo) will be provided as a solution in vials ready for human use 
and treatment administration. The participant will be trained to self-administer the study treatment. 
Treatment should start within 24 hours of randomization and should terminate on last treatment 
day (Day 5).   
Study treatment (Ampion or placebo) will be delivered by inhalation using a nebulizer as a 32mL 
daily dose administered four times daily (8mL per treatment) every four to six hours for five days.  
Study treatment (Ampion or placebo) is presented as a sterile liquid in a glass vial. For each use, 
the contents of are transferred to the drug reservoir in the nebulizer and nebulized continuously 
until the drug is fully administered.  
Study treatment (Ampion or placebo) is aerosolized for inhalation using the Aerogen Ultra 
handheld nebulizer (Aerogen Limited, Galway, Ireland, FDA 510K K133360), which consists of 
the Aerogen Pro-X Controller and the Aerogen Ultra handheld unit. The system is a portable 
medical device for single patient use indicated for aerosolization of physician-prescribed solutions 
for inhalation. Ampion is nebulized using the continuous setting on the Aerogen controller, and 
the study drug is nebulized until it is fully aerosolized.  
Product administration may be temporarily suspended until resolution if a serious, or sudden side 
effects are observed. 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) and/or corticosteroids.  
 
As described in Section 6.1, if any 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. 
 
7.2 
Study Medication Storage and Accountability 
Study treatment (Ampion or placebo) should be stored at room temperature (59º – 77ºF or 15º – 
25ºC) in a secure area with restricted access while at the clinic. 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 

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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. 
Study drug stored at home should be stored at room temperature. 
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 hospitalization or 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 
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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 until study exit 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.  
This is a Phase 1 study and is not intended to be powered for the primary endpoint. The study will 
evaluate safety, tolerability, and efficacy of Ampion in improving the clinical course and outcome 
of adults with prolonged respiratory complications after a COVID-19 infection. 
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 
An interim analysis for safety and efficacy endpoints will be performed once all subjects have 
completed their Day 7 assessments.  
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 
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 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 

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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 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 until study exit (or 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 treatment arm (active or control). 
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 
Adverse events (AEs) will be evaluated from baseline through Day 60. The primary endpoint is 
incidence and severity of adverse events (AEs) and serious adverse events (SAEs) from baseline 
to Day 28.  
 
There will be no statistical tests for incidence and severity of AEs. AEs will be tabulated using 
descriptive statistics and shift tables and presented for safety.  
9.4.2 
Exploratory Endpoints  
Exploratory efficacy endpoints assess the effect of inhaled Ampion compared to placebo on the 
clinical outcomes for participants with prolonged respiratory complications after a COVID-19 
infection per Section 3.3.2. 
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 

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(moderate and severe), and timepoint. Where appropriate, data will be tabulated and presented 
cumulatively across cohorts and/or timepoints. 
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. 

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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 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, 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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11 
REFERENCES 
Alhiyari MA, et al. Post COVID-19 fibrosis, an emerging complication of SARS-CoV-2 infection. 
IDCases. 2020 Dec 31;23:e01041. doi: 10.1016/j.idcr.2020.e01041.  
Channappanavar R, et al. Pathogenic human coronavirus infections: causes and consequences of 
cytokine storm and immunopathology. Semin Immunopathol. 2017 May 02; 39:529-539. 
Coperchini F, et al. The cytokine storm in COVID-19: An overview of the involvement of the 
chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020 Jun;53:25-32. doi: 
10.1016/j.cytogfr.2020.05.003. Epub 2020 May 11. 
 
Del Valle DM, et al. An inflammatory cytokine signature predicts COVID-19 severity and 
survival. Nat Med 26, 24 Aug 2020, 1636-1643. 
Farag E, et al. The perioperative use of albumin. Perioperative Fluid Management. 2016 Jun 23: 
215-234. 
Lechowicz K, et al. COVID-19: The Potential Treatment of Pulmonary Fibrosis Associated with 
SARS-CoV-2 Infection. J Clin Med. 2020 Jun 19;9(6):1917. doi: 10.3390/jcm9061917.  
Loynes CA, et al. PGE2 production at sites of tissue injury promotes an anti-inflammatory 
neutrophil phenotype and determines the outcome of inflammation resolution in vivo. Science 
advances. 2018 Sep 1; 4(9):eaar8320. 
Management of Patients with Confirmed 2019-NCoV. Centers for Disease Control and Prevention, 
Centers for Disease Control and Prevention, 20 Mar. 2020, www.cdc.gov/coronavirus/2019-
ncov/hcp/clinical-guidance-management-patients.html.  
Nalbandian, et al. Post-acute COVID-19 syndrome. Nature Medicine. 22 March 2021. 
https://doi.org/10.1038/s41591-021-01283-z  
Polito C, et al. Albumin: Physiologic and Clinical Effects on Lung Function. Journal of Minverva 
Anesthesiologica. 2013 October; 79(10):1180-1186  
Thomas, et al. The novel immumodulatory biologic LMWF5A for pharmacological attenuation of 
the “cytokine storm” in COVID-19 patients: a hypothesis. Patient Safety in Surgery. 2020. 14:21. 
https://doi.org/10.1186/s13037-020-00248-4 
Vasarmidi E, et al. Pulmonary fibrosis in the aftermath of the COVID-19 era (Review). Exp Ther 
Med. 2020 Sep;20(3):2557-2560. doi: 10.3892/etm.2020.8980.  
Yang J, et al. Serum levels of TNF‐α, IL‐1β, IL‐9, and IL‐15 in acute respiratory distress syndrome. 
Int J Clin Exp Pathol. 2017 Jan 1; 10(1):781-8.