Clinical trial NCT02963376
Conditions: Ischemic Stroke
Sponsor: NuvOx LLC
Start date: 2017-02-01; Completion date: 2018-07-09
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Stroke is the fifth leading cause of death in the United States and is the leading cause of long term disability. Distinct geographic disparities in stroke mortality, with highest rates in the southeast United States including Arkansas, are known as the "stroke belt." There the average stroke mortality is ≈20% to 40% higher than the rest of the nation. Stroke is the leading cause of serious long-term disability. Between 2012 and 2030, disability and medical costs related to stroke are projected to triple, from $71.6 billion to $184.1 billion, with the majority of the projected increase in costs arising from those 65 to 79 years of age.

There are two main forms of stroke, ischemic and hemorrhagic. An ischemic stroke occurs in 85% of cases and is caused by cerebral vessel occlusion, obstructing blood flow to a portion of the brain. Currently, the only approved therapies for acute ischemic stroke are IV tissue plasminogen activator (tPA), a thrombolytic agent that clears the thrombus within the blood vessel, or intra-arterial catheter thrombectomy. Despite the availability of therapy, it reaches only approximately 7% of ischemic stroke victims in the United States5. Delay beyond the effective time window for therapy is a common reason for failure.

To reduce the devastating impact of stroke on individuals and society, the investigators continue to seek ways to improve functional recovery and limit ischemic damage in stroke patients. The potential neuroprotective agent, dodecafluoropentane emulsion (DDFPe) has recently shown strong positive effects in pre-clinical animal models of acute ischemic stroke6-11. Other perfluorocarbons have been tested in humans as potential neuroprotectants and blood substitutes yet none have been successful.

Detailed description:

Arms: arm 1: This study is a randomized, placebo controlled, blinded escalating dose study designed to determine the maximum tolerated dose to intravenous administration of DDFPe. At each of the three dose levels 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. arm 2: This study is a randomized, placebo controlled, blinded escalating dose study designed to determine the maximum tolerated dose to intravenous administration of DDFPe. At each of the three dose levels 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. arm 3: This study is a randomized, placebo controlled, blinded escalating dose study designed to determine the maximum tolerated dose to intravenous administration of DDFPe. At each of the three dose levels 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. arm 4: This study is a randomized, placebo controlled, blinded escalating dose study designed to determine the maximum tolerated dose to intravenous administration of DDFPe. At each of the three dose levels 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. arm 5: This study is a randomized, placebo controlled, blinded escalating dose study designed to determine the maximum tolerated dose to intravenous administration of DDFPe. At each of the three dose levels 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. arm 6: This study is a randomized, placebo controlled, blinded escalating dose study designed to determine the maximum tolerated dose to intravenous administration of DDFPe. At each of the three dose levels 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo.
Interventions: intervention 1: 0.05 mL/kg DDFPe intervention 2: 0.05 mL/kg Placebo intervention 3: 0.10 mL/kg DDFPe intervention 4: 0.10 mL/kg Placebo intervention 5: 0.17 mL/kg DDFPe intervention 6: 0.17 mL/kg Placebo
Intervention descriptions: intervention 1: Prior to injection, DDFPe will be prepared by pharmacy staff. DDFPe will be administered based on weight. Each dose will be prepared on the day of administration and infused directly into the patient using a slow i.v push. The i.v. push shall be 5-10 minutes in duration. DDFPe dosage volume in cc for 0.05 mL/kg based on patient body weight in kilograms (kg). intervention 2: Prior to injection, the placebo will be prepared by pharmacy staff. The placebo will be administered based on weight at designated doses Each dose will be prepared on the day of administration and infused directly into the patient using a slow i.v push. The i.v. push shall be 5-10 minutes in duration. The placebo dosage volume in cc for 0.05 mL/kg is based on patient body weight in kilograms (kg). intervention 3: Prior to injection, DDFPe will be prepared by pharmacy staff. DDFPe will be administered based on weight at designated doses. Each dose will be prepared on the day of administration and infused directly into the patient using a slow i.v push. The i.v. push shall be 5-10 minutes in duration. DDFPe dosage volume in cc for 0.10 mL/kg based on patient body weight in kilograms (kg). intervention 4: Prior to injection, the placebo will be prepared by pharmacy staff. The placebo will be administered based on weight at designated doses. Each dose will be prepared on the day of administration and infused directly into the patient using a slow i.v push. The i.v. push shall be 5-10 minutes in duration. The placebo dosage volume in cc for 0.10 mL/kg is based on patient body weight in kilograms (kg). intervention 5: Prior to injection, DDFPe will be prepared by pharmacy staff. DDFPe will be administered based on weight at designated doses. Each dose will be prepared on the day of administration and infused directly into the patient using a slow i.v push. The i.v. push shall be 5-10 minutes in duration. DDFPe dosage volume in cc for 0.17 mL/kg based on patient body weight in kilograms (kg). intervention 6: Prior to injection, the placebo will be prepared by pharmacy staff. The placebo will be administered based on weight at designated doses. Each dose will be prepared on the day of administration and infused directly into the patient using a slow i.v push. The i.v. push shall be 5-10 minutes in duration. The placebo dosage volume in cc for 0.17 mL/kg is based on patient body weight in kilograms (kg).

Protocol documents:
Prot_SAP_000.pdf: 
Version 11 
February 22, 2018 
Page 1 
CLINICAL TRIAL PROTOCOL 
 
Title: A Phase 1b dose-finding study of DDFPe in acute ischemic stroke 
 
Protocol Number: NVX-208-AIS 
 
UAMS IRB Number: 205529 
 
Phase: 1b 
 
 
Study Principal Investigator: 
William Culp, MD 
 
 
 
 
 
University of Arkansas for Medical Sciences 
 
 
 
 
 
 
Co-Principal Investigator:   
Sanjeeva Onteddu, MD 
 
 
 
 
 
University of Arkansas for Medical Sciences 
 
Sub-Investigator: 
 
 
Krishna NalleBalle, MD 
 
 
 
 
 
University of Arkansas for Medical Sciences 
 
IND Sponsor: 
University of Arkansas for Medical Sciences (UAMS) 
4301 W. Markham Street 
Little Rock, AR 72205 
 
Clinical Site: 
University of Arkansas for Medical Sciences 
Little Rock, AR 
 
Medical Monitors: 
James D. Marsh, MD 
Professor and Chair 
Department of Internal Medicine 
University of Arkansas for Medical Sciences 
 
Manish Joshi, MD 
Associate Professor 
Department of Internal Medicine 
University of Arkansas for Medical Sciences 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 2 
Study Summary 
Title 
A Phase 1b dose-finding study of DDFPe in Acute Ischemic Stroke 
Sponsor 
University of Arkansas for Medical Sciences 
Protocol Number 
NVX-208-AIS 
Phase 
Phase 1b 
Methodology 
Randomized, placebo controlled, blinded escalating dose design; 6:2 DDFPe to 
placebo at each dose level 
Rationale 
To provide dosing guidelines for a Phase 2 study in patients who have an acute stroke 
Study Duration 
Approximately 18 months 
Study Center(s) 
University of Arkansas for Medical Sciences, Little Rock, AR 
Primary Objective 
To determine the maximum tolerated dose (MTD) of Dodecafluoropentane emulsion 
(DDFPe) in subjects with acute ischemic stroke (AIS) 
Secondary Objective 
To determine the safety of DDFPe in subjects who have experienced an AIS event 
Number of Subjects 
Up to 24 completed subjects 
Diagnosis and Main 
Eligibility Criteria 
➢ Inclusion: ages 18years old or older, male or female, AIS with NIH Stroke 
Scale between 2 and 20 
➢ Exclusion: Severe cerebral hemorrhage or severe hemorrhagic stroke, 
intracranial surgery or major head trauma within 3 months, > 12 hours since 
onset of stroke symptoms, clinically significant cardiac or pulmonary disease, 
current anticoagulant therapy (except low doses of aspirin or low molecular 
weight heparin), pregnancy or breastfeeding 
Study Product, Dose, 
Route, Regimen 
Dodecafluoropentane emulsion (DDFPe) 
Dose Range: 0.05, 0.10, and 0.17 mL/kg (Maximum dose: 17 mL/dose) 
Route: Intravenous over 5-10 minutes every 90 ± 10 minutes x 3 doses 
Placebo - Intralipid® 20% IV fat emulsion 
Dose: Sterile 1:101 dilution of Intralipid® in aqueous sodium chloride (0.9% w/v) 
Route: Intravenous over 5-10 minutes every 90 ± 10 minutes x 3 doses 
Duration of 
Administration 
Approximately 3-4 hours 
Reference Therapy 
None 
Primary Outcome 
Measures 
DLT (dose limiting adverse events) including clinically significant changes in vital 
signs, peripheral oxygen saturation (pulse oximetry), clinical symptoms, NIH Stroke 
Scale, laboratory values, and ECG measurements, Grade 3 or higher scores on 
selected CTCAE 4 measures 
 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 3 
ABBREVIATIONS 
AE 
 
Adverse Event 
AIS 
 
Acute ischemic stroke 
ALT 
 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
aPTT  
Activated Partial Thromboplastin Time 
AST 
 
Aspartate Aminotransferase 
AUC  
Area under the Concentration vs. Time Curve 
BP 
 
Blood Pressure 
BUN  
Blood Urea Nitrogen 
CL 
 
Clearance 
Cmax  
Maximum Concentration 
COPD  
Chronic Obstructive Pulmonary Disease 
CRF 
 
Case Report Form 
CT 
 
Computed (Computerized) Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDFP  
Dodecafluoropentane 
DDFPe 
Dodecafluoropentane emulsion 
DBP  
Diastolic Blood Pressure 
DLT 
 
Dose Limiting Toxicity 
DSM  
Data Safety Monitor 
ECG  
Electrocardiogram 
FDA  
Food and Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
 
Heart rate 
IEC 
 
Independent Ethics Committee 
INR 
 
International Normalized Ratio 
IRB 
 
Institutional Review Board 
IV 
 
Intravenous 
LAR  
Legally Authorized Representative 
LFT 
 
Liver Function Tests 
mmHg  
Millimeters of Mercury 
mRS  
modified Rankin Scale 
mSec  
Millisecond 
MTD  
Maximum Tolerated Dose 
N/A 
 
Not Applicable 
ND 
 
Not Done 
NIH 
 
National Institutes of Health 
NIHSS  
National Institutes of Health Stroke Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NYHA  
New York Heart Association 
OTs 
 
Oxygen Transporters 
PHI 
 
Personal Health Information 
PTB 
 
PE-Telomer-B 
RR 
 
Respiratory Rate 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 4 
SAE 
 
Serious Adverse Event 
SBP 
 
Systolic Blood Pressure 
SD 
 
Standard Deviation 
Tmax  
Time at Which the Maximum Concentration (Cmax) Occurs 
tPA 
 
Tissue Plasminogen Activator 
Vd 
 
Volume of Distribution 
UAMS  
University of Arkansas for Medical Sciences 
UPIRTSO 
Unanticipated Problem Involving Risk to Subjects or Others 
 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 5 
TABLE OF CONTENTS 
Study Summary 
2 
Abbreviations 
3 
1.0 Background and Rationale 
7 
1.1 Background 
7 
1.2 Brief Description of the Investigational Product 
8 
1.3 Preclinical Studies 
8 
1.4 Clinical Trials 
9 
1.5 Rationale for Conducting the Trial 
9 
2.0 Objectives 
10 
2.1 Primary Objective 
10 
2.2 Secondary Objectives 
10 
2.3 Exploratory Objective 
10 
3.0 Study Design 
10 
3.1 Study Design  
10 
3.2 Study Schema 
11 
4.0 Trial Registration 
11 
5.0 Investigational Product 
11 
5.1 Description of the Investigational Product 
11 
5.2 Storage and Preparation of the Investigational Product 
12 
5.3 Dose Escalation Plan/Dose Limiting Toxicity 
13 
5.4 Dispensing of the Investigational Product 
14 
5.5 Administration of the Investigational Product 
15 
5.6 Prior and Concomitant Therapy 
15 
5.7 Return and Destruction of the Investigational Product 
15 
6.0 Study Subjects 
16 
6.1 Study Population 
16 
6.2 Inclusion Criteria 
16 
6.3 Exclusion Criteria 
16 
6.4 Withdrawal Criteria 
17 
6.5 Replacement of Subjects 
17 
7.0 Investigational Plan 
17 
7.1 Usual Care Provided by Treating Physician 
17 
7.2 Consent Process 
18 
7.3 Verification of Inclusion/Exclusion Criteria 
18 
7.4 Randomization and Blinding 
18 
7.5 Screening Study Procedures 
19 
7.6 Day 1: Study Procedures 
20 
7.7 Day 4: Study Procedures 
21 
7.8 Day 7 (±1 day) (or Hospital Discharge Day): Study Procedures 
21 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 6 
7.9 Day 30 (±7 days): Study Procedures or Telephone Follow Up 
22 
7.10 Day 90 (±14 days): Study Procedures or Telephone Follow Up 
22 
8.0 Adverse Events 
23 
8.1 Definitions 
23 
8.2 Recording of Adverse Events 
25 
8.3 Reporting Procedures for Adverse and Serious Adverse Events 
25 
8.4 Data Safety and Monitoring Plan 
25 
8.5 Medical Monitor 
25 
8.6 Risks and Benefits 
26 
8.7 Risk Mitigation 
26 
9.0 Data Collection 
26 
9.1 Data Collection and Storage 
26 
9.2 Confidentiality 
26 
9.3 Study Monitoring and Data Queries 
27 
9.4 Source Documents 
27 
9.5 Case Report Forms 
27 
9.6 Study Auditing 
27 
9.7 Record Retention 
28 
10.0 Data Analysis Plan 
28 
10.1 Sample Size 
28 
10.2 Clinical Data 
28 
10.3 Safety Data 
28 
10.4 Exploratory Aim Analysis 
29 
11.0 Ethical and Regulatory Requirements 
29 
11.1 Trial Registration 
29 
11.2 Informed Consent Procedures 
29 
11.3 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
29 
11.4 Subject Confidentiality 
29 
11.5 Protocol Amendments 
29 
11.6 Study Termination 
30 
12.0 Publication Policy 
30 
13.0 References 
31 
Appendices: 
33 
1. CTCAE 4 Selected Adverse Events 
33 
2. DDFPe Dosing by Weight 
34 
3. Modified Rankin Scale 
40 
4. Schedule of Time and Events 
41 
 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 7 
1.0 
Background and Rationale 
1.1 
Background 
Stroke is the fifth leading cause of death in the United States and is the 
leading cause of long term disability1,2. Distinct geographic disparities in 
stroke mortality, with highest rates in the southeast United States including 
Arkansas, are known as the “stroke belt.” There the average stroke mortality is 
≈20% to 40% higher than the rest of the nation3. Stroke is the leading cause of 
serious long-term disability3. Between 2012 and 2030, disability and medical 
costs related to stroke are projected to triple, from $71.6 billion to $184.1 
billion, with the majority of the projected increase in costs arising from those 
65 to 79 years of age4. 
 
There are two main forms of stroke, ischemic and hemorrhagic. An ischemic 
stroke occurs in 85% of cases and is caused by cerebral vessel occlusion, 
obstructing blood flow to a portion of the brain1. Currently, the only approved 
therapies for acute ischemic stroke are IV tissue plasminogen activator (tPA), 
a thrombolytic agent that clears the thrombus within the blood vessel, or intra-
arterial catheter thrombectomy. Despite the availability of therapy, it reaches 
only approximately 7% of ischemic stroke victims in the United States5. Delay 
beyond the effective time window for therapy is a common reason for failure. 
To reduce the devastating impact of stroke on individuals and society, we 
continue to seek ways to improve functional recovery and limit ischemic 
damage 
in 
stroke 
patients. 
The 
potential 
neuroprotective 
agent, 
dodecafluoropentane emulsion (DDFPe) has recently shown strong positive 
effects in pre-clinical animal models of acute ischemic stroke6-11. Other 
perfluorocarbons have been tested in humans as potential neuroprotectants 
and blood substitutes12 yet none have been successful. 
 
DDFPe (2% w/vol) is a liquid perfluorocarbon nanodroplet which transports 
over 200 times as much oxygen per milligram of fluorocarbon as others tested 
as oxygen therapeutics13-15. It is active at doses that have already been safely 
tested as bolus IV injections in humans as an ultrasound contrast agent by 
Sonus Pharmaceutical in over 2200 patients,16,17 and was approved by the 
European Medicines Agency as an ultrasound contrast agent. NuvOx Pharma 
owns these data and the FDA has given NuvOx guidance that the prior human 
data from the ultrasound contrast development can be used in support of 
therapeutic development of DDFPe. NuvOx is currently conducting a Phase 
Ib/II trial of DDFPe as a radiation sensitizer to reverse tumor hypoxia in 
glioblastoma18 and is about to start a study in sickle cell disease for which an 
IND has been granted. NuvOx has received Orphan Drug Designations for 
both the glioblastoma and sickle cell disease applications. 
 
This fluorocarbon with its greater innate oxygen carrying capacity and smaller 
particle size that allows delivery to occluded and ischemic areas is a superior 
oxygen transporter (OT). DDFPe was shown to significantly improve 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 8 
functional recovery within two hours of dosing and full recovery by 3.5 hours 
in the rabbit stroke model6. A small dose of 0.1 ml/kg was effective in the 
animal model and may provide clinical neuroprotection during pre-hospital 
triage and diagnosis10. Recent DDFPe studies confirmed its strong capability 
as a neuroprotectant, which widened the therapeutic window to 9 hours in 
ischemic stroke rabbit models. In those studies >80% of infarct volume was 
protected to 24 hours with only 6 doses over the first 9 hours7. 
 
1.2 
Brief Description of the Investigational Product 
DDFPe is an emulsion of 2% dodecafluoropentane in stabilizers (sucrose, PE-
Telomer B) and phosphate buffered saline (pH 7.0). Compared to higher 
molecular weight liquid fluorocarbons that have already been studied 
extensively as OTs, DDFPe carries far more oxygen per gram of fluorocarbon. 
 
Stoichiometrically, DDFP has 200 times the oxygen carrying capacity 
compared to human hemoglobin. Consequently, if it were administered 
intravenously (IV) and passed through the lungs of patients breathing high 
concentrations of oxygen, it would take up large amounts of oxygen and 
increase the oxygen concentration in blood in a dose-dependent way. 
Hypothetically, by shifting ischemic environments to normal tissue pO2 
environments patient recovery from stroke will be improved. 
 
1.3 
Preclinical Studies 
Extensive work was done to evaluate the toxicity and PK/PD of DDFPe as an 
ultrasound contrast-imaging agent. During development, most work was done 
using "activated" dodecafluoropentane emulsion (DDFPe) referred to as 
EchoGen® when it was studied as a contrast agent. EchoGen was 
administered as bolus IV injections. Activation was achieved by applying 
negative pressure (usually by suction in a syringe) which resulted in 2 micron 
sized microbubbles of gas in the circulation. The “activated” form of DDFPe 
has been shown to have more toxicity than "unactivated" compound (0.2 
micron vesicles of DDFP without microbubbles). Recently, in a single- dose 
rat study, the maximum tolerated dose of "unactivated" DDFPe was 
determined to be 6 mL/kg, which converted to a human equivalent dose 
(HED) of approximately 1 mL/kg. At that dose in the rats, toxicity was 
observed to be impaired locomotion and blanching of the typical red color of 
the eyes and gums. No mortality was observed and all animals recovered 
within 4 hours. 
 
Studies have also been performed in non-human primates. Anaesthetized 
rhesus monkeys received 0.6 mL/kg of activated DDFPe IV every 30 minutes 
for 3 doses without adverse effects19. In addition, conscious cynomolgus 
monkeys showed no adverse reactions to 0.6 mL/kg of activated DDFPe given 
IV every 30 minutes for 3 doses and showed only minor transient changes in 
blood pressure and heart rate at up to 1.1 mL/kg19. 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 9 
Additional information on the preclinical evaluation of DDFPe is presented in 
the Investigator’s Brochure. 
 
1.4 
Clinical Trials 
Pharmacokinetic data collected during studies conducted by Sonus were 
analyzed by NuvOx16,17. The pharmacokinetics of DDFP in human subjects 
exhibits biphasic decline after an IV bolus dose; there is a rapid initial decline 
followed by a slow terminal elimination phase17. The terminal elimination 
phase (t1/2) in humans ranges from 81-99.5 min for doses of 0.15-0.35 mL/kg. 
The values of half-life in dogs (30-48 min) were shorter than humans. The 
half-life is the shortest in rats (0.7-1.9 min). Efficacy was demonstrated in 
lower levels in animal stroke models and higher levels are not thought 
necessary in humans. 
 
DDFP is not metabolized in humans. The major route of excretion of DDFP is 
through expired air. Almost one hundred percent of administered dose was 
recovered in the expired air as DDFP. The clearance of DDFP in humans is 
43.9-65.2 mL/min/kg. 
 
1.5 
Rationale for Conducting the Trial 
A safe, reliable therapy deployed early in the care of acute stroke patients, 
either ischemic or hemorrhagic, that restored critical oxygen supply to brain 
could potentially attenuate ischemic tissue damage and could improve long-
term patient outcomes. Immediate restoration of critical brain oxygenation to 
bridge the time to vascular reperfusion by other methods would be expected to 
decrease ischemic damage, improve immediate outcomes, decrease sequelae, 
and reduce long-term health care costs. 
 
DDFPe (2% w/vol dodecafluoropentane emulsion (NVX-208)) is a liquid 
fluorocarbon, which transports over 200 times as much oxygen per milligram 
of fluorocarbon as liquid fluorocarbons that were previously tested 
extensively as oxygen therapeutics13-15. It can easily be injected intravenously. 
Intravenous drug delivery in the first hour after the onset of the symptoms and 
signs of stroke has been proven practical in the FAST MAG clinical trial of 
acute strokes20. 
 
We hypothesize that administration of DDFPe will provide critical tissue 
oxygenation in acute stroke patients to decrease stroke volumes and symptoms 
in these patients. 
 
The rationale for administering the doses evaluated is: 
1. The dose levels are within the levels already tested in animals and 
humans6-11,16,17. Volunteers received two IV bolus doses of 0.35 mL/kg of 
activated DDFPe 24 hours apart and brain cancer patients received daily 
doses of 0.17 mL/kg of unactivated DDFPe19. 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 10 
2. Therapeutic reversal of tumor hypoxia has already been observed in 
patients administered doses of 0.1 mL/kg and 0.17 mL/kg19,21. 
 
3. Therapeutic reduction in stroke damage has been observed at dose levels 
of 0.1 mL/kg in rabbits6-11. Since drug effects tend to correlate with body 
surface area/weight, one would predict that a dose of approximately 0.03 
mL/kg should be effective in humans compared to rabbits. Therefore, we 
do not believe that it is necessary to explore doses higher than 0.17 mL/kg. 
 
2.0 
Objectives 
2.1 
Primary Objective 
The primary objective of this study is to establish the Maximum Tolerated Dose 
(MTD) of DDFPe given intravenously at intervals of 90 ± 10 minutes x 3 doses 
within 12 hours after subjects have had a documented Acute Ischemic Stroke (AIS). 
 
2.2 
Secondary Objective 
The secondary objective of this study is to assess the frequency and severity of 
adverse events following administration of DDFPe to patients who have had an AIS. 
 
2.3 
Exploratory Objective 
We will evaluate the feasibility of using the National Institutes of Health Stroke Scale 
(NIHSS) to assess the immediate response to intravenous DDFPe in patients with 
AIS. 
 
3.0 
Study Design 
3.1 
Study Design 
This study is a randomized, placebo controlled, blinded escalating dose study 
designed to determine the MTD and adverse events possibly related to intravenous 
administration of DDFPe. At each of three dose levels (0.05, 0.10, 0.17 mL/kg) six 
subjects will receive DDFPe and two will receive placebo. 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 11 
3.2 
Study Schema 
The study flow is shown below in Figure 1: 
 
 
4.0 
Trial Registration 
The trial will be registered in the ClinicalTrials.gov database prior to enrollment of the first 
subject. Updated information will be included in the record every six (6) months or as 
necessary. Results will be included in the ClinicalTrials.gov database within one (1) year 
after the completion of the study. 
 
5.0 
Investigational Product 
5.1 
Description of the Investigational Product 
DDFPe (2% w/vol dodecafluoropentane emulsion (NVX-208)) is a liquid 
fluorocarbon, which transports over 200 times as much oxygen per milligram of 
fluorocarbon as liquid fluorocarbons that were previously tested extensively as 
oxygen therapeutics. The active ingredient dodecafluoropentane (DDFP) is a liquid 
with a boiling point of 28-30°C at atmospheric pressure. It is formulated as a 
nanodroplet dispersion of 2% (w/v) DDFP, stabilized by a 0.3% (w/v) 
fluorosurfactant, PEG Telomer B, in a continuous phase of 30% (w/v) sucrose. 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 12 
Clinical supplies for this study have been manufactured under aseptic conditions at 
NuvOx Pharma in Tucson, Arizona, USA. DDFPe is produced as a stable emulsion, 
which is terminally filtered through 0.2 μm sterile filters, and aseptically sealed in 
vials containing 10 mL of DDFPe. 
 
The placebo will be a sterile 1:101 dilution of Intralipid® 20% IV fat emulsion in 
aqueous sodium chloride (0.9% w/v) for injection prepared by pharmacy staff 
according to instructions in the Pharmacy Manual. Immediately prior to injection, the 
placebo will be aseptically compounded and placed directly into the same dispensing 
syringes as those for dispensing used for the injection of DDFPe22, 23. The placebo 
will not be stored for any length of time. 
 
5.2 
Storage and Preparation of the Investigational Product 
DDFPe will be shipped to the University of Arkansas for Medical Sciences (UAMS) 
Research Pharmacy prior to the start of the study along with instructions for handling, 
storage, dispensing and administration of DDFPe. All instructions are detailed in the 
Pharmacy Manual. 
 
Receipt of drug in proper condition will be recorded by the research pharmacist. 
Upon receipt, any drug that does not meet the conditions established in the Pharmacy 
Manual or arrives with vials that are broken or otherwise damaged will be reported to 
NuvOx and instruction will be sought as to whether the vials can be used or should be 
set aside for later return or destruction. The site will be will be responsible for its own 
drug accountability. 
 
DDFPe will be provided in 10 mL vials and stored upright at 2-8ºC at ambient 
humidity in a monitored refrigerator prior to use. Once a subject has been identified, 
the drug may be removed from the refrigerator and stored at room temperature up to 6 
hours until administered. The study drug may not be frozen. All vials of DDFPe will 
be labelled for investigational use. The number of vials stored in each locked kit will 
be calculated to allow for administration of the maximum dose at each dosing level. 
Each kit will also have a table used to calculate the dose, drug dosing and 
accountability forms and will be labeled for investigational use only. Immediately 
prior to injection, DDFPe or placebo will be prepared as per instructions in the 
Pharmacy Manual by pharmacy staff. The syringes containing either DDFPe or 
placebo will be appropriately labeled for investigational use only and provided to the 
clinical team in a blinded manner. 
 
Once a kit has been opened, it should be returned to the pharmacy after use. 
 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
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5.3 
Dose Escalation Plan 
5.3.1 Dose Escalation 
The plan for dose escalation is shown in Table 5.1. 
Table 5.1: Dose Escalation of DDFPe by Cohort 
Cohort 
DDFPe Dose (mL/kg) 
Maximum Dose (mL) 
1 
0.05 (x 3 doses) 
5 mL/dose x 3 doses 
2 
0.10 (x 3 doses) 
10 mL/dose x 3 doses 
3 
0.17 (x 3 doses) 
17 mL/dose x 3 doses 
* Subjects weighing more than 100kg will be included in the study. Doses will be limited 
to a maximum based on a weight of 100 kg for subjects weighing in excess of 100 kg. 
 
5.3.2 Dose Limiting Toxicity 
Dose limiting toxicity (DLT) will be defined by the following criteria: 
• Clinically significant changes in vital signs: 
o Heart rate ± 50% from baseline 
o Respiratory rate >30 /min 
o Systolic blood pressure < 90 mmHg or >220 mmHg 
o Diastolic blood pressure >110 mmHg 
• New (i.e. not seen at baseline) ECG changes consistent with: 
o Acute right ventricular dilation or strain 
o Incomplete or complete bundle branch block 
o Q waves in leads III and aVF 
o T-wave inversion and/or ST segment changes in the precordial leads 
o Any other clinically significant cardiac arrhythmia 
• Common Terminology Criteria for Adverse Events (CTCAE) 4 Grade 3 
or higher cough, dyspnea, chest pain-cardiac or non-cardiac, chest wall 
pain or hypoxia (See Appendix 1 for specific criteria) 
• NIHSS: sudden worsening of 4 or more from the baseline (pre-DDFPe 
initiation) 
• The Medical Monitor will review all data collected at Post-Dose #3 
(approximately 4-6 hours after the end of the Dose #3 infusion of 
DDFPe or placebo for each subject). Enrollment will be on hold until the 
Medical Monitor has reviewed the data and approves enrollment of an 
additional subject. The Medical Monitor may choose to temporarily halt 
the study if serious concerns arise regarding subject safety. 
 
5.3.3 Maximum Tolerated Dose 
 
The algorithm for determining the MTD is as follows: 
• Up to six subjects and two controls will be enrolled at each dose level 
constituting each cohort. Subjects will be evaluated for four hours after 
receiving the last of the three doses and again at discharge from the 
hospital or one week later, whichever is sooner. 
• DLT is previously defined in Section 5.3.2. 
• If no DLTs are observed in a patient at Post-Dose #3 of DDFPe or 
placebo the Medical Monitor may allow progression to the next patient. 


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• After all 8 subjects have been enrolled in a cohort, the Medical Monitor 
will review the data. A decision as to whether the study may proceed to 
the next cohort will be made. 
• If a total of two or fewer subjects in an 8 subject cohort experience a 
DLT, escalation to the next cohort may proceed if approved by the 
Medical Monitor. If three or more DLTs were observed, the Medical 
Monitor may consult with the Research Pharmacist to determine if the 
observed DLTs occurred in subjects who received DDFPe or placebo. If 
any of the DLTs were observed in the subjects receiving placebo, the 
Medical Monitor may allow the study to proceed as long as two or fewer 
subjects with DLTs received DDFPe. 
• If three or more subjects who received DDFPe in an 8 subject cohort 
experience a DLT, the MTD will be determined to have been exceeded 
and further enrollment in the cohort as well as dose escalation will stop. 
The dose administered to the previous cohort will be considered to be 
the MTD. 
• Subjects who withdraw from the study for reasons other than a DLT 
may be replaced. 
• The Medical Monitor will review all safety data for each patient and 
cohort and must grant approval before proceeding to the next patient 
and/or cohort. 
• Exploration of lower dose levels intermediate to a level previously 
shown to be well tolerated may be considered. In addition to reducing 
the dose, this might include reducing the number of doses, increasing the 
time between doses, and/or altering the infusion time. 
• The dose exploration will be complete when either: (1) the MTD has 
been defined or (2) when no MTD has been reached but six subjects and 
two controls have been treated at the last cohort level approved by the 
Medical Monitor. 
 
5.4 
Dispensing of the Investigational Product 
DDFPe will be stored as detailed in Section 5.2. A written order signed by one of the 
principal investigators must be obtained prior to dispensing. 
 
5.5 
Administration of the Investigational Product 
For each cohort, the dose of DDFPe or placebo will be calculated based on body 
weight according to the table in Appendix 2. Before administration, the drug will be 
prepared for injection per instructions in the Pharmacy Manual. DDFPe will be 
administered intravenously over 5-10 minutes through an IV catheter placed in a 
peripheral vein or through a central venous catheter (Note: a central venous catheter 
will not be placed solely for the study). The site of the intravenous catheter through 
which the study drug is administered will be recorded in the research record. Doses 
will be administered by slow IV push. After the first dose, subsequent doses will be 
administered 90 ± 10 minutes after the end of the previous infusion. Administration 
of all doses should occur with the syringe in the vertical position assuring that any 


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product foaming in the syringe will float near the rubber seal of the syringe plunger 
(NOTE: THIS IS THE MOST CRITICAL SAFETY CONSIDERATION DURING 
INFUSION). The placebo will be placed in identical syringes and administered in the 
same way. The volume of drug product to be used from each syringe will be provided 
on the label from pharmacy. The start and stop times for each infusion will be 
recorded on the source documents. The volume of the infusion will also be recorded. 
 
5.6 
Prior and Concomitant Therapy 
5.6.1 Excluded Drug Therapy Prior to Enrollment 
Blood clot lysing agents normally used in patients with non-hemorrhagic 
stroke may be used as indicated for acute treatment of AIS. Acute or chronic 
dosing with the following medications precludes entry into the study: 
• Anticoagulants with the exception of low dose aspirin, prophylactic 
doses of low molecular weight heparin and warfarin 
• All non-prescription medications and herbal remedies must be reviewed 
and approved by the investigator. 
• NSAIDs are permissible. 
 
5.6.2 Prohibited Drug Therapy During and 24 Hours after the Administration of the 
Investigational Product 
The following drugs are not allowable within 24 hours after the last dose of 
DDFPe: 
• None 
 
5.6.3 Criteria for Stopping the Investigational Product 
The investigational agent will be discontinued in the event that: 
• Life-threatening disease progression occurs 
• Unacceptable adverse events 
• Subject wishes to withdraw from the study 
• Changes in the patient’s condition that, in the opinion of the investigator, 
present unacceptable risk to the subject 
 
5.7 
Return and Destruction of the Investigational Product 
Any doses of DDFPe or placebo that are dispensed but not administered to an 
individual subject will be returned to the Pharmacy, documented in the drug 
accountability record, and handled as per Section 5.5. Any DDFPe or placebo that 
remains at the end of the study will be entered into the drug accountability records 
and returned to NuvOx or destroyed (21 CFR 312.62). Destruction will be witnessed 
and recorded appropriately. 
 
6.0 
Study Subjects 
6.1 
Study Population 
The study population will include any male or female patients, ages 18years old or 
older, who present to UAMS with evidence of an AIS. The potential subjects must 
have a CT scan demonstrating that there is no evidence of hemorrhage or major 


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trauma. Potential subjects must not have had recent (within 3 months) intracranial 
surgery. Subjects must meet all of the inclusion and exclusion criteria prior to 
enrollment. The patient or a legally authorized representative must be able and 
willing to provide informed consent. 
 
6.2 
Inclusion Criteria 
6.2.1 Ages 18 years old or older 
6.2.2 Diagnosis of AIS 
6.2.3 Body weight ≥ 45 kg 
6.2.4 NIHSS between 2 and 20 inclusive. 
6.2.5 Patient or LAR must be willing and able to understand the study and provide 
written informed consent 
 
6.3 
Exclusion Criteria 
6.3.1 Currently pregnant or breastfeeding 
6.3.2 History of significantly impaired renal or hepatic function 
6.3.3 Severe hemorrhage or severe hemorrhagic stroke on CT scan. Mild or 
moderate changes of Fisher Grade 1 or 2 subarachnoid hemorrhage are 
allowed as are hemorrhagic transformation changes of Grade HI-1 and HI-
224,25. 
6.3.4 Prior stroke, intracranial surgery, or major head trauma within three (3) 
months prior to enrollment 
6.3.5 Pre-stroke mRS ≥ 2 (See Appendix 3) 
6.3.6 Myocardial infarction within six (6) months prior to enrollment 
6.3.7 Unstable angina, NYHA Class II or greater congestive heart failure 
6.3.8 Uncontrolled hypertension (SBP > 180 and/or DBP > 110 mmHg) 
6.3.9 Uncontrolled arrhythmia or history of clinically significant arrhythmia within 
the past six (6) months (except atrial fibrillation) 
6.3.10 Clinically significant COPD or other pulmonary condition that is not 
controlled by medication or requires oxygen frequently or continuously 
6.3.11 Pneumonia, bronchitis, or other acute respiratory disease 
6.3.12 Current anticoagulant therapy except for antiplatelet therapy (aspirin, 
NSAIDs) and prophylactic doses of low molecular weight heparin to prevent 
deep vein thrombosis. Note: tPA administered as part of subjects’ therapy for 
AIS is allowed. However, thrombolytic therapy is not a study requirement. 
6.3.13 History of allergic reaction attributed to compounds of similar chemical 
composition to DDFPe or soy or egg allergies (see Investigator’s Brochure). 
6.3.14 Subject has received any investigational drug within thirty (30) days prior to 
enrollment into the study 
6.3.15 Inability to comply with the study procedures 
6.3.16 History or evidence of any other clinically significant condition that, in the 
opinion of the investigator, might pose a safety risk to subjects or interfere 
with study procedures, evaluation, or completion 
 
 


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6.4 
Withdrawal Criteria 
Subjects may choose to withdraw from the study at any time for any reason. 
Additionally, the investigator may choose to remove subjects from the study. Any 
subject withdrawing their consent to participate in the study or their authorization to 
use their protected health information will be withdrawn from the study. 
 
Subjects will be informed that the investigational product may be discontinued by the 
investigator even if the subject and/or the LAR wish to continue. This may occur for 
the following reasons: 
• Serious Adverse Event (SAE) believed to be related to investigational product 
• Intolerable side effects 
• Failure to complete required study procedures 
• Clinically significant laboratory or ECG abnormalities 
• Significant change in oxygenation as measured by pulse oximetry 
• Initiation of treatment with a prohibited drug during the intervention phase 
• Non-compliance with the treatment regimen 
Subjects may also be withdrawn for any reason if the investigator believes that it is in 
the best interest of the subject to discontinue the study. 
6.5 
Replacement of Subjects 
Subjects who withdraw or are withdrawn from the study prior to the completion of 
the Day 7 visit may be replaced at the discretion of the investigator. 
 
7.0 
Investigational Plan  
7.1 
Usual Care Provided by Treating Physician 
Customary (routine) care for patients suffering a stroke will be offered as would be 
the case had the patient not enrolled in the trial. This may include physiological 
monitoring, medical procedures, drug therapy (including tPA), respiratory support, 
and ancillary or accessory care. Routine care will be directed by the patient’s treating 
physician. If the treating physician believes that it is no longer in the best interest for 
the patient to continue in the study, he/she will contact the investigator and 
immediately stop all study-related procedures. 
 
7.2 
Consent Process 
Potential study subjects whose condition has rendered them unable to provide 
informed consent due to aphasia, confusion, impaired consciousness or other 
cognitive impairments such as intellectual disability and dementia will require a 
legally authorized representative (LAR). 
 
Trained study personnel will review the IRB-approved study summary brochure with 
the subject/LAR and answer questions followed by reviewing the informed consent 
document with the subject and/or a LAR. The subject/LAR will be allowed to ask 
questions. If the subject/LAR agrees to participate, the consent will be signed and a 
copy will be provided to the subject. Once the consent process is complete, study 


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personnel will document the process in a note to be placed in the study file along with 
the signed consent document. 
 
All screened and enrolled subjects will be recorded in the Screening and Enrollment 
Log at each participating institution. All enrolled subjects should be reported to Dr. 
Culp within 24 hours using the Study Participant Registration form. Dr. Culp will 
advise all PIs as to when it is acceptable to proceed with the next subject. All pre-
determined stopping points will be observed (i.e. after each subject in each cohort and 
at the end of each cohort prior to proceeding to the next highest dose). 
 
7.3 
Verification of Inclusion/Exclusion Criteria 
After the consent process is complete, trained study personnel will review the 
Inclusion and Exclusion criteria with the subject/LAR. The following options are then 
possible: 
• If the subject meets all criteria, they will be allowed to proceed with the study. 
• If the subject fails to meet criteria, no further study-related procedures will be 
conducted. 
• If the failure to meet criteria is minor, the investigator may choose to approach 
the Medical Monitor for a waiver. A waiver will be granted only if doing so will 
not place the subject at increased risk if allowed to participate in the study. 
 
Study personnel will document the review of Inclusion and Exclusion Criteria on the 
appropriate form and place the signed form in the study file. The investigator will be 
notified of the results of the review. 
 
7.4 
Randomization and Blinding 
7.4.1 A randomization schedule will be created and maintained by the UAMS 
Research Pharmacy. 
7.4.2 Subjects who agree to participate in the study and meet inclusion and 
exclusion criteria will be assigned to the next available treatment. The UAMS 
Research Pharmacy will track enrollment and randomize blinded treatments 
for administration to properly enrolled research subjects. 
7.4.3 The UAMS Research Pharmacy will deliver the blinded investigational 
treatment to the study personnel who will administer the drug to the subject. 
 
7.5 
Screening Study Procedures 
7.5.1 Screening and Enrollment Log 
All subjects who provide informed consent will be entered into the screening 
and enrollment log. Once screening is complete, the log will be updated to 
identify those subjects who pass screening and proceed into the dosing phase 
of the trial. 
 
7.5.2 Review of Head CT Exam 
The investigator will review the CT of the head with the treating physician (if 
not the investigator) or radiologist to assure that the subject meets the 


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eligibility criteria. The CT must be negative for severe hemorrhage or sever 
hemorrhagic stroke. This will be documented in the study record. 
 
7.5.3 Medical History 
A brief medical history reviewing information pertinent to the study will be 
completed by the investigator. The medical history will be documented and 
signed by the investigator (physician). 
 
7.5.4 Physical Exam 
A brief, targeted physical exam will be completed by the investigator to 
document the subjects condition and assure that there are no obvious reasons 
that it would not be in the best interest of the subject to proceed with the 
study. Weight will be measured in light clothing without shoes and recorded 
in the study record. Physical findings will be documented and signed by the 
investigator (physician). 
 
7.5.5 Concomitant Medications 
All medications currently taken by subjects will be reviewed and documented 
on the appropriate form. The form will be included in the study file. 
 
7.5.6 Pregnancy Test 
A serum pregnancy test will be performed on all women of child-bearing 
potential. Dosing with DDFPe will not begin before the test confirms that the 
women are not pregnant. If the test indicates that a woman is pregnant, she 
will be immediately dropped from the study. 
 
7.5.7 NIH Stroke Scale 
The NIHSS will be administered during Screening to assure that subjects 
score between 2 and 20, inclusive, to meet the study Inclusion criteria. Initial 
NIHSS scores from outside originating hospitals or facilities are acceptable 
only if performed by a certified neurologist. The NIHSS will be repeated 
throughout the study as indicated in the Schedule of Time and Events 
(Appendix 4). The NIHSS may be found at: 
https://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf 
 
7.5.8 ECG 
A 12-lead ECG will be performed as part of the Screening process to assure 
that subjects with serious arrhythmias are appropriately excluded from the 
study. The ECG will be inspected by the treating physician and the 
investigator. If a serious rhythm disturbance is observed, a cardiologist may 
be consulted to confirm the findings. If confirmed by the cardiologist, the 
subject will be withdrawn from the study prior to administration of DDFPe. 
After the study is completed, all ECGs will be reviewed by a board certified 
cardiologist to confirm that no new arrhythmias developed during the course 
of treatment. 


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7.5.9 Laboratory Studies 
All subjects will have the following laboratory tests collected prior to 
receiving DDFPe: 
• Complete Blood Count 
• Electrolytes (Na, K, Cl,) 
• BUN 
• Creatinine 
• LFTs (AST, ALT, Total Bilirubin, Direct Bilirubin, Albumin) 
• Calcium 
• Glucose 
 
It is anticipated that many of these tests will be done as part of the subjects’ 
routine care. These tests will provide baseline values prior to administration of 
DDFPe for later comparison with post-dosing test results. The results of these 
tests may or may not be available prior to dosing with DDFPe. None of the 
tests would exclude a subject from participating in the study. 
 
7.6 
Day 1: Study Procedures 
After documentation that the subject passed the screening procedures and meets all 
Inclusion and Exclusion criteria, study personnel will check to assure that a patent 
intravenous catheter is in place for infusion of the DDFPe. The catheter should be 
used solely for infusion of DDFPe and compatible intravenous fluids during the study 
intervention period (from the initiation of Dose #1 to after the Dose #3 infusion is 
complete). 
 
Dose #1: DDFPe will be ordered from the pharmacy and prepared as previously 
described. The time that the infusion begins will be recorded. The drug or placebo 
will be infused over 5-10 minutes. At the end of the infusion, the time will again be 
recorded. Vital signs and pulse oximetry will be monitored. Measurements will be 
recorded every 15 minutes. The subject will be observed for any signs of adverse 
events for 90 minutes after the completion of the infusion. 
 
Dose # 2: Any new concomitant medications will be recorded. The second dose of 
DDFPe or placebo will be administered as previously described over 5-10 minutes. 
Times will be recorded at the beginning and end of the infusion as before. Vital signs 
and pulse oximetry will be monitored. Measurements will be recorded every 15 
minutes. The NIHSS will be repeated within 60 minutes after the end of the DDFPe 
infusion. The subject will be observed for any signs of adverse events for 90 minutes 
after the completion of the infusion. 
 
Dose #3: Any new concomitant medications will be recorded. The third dose of 
DDFPe or placebo will be administered as previously described over 5-10 minutes. 
Times will be recorded at the beginning and end of the infusion as before. Vital signs 
and pulse oximetry will be monitored. Measurements will be recorded every 15 
minutes. The NIHSS will be repeated within 60 minutes after the end of the DDFPe 


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infusion. The subject will be observed for any signs of adverse events for 90 minutes 
after the completion of the infusion. 
 
Vitals should be taken at all scheduled time points (i.e. every 15 minutes); however, 
deviations from scheduled times will not be considered protocol deviations. The exact 
date and time of each measurement will be recorded on the CRF. 
 
Post-Dose #3: Approximately 4±1 hours after the end of Dose #3, the following 
observations will be made: 
• Concomitant medications administered after Dose #3 
• A brief physical examination 
• Vital signs (BP, HR, RR) 
• Pulse oximeter measurement 
• NIHSS 
• ECG 
• Laboratory testing 
 
Any AEs observed during the intervention period will be recorded, assessed, and 
followed to resolution. 
 
7.7 
Day 4: Study Procedures 
All subjects will be contacted to assess AEs. If the subject is still hospitalized, any 
significant change in condition will be recorded as a possible AE and assessed by the 
investigator. All AEs will be graded (mild, moderate, severe), assessed for relatedness 
(not related, possibly related, probably related, definitely related), and followed to 
resolution as described in Section 8.0. 
 
In the event that the subject has been discharged from the hospital before Day 4, 
subjects or their LAR will be contacted by telephone. AEs will be assessed and 
followed as described above. 
 
7.8 
Day 7±1 (or Hospital Discharge Day): Study Procedures 
The subject will be re-examined on the day of discharge or at one week (Day 7±1), 
whichever comes first. At this visit, the following procedures will be completed: 
• A brief interval medical history 
• A brief physical examination 
• Vital signs (BP, HR, RR) 
• Pulse oximeter measurement 
• NIHSS 
• ECG 
• Laboratory testing 
• Modified Rankin Scale 
 
 


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Any AEs observed during the intervention period will be recorded, assessed, and 
followed to resolution. 
 
If subjects are discharged before Day 7, they will be contacted by telephone to assess 
possible AEs seven days after administration of the investigational product. If any 
possible AEs are identified, they will be assessed and followed as previously 
described. 
 
7.9 
Day 30 (±7 days): Study Procedures or Telephone Follow Up 
This visit will occur as part of the routine, clinically indicated follow up. If no routine 
appointment is scheduled, the subject may be contacted by telephone to complete the 
study visit. At this visit, the following procedures will occur: 
• Interval medical history 
• A brief physical examination (omitted for telephone follow up) 
• Vital signs (BP, HR, RR) (omitted for telephone follow up) 
• mRS 
• NIHSS (omitted for telephone follow up) 
• Adverse Events 
 
7.10 
Day 90 (±14 days): Office Visit or Telephone Follow Up 
This visit will occur as part of the routine, clinically indicated follow up. If no routine 
appointment is scheduled, the subject may be contacted by telephone to complete the 
study visit. The purpose of this visit is to assess longer term complications and 
functioning related to stroke. At this visit, the following procedures will occur: 
• Interval medical history 
• mRS 
• Adverse Events 
 
The medical history will focus on additional cardiovascular events that may have 
occurred since the stroke, any changes in functioning at 90 days compared with pre-
stroke. 
 
8.0 
Adverse Events 
8.1 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence that develops or worsens 
in severity during the course of the study, whether or not it has a causal relationship 
to the study treatment. Concurrent illnesses or injuries should be regarded as AEs. 
Abnormal results of diagnostic procedures are considered AEs if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 


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Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event 
(SAE) is any AE that is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but 
are clearly of major clinical significance. They may jeopardize the subject, and may 
require intervention to prevent one of the other serious outcomes noted above. For 
example, drug overdose or abuse, a seizure that did not result in in-patient 
hospitalization or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious should be regarded 
as non-serious adverse events. 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined 
as the period from the initiation of any study procedures to the end of the study 
treatment follow-up. For this study, the study treatment follow-up is defined as within 
90 days following the last administration of study treatment. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period (e.g. if behavior worsens). 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition. At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an AE. 
 
Post-study Adverse Event 
All unresolved AEs should be followed by the investigator until the events are 
resolved, until the events are otherwise stable or the subject is lost to follow-up. At 
the last scheduled visit, the investigator should instruct each subject to report any 
subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study. 
 
 


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Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an AE if any one of the 
following conditions is met: 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm 
the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of 
dose, discontinuation of the investigational product, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as a SAE unless specifically instructed otherwise in this 
protocol. Any condition responsible for surgery should be documented as an AE if the 
condition meets the criteria for an AE. Neither the condition, hospitalization, 
prolonged hospitalization, nor surgery are reported as an AE in the following 
circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an 
outcome of an AE if the purpose of the surgery was elective or diagnostic and 
the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of 
the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
 
8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination. Information on all 
AEs should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF). All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should be recorded in 
the source document and grouped under one diagnosis when possible. 
 
All AEs occurring during the study period must be recorded. The clinical course of 
each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause. Serious adverse 
events that are still ongoing at the end of the study period must be followed up to 
determine the final outcome. 
 
8.3 
Reporting Procedures for Adverse and Serious Adverse Events 
All adverse and SAEs will be reported in accordance with FDA and local IRB 
requirements. In addition, any SAE will be reported to NuvOx and the Sponsor by the 
Investigator within 24 hours after becoming apparent. 


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All SAEs that meet the IRB’s UPIRTSO requirements must be submitted to the IRB 
within 10 working days. All other SAEs will be submitted to the IRB at continuing 
review. Copies of each report and documentation of IRB notification and receipt will 
be kept in the Clinical Investigator’s binder. 
 
8.4 
Data Safety and Monitoring Plan 
All safety data will be reviewed by the Medical Monitor after each patient and after 
the completion of each cohort. All moderate and severe safety signals that are 
unanticipated and probably or definitely related to the investigational product will be 
discussed with the Sponsor and NuVox prior to enrolling additional subjects. A Data 
Safety and Monitoring Board will not be appointed. 
 
8.5 
Medical Monitor 
A Medical Monitor (MM) will be selected. The MM will be a licensed physician who 
is familiar with cardiovascular disease and stroke. The MM will review the data 
collected after each patient and after each dose level and will provide an opinion to 
the investigator as to whether it is advisable to proceed with dose escalation as 
described in Section 5.3.3. As part of the review, the MM will review all AEs and 
assure that any SAEs have been reported appropriately. 
 
8.6 
Risks and Benefits 
Risks may include pain from IV placement, hypotension, reversible inflammatory 
changes in the lungs, nausea, vomiting, drowsiness, dizziness, fever, headache, 
reduced or elevated blood pressure, blanching of the gums, and allergy to soy or eggs. 
There may be unanticipated adverse events or outcomes. It is anticipated that oxygen 
delivery to ischemic areas of the brain may improve thereby changing clinical signs. 
It is unclear as to whether this might result in reduced cerebral tissue loss or any 
improvement in outcome following stroke. There may be no benefit to subjects. 
 
8.7 
Risk Mitigation 
All subjects will be observed in a unit accustomed to treating patients with stroke. 
Customary clinical care will be provided by the patient’s treating physician. No 
standard treatments will be withheld as a result of participation in the study. 
 
Adverse events will be actively sought through the study at multiple time points. All 
AEs will be recorded and evaluated for severity and relatedness and followed to 
resolution. A MM will be appointed to review safety issues as described in Section 
8.5. Repeated measurement of clinical, ECG, and laboratory data have been included 
to detect important safety signals. Careful assessment of all AEs, especially those that 
are probably or definitely related to the investigational product, will be conducted. 
 
9.0 
Data Collection 
9.1 
Data Collection and Storage 
All source data will be recorded on Case Report Forms (CRFs) as described in 
Sections 9.4 and 9.5. CRFs will be placed in the subjects’ study file and stored in a 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 26 
locked file cabinet or on password protected or encrypted electronic media. All data 
will be appropriately monitored by the sponsor to assure data quality and integrity. 
Electronic data capture will not be used in this study. 
 
9.2  
Confidentiality 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Information Portability and Accountability Act 
(HIPAA). Those regulations require a signed subject authorization informing the 
subject of the following: 
• The personal health information (PHI) to be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• To whom the data may be disclosed and the reasons for this disclosure 
• The rights of a research subject to revoke their authorization for use of their PHI 
 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior to 
the revocation of subject authorization. For subjects that have revoked authorization 
to collect or use PHI, attempts should be made to obtain permission to collect at least 
vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
9.3 
Study Monitoring and Data Queries 
The investigator is required to permit the Sponsor to monitor the study data, including 
all communications with the IRB, the manufacturer, all source documents, CRFs, 
pharmacy records, and any other pertinent information. Monitoring visits will be 
scheduled at a time that is convenient for both the monitor and the investigator. The 
monitor will provide a written report to the investigator within one month after the 
conclusion of the monitoring visit. 
 
9.4 
Source Documents 
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents. Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
 
9.5 
Case Report Forms 
The study CRF is the primary data collection instrument for the study. All data 
requested on the CRF must be recorded. All missing data must be explained. If a 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 27 
space on the CRF is left blank because the procedure was not done or the question 
was not asked, write “N/D”. If the item is not applicable to the individual case, write 
“N/A”. All entries should be printed legibly in black ink. If any entry error has been 
made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it. All such changes must be initialed and dated. DO 
NOT ERASE OR WHITE OUT ERRORS. For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 
 
9.6 
Study Auditing 
The investigator will permit study-related monitoring, audits, and inspections by the 
IRB, the study Sponsor, government regulatory bodies, and UAMS compliance 
groups of all study related documents (e.g. source documents, regulatory documents, 
pharmacy documents, data collection instruments, study data etc.). The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable compliance offices. 
FDA may choose to inspect the study records as indicated in 21 CFR 312.58. 
 
9.7 
Record Retention 
It is the investigator’s responsibility to retain study essential documents for 2 years 
following the date a marketing application is approved for the drug for the indication 
for which it is being investigated (21 CFR 312.62). These documents should be 
retained for a longer period if required by an agreement with the funding entity or the 
supplier of the investigational agent. In such an instance, it is the responsibility of the 
funding entity or supplier of the investigational product to inform the 
investigator/institution as to when these documents no longer need to be retained. 
 
10.0 
Data Analysis Plan 
10.1 
Sample Size 
This is a Phase I study. No sample size estimates were done. 
 
10.2 
Clinical Data 
Demographic data will be presented as the mean ± SD (range) for normally 
distributed data (median ± interquartile range for non-normal data). 
 
Clinical data includes vital signs and pulse oximetry (pre- and post-intervention). Pre- 
and post-intervention data will be grouped and examined for differences using a two-
sided t-test or ANOVA, as appropriate. Pre- and post- laboratory data will be 
compared in a similar manner. ECGs will be read by a board-certified cardiologist 
and clinically significant changes will be described. 
 
 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 28 
10.3 
Safety Data 
All safety data will be reported. DLT will be examined and the MTD will be 
determined as previously described. All SAEs will be reported as required. 
 
10.4 
Exploratory Aim Analysis 
There are a number of patient subgroups that could be of interest and might be 
expected to respond differently to DDFPe as evaluated by NIHSS scores: 
a. In those early patients who get some successful therapy and get DDFPe early at 
less than 3 hours from LKWT, the values should drop with the DDFPe and stay 
down with reperfusion. Late DDFPe uncertain. 
b. In those that get Rx and it fails, scores may perhaps go down with early DDFPe 
and come back up when it wears off. With late DDFPe little change is expected. 
c. In those that do not get reperfusion therapy and do get DDFPe in the first 3 hours, 
scores should go down but come back up when it wears off. 
d. In those that do not get reperfusion therapy and get DDFPe late, scores should not 
change much 
e. In those that get placebo, should see little change, early or late, unless they have 
successful reperfusion therapy or spontaneous reperfusion. 
 
Fewer than 20% are likely to get IV tPA or IA reperfusion therapy of the total 24 
patients; the patient numbers in any of these groups will be quite small, obviating the 
ability to make formal statistical comparisons or to draw conclusions about the impact 
of DDFPe therapy on outcome. This is a Phase I safety trial, and not designed to test 
treatment outcomes. As an exploratory analysis, we will compare the patients without 
reperfusion therapy, IV or IA, who got early DDFPe under 3 hours from LKWT, to 
placebo patients of similar characteristics. Due to the small sample sizes and because 
each of the proposed doses were effective in animal studies, we will ignore dose in 
this comparison.  
 
We expect that the NIHSS values should drop with DDFPe but come back up after 5 
or 6 hours and no change is expected in placebo. We will visually examine plots of 
the data for consistency with this hypothesis and if the sample sizes are sufficient, we 
will carry out nonparametric tests comparing the changes as exploratory analyses.  
 
Those patients receiving DDFPe between 3 and 6 hours from LKWT could be 
another group of great interest, and we will make similar exploratory comparisons of 
this group with the two just described. 
 
No claims of efficacy will be possible based on these limited data, but they may 
suggest directions for subsequent study. 
 
11.0 
Ethical and Regulatory Requirements 
11.1 
Trial Registration 
The trial will be registered on ClinicalTrials.gov as previously described in Section 4 
of the protocol. 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 29 
11.2 
Informed Consent Procedures 
This study will be conducted in accordance with all applicable government 
regulations, research policies and procedures. This protocol and any amendments will 
be submitted and approved by the local IRB prior to conducting the study. 
 
The formal consent of each subject/LAR, using the IRB-approved consent form, will 
be obtained before the subject is enrolled into any study procedure. All 
subjects/LARs for this study will be provided a consent form describing this study 
and provided sufficient information in language suitable for subjects/LARs to make 
an informed decision about their participation in this study. The person obtaining 
consent will thoroughly explain each element of the document and outline the risks 
and benefits, alternate treatment(s), and requirements of the study. It is anticipated 
that, due to the nature of the condition under study, some subjects may be unable to 
provide informed consent. The investigators will follow local IRB policies for 
obtaining consent from cognitively impaired subjects. 
 
No coercion or undue influence will be used in the consent process. The consent form 
must be signed by the subject/LAR and the individual obtaining the consent. A copy 
of the signed consent will be given to the subjects/LARs, and the informed consent 
process will be documented in each subject’s research record. 
 
11.3 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
This study is to be conducted according to applicable government regulations and 
Institutional research policies and procedures. The protocol, the consent document, 
and any amendments will be submitted to a properly constituted independent IRB, in 
agreement with local legal prescriptions, for formal approval of the study conduct. 
The decision of the local IRB concerning the conduct of the study will be made in 
writing to the investigator before commencement of this study.  
 
11.4 
Subject Confidentiality 
Every effort will be made to assure that data collected from subjects remains 
confidential. Subjects will be identified by a code. The subject’s name and identifying 
information will be stored in a locked file in the office of the investigator or on a 
password protected or an encrypted drive in the investigators’ personal possession. 
Data may be shared with NuvOx, the Sponsor (UAMS), the IRB, the FDA, and 
appropriate compliance and regulatory authorities. 
 
11.5 
Protocol Amendments 
Any change to the research protocol or consent document must be submitted to and 
receive approval from the Sponsor, NuVox, and the IRB prior to implementation. 
11.6 
Study Termination 
The study may be terminated at any time by the Sponsor or NuvOx. If the study is 
terminated, the FDA will be notified. 
 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 30 
In the event that the study is terminated prior to completion, all investigational 
product will be returned to the pharmacy. The pharmacy will either return the unused 
product to NuvOx or proceed with destruction of the investigational agent per 21 
CFR 312.62. 
 
12.0 
Publication Policy 
Any manuscripts reporting the results of this clinical trial must be provided to NuvOx by the 
Principal Investigator for advisory review and comment prior to submission for publication. 
NuvOx will have 30 days from the date of receipt for review and will also have the right to 
request that publication be delayed for up to an additional 30 days in order to ensure that 
confidential and proprietary data, and intellectual property rights, are protected. Copies of 
meeting abstracts must be provided to NuvOx for courtesy review as soon as possible and at 
least three (3) days prior to submission. Press releases and other media presentations must 
also be forwarded to NuvOx prior to release. 
 
In any publication or presentation, individual subjects will not be identified by name or any 
other means. All data will be published in aggregate form. 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 31 
13.0 
References 
1. 
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de 
Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, 
Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, 
McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar 
RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, 
Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; 
American Heart Association Statistics Committee and Stroke Statistics Subcommittee. 
Heart Disease and Stroke Statistics—2015 Update. A Report From the American Heart 
Association. Circulation. 2016;133:e38-e360. doi: 10.1161/CIR.0000000000000350. 
Epub 2015 Dec 16. 
2. 
Centers for Disease Control and Prevention (CDC). Prevalence and most common 
causes of disability among adults: United States, 2005. MMWR Morb Mortal Wkly Rep. 
2009;58:421–426. 
3. 
Howard G, Anderson R, Johnson NJ, Sorlie P, Russell G, Howard VJ. Evaluation of 
social status as a contributing factor to the stroke belt region of the United States. 
Stroke. 1997;28:936–940. 
4. 
Ovbiagele B, Goldstein LB, Higashida RT, Howard VJ, Johnston SC, Khavjou OA, 
Lackland DT, Lichtman JH, Mohl S, Sacco RL, Saver JL, Trogdon JG; on behalf of the 
American Heart Association Advocacy Coordinating Committee and Stroke Council. 
Forecasting the future of stroke in the United States: a policy statement from the 
American Heart Association and American Stroke Association. Stroke. 2013;44:2361–
2375. 
5. 
Schwamm LH, Ali SF, Reeves MJ, Smith EE, Saver JL, Messe S, Bhatt DL, Grau-
Sepulveda MV, Peterson ED, Fonarow GC. Temporal Trends in Patient Characteristics 
and Treatment With Intravenous Thrombolysis Among Acute Ischemic Stroke Patients 
at Get With the Guidelines–Stroke Hospitals. Circulation: Cardiovascular Quality and 
Outcomes. 2013; 6: 543-549. 
6. 
Arthur MC, Brown A, Carlson K, Lowery J, Skinner RD, Culp WC. 
Dodecafluoropentane improves neurological function following anterior ischemic 
stroke. Molecular Neurobiology. June 2016; Accepted for publication. 
7. 
Culp WC, Brown AT, Lowery JD, Arthur MC, Roberson PK, Skinner RD. 
Dodecafluoropentane emulsion extends window for tPA therapy in a rabbit stroke 
model. Mol Neurobiol. 2015;52:979-84. 
8. 
Fitzgerald RT, Ou X, Nix JS, Arthur MC, Brown AT, Skinner RD, Borrelli MJ, Culp 
WC. Dodecafluoropentane emulsion delays and reduces MRI markers of infarction in a 
rat stroke model. Magnetic Resonance Imaging. 2015; 33:236-239. 
9. 
Brown AT, Arthur MC, Nix JS, Montgomery JA, Skinner RD, Roberson PK, Borrelli 
M, Culp WC. Dodecafluoropentane emulsion (DDFPe) decreases stroke size and 
improves neurological scores in a permanent occlusion rat stroke model. The Open 
Neurology Journal. 2014; 8:27-33. 
10. Woods SD, Skinner RD, Ricca AM, Brown AT, Lowery JD, Borrelli MJ, Lay JO, Culp 
WC. Progress in dodecafluoropentane emulsion as a neuroprotective agent in a rabbit 
stroke model. Mol Neurobiol. 2013;48:363-7. 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 32 
11. Culp WC, Woods SD, Skinner RD, Brown AT, Lowery JD, Johnson JLH, Unger EC, 
Hennings LJ, Borrelli MJ, Roberson PK. Dodecafluoropentane emulsion decreases 
infarct volume in a rabbit ischemic stroke model. JVIR. 2012;23:116-21. 
12. Spahn DR. Blood substitutes Artificial oxygen carriers: perfluorocarbon emulsions. Crit 
Care. 1999;3: R93–R97. 
13. Johnson, J. L., Dolezal, M. C., Kerschen, A., Matsunaga, T. O., & Unger, E. C. In vitro 
comparison 
of 
dodecafluoropentane 
(DDFP), 
perfluorodecalin 
(PFD), 
and 
perfluoroctylbromide (PFOB) in the facilitation of oxygen exchange. Artificial Cells, 
Blood Substitutes and Biotechnology.2009;37:156‐162. 
14. Lowe KC. Fluorinated blood substitutes and oxygen carriers. Journal of Fluorine 
Chemistry. 2001;109:59-65. 
15. Riess JG. Understanding the fundamentals of perfluorocarbons and perfluorocarbon 
emulsions relevant to in vivo oxygen delivery. Artificial Cells, Blood Substitutes and 
Biotechnology. 2005;33:47-63. 
16. Grayburn, Paul A., et al. "Phase III multicenter trial comparing the efficacy of 2% 
dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) 
as ultrasound contrast agents in patients with suboptimal echocardiograms." Journal of 
the American College of Cardiology. 1998;32.1:230-236. 
17. Correas, Jean-Michel, et al. "Human pharmacokinetics of a perfluorocarbon ultrasound 
contrast agent evaluated with gas chromatography." Ultrasound in medicine & biology. 
2001;27.4: 565-570. 
18. ClinicalTrials.gov NCT02189109 
19. Investigators Brochure for NVX-508-SCD, v.5, 2016. 
20. Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S, Conwit R, 
Liebeskind DS, Sung G, Kramer I, Moreau G, Goldweber R, Sanossian N, for the 
FAST-MAG Investigators and Coordinators. Prehospital use of magnesium sulfate as 
neuroprotection in acute stroke. NEJM. 2015; 372:528-536. 
21. Investigators Brochure for NVX-208-AIS. 
22. Rogers Chris A, et al. Propofol cardioplegia: A single-center, placebo-controlled, 
randomized controlled trial. J Thorac Cardiovasc Surg, 2015;150:1610-9. 
23. Shah, Amit, et al. A blinded, randomized controlled trial to evaluate Ketamine/Propofol 
versus Ketamine alone for procedural sedation in children. Ann Emerg Med. 
2011;57:425-433. 
24. Trouillas P, von Krummer R. Classification and Pathogenisis of cerebral hemorrhages 
after thrombolysis in ischemic stroke. Stroke, 2006;37:556-561. 
25. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid 
hemorrhage visualized by computerized tomographic scanning. Neurosurgery, 
1980;6:1-9. 
 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 33 
Appendices: 
Appendices 1 – 4 are attached below. 
 
Appendix 1: CTCAE 4 Selected Adverse Events 
 
Respiratory, thoracic, and mediastinal disorders 
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Cough 
Definition: A disorder characterized by 
sudden, often repetitive, spasmodic 
contraction of the thoracic cavity, 
resulting in violent release of air from 
the lungs and usually accompanied by a 
distinctive sound. 
Mild symptoms; 
nonprescription 
intervention 
indicated 
Moderate symptoms, 
medical intervention 
indicated; limiting 
instrumental ADL 
Severe symptoms; 
limiting self care ADL 
 
 
Dyspnea 
Definition: A disorder characterized by 
an uncomfortable sensation of difficulty 
breathing. 
Shortness of 
breath with 
moderate 
exertion 
Shortness of breath 
with minimal 
exertion; limiting 
instrumental ADL 
Shortness of breath at 
rest; limiting self care 
ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Chest Pain Cardiac 
Definition: A disorder characterized by 
substernal discomfort due to 
insufficient myocardial oxygenation. 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Pain at rest; limiting 
self care ADL 
 
 
Chest Wall Pain 
Definition: A disorder characterized by 
marked discomfort sensation in the 
pleura. 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; limiting 
self care ADL 
 
 
Hypoxia 
Definition: A disorder characterized by 
a decrease in the level of oxygen in the 
body. 
 
Decreased oxygen 
saturation with 
exercise (e.g., pulse 
oximeter <88%); 
intermittent 
supplemental oxygen 
Decreased oxygen 
saturation at rest (e.g., 
pulse oximeter <88% 
or PaO2 <=55 mm Hg 
Life-threatening airway 
compromise; urgent 
intervention indicated 
(e.g., tracheotomy or 
intubation) 
Death 
 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 34 
Appendix 2: DDFPe Dosing by Weight 
 
 
 
 
 
DDFPe dosage volume in cc for 0.05 mL/kg based on patient body weight in kilograms (kg). 
Body 
Weight 
(kg) 
DDFPe 
Dose 
0.05mL/ kg 
(mL) 
Number of 
DDFPe 
10mL Vials 
Required 
Number 
of 10mL 
Syringes 
Total Volume 
to be Prepared 
(mL) 
Volume to be 
Administered 
from syringe 
(mL) 
45* 
2.2 
1 
1 
10 
2.2 
46 
2.3 
1 
1 
10 
2.3 
47 
2.4 
1 
1 
10 
2.4 
48 
2.4 
1 
1 
10 
2.4 
49 
2.4 
1 
1 
10 
2.4 
50 
2.5 
1 
1 
10 
2.5 
51 
2.6 
1 
1 
10 
2.6 
52 
2.6 
1 
1 
10 
2.6 
53 
2.6 
1 
1 
10 
2.6 
54 
2.7 
1 
1 
10 
2.7 
55 
2.8 
1 
1 
10 
2.8 
56 
2.8 
1 
1 
10 
2.8 
57 
2.8 
1 
1 
10 
2.8 
58 
2.9 
1 
1 
10 
2.9 
59 
3.0 
1 
1 
10 
3.0 
60 
3.0 
1 
1 
10 
3.0 
61 
3.0 
1 
1 
10 
3.0 
62 
3.1 
1 
1 
10 
3.1 
63 
3.2 
1 
1 
10 
3.2 
64 
3.2 
1 
1 
10 
3.2 
65 
3.2 
1 
1 
10 
3.2 
66 
3.3 
1 
1 
10 
3.3 
67 
3.4 
1 
1 
10 
3.4 
68 
3.4 
1 
1 
10 
3.4 
69 
3.4 
1 
1 
10 
3.4 
70 
3.5 
1 
1 
10 
3.5 
71 
3.6 
1 
1 
10 
3.6 
72 
3.6 
1 
1 
10 
3.6 
73 
3.6 
1 
1 
10 
3.6 
74 
3.7 
1 
1 
10 
3.7 
75 
3.8 
1 
1 
10 
3.8 
76 
3.8 
1 
1 
10 
3.8 
77 
3.8 
1 
1 
10 
3.8 
78 
3.9 
1 
1 
10 
3.9 
79 
4.0 
1 
1 
10 
4.0 
80 
4.0 
1 
1 
10 
4.0 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 35 
 
 
Body 
Weight 
(kg) 
DDFPe 
Dose 
0.05mL/ kg 
(mL) 
Number of 
DDFPe 
10mL Vials 
Required 
Number 
of 10 mL 
Syringes 
Total 
Volume to 
be Prepared 
(mL) 
Volume to be 
Administered 
from syringe 
(mL) 
81 
4.0 
1 
1 
10 
4.0 
82 
4.1 
1 
1 
10 
4.1 
83 
4.2 
1 
1 
10 
4.2 
84 
4.2 
1 
1 
10 
4.2 
85 
4.2 
1 
1 
10 
4.2 
86 
4.3 
1 
1 
10 
4.3 
87 
4.4 
1 
1 
10 
4.4 
88 
4.4 
1 
1 
10 
4.4 
89 
4.4 
1 
1 
10 
4.4 
90 
4.5 
1 
1 
10 
4.5 
91 
4.6 
1 
1 
10 
4.6 
92 
4.6 
1 
1 
10 
4.6 
93 
4.6 
1 
1 
10 
4.6 
94 
4.7 
1 
1 
10 
4.7 
95 
4.8 
1 
1 
10 
4.8 
96 
4.8 
1 
1 
10 
4.8 
97 
4.8 
1 
1 
10 
4.8 
98 
4.9 
1 
1 
10 
4.9 
99 
5.0 
1 
1 
10 
5.0 
100** 
5.0 
1 
1 
10 
5.0 
Total DDFPe Dose = 0.05 mL/kg x weight in kg. 
*Minimum subject weight = 45 kg. 
**Maximum subject weight used for dose calculation = 100 kg. For subjects weighing more 
than 100 kg, dose will be calculated based on a weight of 100 kg. 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 36 
DDFPe dosage volume in cc for 0.10 mL/kg based on patient body weight in kilograms (kg). 
Body 
Weight 
(kg) 
DDFPe 
Dose 
0.10mL/kg 
Number of 
DDFPe 
10mL 
Vials 
Required 
Number of 
10mL 
Syringes to be 
Prepared 
Total Volume 
to be 
Prepared 
(mL) 
Volume to be 
Administered 
from 1st 
syringe (mL) 
Volume to be 
Administered 
from 2nd 
Syringe (mL) 
45* 
4.5 
1 
1 
10 
4.5 
N/A 
46 
4.6 
1 
1 
10 
4.6 
N/A 
47 
4.7 
1 
1 
10 
4.7 
N/A 
48 
4.8 
1 
1 
10 
4.8 
N/A 
49 
4.9 
1 
1 
10 
4.9 
N/A 
50 
5.0 
1 
1 
10 
5.0 
N/A 
51 
5.1 
1 
1 
10 
5.1 
N/A 
52 
5.2 
1 
1 
10 
5.2 
N/A 
53 
5.3 
1 
1 
10 
5.3 
N/A 
54 
5.4 
1 
1 
10 
5.4 
N/A 
55 
5.5 
1 
1 
10 
5.5 
N/A 
56 
5.6 
1 
1 
10 
5.6 
N/A 
57 
5.7 
1 
1 
10 
5.7 
N/A 
58 
5.8 
1 
1 
10 
5.8 
N/A 
59 
5.9 
1 
1 
10 
5.9 
N/A 
60 
6.0 
1 
1 
10 
6.0 
N/A 
61 
6.1 
1 
1 
10 
6.1 
N/A 
62 
6.2 
1 
1 
10 
6.2 
N/A 
63 
6.3 
1 
1 
10 
6.3 
N/A 
64 
6.4 
1 
1 
10 
6.4 
N/A 
65 
6.5 
1 
1 
10 
6.5 
N/A 
66 
6.6 
1 
1 
10 
6.6 
N/A 
67 
6.7 
1 
1 
10 
6.7 
N/A 
68 
6.8 
1 
1 
10 
6.8 
N/A 
69 
6.9 
1 
1 
10 
6.9 
N/A 
70 
7.0 
1 
1 
10 
7.0 
N/A 
71 
7.1 
1 
1 
10 
7.1 
N/A 
72 
7.2 
1 
1 
10 
7.2 
N/A 
73 
7.3 
1 
1 
10 
7.3 
N/A 
74 
7.4 
1 
1 
10 
7.4 
N/A 
75 
7.5 
1 
1 
10 
7.5 
N/A 
76 
7.6 
1 
1 
10 
7.6 
N/A 
77 
7.7 
1 
1 
10 
7.7 
N/A 
78 
7.8 
1 
1 
10 
7.8 
N/A 
79 
7.9 
1 
1 
10 
7.9 
N/A 
80 
8.0 
2 
2 
20 
4.0 
4.0 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 37 
 
 
Body 
Weight 
(kg) 
DDFPe 
Dose 
0.10mL/kg 
Number of 
DDFPe 
10mL 
Vials 
Required 
Number of 
10mL Syringes 
to be Prepared 
Total 
Volume to 
be Prepared 
(mL) 
Volume to be 
Administered 
from 1st 
syringe (mL) 
Volume to be 
Administered 
from 2nd 
Syringe (mL) 
81 
8.1 
2 
2 
20 
4.1 
4.0 
82 
8.2 
2 
2 
20 
4.2 
4.0 
83 
8.3 
2 
2 
20 
4.3 
4.0 
84 
8.4 
2 
2 
20 
4.4 
4.0 
85 
8.5 
2 
2 
20 
4.5 
4.0 
86 
8.6 
2 
2 
20 
4.6 
4.0 
87 
8.7 
2 
2 
20 
4.7 
4.0 
88 
8.8 
2 
2 
20 
4.8 
4.0 
89 
8.9 
2 
2 
20 
4.9 
4.0 
90 
9.0 
2 
2 
20 
5.0 
4.0 
91 
9.1 
2 
2 
20 
5.1 
4.0 
92 
9.2 
2 
2 
20 
5.2 
4.0 
93 
9.3 
2 
2 
20 
5.3 
4.0 
94 
9.4 
2 
2 
20 
5.4 
4.0 
95 
9.5 
2 
2 
20 
5.5 
4.0 
96 
9.6 
2 
2 
20 
5.6 
4.0 
97 
9.7 
2 
2 
20 
5.7 
4.0 
98 
9.8 
2 
2 
20 
5.8 
4.0 
99 
9.9 
2 
2 
20 
5.9 
4.0 
100** 
10.0 
2 
2 
20 
5.0 
5.0 
Total DDFPe Dose = 0.10 mL/kg x weight in kg. 
*Minimum subject weight = 45 kg. 
**Maximum subject weight used for dose calculation = 100 kg. For subjects weighing more than 100 kg, 
dose will be calculated based on a weight of 100 kg. 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 38 
 
 
DDFPe dosage volume in cc for 0.17 mL/kg based on patient body weight in kilograms (kg). 
Body 
Weight 
(kg) 
DDFPe 
Dose 
0.17mL/k
g (mL) 
Number 
of DDFPe 
10mL 
Vials 
Required 
Number 
of 10mL 
Syringes 
 
 
Total 
Volume to 
be 
Prepared 
(mL) 
Volume to be 
Administered 
from 1st 
syringe (mL) 
Volume to be 
Administered 
from 2nd 
syringe (mL) 
Volume to be 
Administered 
from 3rd 
syringe (mL) 
45* 
7.6 
1 
1 
10 
7.6 
N/A 
N/A 
46 
7.8 
1 
1 
10 
7.8 
N/A 
N/A 
47 
8.0 
1 
1 
10 
8.0 
N/A 
N/A 
48 
8.2 
1 
1 
10 
8.2 
N/A 
N/A 
49 
8.3 
1 
1 
10 
8.3 
N/A 
N/A 
50 
8.5 
1 
1 
10 
8.5 
N/A 
N/A 
51 
8.7 
1 
1 
10 
8.7 
N/A 
N/A 
52 
8.8 
1 
1 
10 
8.8 
N/A 
N/A 
53 
9.0 
2 
2 
20 
4.5 
4.5 
N/A 
54 
9.2 
2 
2 
20 
4.6 
4.6 
N/A 
55 
9.4 
2 
2 
20 
4.7 
4.7 
N/A 
56 
9.5 
2 
2 
20 
4.8 
4.7 
N/A 
57 
9.7 
2 
2 
20 
4.9 
4.8 
N/A 
58 
9.9 
2 
2 
20 
5.0 
4.9 
N/A 
59 
10.0 
2 
2 
20 
5.0 
5.0 
N/A 
60 
10.2 
2 
2 
20 
5.1 
5.1 
N/A 
61 
10.4 
2 
2 
20 
5.2 
5.2 
N/A 
62 
10.5 
2 
2 
20 
5.3 
5.2 
N/A 
63 
10.7 
2 
2 
20 
5.4 
5.3 
N/A 
64 
10.9 
2 
2 
20 
5.5 
5.4 
N/A 
65 
11.0 
2 
2 
20 
5.5 
5.5 
N/A 
66 
11.2 
2 
2 
20 
5.6 
5.6 
N/A 
67 
11.4 
2 
2 
20 
5.7 
5.7 
N/A 
68 
11.6 
2 
2 
20 
5.8 
5.8 
N/A 
69 
11.7 
2 
2 
20 
5.9 
5.8 
N/A 
70 
11.9 
2 
2 
20 
6.0 
5.9 
N/A 
71 
12.1 
2 
2 
20 
6.1 
6.0 
N/A 
72 
12.2 
2 
2 
20 
6.1 
6.1 
N/A 
73 
12.4 
2 
2 
20 
6.2 
6.2 
N/A 
74 
12.6 
2 
2 
20 
6.3 
6.3 
N/A 
75 
12.8 
2 
2 
20 
6.4 
6.4 
N/A 
76 
12.9 
2 
2 
20 
6.5 
6.4 
N/A 
77 
13.1 
2 
2 
20 
6.6 
6.5 
N/A 
78 
13.3 
2 
2 
20 
6.7 
6.6 
N/A 
79 
13.4 
2 
2 
20 
6.7 
6.7 
N/A 
80 
13.6 
2 
2 
20 
6.8 
6.8 
N/A 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 39 
 
 
Body 
Weight 
(kg) 
DDFPe 
Dose 
0.17mL/
kg (mL) 
Number 
of DDFPe 
10mL 
Vials 
Required 
Number 
of 10mL 
Syringes 
 
 
Total 
Volume to 
be 
Prepared 
(mL) 
Volume to be 
Administered 
from 1st 
syringe (mL) 
Volume to be 
Administered 
from 2nd 
syringe (mL) 
Volume to be 
Administered 
from 3rd 
syringe (mL) 
81 
13.8 
2 
2 
20 
6.9 
6.9 
N/A 
82 
13.9 
2 
2 
20 
7.0 
6.9 
N/A 
83 
14.1 
2 
2 
20 
7.1 
7.0 
N/A 
84 
14.3 
2 
2 
20 
7.2 
7.1 
N/A 
85 
14.4 
2 
2 
20 
7.2 
7.2 
N/A 
86 
14.6 
2 
2 
20 
7.3 
7.3 
N/A 
87 
14.8 
2 
2 
20 
7.4 
7.4 
N/A 
88 
15.0 
2 
2 
20 
7.5 
7.5 
N/A 
89 
15.1 
2 
2 
20 
7.6 
7.5 
N/A 
90 
15.3 
2 
2 
20 
7.7 
7.6 
N/A 
91 
15.5 
2 
2 
20 
7.8 
7.7 
N/A 
92 
15.6 
2 
2 
20 
7.8 
7.8 
N/A 
93 
15.8 
2 
2 
20 
7.9 
7.9 
N/A 
94 
16.0 
2 
2 
20 
8.0 
8.0 
N/A 
95 
16.2 
3 
3 
30 
6.0 
6.0 
4.2 
96 
16.3 
3 
3 
30 
6.0 
6.0 
4.3 
97 
16.5 
3 
3 
30 
6.0 
6.0 
4.5 
98 
16.7 
3 
3 
30 
6.0 
6.0 
4.7 
99 
16.8 
3 
3 
30 
6.0 
6.0 
4.8 
100** 
17.0 
3 
3 
30 
6.0 
6.0 
5.0 
Total DDFPe Dose = 0.17 mL/kg x weight in kg. 
*Minimum subject weight = 45 kg. 
**Maximum subject weight used for dose calculation = 100 kg. For subjects weighing more than 100 kg, dose 
will be calculated based on a weight of 100 kg. 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 40 
Appendix 3: Modified Rankin Scale 
 
Subject Name: __________________________ 
Rate Name: 
__________________________ 
Date: 
__________________________ 
 
Scale to be administered as part of the exclusion criteria and again at follow up (discharge and end of 
study) 
 
SCORE 
DESCRIPTION 
0 
No symptoms at all 
 
1 
No significant disability despite symptoms; able to carry out all usual duties and 
activities 
 
2 
Slight disability; unable to carry out all previous activities, but able to look after 
own affairs without assistance 
 
3 
Moderate disability; requiring some help, but able to walk without assistance 
 
4 
Moderately severe disability: unable to walk without assistance and unable to 
attend to own bodily needs without assistance 
 
5 
Severe disability; bedridden, incontinent and requiring constant nursing attention 
 
6 
Dead 
 
 
 
Score (0-6): 
______ 
 
 
References 
Rankin J. Cerebral vascular accidents in patients over the age of 60. Scot Med J 1957;2:200-215. 
 
Bonita R, Beaglehole R. Modification of Rankin Scale: Recovery of motor function after stroke. 
Stroke 1988;19(12):1497-1500. 
 
 
 


Title: A phase 1b dose-finding study of DDFPe in acute ischemic stroke 
PIs: William C. Culp, MD & Sanjeeva Onteddu, MD 
Institution: UAMS 
Sponsor: UAMS 
Version 11 
February 22, 2018 
Page 41 
Appendix 4: Schedule of Time and Events 
 
Day 1 
Day 4 
Day 7±1 or 
Day of 
Discharge 
Day 
30 ±7 
Day 
90 ±14 
 
Study Procedures 
Screening 
(Baseline) 
 
Dose #1a 
 
Dose #2a 
 
Dose #3a 
Post-
Dose #3b 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
Concomitant 
Meds 
X 
X 
X 
X 
X 
 
 
 
 
Medical Historyc 
X 
 
 
 
 
 
X 
X 
X 
Physical Examc 
X 
 
 
 
X 
 
X 
X 
 
Weight 
X 
 
 
 
 
 
 
 
 
Vital Signsd 
X 
X 
X 
X 
X 
 
X 
X 
 
Pulse Oximetrye 
X 
X 
X 
X 
X 
 
X 
 
 
Modified Rankin 
Scale 
X 
 
 
 
 
 
X 
X 
X 
NIHSS 
X 
 
Xf 
Xf 
X 
 
X 
X 
 
ECGg 
X 
 
 
 
X 
 
X 
 
 
Pregnancy Testh 
X 
 
 
 
 
 
 
 
 
Lab Studiesi 
X 
 
 
 
X 
 
X 
 
 
Administer 
DDFPej 
 
X 
X 
X 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a  Each dose of DDFPe or placebo is to be administered intravenously over 5-10 minutes. Start and stop times 
will be recorded as will the volume infused. 
b  Post-dose #3 concludes approximately 4-6 hours after the end of the Dose #3 infusion. 
c  Brief, targeted medical history and physical exam. 
d  Vital signs (blood pressure, heart rate, respiratory rate) will be done every 15 minutes through the end of 
Post-Dose #3 (approximately 4-6 hours) and then consistent with standard procedures for the hospital unit. 
Temperature will be done every 1-4 hours consistent with the hospital unit standard procedures. 
e  Continuous or spot readings may be taken; if continuous readings are used, record the measurement every 
15 minutes. 
f  
To be performed within 60 minutes following the dose. 
g  12-lead ECG to be examined at the bedside by the study personnel and later reviewed by a board certified 
cardiologist. 
h  Serum pregnancy test will be done in pre-menopausal women. 
i  
To include: CBC, electrolytes (Na, K, Cl,), BUN, creatinine, LFTs, calcium, albumin, glucose 
j  
DDFPe or placebo to be administered over 5-10 minutes intravenously through a peripheral or central IV. 
The interval between the end of one dose and the beginning of the next should be 90 ± 10 minutes.