A Phase Ib/II in Patients With Acute Ischemic Stroke

Study Overview
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Brief Summary
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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.

Official Title
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A Phase Ib/II Dose-finding Study of DDFPe in Patients With Acute Ischemic Stroke

Conditions
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Ischemic Stroke

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 0.05 mL/kg DDFPe<br>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<br>* 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).<br>* Other names: Dodecafluoropentane emulsion (DDFPe), NanO2TM;|
| Placebo Comparator: 0.05 mL/kg Placebo<br>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<br>* 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).<br>|
| Active Comparator: 0.10 mL/kg DDFPe<br>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<br>* 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).<br>* Other names: Dodecafluoropentane emulsion (DDFPe), NanO2TM;|
| Placebo Comparator: 0.10 mL/kg Placebo<br>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<br>* 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).<br>|
| Active Comparator: 0.17 mL/kg DDFPe<br>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<br>* 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).<br>* Other names: Dodecafluoropentane emulsion (DDFPe), NanO2TM;|
| Placebo Comparator: 0.17 mL/kg Placebo<br>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<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of DDFPe Evaluated by Number of Dose Limiting Toxicities | 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. | 12 hours after subjects have had a documented Acute Ischemic Stroke (AIS) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NIHSS Assessment | 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. | 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. | 
| Modified Rankin Scale (mRS) | 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. | mRS values were obtained on Day 7 or Day of Discharge, Day 30 and Day 90. |