A Phase Ib/II in Patients With Acute Ischemic Stroke

• Sponsor: NuvOx LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02963376
• Collaborator: University of Arkansas (Other)
• Enrollment: 24
• Location: 1
• Arms: 6
• Actual Duration (Months): 17.2
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke	Drug: 0.05 mL/kg DDFPe; Drug: 0.05 mL/kg Placebo; Drug: 0.10 mL/kg DDFPe; Drug: 0.10 mL/kg Placebo; Drug: 0.17 mL/kg DDFPe; Drug: 0.17 mL/kg Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/II Dose-finding Study of DDFPe in Patients With Acute Ischemic Stroke
• Actual Study Start Date: Feb 1, 2017
• Actual Primary Completion Date: Jul 9, 2018
• Actual Study Completion Date: Jul 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 0.05 mL/kg DDFPe 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.	Drug: 0.05 mL/kg DDFPe; 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).; Other Names: Dodecafluoropentane emulsion (DDFPe), NanO2TM
Placebo Comparator: 0.05 mL/kg Placebo 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.	Drug: 0.05 mL/kg Placebo; 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).
Active Comparator: 0.10 mL/kg DDFPe 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.	Drug: 0.10 mL/kg DDFPe; 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).; Other Names: Dodecafluoropentane emulsion (DDFPe), NanO2TM
Placebo Comparator: 0.10 mL/kg Placebo 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.	Drug: 0.10 mL/kg Placebo; 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).
Active Comparator: 0.17 mL/kg DDFPe 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.	Drug: 0.17 mL/kg DDFPe; 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).; Other Names: Dodecafluoropentane emulsion (DDFPe), NanO2TM
Placebo Comparator: 0.17 mL/kg Placebo 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.	Drug: 0.17 mL/kg Placebo; 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).

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of DDFPe Evaluated by Number of Dose Limiting Toxicities [12 hours after subjects have had a documented Acute Ischemic Stroke (AIS)]

   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). The algorithm for determining the MTD is based on the number of subjects who experience a Dose Limiting Toxicity (DLT) in each cohort, as defined in the clinical protocol. 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.

Secondary Outcome Measures

1. NIHSS Assessment [NIHSS scores were recorded at outside hospitals when appropriate and also at the study center as inside baseline NIHSS score. Repeat NIHSS scores were recorded at 2, 3.5, and 7.5 hours after drug injection and on discharge.]

   The NIH Stroke Scale (NIHSS) is an assessment tool that provides a quantitative measure of stroke-related neurologic deficit. The NIHSS is a 15-item neurologic examination. Ratings for each item are scored on a 3- to 5-point scale with 0 as normal. Scores range from 0 to 42, with higher scores indicating greater severity.

2. Modified Rankin Scale (mRS) [mRS values were obtained on Day 7 or Day of Discharge, Day 30 and Day 90.]

   The modified Rankin Scale is a measure of the degree of disability in patients who have had a stroke with 0 being no symptoms at all to 6 being death. Thus, a higher score indicates greater severity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ages 18-80 years

• Diagnosis of AIS

• Body weight ≥ 45 kg

• NIHSS between 2 and 20

• Patient or legal authorized representative (LAR) must be willing and able to understand the study and provide written informed consent

Exclusion Criteria:

Currently pregnant or breastfeeding

• History of significantly impaired renal or hepatic function

• Hemorrhage or hemorrhagic stroke on CT scan

• Prior stroke, intracranial surgery, or major head trauma within three months prior to enrollment

• Pre-stroke modified Rankin Scale (mRS) ≥ 2

• Myocardial infarction within six (6) months prior to enrollment

• Unstable angina, New York Heart Association (NYHA) Class II or greater congestive heart failure

• Uncontrolled hypertension (SBP > 180 and/or diastolic blood pressure (DBP) > 110 mmHg)

• Known long QT syndrome or QTc > 450 milliseconds (ms) in males and > 470 ms in females

• Uncontrolled arrhythmia or history of clinically significant arrhythmia within the past six (6) months (except atrial fibrillation)

• Clinically significant chronic obstructive pulmonary disease (COPD) or other pulmonary condition that is not controlled by medication or requires oxygen frequently or continuously

• Pneumonia, bronchitis, or other acute respiratory disease

• 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.

• History of allergic reaction attributed to compounds of similar chemical composition to DDFPe (see Investigator's Brochure).

• Subject has received any investigational drug within thirty (30) days prior to enrollment into the study

• Inability to comply with the study procedures

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205

Sponsors and Collaborators

• NuvOx LLC
• University of Arkansas

Investigators

• Principal Investigator: William Culp, MD, University of Arkansas
• Principal Investigator: Sanjeeva Onteddu, MD, University of Arkansas

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 22, 2018

More Information

Additional Information:

• Dodecafluoropentane Emulsion in Acute Ischemic Stroke: A Phase Ib/II Randomized and Controlled Dose-Escalation Trial

Publications

None provided.

• Responsible Party: NuvOx LLC
• ClinicalTrials.gov Identifier: NCT02963376
• Other Study ID Numbers: 205529
• First Posted: Nov 15, 2016
• Last Update Posted: Sep 24, 2021
• Last Verified: Aug 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Stroke; Ischemic Stroke; Cerebral Infarction; Ischemia

Study Results

Participant Flow

Pre-assignment Detail	During the study period, 26 patients or their legal authorized representatives were contacted and agreed to participate. Of these, 24 give written informed consent and were included in the study.

Arm/Group Title	0.05 mL/kg DDFPe	0.05 mL/kg Placebo	0.10 mL/kg DDFPe	0.10 mL/kg Placebo	0.17 mL/kg DDFPe	0.17 mL/kg Placebo
Arm/Group Description	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. 0.05 mL/kg DDFPe: 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).	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. 0.05 mL/kg Placebo: 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).	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. 0.10 mL/kg DDFPe: 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).	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. 0.10 mL/kg Placebo: 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).	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. 0.17 mL/kg DDFPe: 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).	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. 0.17 mL/kg Placebo: 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).
Period Title: Overall Study
STARTED	6	2	6	2	6	2
COMPLETED	6	2	6	2	6	2
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Controls (n=6)	DDFPe - 0.05 mL/kg (n=6)	DDFPe - 0.10 mL/kg (n=6)	DDFPe - 0.17 mL/kg (n=6)	Total
Arm/Group Description	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. For analysis, all control subjects are grouped.	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo.	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo.	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo.	Total of all reporting groups
Overall Participants	6	6	6	6	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.0 (7.1)	61.2 (4.4)	53.2 (4.8)	56.2 (4.6)	56.6 (2.6)
Sex: Female, Male (Count of Participants)
Female	1 16.7%	2 33.3%	2 33.3%	2 33.3%	7 29.2%
Male	5 83.3%	4 66.7%	4 66.7%	4 66.7%	17 70.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 16.7%	1 16.7%	0 0%	1 16.7%	3 12.5%
White	5 83.3%	5 83.3%	6 100%	5 83.3%	21 87.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	6 100%	6 100%	6 100%	6 100%	24 100%
NIHSS Assessment (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	9.5	6.5	8	4	6.5

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of DDFPe Evaluated by Number of Dose Limiting Toxicities
Description	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). The algorithm for determining the MTD is based on the number of subjects who experience a Dose Limiting Toxicity (DLT) in each cohort, as defined in the clinical protocol. 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.
Time Frame	12 hours after subjects have had a documented Acute Ischemic Stroke (AIS)

Outcome Measure Data

Analysis Population Description

No signs of dose-limiting episodes were identified at any dose level, and no MTD was defined.

Arm/Group Title	0.05 mL/kg DDFPe	0.05 mL/kg Placebo	0.10 mL/kg DDFPe	0.10 mL/kg Placebo	0.17 mL/kg DDFPe	0.17 mL/kg Placebo
Arm/Group Description	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.	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.	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.	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.	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.	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.
Measure Participants	6	2	6	2	6	2
Number [Dose Limiting Toxicities]	0	0	0	0	0	0

2. Secondary Outcome

Title	NIHSS Assessment
Description	The NIH Stroke Scale (NIHSS) is an assessment tool that provides a quantitative measure of stroke-related neurologic deficit. The NIHSS is a 15-item neurologic examination. Ratings for each item are scored on a 3- to 5-point scale with 0 as normal. Scores range from 0 to 42, with higher scores indicating greater severity.
Time Frame	NIHSS scores were recorded at outside hospitals when appropriate and also at the study center as inside baseline NIHSS score. Repeat NIHSS scores were recorded at 2, 3.5, and 7.5 hours after drug injection and on discharge.

Outcome Measure Data

Analysis Population Description

At each of the three dose levels (0.05, 0.10, 0.17 mL/kg) six subjects received DDFPe and two received placebo in this study. All control subjects are grouped for the NIHSS results. DDFPe results are shown separately for each cohort as well as combined.

Arm/Group Title	Controls (n=6)	DDFPe (n=18)	0.05 mL/kg DDFPe	0.10 mL/kg DDFPe	0.17 mL/kg DDFPe
Arm/Group Description	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. All control patients are grouped for the NIHSS results.	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. This column groups the NIHSS results of all DDFPe treated patients.	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.	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.	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.
Measure Participants	6	18	6	6	6
Baseline (PreRx)	9.5	6.5	6.5	8	4
2 hours	8	5	6	6.5	2
3.5 hours	5.5	4.5	5.5	7	2.5
7.5 hours	4.5	2.5	5.5	5.5	2
Day 7 or Day of Discharge	3.5	1	2	4	1

3. Secondary Outcome

Title	Modified Rankin Scale (mRS)
Description	The modified Rankin Scale is a measure of the degree of disability in patients who have had a stroke with 0 being no symptoms at all to 6 being death. Thus, a higher score indicates greater severity.
Time Frame	mRS values were obtained on Day 7 or Day of Discharge, Day 30 and Day 90.

Outcome Measure Data

Analysis Population Description

At each of the three dose levels (0.05, 0.10, 0.17 mL/kg) six subjects received DDFPe and two received placebo in this study. All control subjects are grouped for the mRS results. DDFPe results are shown separately for each cohort as well as combined.

Arm/Group Title	Controls (n=6)	DDFPe (n=18)	0.05 mL/kg DDFPe	0.10 mL/kg DDFPe	0.17 mL/kg DDFPe
Arm/Group Description	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. All control patients are grouped for the mRS results.	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. This column groups the mRS results of all DDFPe treated patients.	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. 0.05 mL/kg DDFPe: 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).	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. 0.10 mL/kg DDFPe: 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).	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. 0.17 mL/kg DDFPe: 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).
Measure Participants	6	18	6	6	6
Day 7 or Day of Discharge	2	2	2	3	1.5
30 day	2.5	1	2	2	0
90 day	3	1	1.5	2	0

Adverse Events

Time Frame	The study treatment follow-up was within 90 days following the last administration of study treatment.
Adverse Event Reporting Description	At each of the three dose levels (0.05, 0.10, 0.17 mL/kg) six subjects received DDFPe and two received placebo in this study. For this reason, all control subjects are grouped.
Arm/Group Title	Controls (n=6)		DDFPe - 0.05 mL/kg (n=6)		DDFPe - 0.10 mL/kg (n=6)		DDFPe - 0.17 mL/kg		DDFPe Total (n=18)
Arm/Group Description	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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo. For this reason, all control subjects are grouped.		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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo.		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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo.		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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo.		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 (0.05, 0.10, 0.17 mL/kg) six subjects will receive DDFPe and two will receive placebo.
All Cause Mortality
	Controls (n=6)		DDFPe - 0.05 mL/kg (n=6)		DDFPe - 0.10 mL/kg (n=6)		DDFPe - 0.17 mL/kg		DDFPe Total (n=18)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/18 (5.6%)
Serious Adverse Events
	Controls (n=6)		DDFPe - 0.05 mL/kg (n=6)		DDFPe - 0.10 mL/kg (n=6)		DDFPe - 0.17 mL/kg		DDFPe Total (n=18)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		1/6 (16.7%)		0/6 (0%)		0/6 (0%)		1/18 (5.6%)
Gastrointestinal disorders
Abdominal Pain	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/18 (0%)	0
Infections and infestations
Pneumonia	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Nervous system disorders
Cerebrovascular Accident, Secondary Stroke	2/6 (33.3%)	2	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/18 (0%)	0
Migraine	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/18 (0%)	0
Psychiatric disorders
Confusional State	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/18 (0%)	0
Depression	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/18 (0%)	0
Surgical and medical procedures
Cardiac Pacemaker Replacement	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/18 (0%)	0
Other (Not Including Serious) Adverse Events
	Controls (n=6)		DDFPe - 0.05 mL/kg (n=6)		DDFPe - 0.10 mL/kg (n=6)		DDFPe - 0.17 mL/kg		DDFPe Total (n=18)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		6/6 (100%)		3/6 (50%)		15/18 (83.3%)
Blood and lymphatic system disorders
Anemia	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1
Leukocytosis	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Cardiac disorders
Arrythmia	0/6 (0%)	0	1/6 (16.7%)	4	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	4
Cardiac Failure Congestive	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1
Electrocardiogram Abnormal	1/6 (16.7%)	2	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/18 (0%)	0
Sinus Bradycardia	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1
Myocardial Infarction	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1
Gastrointestinal disorders
Nausea	1/6 (16.7%)	1	2/6 (33.3%)	2	0/6 (0%)	0	0/6 (0%)	0	2/18 (11.1%)	2
General disorders
Infusion Related Reaction	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	2/6 (33.3%)	4	2/18 (11.1%)	4
Oedema Peripheral	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Pyrexia	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Vascular device occlusion	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2	1/18 (5.6%)	2
Injury, poisoning and procedural complications
Fall	0/6 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	0/6 (0%)	0	2/18 (11.1%)	2
Thermal Burn	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Metabolism and nutrition disorders
Hypoglycaemia	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1
Musculoskeletal and connective tissue disorders
Back Pain	1/6 (16.7%)	2	0/6 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	2/18 (11.1%)	2
Pain in Extremity	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1
Nervous system disorders
Akathisia	1/6 (16.7%)	1	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Cerebrovascular Accident	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Dizziness	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/18 (0%)	0
Headache	2/6 (33.3%)	2	1/6 (16.7%)	2	2/6 (33.3%)	3	0/6 (0%)	0	3/18 (16.7%)	5
Hypoaesthesia	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Neuralgia	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	1/18 (5.6%)	1
Psychiatric disorders
Agitation	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/18 (0%)	0
Renal and urinary disorders
Acute Kidney Injury	1/6 (16.7%)	1	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/6 (16.7%)	1	2/6 (33.3%)	2	1/6 (16.7%)	1	1/6 (16.7%)	1	4/18 (22.2%)	4
Hyperventilation	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Respiration abnormal	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Sleep Apnoea Syndrome	1/6 (16.7%)	1	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Tachypnea	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1
Skin and subcutaneous tissue disorders
Pruritus	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1
Surgical and medical procedures
Carotid Endarterectomy	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	1/18 (5.6%)	1
Vascular disorders
Flushing	1/6 (16.7%)	1	2/6 (33.3%)	5	0/6 (0%)	0	0/6 (0%)	0	2/18 (11.1%)	5
Haemorrhoids	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1
Hypertension	1/6 (16.7%)	1	2/6 (33.3%)	6	2/6 (33.3%)	2	0/6 (0%)	0	4/18 (22.2%)	8
Hypotension	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	1/18 (5.6%)	1

Limitations/Caveats

Limitations of the current study primarily concern the exploratory aim toward efficacy, which was greatly underpowered for any purpose other than designing the next study. As with any phase I trial, the small number of cases may only demonstrate side effects and complications that are common.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.