An Open Label Extension Study to Assess the Safety of Long-Term Treatment With a 4 mL Intra-Articular Injection of Ampion in Adults With Pain Due to Severe Osteoarthritis of the Knee
Phase: PHASE3
Conditions: Severe Osteoarthritis of the Knee
Sponsor: Ampio Pharmaceuticals. Inc.

 
 
 
 
AN OPEN LABEL EXTENSION STUDY 
TO ASSESS THE SAFETY OF LONG-
TERM TREATMENT WITH A 4-ML 
INTRA-ARTICULAR INJECTION OF 
AMPION IN ADULTS WITH PAIN DUE 
TO SEVERE OSTEOARTHRITIS OF 
THE KNEE 
 
STUDY PROTOCOL 
 
STUDY NUMBER: AP-003-C-OLE 
 
NCT 03349645 
 
26 MARCH 2018 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
Page 1 
 
 
0BCLINICAL STUDY PROTOCOL 
1BAN OPEN LABEL EXTENSION STUDY TO ASSESS THE SAFETY 
OF LONG-TERM TREATMENT WITH A 4-ML INTRA-ARTICULAR 
INJECTION OF AMPION™ IN ADULTS WITH PAIN DUE TO 
SEVERE OSTEOARTHRITIS OF THE KNEE  
2BSTUDY NUMBER: AP-003-C-OLE 
Drug Development Phase: 
Phase 3 
Investigational Product: 
Ampion™ 
Indication: 
Osteoarthritis of the knee 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
373 Inverness Parkway, Suite 200 
Englewood, CO 80112 
Date: 
Version 3.0  26 March 2018 
Conduct:  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 
This document is the sole property of Ampio Pharmaceuticals, Inc.  This document and 
any and all information contained herein has to be considered and treated as strictly 
confidential.  This document shall be used only for the purpose of the disclosure herein 
provided.  No disclosure or publication shall be made without the prior written consent of 
Ampio Pharmaceuticals, Inc. 
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
Page 2 
 
 
3BPROTOCOL SIGNATURE PAGE 
I have read and understand the contents of this clinical protocol for Study No. AP-003-C-
OLE dated 26 March 2018 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-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
Page 3 
 
 
PROTOCOL SYNOPSIS 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Developmental Phase: 
Phase 3 
Title of Study:   
An Open Label Extension (OLE) study to assess the safety of long-term treatment with a 4-
mL intra-articular injection of Ampion ™ in adults with pain due to severe osteoarthritis of 
the knee 
Protocol Number:   
AP-003-C-OLE 
Study Center(s):   
Approximately 14 sites  
Indication:   
Severe osteoarthritis of the knee (OAK) (Kellgren Lawrence Grade 4, KL 4) 
Number of subjects:  
Up to 161 subjects 
Objectives:  
The primary trial objective is to carry on from the AP-003-C main study (one injection) and 
evaluate the safety of a 4-mL intra-articular (IA) injection of Ampion™ with repeat dosing 
every 12 weeks for 52 weeks and/or with five total injections of Ampion™. 
The exploratory objectives are to analyze the efficacy of a 4-mL intra-articular (IA) injection 
of Ampion™ with repeat dosing every 12 weeks for 52 weeks and/or with five total 
injections of Ampion™. 
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
Page 4 
 
 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Developmental Phase: 
Phase 3 
Methods:   
Subjects who have completed the AP-003-C main study (n=161) will be offered the option to 
roll-over to the open label extension study (AP-003-C-OLE). At their final visit of the AP-
003-C main study (Visit 7), subjects will be offered the option to participate in the AP-003-
C-OLE study. Enrollment into the AP-003-C-OLE study (Visit 9) allows a 170-day 
screening window from the AP-003-C main study Visit 7.   
AP-003-C-OLE study will include the following visits: 
Visit 9 
Enrollment (Day 0 = Day 84 of AP-003-C main study ± 170 days, but not to 
occur before completion of AP-003-C main study), in-office visit 
Visit 10 
(24 hours after Visit 9), post injection follow-up telephone call 
Visit 11 
Week 12 (Day 84 ± 14 days), in-office visit 
Visit 12 
(24 hours after Visit 11), post injection follow-up telephone call 
Visit 13 
Week 24 (Day 168 ± 14 days), in-office visit 
Visit 14 
(24 hours after Visit 13), post injection follow-up telephone call 
Visit 15 
Week 36 (Day 252 ± 14 days), in-office visit 
Visit 16 
(24 hours after Visit 15), post injection follow-up telephone call 
Visit 17 
Week 40 (Day 280 ± 14 days), in-office final visit 
 
The safety of repeat dosing will be evaluated at all visits; in-office visit safety assessments 
will include vital signs, physical exams, evaluation of AEs, and laboratory analysis (Visit 17, 
Week 40, visit only) and phone visits will evaluate for AEs. 
The clinical effects of treatment on the signs and symptoms of OAK will be evaluated during 
all in-clinic visits using the Western Ontario and McMaster Universities Arthritis Index 
(WOMAC®) osteoarthritis Index 3.1, and the Patients’s Global Assessment of disease 
severity (PGA). The WOMAC will also be utilized to assess the contra-lateral knee pain, 
stiffness, and function at Enrollment and Week 40 (or Early Termination Visit). 
The WOMAC® is a validated pain scoring system and sets the standard for the subject 
response. In order not to bias the collection of data, only questions from the validated 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
Page 5 
 
 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Developmental Phase: 
Phase 3 
WOMAC pain scale will be asked of subjects.  
 
Diagnosis and Main Criteria for Inclusion:  
1. Subjects who completed the AP-003-C main study and have not developed any 
exclusionary criteria 
2. Able to provide written informed consent to participate in the study 
3. Willing and able to comply with all study requirements and instructions of the site study 
staff 
4. Male or female, 40 years to 85 years old (inclusive), as assessed in the AP-003-C main 
study 
5. Must be ambulatory, as assessed in the AP-003-C main study 
6. Study knee must have a clinical diagnosis of OA and supported by radiological evidence 
(Kellgren Lawrence Grade 4) as assessed in the AP-003-C main study.   
7. Moderate to moderately-severe OA pain in the study knee (rating of at least 1.5 on the 
WOMAC Index 3.1 5-point Likert Pain Subscale), as assessed in the AP-003-C main 
study 
8. Moderate to moderately-severe OA function in the study knee (rating of at least 1.5 on 
the WOMAC Index 3.1 5-point Likert Function Subscale), as assessed in the AP-003-C 
main study 
9. WOMAC A, 5-point Likert pain subscale <1.5 in the contralateral knee, as assessed in 
the AP-003-C main study 
10. Ability to discontinue NSAID ± 72 hours before/after injections (in-office visits). Low-
dose Aspirin (81 mg) is allowed during the study but must not be taken at least 24 hours 
prior to in-office visits 
11. No analgesia (including acetaminophen [paracetamol]) taken 24 hours prior to an 
efficacy measure 
 
 
Main Criteria for Exclusion: 
1. As a result of medical review and screening investigation, the Principal Investigator 
considers the subject unfit for the study 
2. Known clinically significant liver abnormality (e.g., cirrhosis, transplant, etc.) 
3. A history of allergic reactions to human albumin (reaction to non-human albumin such as 
egg albumin is not an exclusion criterion) 
4. A history of allergic reactions to excipients in 5% human albumin (N-acetyltryptophan, 
sodium caprylate) 
5. Presence of tense effusions 
6. Inflammatory or crystal arthropathies, acute fractures, history of aseptic necrosis or joint 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
Page 6 
 
 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Developmental Phase: 
Phase 3 
replacement in the affected knee 
7. Isolated patella femoral syndrome, also known as chondromalacia  
8. Any other disease or condition interfering with the free use and evaluation of the index 
knee for the duration of the trial (e.g. cancer, congenital defects, spine osteoarthritis)  
9. Major injury to the index knee within the last 12 months 
10. Severe hip osteoarthritis ipsilateral to the index knee 
11. Any pain that could interfere with the assessment of study knee pain (e.g. pain in any 
other part of the lower extremities, pain radiating to the knee) 
12. Any pharmacological or non-pharmacological treatment targeting OA started or changed 
4 weeks prior to entry into the AP-003-C-OLE study, or likely to be changed during the 
duration of the AP-003-C-OLE study 
13. Pregnancy or planning to become pregnant during the study 
14. Use of the following medications: 
a. No IA injected pain medications in the study knee during the study.  HA and steroid 
injections in the contralateral knee (non-study knee) are acceptable while on study 
except ± 14 days of an Ampion injection in the study knee 
b. No analgesics containing opioids 
c. NSAIDs are not permitted ± 72 hours before/after injections at in-office visits; 
acetaminophen is available as a rescue medication during the study from the provided 
supply 
d. No topical treatment on the study knee during the study  
e. No significant anticoagulant therapy (e.g. Heparin or Lovenox) during the study 
(treatment such as Aspirin and Plavix are allowed) 
f. No systemic treatments that may interfere with safety or efficacy assessments during 
the study 
g. No immunosuppressants 
h. No use of corticosteroids  
i. No human albumin treatment in the 3 months prior to the AP-003-C main study or 
interim period prior to enrollment into the AP-003-C-OLE study.  No human albumin 
treatment throughout the duration of the AP-003-C-OLE study 
Test Product, Dose and Mode of Administration: 
Ampion™ 4-mL intra-articular injection in the knee  
Reference Therapy, Dose and Mode of Administration: 
Not applicable  
Study Duration:   
40 weeks 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
Page 7 
 
 
Sponsor: 
Ampio Pharmaceuticals, Inc. 
Investigational Product: 
Ampion™ 
Developmental Phase: 
Phase 3 
Main Study + Extension Study = 52 weeks 
 
Criteria for Evaluation: 
Safety:  
Adverse events, physical examination, vitals, and blood tests  
Efficacy: 
WOMAC osteoarthritis Index 3.1 and PGA 
Statistical Methods:   
Descriptive Statistics will be utilized for the primary and exploratory endpoints.  No formal 
hypothesis testing will be done. 
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
Page 8 
 
 
TABLE OF CONTENTS 
45TPROTOCOL SYNOPSIS45T ..........................................................................................................3 
45TLIST OF ABBREVIATIONS AND DEFINITION OF TERMS45T ............................................12 
45T145T 
45TINTRODUCTION45T ...........................................................................................................14 
45T1.145T 
45TStudy Drug45T .............................................................................................................14 
45T1.245T 
45TBackground to the Disease45T .....................................................................................15 
45T1.345T 
45TPrevious Human Experience45T ..................................................................................17 
45T1.45T 
45TPreclinical Data45T ......................................................................................................17 
45T1.4.145T 
45TPharmacology Studies45T ..................................................................................17 
45T1.4.245T 
45TToxicity and Safety Studies45T .........................................................................18 
45T1.545T 
45TClinical Experience45T ................................................................................................18 
45TTable 1.5.345T ....................................................................................................................22 
45TTable 1.5.45T ...................................................................................................................22 
45T245T 
45TRATIONALE FOR THE STUDY45T ...................................................................................24 
45T2.145T 
45TRationale for the Doses and the Dosing Regimen45T .................................................24 
45T345T 
45TSTUDY DESIGN45T.............................................................................................................25 
45T3.145T 
45TStudy Design Overview45T .........................................................................................25 
45T3.245T 
45TSTUDY OBJECTIVES45T ..........................................................................................25 
45T3.2.145T 
45TPrimary Objective45T ........................................................................................25 
45T3.2.245T 
45TExploratory Objectives45T ................................................................................25 
45T3.345T 
45TSafety Monitoring committee45T ................................................................................26 
45T3.45T 
45TStopping Rules45T .......................................................................................................26 
45T3.545T 
45TStudy Endpoints45T .....................................................................................................26 
45T3.5.145T 
45TPrimary Endpoint45T .........................................................................................26 
45T3.5.245T 
45TExploratory Endpoints45T .................................................................................26 
45T3.645T 
45TBlinding and Randomization45T .................................................................................27 
45T45T 
45TSELECTION OF SUBJECTS45T..........................................................................................28 
45T4.145T 
45TNumber of Subjects45T................................................................................................28 
45T4.245T 
45TInclusion Criteria45T ...................................................................................................28 
45T4.345T 
45TExclusion Criteria45T ..................................................................................................28 
45T4.45T 
45TInclusion of Subjects Incapable of Giving Informed Consent45T ...............................29 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
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45T545T 
45TSTUDY PLAN AND PROCEDURES45T ............................................................................30 
45T5.145T 
45TDescription of Study visits45T .....................................................................................30 
45T5.1.145T 
45TVisit 9 (Day -170 to Day 0, in-clinic); Day 045T ..............................................30 
45T5.1.245T 
45TVisit 10 (24-hours following Visit 9, post-injection follow-up call)45T ...........31 
45T5.1.345T 
45TVisit 11 (Day 84  ± 14 days, in-clinic); Week 1245T ........................................31 
45T5.1.45T 
45TVisit 12 (24-hours following Visit 11, post-injection follow-up call )45T ........31 
45T5.1.545T 
45TVisit 13 (Day 168 ± 14 days, in-clinic); Week 245T .......................................31 
45T5.1.645T 
45TVisit 14 (24-hours following Visit 13, post-injection follow-up call )45T ........32 
45T5.1.745T 
45TVisit 15 (Day 252 ± 14 days, in-clinic); Week 3645T .......................................32 
45T5.1.845T 
45TVisit 16 (24-hours following Visit 15, post-injection follow-up call )45T ........32 
45T5.1.945T 
45TVisit 17 (Day 280 ± 14 days, in-clinic); Week 4045T .......................................32 
45T5.1.1045T 
45TEarly Termination Visit45T ...............................................................................33 
45T5.1.1145T 
45TUnscheduled Visits45T ......................................................................................33 
45T5.1.1245T 
45TMissed Visits45T ................................................................................................33 
45T5.1.1345T 
45TCONCOMITANT MEDICATIONS45T ...........................................................34 
45T645T 
45TMETHODS OF ASSESSMENT45T......................................................................................35 
45T6.145T 
45TEfficacy Assessments45T.............................................................................................35 
45T6.1.145T 
45TWOMAC® Osteoarthritis Index (Bellamy 1988)45T ........................................36 
45T6.1.245T 
45TPatient’s Global Assessment of Disease Severity (PGA)45T ............................36 
45T6.245T 
45TSafety Parameters45T...................................................................................................36 
45T6.2.145T 
45TVital Signs45T ....................................................................................................37 
45T6.2.245T 
45TClinical laboratory tests45T ...............................................................................37 
45T745T 
45TDISCONTINUATION CRITERIA45T .................................................................................40 
45T7.145T 
45TEarly Discontinuation of the Study45T ........................................................................40 
45T7.245T 
45TEarly Discontinuation of Individual Subjects45T ........................................................40 
45T845T 
45TTREATMENT45T .................................................................................................................42 
45T8.145T 
45TDosing and administration of study medication45T ....................................................42 
45T8.245T 
45TDrug Storage and Accountability45T ...........................................................................42 
45T8.345T 
45TTreatment Compliance45T ...........................................................................................43 
45T945T 
45TADVERSE EVENTS45T .......................................................................................................44 
45T9.145T 
45TDefinition of an adverse event45T ...............................................................................44 
45T9.245T 
45TDefinition of a Serious Adverse Event45T ..................................................................44 
45T9.345T 
45TRecording of adverse events and serious adverse events45T .......................................45 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
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45T9.3.145T 
45TAE Follow up45T ...............................................................................................45 
45T9.3.245T 
45TOverdose45T ......................................................................................................46 
45T9.45T 
45TSerious Adverse Event Reporting45T ..........................................................................46 
45T9.4.145T 
45TReporting Requirements45T ..............................................................................46 
45T9.4.245T 
45TSAE Contact Information45T ............................................................................46 
45T1045T 
45TSTATISTICAL METHODS45T ............................................................................................47 
45T10.145T 
45TGENERAL CONSIDERATIONS45T .........................................................................47 
45T10.1.145T 
45TStatistical and Analytical Plan:45T ....................................................................47 
45T10.245T 
45TSTUDY OBJECTIVES45T ..........................................................................................47 
45T10.345T 
45TANALYSIS POPULATIONS45T ...............................................................................47 
45T10.3.145T 
45TSafety Analysis Population:45T .........................................................................47 
45T10.3.245T 
45TIntent-to-treat Population:45T ............................................................................47 
45T10.3.345T 
45TPer Protocol Population:45T ..............................................................................47 
45T10.3.45T 
45TStatistical Analysis of Primary Effectiveness Endpoint45T ..............................48 
45T10.3.545T 
45TPrimary Hypotheses45T .....................................................................................48 
45T10.3.645T 
45TDefinition of Study Visits45T ............................................................................48 
45T10.3.745T 
45TNumber of subjects to receive study drug45T....................................................48 
45T10.3.845T 
45TDisposition of subjects45T .................................................................................48 
45T10.3.945T 
45TInterim analysis45T ............................................................................................48 
45T10.3.1045T 
45TBlinding and randomization45T .........................................................................48 
45T10.3.1145T 
45TData presentation45T .........................................................................................48 
45T10.3.11.145T 
45TDemographic and Baseline Characteristics:45T ......................................48 
45T10.3.11.245T 
45TMedical History and Physical Examination:45T......................................49 
45T10.3.11.345T 
45TConcomitant Medications or Treatments:45T ..........................................49 
45T10.3.11.45T 
45TSafety data:45T.........................................................................................49 
45T10.3.11.545T 
45TEfficacy data:45T .....................................................................................49 
45T10.45T 
45TSTUDY ENDPOINTS45T ...........................................................................................50 
45T10.4.145T 
45TPrimary Endpoint45T .........................................................................................50 
45T10.4.245T 
45TExploratory Endpoints45T .................................................................................50 
45T10.545T 
45TMissing and Spurious Data45T ....................................................................................52 
45T1145T 
45TREGULATORY, ETHICAL AND LEGAL OBLIGATIONS45T ........................................53 
45T11.145T 
45TDeclaration of Helsinki45T ..........................................................................................53 
45T11.245T 
45TGood Clinical Practice45T ...........................................................................................53 
45T11.345T 
45TInstitutional Review Boards/Ethics Committees45T ...................................................53 
45T11.45T 
45TRegulatory Authority Approval45T .............................................................................53 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
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45T11.545T 
45TInformed Consent45T...................................................................................................53 
45T11.645T 
45TSubject Confidentiality and Disclosure45T .................................................................53 
45T11.745T 
45TCollection, Monitoring and Auditing Study Documentation, and Data 
Storage45T ...................................................................................................................54 
45T11.7.145T 
45TCollection of Data and Monitoring Procedures45T ...........................................54 
45T11.7.245T 
45TAuditing Procedure45T ......................................................................................54 
45T11.7.345T 
45TRetention of Documents45T ..............................................................................54 
45T11.845T 
45TDisclosure of Information45T ......................................................................................55 
45T11.945T 
45TDiscontinuation of the Study45T .................................................................................55 
45T11.1045T 
45TStudy Report, Publication Policy and Archiving of Study Documentation45T ...........55 
45T11.10.145T 
45TStudy Report and Publication Policy45T ...........................................................55 
45T11.10.245T 
45TStudy Documents45T .........................................................................................55 
45T11.10.345T 
45TArchiving of Documents45T ..............................................................................55 
45T1245T 
45TREFERENCES45T ................................................................................................................57 
45T1345T 
45TAPPENDICES45T .................................................................................................................60 
45TSPONSOR:45T...................................................................................................................60 
 
LIST OF IN-TEXT TABLES 
45TTable 1.5.145T 
45TSummary of Studies Conducted with Ampion™ adminstered as IA 
injection to the knee45T .........................................................................................19 
45TTable 1.5.245T 
45TDescriptive Statistics and Analsysis Results for KL 4 Subjects for each 
study and all studies Combined45T .......................................................................38 
45TTable 1.5.345T 
45TResponder Analysis in KL 4 Subjects across single-injection studies 
using OMERACT-OARSI criteria45T ...................................................................22 
45TTable 1.5.45T 
45TSummary of Treatment-Emergent Adverse Events45T .........................................22 
45TTable 6.245T 
45TSchedule of Assessments and Procedures45T........................................................38 
45TTable 9.1 
Definitions of AE Severity...............................................................................44 
45TTable 9.245T 
45TGuidelines for Determining the Relationship (if any) Between Adverse 
Event and the Study Drug45T ................................................................................44 
 
LIST OF IN-TEXT FIGURES 
45TFigure 1 
LS Mean Change for Ampion-Treated Subjects Over Time and by Study .....21 
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2 
Kellgren Lawrence Grading System ................................................................44 
 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
Version 3.0 26 March 2018 
 
 
 
CONFIDENTIAL 
 
Page 12 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
°C 
degrees Celsius 
°F 
degrees Fahrenheit 
µg 
microgram 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase (SGPT) 
ARDS 
adult respiratory distress syndrome 
AST 
aspartate transaminase (SGOT) 
BP 
Blood pressure 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
cm 
centimeter 
CRF 
case report form 
CRO 
Clinical Research Organization 
Da 
dalton 
DA-DKP 
Asp-Ala diketopiperazine 
dL 
deciliter 
eDC 
electronic data capture 
FDA 
Food and Drug Administration 
g 
11.26 x (RPM/1000)2 x Radius (cm) 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HSA 
human serum albumin 
IA 
intra-articular 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
kDa 
kilodalton 
LDH 
lactic dehydrogenase 
MCH 
mean cell hemoglobin 
MCHC 
mean cell hemoglobin concentration 
MCV 
mean cell volume 
mg 
milligram 
mL 
milliliter 
NA 
not applicable 
ng 
nanogram 
NSAID 
non-steroidal anti-inflammatory drug 
OA 
osteoarthritis 

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Abbreviation 
Definition 
OMERACT-OARSI 
Outcome Measures in Rheumatology Clinical Trials- Osteoarthritis 
Research Society International 
PGA 
patient’s global assessment of disease severity 
PP 
per protocol population 
Radius 
Distance (in Centimeters) from the center of rotation to the bottom of tube 
in the rotor  
RBC 
red blood cell 
REB 
Research Ethics Board 
RPM 
Rounds Per Minute  
SAE 
serious adverse event 
SD 
standard deviation 
SEM 
standard error of the mean 
SMC 
Safety Monitoring Committee 
SOP 
standard operation procedure 
TEAE 
treatment-emergent adverse event 
TEER 
Trans Endothelial Electrical Resistance 
TKR 
Total Knee Replacement 
WBC 
white blood cell 
WCC 
white cell count 
WO 
washout 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 
 

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1 
INTRODUCTION 
HSA has a long history of clinical use as a colloid replacement therapy, dating back over  
60 years. Currently, HSA is approved for the indications of hypovolemia, hypoalbuminemia, 
prevention of central volume depletion after paracentesis due to cirrhotic ascites, ovarian 
hyperstimulation, adult respiratory distress syndrome (ARDS), acute nephrosis, hemolytic 
disease of the newborn and burns. In addition to its effects on oncotic pressure, HSA has 
pharmacological effects including decreased inflammation (Quinlan 2005), decreased 
vascular permeability (Evans 2002) and no adverse effect on cardiac safety (Vincent JL, 
2004).  
 
Ampion™, the < 5 kilodalton (kDa) ultrafiltrate of 5% human serum albumin (HSA), is  
being developed to provide relief for the pain of severe osteoarthritis of the knee. There are 
no currently FDA approved drugs for the indication of pain from severe (KL 4) osteoarthritis 
of the knee for which Ampion is indicated. Ampion is a heterogeneous solution that contains 
several known small molecules and unknown components that may act synergistically. The 
individual contribution(s) of the unknown components to the biologic activity of Ampion 
may not be quantifiable since over 1200 peptides and proteins have been identified in 
commercial HSA preparations [Gay, 2010].  
 
Bar-Or et al found that commercial preparations of HSA are heterogeneous in terms of 
posttranslational modifications, including C- and N-terminal truncation, cysteinylation, 
glycation and nitrosylation (Bar-Or D, 2005). An important modification is the cleavage of 
the two N-terminal amino acids Aspartate (D) and Alanine (A). This occurs by the action of a 
naturally occurring dipeptidase (Bar-Or 2013) present in plasma and also bound to or 
associated with leukocytes and endothelial cells (Ohnuma 2006), and activated during the 
FDA required heat-treatment of commercial preparations of HSA. After cleavage, the 
dipeptide undergoes cyclisation to form a diketopiperazine (aspartylalanyl diketopiperazine 
[DA-DKP]). DA-DKP is found in the low molecular weight fraction (< 5000 Da) of 
commercial lots of HSA at concentrations ranging from approximately 100 μM.in vitro 
studies and its action in human subjects suggest that it is an active ingredient in the 
pharmacological effects of HSA and of Ampion™. Other components, such as N-acetyl 
tryptophan and its metabolites and sodium caprylate present in HSA and Ampion, act 
synergistically with DA-DKP on numerous molecular pathways involved in inflammation, 
nociceptive and neuropathic pain, vascular permeability and the resolution of inflammation 
in various cell types including synoviocytes, chondrocytes, PBMC, macrophages, memory T 
cells, endothelial cells and mesenchymal stem cells (Thomas, GW 2016) (Fredrick ED 2016) 
(Bar-Or 2015) ( Shimonkevitz 2008) (Bar-Or 2006) (Bar-Or 2005) 
1.1 
STUDY DRUG 
Ampion™ is the < 5 kDa ultrafiltrate of 5% HSA. 

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1.2 
BACKGROUND TO THE DISEASE 
Osteoarthritis (OA) remains a leading contributor to global disability, with both hip and knee 
OA accounting for over 17 million years lived with disability (Cross 2014). OA is the most 
common form of arthritis and affects up to 38 million adults in the US alone. OA is caused 
by inflammation of the soft tissue and bony structures of the joint which worsens over time 
and leads to progressive thinning of articular cartilage, narrowing of the joint space, synovial 
membrane thickening, osteophyte formation and increased density of subchondral bone. 
These changes eventually result in chronic pain and disability and deterioration of the joint 
despite drug therapy may require eventual surgery for total joint replacement. OA of the knee 
is defined in stages as noted by Kellgren Lawrence grading: Grade 0 (normal knee; no 
osteophytes or joint space narrowing), Grade 1 (possible osteophytic lipping and doubtful 
narrowing of joint space), Grade 2 (definite osteophytes and possible narrowing of joint 
space), Grade 3 (moderate multiple osteophytes, definite narrowing of joint space and some 
sclerosis, and possible deformity of the bone ends) and Grade 4 (large osteophytes, marked 
narrowing of joint space, severe sclerosis, and definite deformity of bone ends).  
 
Patients with severe OAK, defined radiologically as KL grade 4, have few treatment options 
for pain management. Even with reported difficulties in managing symptoms, including pain, 
a large number of KL 4 patients do not discuss pain or OA during consultations. Many 
patients perceived that they just had to put up with pain until their joint replacement because 
there was nothing else that could be done (McHugh 2007). The net result is that the patients 
control their pain by limiting their activity, and this can progress to the point of losing the 
ability to ambulate in the community. There is a consequent loss of the benefits of activity 
and the conditioning that this provides, leading to a deterioration of health in general, 
including both physical and psychological effects (Cisternas 2016). Difficult-to-treat pain 
conditions, such as severe OAK, are a challenge for both medical and surgical doctors and 
patients. There is no doubt that patients with chronic pain in general suffer from an unmet 
need, as FDA agreed stating that there is an unmet medical need among patients with severe 
osteoarthritis.  
 
The pain associated with osteoarthritis is now thought to be multifactorial. The pathogenesis 
of pain from OA is comprised of both nociceptive and neuropathic pain pathways resulting 
from severely damaged cartilage, exposed subchondral bone, joint innervation, and less 
defined pathways including the synovium. A recent publication in January 2016 (Akinci 
2016) noted that the balance between nociceptive and neuropathic pain shifts towards 
neuropathic pain as the severity of the condition increases. The multifactorial nature of the 
pain of osteoarthritis may make pain control more difficult, particularly in patients with 
severe OA (KL4) The presence of synovitis in KL 4 patients indicates active ‘inflammatory’ 
disease process. These findings were supported with a linear observation of an increasing 
trend correlated with the severity of synovitis related to advancing KL grades. Additionally, 
KL 4 patients have been shown to have lesions that fluctuate with pain, (i.e., fluctuating bone 
marrow lesions and synovitis) related to a high grade of cartilage loss in KL 4 patients 
(Guermazi 2015). These findings were further supported using a unique in vivo imaging 
technique that detected activated and not resting macrophages (Kraus 2016). In a patient 

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cohort that included patients with severe (KL 4) OAK, the quantity of knee-related activated 
macrophages was statistically associated with more severe knee pain and radiographic 
severity of knee OAK.  
 
These data demonstrated that greater macrophage mediated inflammation is a cause of more 
severe pain in KL 4 OAK and provides a rationale whereby Ampion, demonstrated in vitro 
with anti-inflammatory and anti-macrophage activity, may mediate symptomatic relief in this 
patient group. These data further demonstrate the need to examine patients by disease 
severity and supply treatment options for severely diseased patients (Guermazi 2015). 
Ampion has shown anti-inflammatory activity in vitro against macrophages, monocytes, and 
immune cells.  
 
When the clinical trials of Ampion were designed, it was assumed that the vehicle for the 
product, saline, would have little to no effect in reducing pain, stiffness, or improving 
physical function. This control was determined not to be a true placebo, but rather turned out 
to be active treatment.  To address this, Ampio proposed a 12-week Main Study (AP-003-C) 
with a 6:1 randomization to protect the blind and prevent any potential bias associated with 
an open label assessment.  In follow up to the Main Study, Ampio is adding a 40-week add-
on, open label study to address the safety of repeat injections for a year.  The Open Label 
Study will also analyze efficacy using the Western Ontario and McMaster Universities 
Arthritis Index (WOMAC®) osteoarthritis Index 3.1, and the Patient’s Global Assessment of 
disease severity (PGA).  This study will analyze response according to these individual 
criteria as well as responder analysis of OMERACT-OARSI criteria. 
 
The Osteoarthritis Research Society International (OARSI) and Standing Committee for 
Clinical Trials Response Criteria Initiative Outcome Measures in Rheumatology 
(OMERACT) committee, in concert with the international rheumatology community, worked 
to develop a uniform core set of outcome measures for osteoarthritis. While the committee 
initially developed two sets of responder criteria to present the results of changes after 
treatment in three symptomatic domains (pain, function, and patient’s global assessment) as a 
single variable for clinical trials, the committee ultimately worked to create a simplified set 
of responder criteria, Scenario D, which captured the criteria for response.  
 
In the original plan, for each domain, a response was defined by both a relative and an 
absolute change, with different cut-offs with regard to the drug, the route of administration 
and the OA localization. The formal OMERACT-OARSI scenarios defined a responder as: 
 
a. having achieved a high degree of improvement in pain or a moderate degree of 
improvement in 2 of the 3 response domains (pain, function, global assessment) 
(scenario A)  
OR  
b.  as having achieved a high degree of improvement in either pain or function, or a 
moderate degree of improvement in 2 of the 3 response domains (scenario B)  

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The composite index permits presentation of results of symptom modifying clinical trials in 
OA based on individual patient responses (responder yes/no). The use of composite indices 
was still somewhat controversial in that the original OARSI criteria did not account for 
multiplicity of comparisons, however OMERACT-OARSI worked to rectify this and their 
conclusions were presented at the OMERACT 6 conference.  
 
OMERACT and OARSI established a task force aimed at evaluating: (1) the variability of 
observed placebo and active treatment effects using the OARSI responder criteria; and (2) 
the possibility of proposing a simplified set of criteria. Because individual study endpoints in 
studies of NSAIDs in patients with hip or knee osteoarthritis were highly correlated, 
OMERACT-OARSI evaluated six different scenarios to determine whether a simplified set 
of criteria could be developed. The conclusions of the task force were presented and 
discussed during the OMERACT 6 conference, where a simplified set of responder criteria 
(OMERACT-OARSI set of criteria) was proposed. Scenario D was chosen by the members, 
indicating the importance of having both a relative change and an absolute change as part of 
the criteria for response.  
 
The criteria for a responder using the Likert Scale, where the 20-point change on the VAS 
scale is the same as a 1-point change on the Likert Scale and, similarly, the 10-point change 
in the VAS scale is the same as a 0.5-point change on the Likert Scale, are defined as:  
 
1. High improvement in pain or in function ≥ 50% and absolute change in Likert pain 
scale of ≥1 OR  
2. Improvement in at least two of the 3 following:  
a. pain ≥ 20% and absolute change in Likert score ≥0.5  
b. function ≥ 20% and absolute change in Likert score ≥0.5  
c. patient’s global assessment ≥ 20% and absolute change in Likert score ≥0.5  
 
1.3 
PREVIOUS HUMAN EXPERIENCE 
In addition to the extensive clinical experience with HSA, Ampio Pharmaceuticals, Inc. has 
completed multiple clinical studies to evaluate the safety and treatment effect of Ampion in 
subjects with OAK. The study is summarized in Section 1.5. 
1.4 
PRECLINICAL DATA 
1.4.1 
Pharmacology Studies 
In vitro pharmacology studies demonstrated that a low molecular weight fraction (< 3000 
daltons [Da]) of more than five commercial preparations of HSA, and a cyclized dipeptide 

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contained in that fraction, Asp-Ala diketopiperazine (DA-DKP) have a range of anti-
inflammatory properties, which may be expected to ameliorate the symptoms of 
inflammation, including pain, in man (Bar-Or et al 2006). These studies showed reduced 
inflammatory cytokine production from human T lymphocytes in vitro via modulation of 
signal transduction through increased expression of Rap-1, and inhibition of macrophage 
activation. In addition, DA-DKP enhanced integrity of human endothelial cell junctions in 
the transendothelial electrical resistance (TEER) assay, which would result in decreased 
vascular permeability to the influx of inflammatory cells in vivo. No pharmacokinetics 
studies were performed as the plasma levels of the constituents of the < 5000 Da preparation, 
including DA-DKP, after intra-articular injection of a therapeutic dose in man or in 
laboratory animals are anticipated to be below the limits of detection. For more information, 
consult the Investigator Brochure. 
1.4.2 
Toxicity and Safety Studies 
HSA and other components of serum albumin preparations are species specific and may be 
expected to be immunogenic if repeatedly injected into non-human species, even at very low 
concentrations.  For this reason, it was not possible to perform formal toxicological studies in 
animals. 
1.5 
CLINICAL EXPERIENCE 
Ampio has conducted multiple clinical studies to evaluate the treatment effect and safety of 
Ampion in subjects with OAK. Ampion has been administered across 6 clinical studies as a 
single intra articular (IA) injection or as three IA injections administered every two weeks. 3 
single-dose pivotal Phase 3 studies, 2 multi-dose studies, and 1 multiphase single-dose phase 
1b study have been completed. An overview of the efficacy studies is provided in the Table 
1.5.1  
 
For the clinical development program, all studies were conducted in subjects with moderate 
to moderately severe pain due to OA of the knee. Subjects were required to have x-ray 
findings demonstrating KL grade 2, 3, or 4. All studies enrolled subjects with KL 4. In 
addition, eligible subjects had at least moderate pain at Baseline (defined as a score of at least 
1.5 on the WOMAC Index 3.1, 5-point Likert pain subscale at screening) in the study knee, 
which was to have been symptomatic for greater than 6 months with a clinical diagnosis of 
OA confirmed by radiological evidence. The clinical effects of treatment on OA pain were 
evaluated during clinic visits, with phone call follow-ups at intermittent times.  
 
 
 
 
 
 

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Table 1.5.1 
Summary of the Studies Conducted with Ampion™ Administered as an Intra Articular 
Injection to the Knee 
 
Study 
Phase 
N 
N, 
KL 2, 3, 4 
Route of 
Administration 
Primary 
outcome 
Primary 
endpoint 
Additional 
outcomes 
Test product 
Single-Injection Phase 3 Studies in Support of Efficacy & Safety 
AP-003- A 
3 
329 
115 / 139 / 75 
Single IA 
injection 
WOMA 
C A 
pain, 5- 
point 
Likert 
scale 
Week 12 WOMAC B 
WOMAC C 
PGA 
OMERACT 
-OARSI 
Rescue 
analgesia 
Ampion, 4-
mL or 
10ml* 
AP-004 
3 
538 
133 / 195/ 
210 
Single IA 
injection 
WOMA 
C A 
pain, 5- 
point 
Likert 
scale 
Week 12 WOMAC C 
PGA 
WOMAC A 
pain over 12 
weeks 
Ampion, 4-
mL 
AP-003- B 
3 
480 
101 / 247 / 
132 
Single IA 
injection 
WOMA 
C A 
pain, 5- 
point 
Likert 
scale 
Week 12 WOMAC B 
WOMAC C 
PGA 
Rescue 
analgesia 
WOMAC A 
pain with 
movement, 
pain at rest 
Ampion, 4-
mL 
Additional Clinical Studies in Support of Safety 
AP-007 
1 / 2 
47 
2 / 23/ 15 
Multiple IA 
injection; 
3 injections, 
every 2 weeks 
WOMA 
C A 
pain, 5- 
point 
Likert 
scale 
Week 20 
WOMAC B 
WOMAC C 
PGA 
Physical 
activity 
Radiologic 
changes 
Ampion, 4-mL 

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AP-008 
3 
342 
0 / 114 / 228 
Multiple IA 
injection; 
3 injections, 
every 2 weeks 
WOMA 
C A 
pain, 5- 
point 
Likert 
scale 
Week 20 
WOMAC B 
WOMAC C 
PGA 
Physical 
activity 
WOMAC A 
pain with 
movement 
Ampion, 4-mL 
AIK 
1 / 2 
103 
33 / 69 / 1 
Single IA 
injection 
Pain, 10- 
point 
NRS 
Day 3, 8, 
30 and 
84 
WOMAC 
total, parts 
A, B, C 
Range in 
motion 
Rescue 
analgesia 
Ampion 10 ml, 
alone or in 
solution with 
betamethasone 
and/or 
lidocaine 
and/or 
saline 
Total 
1839 
*Both doses of Ampion, 4-mL and 10 mL, are safe, efficacious and well tolerated. In the absence of a difference in 
efficacy for the 4-mL and 10 mL Ampion doses, the lower dose of 4-mL will be used for subsequent phase 3 studies. 
 
In all three well-controlled, single-injection studies, Ampion demonstrated a numerically 
greater effect in the KL 4 subjects compared to saline, indicating a reproducible and 
consistent response. Analysis of the combined data demonstrate a statistically significant 
result in this underserved patient population. Table 1.5.2 presents the data for KL 4 subjects 
from all single-injection studies, analyzed according to the SAP for the respective study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1.5.2 
Descriptive Statistics and Analysis Results for KL 4 Subjects for Each Study and All Studies 
Combined 
 
 
 
Figure 1 visually represents the consistent reduction in pain for Ampion-treated subjects over 
a 12-week period. 
 
 
Figure 1. 
LS Mean Change for Ampion-Treated Subjects Over Time and by Study 
 
 
 
 
 
 
 
 

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In accordance with FDA guidance on osteoarthritis, responder analysis according to the 
OMERACT-OARSI criteria was applied to previously conducted clinical trials, Table 1.5.3. 
 
Table 1.5.3 
Responder analysis in KL 4 subjects across single injection studies using OMERACT-OARSI criteria 
 
Study ID 
Ampion Responder 
(%) 
AP-003-A 
59.4% 
AP-003-B 
59.7% 
AP-004 
57.7% 
Combined 
58.6% 
 
In addition to the efficacy analysis described in this section, Ampion has also demonstrated a 
robust safety profile across the three well-controlled, single-injection studies, as well as the 
multiple-injection and early phase trials (Table 1.5.4). No drug-related Serious Adverse 
Events (SAEs) have been reported in 1,839 subjects treated during the clinical development 
program. The Adverse Event (AE) profile is similar for Ampion and saline, with a majority 
of the AEs of minor or moderate severity and unrelated to treatment. 
 
Table 1.5.4 
Summary of Treatment-Emergent Adverse Events 
 
Treatment emergent AE 
Saline 
Ampion 
Overall 
N=907 
N=932 
One or more TEAE 
425 (47%) 
421 (45%) 
One or more related TEAE 
63 (7%) 
73 (8%) 
KL grade 4 
N=338 
N=326 

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One or more TEAE 
150 (44%) 
145 (44%) 
One or more related TEAE 
20 (6%) 
24 (7%) 
 
Conclusions 
 
Clinical efficacy observed in previous single-injection studies suggest that Ampion safely 
relieves pain due to severe, KL 4, osteoarthritis of the knee, the most severe form of OAK, 
for which there is no FDA approved treatment alternative. While opioids can treat pain, and 
total knee replacement can excise the affected tissues, the ability to treat OAK pain and 
inflammation locally is an unmet medical need. Currently, when KL 4 subjects are treated for 
OAK, they are receiving treatment using intra-articular therapy (such as 
viscosupplementation) that were not studied, nor required in their device approvals to 
demonstrate efficacy in the KL 4 population (Rutjes 2012). Without surgery, with only a 
single intra-articular injection of Ampion, KL 4 subjects are able to achieve clinically 
meaningful pain relief. 
 

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2 
RATIONALE FOR THE STUDY 
This study is designed to follow on from the 12-week AP-003-C main study. This is an open 
label extension (OLE) to evaluate the safety of repeated dosing of a 4-mL IA injection of 
Ampion™ every 12 weeks for a total of 52 weeks of study visits.   
2.1 
RATIONALE FOR THE DOSES AND THE DOSING REGIMEN 
This trial will use the 4-mL volume of Ampion™ used in previous single-injection studies 
(AP-003-A, AP-004, AP-003-B, and AP-003-C). 

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3 
STUDY DESIGN 
3.1 
STUDY DESIGN OVERVIEW 
Subjects who have completed the AP-003-C main study (n=161) will be offered the option to 
roll-over to the open label extension study (AP-003-C-OLE) at their final visit of the AP-
003-C main study (Visit 7). Enrollment into the AP-003-C-OLE study (Visit 9) allows a 170-
day screening window from the AP-003-C main study Visit 7.  AP-003-C-OLE study will 
include the following visits: 
Visit 9/Enrollment (Day-170 to Day 0, but not to occur before completion of AP-003-C main 
study) in-office visit, Visit 10 (24 hours after enrollment post injection follow-up telephone 
call), Visit 11 in-office visit (Day 84 ±14 days), Visit 12 (24 hours after Visit 11 post 
injection follow-up telephone call), Visit 13 in-office visit (Day 168 ± 14 days), Visit 14 (24 
hours after Visit 13 post injection follow-up telephone call), Visit 15 in-office visit (Day 252 
± 14 days), Visit 16 (24 hours after visit 15 post injection follow-up telephone call), Visit 17 
final in-office visit (Day 280 ± 14 days). 
The safety of repeat dosing will be evaluated at all visits; in-office visit safety assessments 
will include vital signs, physical exams, evaluation of AEs, and laboratory analysis. Phone 
visits will evaluate for AEs. 
The clinical effects of treatment on OA pain will be evaluated during all in-clinic visits using 
the Western Ontario and McMaster Universities Arthritis Index (WOMAC®) osteoarthritis 
Index 3.1 and the Patient’s Global Assessment of disease severity (PGA). The WOMAC will 
also be utilized to assess the contralateral knee pain at Enrollment/Visit 9 and Visit 17 (or 
Early Termination Visit). 
The WOMAC® is a validated pain scoring system and sets the standard for the subject 
response. In order not to bias the collection of data, only questions from the validated 
WOMAC pain scale will be asked of subjects. 
3.2 
STUDY OBJECTIVES 
3.2.1 
Primary Objective 
The primary trial objective is to carry on from the AP-003-C main study (one injection) and 
evaluate the safety of a 4-mL intra-articular (IA) injection of Ampion™ with repeat dosing 
every 12 weeks for 52 weeks and/or with five total injections of Ampion™. 
3.2.2 
Exploratory Objectives 
The exploratory objectives are to analyze the efficacy of a 4-mL intra-articular (IA) injection 
of Ampion™ with repeat dosing every 12 weeks for 52 weeks and/or with five total 
injections of Ampion™. 

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3.3 
SAFETY MONITORING COMMITTEE 
A Safety Monitoring Committee (SMC) will be established to review the safety of Ampion™ 
as the study progresses.  The SMC will consist of independent clinicians not involved in the 
clinical trial, the Medical Monitor and Ampio Pharmaceuticals, Inc. representatives.  The 
SMC 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.  A charter will be developed to detail the SMC review responsibilities, the 
frequency of meetings, and data evaluation plans. 
3.4 
STOPPING RULES 
The entire study may be stopped under defined circumstances as outlined in Section 7. 
3.5 
STUDY ENDPOINTS 
3.5.1 
Primary Endpoint 
• Evaluate the incidence and severity of treatment-emergent adverse events (TEAEs) 
3.5.2 
Exploratory Endpoints 
• Responder status based on the OMERACT-OARSI responder criteria  
• Evaluate OMERACT-OARSI ‘controlled’ responder defined as a 20% improvement in 
Pain and Function and 0.5 point absolute change in the 5-point Likert Scale  
• Evaluate 20% improvement in PGA and 0.5 point absolute change in the 5-point Likert 
Scale 
• Mean change and percent change in WOMAC A pain subscore  
• Mean change and percent change in WOMAC B stiffness subscore  
• Mean change and percent change in WOMAC C physical function subscore  
• Mean change and percent change in PGA  
• Mean Change and percent change in WOMAC A pain subscore questions 1 and 2 (pain 
with movement)  
• Mean Change and percent change in WOMAC A pain subscore questions 3−5 (resting 
pain)  
• Change in contralateral knee pain (WOMAC A)  
• Change in contralateral knee stiffness (WOMAC B)  
• Change in contralateral knee function (WOMAC C)  
• Time to Total Knee Replacement (TKR) 
• Use of rescue analgesia (amount of acetaminophen used) 

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3.6 
BLINDING AND RANDOMIZATION 
All subjects will receive Ampion 4-mL which is provided in study kits.  Each kit will contain 
labeled vials, a syringe, a needle and rescue medication.   

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4 
SELECTION OF SUBJECTS 
4.1 
NUMBER OF SUBJECTS 
A total of approximately 161 subjects will be enrolled from the AP-003-C main study into 
the AP-003-C-OLE study.  
4.2 
INCLUSION CRITERIA 
1. Participation and completion in the AP-003-C study 
2. Able to provide written informed consent to participate in the study 
3. Willing and able to comply with all study requirements and instructions of the site study 
staff 
4. Male or female, 40 years to 85 years old (inclusive), as assessed in the AP-003-C main 
study 
5. Must be ambulatory, as assessed in the AP-003-C main study   
6. Study knee must have a clinical diagnosis of OA and supported by radiological evidence 
(Kellgren Lawrence Grade 4) as assessed in the AP-003-C main study.  
7. Moderate to moderately-severe OA pain in the index knee (rating of at least 1.5 on the 
WOMAC Index 3.1 5-point Likert Pain Subscale), as assessed in the AP-003-C main 
study 
8. Moderate to moderately-severe OA function in the index knee (rating of at least 1.5 on 
the WOMAC Index 3.1 5-point Likert Function Subscale), as assessed in the AP-003-C 
main study 
9. WOMAC A, 5-point Likert pain subscale <1.5 in the contralateral knee, as assessed in 
the AP-003-C main study 
10. Ability to discontinue NSAID ±72 hours before/after injections (in-office visits). Low-
dose Aspirin (81 mg) is allowed during the study but must not be taken at least 24 hours 
prior to in-office visits. 
11. No analgesia (including acetaminophen [paracetamol]) taken 24 hours prior to an 
efficacy measure 
4.3 
EXCLUSION CRITERIA 
Subjects fulfilling one or more of the following criteria may not be enrolled in the study: 
1. As a result of medical review and screening investigation, the Principal Investigator 
considers the subject unfit for the study 
2. Known clinically significant liver abnormality (e.g. cirrhosis, transplant, etc.) 
3. A history of allergic reactions to human albumin (reaction to non-human albumin such as 
egg albumin is not an exclusion criterion) 
4. A history of allergic reactions to excipients in 5% human albumin (N-acetyltryptophan, 
sodium caprylate) 
5. Presence of tense effusions 

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6. Inflammatory or crystal arthropathies, acute fractures, history of aseptic necrosis or joint 
replacement in the affected knee 
7. Isolated patella femoral syndrome, also known as chondromalacia 
8. Any other disease or condition interfering with the free use and evaluation of the index 
knee for the duration of the trial (e.g. cancer, congenital defects, spine OA) 
9. Major injury to the index knee within the past 12 months  
10. Severe hip OA ipsilateral to the index knee 
11. Any pain that could interfere with the assessment of index knee pain (e.g. pain in any 
other part of the lower extremities, pain radiating to the knee) 
12. Any pharmacological or non-pharmacological treatment targeting OA started or changed 
during the 4 weeks prior to enrollment in the OLE study or likely to be changed during 
the duration of the study 
13. Pregnancy or planning to become pregnant during the study 
14. Use of the following medications: 
a. No IA injected pain medications in the study knee during the study. HA and steroid 
injections in the contralateral knee (non-study knee) are acceptable while on study 
except ± 14 days of an Ampion™ injection in the study knee.                
b. No analgesics containing opioids.  
c. NSAIDs are not permitted ± 72 hours before/after IA injections (in-office visits); 
acetaminophen is available as a rescue medication during the study from the provided 
supply. 
d. No topical treatment on the study knee during the study  
e. No significant anticoagulant therapy (e.g. Heparin or Lovenox) during the study 
(treatment such as Aspirin and Plavix are allowed) 
f. No systemic treatments that may interfere with safety or efficacy assessments during 
the study 
g. No immunosuppressants 
h. No use of corticosteroids  
i. No human albumin treatment in the 3 months prior to the AP-003-C main study or 
interim period prior to enrollment into the OLE study.  No human albumin treatment 
throughout the duration of the OLE study. 
4.4 
INCLUSION OF SUBJECTS INCAPABLE OF GIVING INFORMED 
CONSENT 
No subject incapable of giving informed consent may be enrolled in the study. 

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5 
STUDY PLAN AND PROCEDURES 
Subjects will receive an IA injection of Ampion™ at Visit 9, Visit 11, Visit 13 and Visit 15 
of AP-003-C-OLE. Telephone contact will be made with the subject 24 hours after each IA 
injection. The subject will be followed until Visit 17.  Safety of repeat injections every 12 
weeks for 36 weeks will be evaluated during every visit (in-clinic and telephone); in office- 
visits will evaluate vital signs, physical exam, adverse events, and blood tests (Visit 17 or 
Early Termination Visit 18 only).  Clinical effects of treatment on OA pain will be evaluated 
during in-clinic visits at Visit 9, Visit 11, Visit 13, Visit 15 and Visit 17 using the WOMAC 
osteoarthritis Index 3.1 (pain subscore, stiffness subscore and function subscore) and an 
overall global severity assessment (Patient’s Global Assessment [PGA]). The WOMAC will 
also be utilized to assess the contralateral knee pain at Visit 9 and Visit 17 (or Early 
Termination Visit). 
The assessments and procedures performed at each subject visit or contact are described in 
Section 5.1 Description of Study Visits and in Table 6.1, Schedule of Assessments and 
Procedures. 
5.1 
DESCRIPTION OF STUDY VISITS 
5.1.1 
Visit 9 (day -170 to Day 0, in-clinic); Enrollment 
The following procedures will be performed at Visit 9 (Day 0): 
• Obtain written informed consent for AP-003-C-OLE study before the start of any study 
specific procedure. 
• Review medical history including all previous treatments for OA. 
• Evaluate for any AEs ongoing from AP-003-C main study and/or new AEs pre-
injection. 
• Record prior and concomitant medications including start/stop dates, indication, dose 
and frequency. 
• Record demographic data including year of birth, age, gender and race. 
• Measure and record height and weight. 
• Obtain hCG urine analysis for women of child-bearing potential 
• Perform and record physical examination (prior to injection) 
• Record Kellgren Lawrence Grade from radiological assessment, as assessed in AP-003-
C main study.  
• Complete the WOMAC Index 3.1. for the study knee (prior to injection) 
• Complete the WOMAC Index 3.1 for the contralateral knee (prior to injection) 
• Complete the PGA for the study knee (prior to injection) 
• Evaluate all inclusion and exclusion criteria to ensure that subjects meet all inclusion 
criteria and none of the exclusion criteria. 

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• Record vital signs. (Measure body temperature, systolic / diastolic blood pressure [BP] 
and pulse rate) pre- and post-injection. 
• Perform intra-articular injection of study drug. 
• Record post-injection AEs if observed. 
• Record concomitant medications. 
• Issue rescue medication (acetaminophen [paracetamol]). 
5.1.2 
Visit 10 (24 hours following Visit 9, post-injection follow-up telephone 
call) 
The following procedures will be performed at Visit 10 
• Record AEs. 
• Record concomitant medications. 
• Review rescue medication use. 
5.1.3 
Visit 11 (Day 84 ± 14 days, in-clinic); Week 12 
The following procedures will be performed at Visit 11: 
• Perform and record physical examination.(prior to injection) 
• Record vital signs. (Measure body temperature, systolic / diastolic blood pressure [BP] 
and pulse rate) pre- and post-injection. 
• Complete the WOMAC Index 3.1. for the study knee (prior to injection) 
• Complete the PGA for the study knee (prior to injection) 
• Perform intra-articular injection of study drug. 
• Record post-injection AEs if observed. 
• Record concomitant medications. 
• Review/Issue rescue medication (acetaminophen [paracetamol]). 
5.1.4 
Visit 12 (24 hours following Visit 11, post-injection telephone call) 
The following procedures will be performed at Visit 12: 
• Record AEs. 
• Record concomitant medications. 
• Review rescue medication use. 
5.1.5 
Visit 13 (Day 168 ± 14 days, in-clinic); Week 24 
The following procedures will be performed at Visit 13: 
• Perform and record physical examination.(prior to injection) 
• Record vital signs. (Measure body temperature, systolic / diastolic blood pressure [BP] 
and pulse rate) pre- and post-injection. 

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• Complete the WOMAC Index 3.1. for the study knee (prior to injection) 
• Complete the PGA for the study knee (prior to injection) 
• Perform intra-articular injection of study drug. 
• Record post-injection AEs if observed. 
• Record concomitant medications. 
• Review/Issue rescue medication (acetaminophen [paracetamol]). 
5.1.6 
Visit 14 (24 hours following Visit 13, post-injection telephone call) 
The following procedures will be performed at Visit 14: 
• Record AEs. 
• Record concomitant medications. 
• Review rescue medication use. 
5.1.7 
Visit 15 (Day 252 ± 14 days, in-clinic); Week 36 
The following procedures will be performed at Visit 15: 
• Perform and record physical examination.(prior to injection) 
• Record vital signs. (Measure body temperature, systolic / diastolic blood pressure [BP] 
and pulse rate) pre- and post-injection. 
• Complete the WOMAC Index 3.1. for the study knee (prior to injection) 
• Complete the PGA for the study knee (prior to injection) 
• Perform intra-articular injection of study drug. 
• Record post-injection AEs if observed. 
• Record concomitant medications. 
• Review/Issue rescue medication (acetaminophen [paracetamol]). 
5.1.8 
Visit 16 (24 hours following Visit 15, post-injection telephone call) 
The following procedures will be performed at Visit 16: 
• Record AEs. 
• Record concomitant medications. 
• Review rescue medication use. 
5.1.9 
Visit 17 (Day 280 ± 14 days, in-clinic final visit); Week 40 
The following procedures will be performed at Visit 17: 
• Perform and record physical examination. 

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• Record vital signs. (Measure body temperature, systolic / diastolic blood pressure [BP] 
and pulse rate)  
• Complete the WOMAC Index 3.1. for the study knee 
• Complete the WOMAC Index 3.1 for the contralateral knee  
• Complete the PGA for the study knee  
• Record if subject was able to delay TKR by participation in study 
• Record AEs if observed. 
• Record concomitant medications. 
• Draw safety labs 
• Obtain x-ray of study knee 
• Review/Collect rescue medication (acetaminophen [paracetamol]). 
5.1.10 
Early Termination Visit  
The following procedures will be performed at Early Termination Visit: 
• Perform and record physical examination. 
• Record vital signs. (Measure body temperature, systolic / diastolic blood pressure [BP] 
and pulse rate)  
• Complete the WOMAC Index 3.1. for the study knee  
• Complete the WOMAC Index 3.1 for the contralateral knee 
• Complete the PGA for the study knee  
• Record if subject was able to delay TKR by participation in study 
• Record AEs if observed. 
• Record concomitant medications. 
• Draw safety labs 
• Obtain x-ray of study knee (excluding subjects who terminate in order to receive TKR) 
• Review/Collect rescue medication (acetaminophen [paracetamol]). 
5.1.11 
Unscheduled Visits 
Additional visits may be scheduled at the discretion of the Investigator, for example as part 
of follow up of AEs.  
5.1.12 
Missed Visits 
Subjects unable to complete a study visit as scheduled should be re-scheduled for a 
replacement visit as soon as possible. If a subject misses any scheduled follow up visit and 
cannot be seen prior to the start of the visit range for the next follow up visit, the visit is 
considered missed.  
 
 

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5.1.13 
CONCOMITANT MEDICATIONS 
The following medications / therapies are NOT allowed during this clinical study:  
1. No IA injected pain medications in the study knee during the study. HA and steroid 
injections in the contralateral knee are acceptable while on study except ± 14 days of 
Ampion injection in the study knee. 
2. No analgesics containing opioids.  
3. NSAIDS may not be used ± 72 hours before/after IA injection of Ampion (in-office 
visits).  Low-dose Aspirin (81 mg) is allowed but should not be used at least 24 hours 
prior to an in-office visit.  Acetaminophen is available as a rescue medication during 
the study from the provided supply. 
4. No non-pharmacological treatment targeting OA started or changed during the study. 
5. No topical treatment on osteoarthritis study knee during the study. 
6. No significant anticoagulant therapy (e.g. Heparin or Lovenox) during the study 
(treatment such as Aspirin or Plavix is allowed). 
7. No systemic treatments that may interfere with safety or efficacy assessments during 
the study. 
8. No immunosuppressants. 
9. No use of systemic or intra-articular corticosteroids. 
10. No human albumin treatment during the study. 
Any medication used during the study should be recorded.  All concomitant medication start 
and stop dates, total daily dose, route, and indication should be recorded. 
The provided rescue medication during the 40-week extension study is 500 mg of 
acetaminophen, 1 tablet every 4 hours as required by the subject, not to exceed 3,000 mg of 
acetaminophen in a 24-hour period.  Dose must be reduced if using other medications that 
contain acetaminophen (cold medicines, etc.).  

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6 
METHODS OF ASSESSMENT 
Demographic Data 
At Visit 9 (Day 0), subject demographic data will be collected.  These include: year of birth, 
age, gender and race. 
Medical History 
At Visit 9 (Day 0) a complete medical history, including prior interventions to the study 
knee, will be obtained from each subject. 
Concomitant Medications 
Detailed history of medications will be documented for each subject at Visit 9 (Day 0). 
Concomitant medications (especially any changes in medication) will be documented for 
each subject at each scheduled visit. 
Physical Examination and Vital signs 
Height in feet and inches will be measured at Visit 9 (Day 0). 
Body weight in pounds (lb) will be measured at Visit 9 (Day 0). 
Body temperature (deg. F) will be measured at each visit. 
Systolic and diastolic BP and pulse rate will be measured with the subject in a seated 
position.  
The full physical examination will consist of examining the following body systems: 
cardiovascular, respiratory, abdominal, skin and musculoskeletal other than the knee. The 
physical examination of the study knee will consist of evaluating the knee joint for effusion 
and tenderness on palpation. 
Kellgren-Lawrence Grading Scale 
Radiographic images are evaluated according to the Kellgren-Lawrence Grading Scale as 
noted below in Figure 2, as assessed in the Main Study 
FIGURE 2: Kellgren-Lawrence Grading System 
Grade 
Description 
0 
Normal knee without osteophytes or joint space narrowing 
1 
Possible osteophytic lipping and doubtful narrowing of joint space 

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2 
Definite osteophytes and possible narrowing of joint space 
3 
Moderate multiple osteophytes, definite narrowing of joint space and some 
sclerosis and possible deformity of bone ends 
4 
Large osteophytes, marked narrowing of joint space, severe sclerosis and 
definite deformity of bone ends 
6.1 
EFFICACY ASSESSMENTS 
Note: Efficacy questionnaire questions will be asked “with reference to study knee” i.e. to 
obtain scores specific for the treated knee. 
6.1.1 
WOMAC® Osteoarthritis Index (Bellamy 1988) 
WOMAC Index 3.1 should be completed by subjects at each in-clinic visit, pre-dose. All 
subjects are required to take at least 5 minutes to complete the questionnaire. 
Subjects are asked about their pain, stiffness, and function in the study knee (study joint) due 
to arthritis during the last 24 hours.  This will be assessed at every in-office visit. 
Subjects will also be asked about their pain, stiffness, and function in the non-study knee.  
This will be assessed at Enrollment and Visit 17 (or early termination visit). 
Subjects respond to each subscale by using a 5-point adjectival Likert score (0 = none, 
1 = mild, 2 = moderate, 3 = severe, 4 = extreme). 
6.1.2 
Patient’s Global Assessment of Disease Severity (PGA) 
The PGA should be completed by subjects at each in-clinic visit (prior to injection). 
Subjects are asked the following question: “Considering all the ways in which your arthritis 
affects you, please indicate how you are doing.” 
Subjects respond by using a 5-point adjectival Likert score (0 = very well, 1 = well, 2 = fair,  
3 = poor, 4 = very poor). 
6.2 
SAFETY PARAMETERS 
Based on results of previous studies of a single intra-articular injection of Ampion™ < 5 kDa 
ultrafiltrate of 5% HSA in adults with OA of the knee in which no clinically significant 
differences between active and placebo were found, safety will be assessed by recording 
adverse events, vital signs, results of physical examination, by recording prior and 
concomitant medications, and safety labs (at the Visit 17/Early Termination visit only).  

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6.2.1 
Vital Signs 
Vital signs (radial pulse rate, blood pressure, and body temperature) should be recorded at 
each in-clinic visit, both pre-and post-dose (as applicable). 
Vital signs should be taken after the subject has rested in a seated position for at least 
5 minutes. 
6.2.2 
Clinical laboratory tests 
Subjects will have lab tests at Visit 17 (or Early Termination) to evaluate for changes from 
Screening (Visit 1) of the Main Study. 
The following analysis will be conducted: 
Serum biochemistry: Sodium, potassium, chloride, bicarbonate, glucose, urea, creatinine, 
creatine kinase, urate, phosphate, total calcium, cholesterol, albumin, globulins, protein, total 
bilirubin, conjugated bilirubin, gamma glutamyltransferase (GGT), alkaline phosphatase 
(ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate 
dehydrogenase (LD). 
Hematology: Hemoglobin, red blood cell count, hematocrit, mean cell volume (MCV), mean 
cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), platelets, white cell 
count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. 

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TABLE 6.1 SCHEDULE OF ASSESSMENTS AND PROCEDURES 
 
Enrollment1 
Post- 
treatment  
phone contact 
Week 12 
Post-
treatment 
phone 
contact 
Week 24 
Post-
treatment 
phone 
contact 
 
Week 36 
Post-
treatment 
phone 
contact 
Week 40 
Final Visit 
 
Early 
Termination 
Visit # 
Day # 
91 
Day -170 to 
 Day 0 
10 
24 hours 
following 
Visit 9 
11 
Day 84 ± 
14 days 
12 
24 hours 
following 
Visit 11 
13 
Day 168 ± 
14 days 
14 
24 hours 
following 
Visit 13 
15 
Day 252 ± 
14 days 
16 
24 hours 
following 
Visit 15 
17 
Day 280 ± 
14 days 
18 
Early 
Termination 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusio
n criteria 
X 
 
 
 
 
 
 
 
 
 
Medical 
history/prior 
medications 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital Signs 
X 
 
X 
 
X 
 
X 
 
X 
X 
WOMAC2 
X2 
 
X 
 
X 
 
X 
 
X2 
X2 
Subject’s global 
assessment (PGA) 
X 
 
X 
 
X 
 
X 
 
X 
X 
X-ray 
X3 
 
 
 
 
 
 
 
X 
X8 
Clinical laboratory 
tests 
 
 
 
 
 
 
 
 
X 
X 
Urine Analysis4 
X4 
 
 
 
 
 
 
 
 
 
Treatment with 
study drug 
X 
 
X 
 
X 
 
X 
 
 
 
Rescue 
medication5 
X5 
 
X 
 
X 
 
X 
 
X 
X 
Review Rescue 
medication6 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Subjects have 170 days to roll over from the AP-003-C main study (Visit 7) to this AP-003-C-OLE study (Visit 9).  The first injection of the AP-003-C-OLE study is 
considered “Day 0”.  Visit 8 is accounted for in the AP-003-C main study in the event of Early Termination.  
2. 
WOMAC also assessed for contralateral knee at Visit 9 and Visit 17 (or Early Termination visit, if applicable). 
3. 
X-ray as assessed during Screening of AP-003-C main study. 

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4. 
For women of child-bearing potential, a HCG urine analysis must be completed at Visit 9 prior to enrollment in AP-003-C-OLE study to verify subject is not pregnant. 
5. 
Rescue medication provided at Visit 9 and then as needed throughout the study.  Bottles must be collected prior to dispensing a new bottle and at termination of AP-
003-C-OLE study.  
6. 
Use of rescue medication should be reviewed during each visit. 
7. 
AEs at Visit 9 should be evaluated for ongoing AEs from the AP-003-C main study (pre-injection) and AEs occurring after injection. 
8. 
X-ray to be obtained at Visit 18 unless subject terminates in order to get TKR.  X-ray is unnecessary in this case. 

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7 
DISCONTINUATION CRITERIA 
7.1 
EARLY DISCONTINUATION OF THE STUDY 
It is agreed that for reasonable cause, either the investigator or the Sponsor may terminate this 
study, provided a 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 Safety 
Monitoring Committee 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 SMC if 1 or more subjects 
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 
• Anaphylaxis (angioedema, hypotension, shock, bronchospasm, hypoxia, or respiratory 
distress) 
• Induction of autoimmune arthritis  
• Hepatic failure 
• Aplastic anemia.  
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. 
7.2 
EARLY DISCONTINUATION OF INDIVIDUAL SUBJECTS 
Subjects are to be withdrawn from the study for any of the following reasons: 
• Withdrawal of informed consent 
• Subject is lost to follow up. 
Subjects will also be withdrawn at any time if the investigator concludes that it would be in the 
subject’s best interest for any reason.  Protocol violations do not lead to subject withdrawal 
unless they constitute a significant risk to the subject’s safety. 
Subjects can voluntarily withdraw from the trial for any reason at any time. Sites should record 
the specific reason for withdrawing. Subjects are to be considered withdrawn if they state an 
intention to withdraw, fail to return for visits, or become lost to follow up for any reason. 
Subjects withdrawing from the study because of an AE should be followed for at least 30 days, 
resolution of the AE or until no further improvement is expected, whichever comes first.   
 
 

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8 
TREATMENT 
Eligible subjects will receive a single intra-articular injection every 12 weeks into one knee of 
Ampion™ at a volume of 4ml. 
8.1 
DOSING AND ADMINISTRATION OF STUDY MEDICATION 
Appropriately trained site personnel should administer the study treatment. 
It is required that the same study knee assessed in the AP-003-C main study be the same study 
knee in the AP-003-C-OLE study.  At the time of dose administration, the study knee should be 
treated with received investigational product.  The other knee should receive standard of care. 
It is recommended that the study treatment be administered as an injection into the knee joint 
space under sterile prep conditions, (i.e. prior to injection, the knee should be cleaned with an 
antiseptic) to a subject who is in the seated position with the treatment knee flexed at 90̊. The 
area of injection is inferior lateral to the patella; lateral level of the joint line. The Principal 
Investigator may determine whether anesthesia of the treatment area with a topical anesthesia, 
sub-dermal anesthesia, or nothing is appropriate. Intra-articular injection of lidocaine or other 
numbing agents are not allowed. 
The recommended needle of choice for this injection is a 25-gauge needle that is 1.5 inches 
long. The needle may be passed through the fat pad to the firm surface of the intercondylar 
notch. Following the withdrawal of the needle, it is recommended that fingertip pressure be 
applied to the injection site, and then a sterile dressing (band aid) is used to cover the injection 
site. Injection should proceed easily. Failure to easily inject should be documented as a 
potential non-inter-articular injection.  
The date of administration should be recorded in the study source notes/eCRF. 
Subjects should be advised to abstain from submersing their knee in water for at least 24 hours 
(swimming pool, baths, lakes, etc.).  Showering is acceptable. 
8.2 
DRUG STORAGE AND ACCOUNTABILITY 
Study drug should be stored at room temperature (59º – 77ºF or 15º – 25ºC) in a secure area 
with restricted access. Temperature monitors, and instructions to download the temperature 
data to Ampio Pharmaceuticals, Inc., will be included with each site shipment of study drug. 
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 
and it is the Investigator’s responsibility to ensure that an accurate record is maintained of 
investigational product issued and returned. 
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, temperature, etc.), Ampio Pharmaceuticals, Inc. must be promptly notified. 

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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. 
All investigational product, used or unused during the study, must be retained in the study kit 
until notification from Ampio, or designated representative. Ampio, or designated 
representative, will instruct sites on study drug returns and/or destruction of study drug.  
8.3 
TREATMENT COMPLIANCE 
The injection of study drug will be performed by the Investigator or a designated member of 
the site clinical staff.  A 5mL syringe, 25-gauge needle, and a bottle of rescue medication will 
be included in every subject kit.  
During monitoring visits, monitors will visually inspect each vial to ensure the full 4.0 mL 
injection volume was administered.  Compliance with treatment is thus assured. 

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9 
ADVERSE EVENTS 
9.1 
DEFINITION OF AN ADVERSE EVENT 
An adverse event (AE) is defined as any undesired medical occurrence in a subject or clinical 
investigation subject receiving a pharmaceutical product and 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 categories listed in TABLE 9.1. 
TABLE 9.1 
DEFINITIONS OF AE SEVERITY 
Grade 1 (MILD): 
The symptom is barely noticeable to the study subject 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 subject 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 subject 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 
guidelines presented in TABLE 9.2. 
TABLE 9.2  GUIDELINES FOR DETERMINING THE RELATIONSHIP (IF ANY)  
BETWEEN ADVERSE EVENT AND THE STUDY DRUG 
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 study drug.  
Related 
The adverse event is likely to have been caused by study drug.  
 
9.2 
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 (subject is at immediate risk of death from the event as it occurred) 
• Requires in-subject hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
 

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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 subject 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 in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-subject hospitalization, or the development of drug 
dependency or drug abuse. 
Hospitalizations for elective surgery or other medical procedures that are not related to a 
treatment-emergent AE are not considered SAEs. 
9.3 
RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS 
Recording and reporting of adverse events should be in accordance with the FDA 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 
subject’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 subject; 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 subject receives their first IA injection at the 
Baseline visit of the AP-003-C main study through subject’s Final Visit 17 at 40 weeks of AP-
003-C-OLE study. 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 subject 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. 
9.3.1 
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. 

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9.3.2 
Overdose 
No information on treatment of overdose of Ampion™ is currently available.  In the case of 
overdose the subject should be followed as for an AE and appropriate supportive medical 
treatment instigated. 
9.4 
SERIOUS ADVERSE EVENT REPORTING 
9.4.1 
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.  It is important that the investigator provide his/her assessment of relationship 
to study drug at the time of the initial report.  Entry of an SAE into the eCRF triggers an 
automatic alert to the CRO safety team.  The following information must be reported: 
• Protocol number 
• Site and/or Investigator number 
• Subject 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 9.4.2 
9.4.2 
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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10 STATISTICAL METHODS 
10.1 GENERAL CONSIDERATIONS 
This section describes the rules and conventions to be used in the presentation and analysis of 
the data.   
10.1.1 
Statistical and Analytical Plan: 
This is an open-label study to evaluate the safety of intra-articular Ampion™ every 12 weeks 
over a total course of 52 weeks (12 weeks in AP-003-C main study and an additional 40 weeks 
in AP-003-C-OLE study) in subjects with OA of the knee. Safety will be assessed by recording 
AEs at all visits, recording concomitant medications, physical exams, and vital signs at all in-
clinic visits, and obtaining labs at the final study visit (Visit 17 or Early Termination Visit 18 
only). 
Efficacy of repeat injections will be analyzed as exploratory endpoints. Efficacy variables will 
be assessed at all in-clinic visits.  
10.2 STUDY OBJECTIVES 
The primary trial objective is to carry on from the AP-003-C main study (one injection) and 
evaluate the safety of a 4-mL intra-articular (IA) injection of Ampion™ with repeat dosing 
every 12 weeks for 52 weeks and/or with five total injections of Ampion™. 
The exploratory objectives are to analyze the efficacy of a 4-mL intra-articular (IA) injection of 
Ampion™ with repeat dosing every 12 weeks for 52 weeks and/or with five total injections of 
Ampion™. Exploratory efficacy will evaluate changes in pain, stiffness and function using the 
validated WOMAC 3.1 Index and PGA. 
10.3 ANALYSIS POPULATIONS 
10.3.1 
Safety Analysis Population: 
The safety analysis population is defined as all subjects who are enrolled in the AP-003-C-OLE 
study and receive at least one dose of study medication (Ampion™). Subjects will be analyzed 
as treated. 
10.3.2 
Intent-to-treat Population: 
The intent-to-treat (ITT) analysis population is defined as all subjects who are enrolled and 
receive at least one dose of study medication (Ampion™).  Subjects will be analyzed as treated. 
10.3.3 
Per Protocol Population: 
The per protocol analysis population is defined as all subjects included in the ITT analysis who 
met all entry criteria and had no major protocol violations as determined by the sponsor prior to 
analysis. All efficacy analyses will be repeated in the per-protocol population. These analyses 
will be supportive of the ITT analysis. Subjects will be analyzed as treated. 

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10.3.4 
Statistical Analysis of Exploratory Effectiveness Endpoint 
Since there are multiple injections administered over time, the stability and/or improvement of 
WOMAC and PGA scores between successive administrations will be investigated.   
10.3.5 
Primary Hypotheses for Exploratory Endpoints 
The evaluation of efficacy is an exploratory endpoint and as such no formal hypothesis testing 
will be performed against a threshold of success.  However, since there are multiple injections 
administered over time, the stability of pain scores will be evaluated between successive 
administrations to determine if the difference is zero.  This will be evaluated by utilizing two 
sided 95% confidence intervals. 
10.3.6 
Definition of Study Visits 
This clinical trial has a total of 9 study visits, including telephone contacts, during the  
40-week study (see Table 6.2).  The time-on-study for each subject observation will be defined 
relative to Day 0 of the initial dose of the AP-003-C main study.  For the proposed summaries 
of the data, several “baseline” measures will be utilized.  
10.3.7 
Number of subjects to receive study drug 
Planned enrollment is up to 161 subjects; all subjects that consent to participate in the AP-003-
C-OLE study.  Assuming a 15% dropout rate, a total of 136 subjects will be enrolled. 
10.3.8 
Disposition of subjects 
Disposition of subjects, including study completion status, safety profile, and response to 
therapy as measured by WOMAC and PGA, will be summarized by age group, race and gender 
for each of the analysis populations. 
10.3.9 
Interim analysis 
An interim analysis will occur when approximately 80 subjects have reached 52 weeks of time 
following the first injection at Visit 1 of the AP-003-C main study, regardless of what study 
visit they have completed in the AP-003-C-OLE study. 
10.3.10 Blinding and randomization 
No blinding or randomization is required for the AP-003-C-OLE study. All subjects will 
receive Ampion™ 4-mL at each in-clinic visit. 
10.3.11 Data presentation 
10.3.11.1 Demographic and Baseline Characteristics: 
Demographic (e.g., age, sex, race, ethnicity) and baseline characteristics (e.g., weight, height) 
summarized using descriptive statistics, overall and by treatment group for the ITT analysis 
population. 

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10.3.11.2 Medical History and Physical Examination: 
The number and percent of subjects with past and current medical disorders at the time of 
enrollment will be presented overall and by treatment group for the ITT analysis population.  
Results of any abnormalities documented from the physical examination will be summarized 
overall and by treatment group for the safety and ITT analysis populations. 
10.3.11.3 Concomitant Medications or Treatments: 
The number and percent of subjects receiving concomitant medications or treatments 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. 
10.3.11.4 Safety data: 
Safety data will be evaluated by changes in vital sign measurements and the frequency and 
severity of AEs. Concomitant medication will be recorded for safety.  
Adverse events: 
The Investigator is responsible for monitoring the safety of subjects who have enrolled in the 
study. All AEs considered to be possibly related to Ampion™ will be followed until the event 
resolves or stabilized without further change. Subjects will be followed for the occurrence of 
AEs until completion of the study at Visit 17 or until early termination from the study (if 
applicable). 
Investigators are required to document all AEs occurring during the clinical trial, commencing 
with the first day of treatment and including the protocol-defined post-treatment follow-up 
period on the appropriate CRF pages. 
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.  In addition, events meeting the criteria of a Serious Adverse Event (SAE) must be 
reported to the Sponsor within 24 hours on the SAE reporting forms. 
10.3.11.5 Efficacy data:  
All efficacy variables will be assessed at Visit 9 (Day 0), Visit 11 (Day 84 ± 14), Visit 13 
(Day 168 ± 14), Visit 15 (Day 252 ± 14), and Visit 17 (Day 280 ± 14). Except where noted to 
be otherwise, all statistical tests will be two-sided and will be at the 5% level of significance. 
Unless otherwise specified, continuous variables will be summarized with the number of non-
missing observations, mean, standard deviation, median, minimum, and maximum displayed.  
Categorical data will be summarized as counts and percentages. All efficacy assessments will 
be summarized as the measured value and as the change from baseline by treatment at each 
time point. Summary statistics will include number of observations, mean, standard deviation, 
median, minimum and maximum. Change from baseline will also include a 95% confidence 
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Except where otherwise specified, missing data will not be estimated or carried forward in any 
of the descriptive analyses. No multiple comparison adjustment will be made for the secondary 
efficacy analyses. Data transformation or use of rank-based tests may be used if endpoints 
depart substantially from a normal distribution. 
Baseline (Day 0 of AP-003-C main study) is defined as the last pre-treatment assessment. 
Because the secondary analyses are considered supportive to the primary analysis (i.e., not 
required to demonstrate efficacy of the test article), there is no requirement under ICH to adjust 
for multiplicity 
10.4 STUDY ENDPOINTS 
10.4.1 
Primary Endpoint 
• Incidence and severity of treatment-emergent adverse events (TEAEs). 
 
These incidents will be summarized by number and percent of subjects having an event, the 
number of events per subject, and frequency of events in study population. 
10.4.2 
Exploratory Endpoints  
• Responder status based on the OMERACT-OARSI responder criteria from 
Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17  
• Evaluate 20% improvement in Pain and Function and 0.5 point absolute change in the 5-
point Likert Scale from Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17  
• Evaluate 20% improvement in PGA and 0.5 point absolute change in the 5-point Likert 
Scale 
• Mean change in WOMAC A pain subscore between Visit 1/Day 0 (AP-003-C main 
study) and Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17 (AP-003-C-OLE) 
• Percent change in WOMAC A pain subscore between Visit 1/Day 0 (AP-003-C main 
study) and Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17 (AP-003-C-OLE) 
• Mean change in WOMAC B stiffness subscore between Visit 1/Day 0 (AP-003-C main 
study) and Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17 (AP-003-C-OLE) 
• Percent change in WOMAC B stiffness subscore between Visit 1/Day 0 (AP-003-C main 
study) and Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17 (AP-003-C-OLE) 
• Mean change in WOMAC C physical function subscore between Visit 1/Day 0 (AP-003-
C main study) and Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17 (AP-003-C-
OLE) 
• Percent change in WOMAC C physical function subscore between Visit 1/Day 0 (AP-
003-C main study) and Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17 (AP-003-
C-OLE) 
• Mean change in PGA between Visit 1/Day 0 (AP-003-C main study) and 
Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17 (AP-003-C-OLE) 
• Percent change in PGA between Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 17 
(AP-003-C-OLE) 
• Mean Change in WOMAC A pain subscore questions 1 and 2 (pain with movement) 
between Visit 1/Day 0 (AP-003-C main study) and Enrollment/Visit 9 (Day 0) to Visits 
11, 13, 15, and 17 (AP-003-C-OLE) 

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• Percent Change in WOMAC A pain subscore questions 1 and 2 (pain with movement) 
between Visit 1/Day 0 (AP-003-C main study) and Enrollment/Visit 9 (Day 0) to Visits 
11, 13, 15, and 17 (AP-003-C-OLE) 
• Mean Change in WOMAC A pain subscore questions 3−5 (resting pain) between Visit 
1/Day 0 (AP-003-C main study) and Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 
17 (AP-003-C-OLE) 
• Percent Change in WOMAC A pain subscore questions 3−5 (resting pain) between Visit 
1/Day 0 (AP-003-C main study) and Enrollment/Visit 9 (Day 0) to Visits 11, 13, 15, and 
17 (AP-003-C-OLE) 
• Change in contralateral knee pain (WOMAC A) between Visit 9 and Visit 17  
• Change in contralateral knee stiffness (WOMAC B) between Visit 9 and Visit 17  
• Change in contralateral knee function (WOMAC C) between Visit 9 and Visit 17  
• Time to Total Knee Replacement (TKR) 
• Use of rescue analgesia (amount of acetaminophen used) 
 
Exploratory efficacy analyses include the mean change and percent change in WOMAC A, 
WOMAC B, WOMAC C, WOMAC A1-2, WOMAC A3-5, PGA and amount of 
acetaminophen used from Visit 1 to Visit 17 using an analysis of covariance model, adjusted 
for baseline value.  
Percent responders using the OMERACT-OARSI responder criteria will be analyzed defined as 
the percent of subjects whom respond to treatment from Visit 1 to Visit 17.  Interim visits will 
also be analyzed.   
1. High improvement in pain or in function ≥ 50% and absolute change in Likert pain 
scale of ≥1 OR 
2. Improvement in at least two of the 3 following: 
a. pain ≥ 20% and absolute change in Likert score ≥0.5 
b. function ≥ 20% and absolute change in Likert score ≥0.5 
c. subject’s global assessment ≥ 20% and absolute change in Likert score ≥0.5 
All of the above endpoints will be evaluated via descriptive statistics and confidence intervals. 
The WOMAC Pain Score, the WOMAC Function Score, then PGA score and the OMERACT-
OARSI responder criteria, will be analyzed via a repeated measures analysis of variance to 
determine if there is a significant time effect for these endpoints.  Also, to aid in the 
interpretation of these results, a stability analysis will be performed on these same endpoints.  
That is, mean pairwise differences between administration time points will be calculated along 
with their 95% confidence intervals.  If stability is achieved at some time point, then the 
following mean differences should be not be different from zero, in that the confidence interval 
should include zero. 
Adverse events will be tabulated for both number of subjects and number of events by subject 
and overall study population, summarized by any event, body system, and preferred term.  
Summaries by serious, severity, and relationship will also be done. 

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10.5 MISSING AND SPURIOUS DATA 
All data collected under this study protocol will be included in the assessment of subject safety.  
Missing or incomplete AE data will assume greatest relationship to study drug and/or severity. 
For the exploratory effectiveness endpoint analyses (WOMAC and PGA), missing scores will 
be imputed in when the worst observation carried forward to aid in the assessment of the 
robustness of the results. 

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11 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
11.1 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. 
11.2 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. 
11.3 INSTITUTIONAL REVIEW BOARDS/ETHICS COMMITTEES 
Before implementing this study, the protocol, the proposed subject informed consent forms and 
other information for the subjects, 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 subject 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. 
11.4 REGULATORY AUTHORITY APPROVAL 
Before this study is implemented, the protocol must be approved by the relevant regulatory 
authority. 
11.5 INFORMED CONSENT 
The investigator must fully inform the subject 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 subject 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 subject and one copy must be retained in the investigator's study records. 
11.6 SUBJECT CONFIDENTIALITY AND DISCLOSURE 
Data on subjects collected on eCRFs during the trial will be documented in an anonymous 
fashion and the subject will only be identified by the subject number, and by his/her initials If, 
as an exception, it is necessary for safety or regulatory reasons to identify the subject, all parties 
are bound to keep this information confidential. 
The investigator will guarantee that all persons involved will respect the confidentiality of any 
information concerning the trial subjects.  All parties involved in the study will maintain strict 
confidentiality to assure that neither the person nor the family privacy of a subject participating 

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in the trial is violated.  Likewise, the appropriate measures shall be taken to prevent access of 
non-authorized persons to the trial data. 
11.7 COLLECTION, MONITORING AND AUDITING STUDY 
DOCUMENTATION, AND DATA STORAGE 
11.7.1 
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 
subject 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 subjects 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. 
11.7.2 
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. 
11.7.3 
Retention of Documents 
The investigator must maintain source documents for each subject in the study, consisting of all 
demographic and medical information, including laboratory data, x-ray, etc., and keep a copy 

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of the signed informed consent form.  All information on case report forms must be traceable to 
these source documents in the subject'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. 
11.8 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. 
11.9 DISCONTINUATION OF THE STUDY 
It is agreed that, for reasonable cause, either the investigator or Ampio Pharmaceuticals, Inc., 
may terminate the investigator’s participation in this study after submission of a written notice.  
Ampio Pharmaceuticals, Inc., may terminate the study at any time upon immediate notice for 
any reason, including the Sponsor’s belief that discontinuation of the study is necessary for the 
safety of subjects. 
11.10 STUDY REPORT, PUBLICATION POLICY AND ARCHIVING OF 
STUDY DOCUMENTATION 
11.10.1 Study Report and Publication Policy 
An ICH-compliant integrated clinical and statistical report will be prepared upon completion of 
the study and data analysis.  The results of the study will 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. 
11.10.2 Study Documents 
The investigator must maintain source documents for each subject in the study, consisting of all 
demographic and medical information, questionnaires, including laboratory data, x-ray, 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 subject's file.  Data without a written 
or electronic record will be defined before trial start and will be recorded directly on the eCRFs, 
which will be documented as being the source data. 
11.10.3 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 

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• All source documents and laboratory records 
• CRF copies (electronic copies on a CDROM) 
• Subjects' informed consent forms (with study number and title of trial) 
• FDA form 1572 
• Any other pertinent study document. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12 REFERENCES 
 
1. Akinci A. Predictive factors and clinical biomarkers for treatment in patients with 
chronic pain caused by osteoarthrosis with a central sensitization component. 
International Journal of Clinical Practice. 2016; 70; 31-44. 
 
2. Bar-Or D. The filamentous actin cytoskeleton organization and the endothelial 
cell barrier. Crit Care Med. 2013 Feb;41(2):686-7. 
 
3. Bar-Or D, Bar-Or R, Rael LT, et al. Heterogeneity and oxidation status of 
commercial human albumin preparations in clinical use. Crit Care Med. 
2005;33:1638-41. 
 
4. Bar-Or D, Thomas GW, Bar-Or R, et al. Commercial human albumin preparations 
for clinical use are immunosuppressive in vitro. Crit Care Med. 2006;34:1707-12. 
 
5. Bar-Or D, Rael LT, Thomas GW, Brody EN. Inflammatory pathways in 
knee osteoarthritis: potential targets for treatment. Curr Rheumatol Rev. 
2015. 
 
6. Bar-Or D, Thomas GW, Rael LT, Gersch ED, Rubinstein P, Brody E. Low Molecular 
Weight Fraction of Commercial Human Serum Albumin Induces Morphologic and 
Transcriptional Changes of Bone Marrow-Derived Mesenchymal Stem Cells. Stem Cells 
Translational Medicine. 2015; 4: 1-11. 
 
7. Bar-Or D, Slone DS, Mains CW, Rael LT. Dipeptidyl peptidase IV activity in 
commercial solutions of human serum albumin. Anal Biochem. 2013 Oct 1;441(1):13-
7. 
 
8. Bellamy N, Buchanan WW, Goldsmith CH et al.  Validation study of WOMAC: a health 
status instrument for measuring clinically important subject relevant outcomes to 
antirheumatic drug therapy in subjects with osteoarthritis of the hip or knee. J 
Rheumatol. 1988 Dec;15(12):1833-40. 
 
9. Cisternas 2016, Royal College of Physicians of London, (1993). // Center for 
Disease Control and Prevention, Arthritis // Litwic, A., Dennison, E., Cooper, C. 
2013, Epidemiology and Burden of Osteoarthritis. Br Med Bull. (2013); 105: 185-
199. 
 
10. Dillon CF, Rasch EK, Gu Q, Hirsch R. Prevalence of knee osteoarthritis in the United 
States: arthritis data from the Third National Health and Nutrition Examination 
Survey 1991-94. J Rheumatol. 2006 Nov;33(11):2271-9. 
 
11. Dworkin et al. The Journal of Pain, Vol. 9, No 2, 2008 
 
12. Evans TW. Review article: albumin as a drug – biological effects of albumin unrelated 
to oncotic pressure. Aliment Pharmacol Ther. 2002;16 (Suppl. 5); 6-11. 
 
13. Felson DT, Anderson JJ, Naimark A, et al.  Obesity and knee osteoarthritis: 
The Framingham study. Ann Int Med. 1988;109:18-24 

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Clinical Study Protocol: AP-003-C-OLE 
 
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14. Frederick ED, Hausburg MA, Thomas GW, Rael LT, Brody E, Bar-Or D. The low 
molecular weight fraction of human serum albumin upregulates COX2, prostaglandin E2, 
and prostaglandin D2 under inflammatory conditions in osteoarthritic knee synoviocytes. 
Biochemistry and Biophysics Reports. 2016; (8), pp. 68-74. 
 
15. Greco et al. The American Journal of Sports Medicine, Vol. 38, No. 5. 2010 
 
16. Guccione AA. Arthritis and the process of disablement. Phys Ther. 1994 
May;74(5):408- 14. 
 
17. Kraus V. Direct in vivo evidence of activated macrophages in human osteoarthritis. 
Osteoarthritis and Cartilage. 2016; 24(9):1613-1621. 
 
18. Mallinckrodt CH, Clark WS, David SR. Accounting for dropout bias using mixed-effects 
models. J Biopharm Stat. 2001 Feb-May;11(1-2):9-21. 
 
19. Navarro-Sarabia F, Coronel P, Collantes E, Navarro FJ, de la Serna AR, Naranjo A, 
Gimeno M, Herrero-Beaumont G; AMELIA study group.  A 40-month multicentre, 
randomized placebo-controlled study to assess the efficacy and carry-over effect of 
repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the 
AMELIA project. Ann Rheum Dis. 2011;70:1957-62. 
 
20. Ohnuma K, Inoue H, Uchiyama M, Yamochi T, Hosono O, Dang NH, Morimoto C. 
T- cell activation via CD26 and caveolin-1 in rheumatoid synovium. Mod Rheumatol. 
2006;16(1):3-13. 
 
21. Peterfy C.G., M.D. Ph.D., Guermazi A M.D., S. Zaim M.D., P. F. J. Tirman M.D., Y. 
Miaux M.D., D. White Ph.D., M. Kothari Ph.D., Y. Lu Ph.D., K. Fye M.D., S. Zhao 
Ph.D. H. K. Genant M.D.  Whole-Organ Magnetic Resonance Imaging Score (WORMS) 
of the knee. OsteoArthritis and Cartilage (2004) 12, 177–190. 
 
22. Quinlan GJ, Martin GS, Evans TW. Albumin: biochemical properties and therapeutic 
potential. Hepatology. 2005;41:1211-1219. 
 
23. Rutjes A, Juni P, et al. Viscosupplementation for Osteoarthritis of the Knee. Annals 
of Internal Medicine. 2012; 157:180-191. 
 
24. Shimonkevitz R, Thomas GW, Slone DS, et al. A diketopiperazine fragment of human 
serum albumin modulates T-lymphocyte cytokine production through Rap1. J 
Trauma. 2008;64:35-41. 
 
25. Thomas GW, Rael LT, Hausburg M, Frederick ED, Brody E, Bar-Or D. The Low 
Molecular Weight Fraction of Commercial Human Serum Albumin Induces 
Acetylation of α-Tubulin and Reduces Transcytosis in Retinal Endothelial Cells. 
Biochemical and Biophysical Research Communications. 2016 Sep 30;478(4):1780-5. 
 
26. Thomas GW, Rael LT, Hausburg M, Frederick ED, Mains CW, Slone D, Carrick MM, 
Bar-Or D. The low molecular weight fraction of human serum albumin upregulates 
production of 15d-PGJ(2) in Peripheral Blood Mononuclear Cells. Biochem Biophys 

Ampion™ 
 
Ampio Pharmaceuticals, Inc. 
Clinical Study Protocol: AP-003-C-OLE 
 
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Res Commun. 2016 May 13;473(4):1328-33. Epub 2016 Apr 16. 
 
27. Thomas GW, Rael LT, Mains CW, Slone D, Carrick MM, Bar-Or R, Bar-Or D. 
Anti- Inflammatory Activity in the Low Molecular Weight Fraction of Commercial 
Human Serum Albumin (LMWF5A). J Immunoassay Immunochem. 2016;37(1):55-
67. 
 
28. Vincent JL, Navickis RJ, Wilkes MM. Morbidity in hospitalized subjects receiving 
human albumin: A meta-analysis of randomized, controlled trials* Crit Care Med. 
2004;32:2029–38. 
 
29. Zhang W, Nuki G, Moskowitz R.W. et al.  OARSI recommendations for the management 
of hip and knee osteoarthritis Part III: changes in evidence following systematic 
cumulative update of research published through January 2009. Osteoarthritis and 
Cartilage. 2010;18:476-499. 

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13 APPENDICES 
 
14.1 CONTACT LIST 
SPONSOR: 
Ampio Pharmaceuticals, Inc. 
373 Inverness Parkway, Suite 200 
Englewood, CO 80112 
720-437-6500