Conditions: Stroke, Acute
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
This study will assess the potential efficacy and safety of TSC as early treatment for both ischemic and hemorrhagic stroke when administered while subject is in ambulance being transported to hospital.

Detailed description:
This is a multicenter, randomized, placebo-controlled, double-blind, parallel group trial of intravenous trans sodium crocetinate (TSC) initiated by emergency medical service (EMS) responders in the field within 2 hours of symptom onset in 160 subjects with acute stroke. The primary objectives of the study are to evaluate the efficacy and safety of field-initiated TSC in improving the long-term functional outcome of subjects with acute stroke.

Subjects with acute stroke will be identified and screened in the ambulance by (EMS) responders who have received training in basic and advanced cardiac life support, stroke recognition, and specific procedures relevant to the proposed study. The EMS responders will contact a Study Neurologist, who will enroll eligible stroke patients into the study. Effort will be made to obtain prospective informed consent in the ambulance when deemed to be feasible. If not feasible, subjects will be enrolled under regulations for exception from explicit informed consent (EFIC) in emergency research circumstances, after public disclosure and community consultation. Written informed consent to continue in the study is obtained from subjects or their legally authorized representatives as soon as possible after hospital arrival.

EMS responders will deliver the single, field, bolus dose of study agent, TSC at 0.25 mg/kg or matched placebo, followed after hospital arrival by standard of care (SOC). No additional study drug will be administered in the hospital. Follow-up assessments will be performed at Emergency Department (ED) arrival, 24 hours, 48 hours, Day 4, Day 30, and Day 90. The study will be performed at up to 30 receiving hospital sites in Los Angeles County, CA, and central Virginia.

Arms:
arm 1: Trans sodium crocetinate (TSC) will be administered intravenously as a bolus to subjects randomized to experimental drug. The bolus dose will consist of 0.25 mg/kg of TSC based on the estimated subject weight. arm 2: The placebo consists of commercially available sterile saline. Placebo will be administered intravenously as a bolus to subjects randomized to placebo. The volume of sterile saline will be based on the estimated subject weight.

Interventions: intervention 1: Trans-Sodium Crocetinate intervention 2: Placebo
Intervention descriptions: intervention 1: In the study drug kit containing the experimental drug (TSC), TSC will be reconstituted with the Sterile Water for Injection (USP) supplied in the same kit. There will be an unblinded paramedic who will reconstitute and inject the TSC on the ambulance. intervention 2: The study drug kit containing placebo (sterile saline for Injection) will be prepared and injected by the unblinded paramedic on the ambulance.

Protocol document:
Prot_000.pdf: 
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DOCUMENT TYPE: 
Clinical protocol 
DOCUMENT NUMBER: 
100-501
COMPOUND: 
Trans Sodium Crocetinate 
STUDY TITLE: 
Double-Blind, Randomized, Placebo-Controlled, Phase 2 
Study of Efficacy and Safety of Trans Sodium 
Crocetinate (TSC) Administered Onboard Emergency 
Vehicles for Treatment of Suspected Stroke:  PHAST-
TSC 
CLINICAL PHASE: 
2 
INDICATION: 
Treatment of suspected stroke victims in the emergency 
vehicle 
IND NUMBER: 
138575 
SPONSOR: 
Diffusion Pharmaceuticals Inc. 
1317 Carlton Avenue, Suite 200 
Charlottesville, VA 22902 
DOCUMENT 
VERSION/STATUS: 
Final 
DOCUMENT 
RELEASE/AMENDMENT 
DATE: 
Amendment 5: November 18, 2019 
Amendment 4: November 19, 2018 
Amendment 3: August 22, 2018 
Amendment 2: August 2, 2018 
Amendment 1: March 19, 2018 
February 16, 2018 
Confidential – Property of Diffusion Pharmaceuticals Inc. 
This document or its contents may not be used, divulged, published, or disclosed without 
consent of Diffusion Pharmaceuticals Inc. 
NCT: NCT03763929


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SYNOPSIS 
Title 
Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study of 
Efficacy and Safety of Trans Sodium Crocetinate (TSC) Administered 
Onboard Emergency Vehicles for Treatment of Suspected Stroke:  
PHAST-TSC 
Protocol No. 
100-501 
Study Phase 
2 
Study Design 
Double-blind, randomized, placebo-controlled, phase 2 preliminary 
efficacy and safety trial of Trans Sodium Crocetinate (TSC) as first-
line treatment of suspected stroke subjects in the emergency vehicle. 
Study 
Population 
Ambulance-transported subjects identified as having an acute stroke 
using the modified Los Angeles Prehospital Stroke Screen (mLAPSS) 
screen, who are within 2 h of last known well time.  
Number of 
Subjects 
160 subjects that meet all protocol inclusion/exclusion criteria. 
Study Centers 
Up to 30 stroke receiving hospitals.  
Objective 
To assess the potential efficacy and safety of TSC as early treatment 
for both ischemic and hemorrhagic stroke when administered while 
subject is in ambulance being transported to hospital. 
Endpoints 
Primary Efficacy Endpoint: 
• Global disability level on the utility-weighted modified Rankin 
Score (UW-mRS) Assessment at 90 days in all subjects 
Secondary Efficacy Endpoints: 
• Functional independence (mRS 0-2) in all subjects 
• Global disability level on the UW-mRS in ischemic stroke 
subjects 
• Functional independence (mRS 0-2) in ischemic stroke 
subjects 
Exploratory Efficacy Endpoints: 
• Freedom from disability (mRS 0-1) 
• Barthel Index (BI) 
• National Institutes of Health Stroke Scale (NIHSS) 
• Stroke Impact Scale (SIS-16) 
• AMC-Linear Disability Scale 
 
 
 


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2 
STUDY METHODS 
 
Rationale 
Neuroprotection is a promising treatment strategy, complementary to reperfusion.  
Neuroprotective agents interrupt the cellular, biochemical and metabolic processes that 
mediate cerebral tissue injury during or following exposure to ischemia.  Since they are 
safe and potentially beneficial in hemorrhagic as well as ischemic stroke, neuroprotective 
agents can, in principle, be given prior to brain imaging, including in the prehospital 
setting, to stabilize threatened tissues until definitive rescue by therapeutic or 
spontaneous reperfusion.  In past studies, more than 70 neuroprotective agents were 
tested in randomized controlled clinical trials in acute ischemic stroke and none were 
found unequivocally beneficial in definitive Phase 3 trials (Kidwell et al, 2001; Moretti et 
al, 2015).  However, the crucial factor of delayed time to treatment hindered almost all 
trials. Although it is in the first 2 h that neuroprotective agents are most beneficial in 
rodent and primate focal stroke models, no prior pivotal human clinical neuroprotective 
agent trial before the FAST-MAG trial enrolled any substantial cohort of subjects in this 
time window (Ferguson et al, 2004).  The FAST-MAG trial (Saver et al 2014; Saver et al, 
2015), which utilized magnesium sulfate as the tested neuroprotective agent, did enroll 
1700 subjects in a Phase 3 trial. Although the tested agent had neutral effects, the trial 
demonstrated that ambulance start of neuroprotective study agents in suspected stroke 
subjects allows rapid attainment of serum target levels, in the time period when the 
greatest volume of threatened tissues is still salvageable (Shkirkova et al, 2017). Building 
upon this successful protocol for field agent delivery, the current trial will test a new 
neuroprotective agent.  TSC, a different type of neuroprotective agent, has shown 
positive results in animal models of stroke.  
 
The ideal neuroprotective agent for stroke would have few adverse side effects and be 
safe and potentially beneficial in both ischemic and hemorrhagic stroke.  Diffusion 
Pharmaceuticals Inc. has developed TSC, indicated as a drug to treat hypoxia by 
selectively enhancing the re-oxygenation of hypoxic tissues.  The ability of TSC to 
increase the diffusion (movement) of oxygen is the underlying mechanism by which TSC 
exerts its pharmacodynamic effects.  In vitro studies demonstrate that TSC increases the 
diffusion of oxygen by altering the molecular arrangement of the water molecules which 
constitute the bulk of blood plasma.  This effect creates a more ordered water structure 
which is less dense, reducing resistance to oxygen diffusion and allowing a more rapid 
movement of oxygen through the plasma (Laidig et al., 1998; Stennett et al., 2006).  This 
is the reason for the ability of TSC to increase the diffusion of oxygen through blood 
plasma to hypoxic tissues. 
 
Since FAST-MAG established that an ambulance-based study could be done successfully 
and enable agent delivery in the early time window when benefit was maximal in 
preclinical models, it is deemed appropriate and advantageous to do a similar study using 


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TSC as the neuroprotective agent.  TSC can be easily administered and has been shown 
to be safe thus far in both animal and human trials.   
 
Design Overview 
This is a multicenter, randomized, placebo-controlled, double-blind, parallel group trial 
of intravenous trans sodium crocetinate (TSC) initiated by paramedics in the field within 
2 hours of symptom onset in 160 subjects with acute stroke.  The primary objectives of 
the study are to evaluate the efficacy and safety of field-initiated TSC in improving the 
long-term functional outcome of subjects with acute stroke.  Subjects with acute stroke 
will be identified in the field by emergency medical service responders who have 
received training in basic and advanced cardiac life support, stroke recognition, and 
specific procedures relevant to the proposed study.    Paramedics will deliver the single, 
field, bolus dose of study agent, TSC at 0.25 mg/kg or matched placebo, followed after 
hospital arrival by standard of care (SOC).  No additional study drug will be administered 
in the hospital.  Follow-up assessments will be performed at Emergency Department 
(ED) arrival, 24 hours, 48 hours, Day 4, Day 30, and Day 90.  The study will be 
performed at up to 30 receiving hospital sites. 
 
Across all preclinical models and in human acute ischemic stroke, the relation 
between time from onset and response to beneficial therapy in acute ischemic stroke 
is a graded one of continuous decline with time, rather than square-shaped, 
characterized by uniform high benefit until a sudden drop to no benefit at a 
particular time point. Across all neuroprotective and reperfusion treatments in 
preclinical models, and for both the proven human reperfusion therapies (IV 
fibrinolysis and endovascular mechanical thrombectomy), treatment is most 
efficacious if started at 30 mins rather than 60 mins, at 1h rather than 2h, at 2h rather 
than 3h, and at 3h rather than 4h.  
 
A consequence of this graded relationship is that the sample sizes required to detect 
beneficial effect of a treatment agent are moderate for subjects treated sooner after 
onset, when the magnitude of benefit is largest. But the sample sizes required to 
detect beneficial effect of a treatment agent are extremely large for subjects treated 
near the end of the therapeutic window, when the magnitude of benefit is small.  
 
As a result, successful development programs for treatments for acute ischemic 
stroke have used a “sweet spot and expand” strategy. For tPA (atleplase, Activase), 
initial US trials stratified therapy in the 0-90m and 91-180m window. Later trials 
explored the 181-270m and 271-306m window. Similarly, for endovascular 
mechanical thrombectomy, the initial US registration trial evaluated the 0-6h 
window only for clinical benefit, even though the devices were cleared for technical 
use up to 8h after onset. Conversely, many of the unsuccessful trials of 
neuroprotective agents in the past did not follow this approach, and enrolled subjects 


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up to 4h or more after onset, likely resulting in their being severely underpowered to 
detect the smaller treatment effects potentially present in late enrolled subjects.  
 
Based on the above considerations, the current trial was designed to enroll subjects within 
2h of onset, when the magnitude of benefit from TSC is likely to be larger and more 
feasibly detectable. The trial was designed to be performed in the prehospital setting, 
because that is the only setting in which treatment within the 2h time window in large 
numbers of subjects has been shown to be attainable. We anticipate that, should the initial 
under 2h treatment study indicate robust therapeutic benefits persisting up to the 2h 
administration timepoint, we will in the future perform additional trials with later, 2-4h, 
enrollment windows, and that those could be performed in the Emergency Department 
setting. 
 
Diffusion investigated many approaches to blinding this trial and it was determined that it 
would be very difficult because of the highly colored nature of the test article and the 
necessity for it to be delivered by emergency medical personnel in an ambulance setting. 
Amber syringes are designed to deliver much larger volumes or ones which are for other 
purposes, such as oral dosing of liquids to animals.  The dosages in this stroke study vary 
from less than 1 mL to over 2 mL, depending on body size.  That can be accommodated 
with a standard 3 mL syringe.  A manufacturer who, upon Diffusion’s request, attempted 
to make 3 mL amber syringes gave up after a month because they found that they could 
not put volume markings on the syringes, rendering them useless for this trial.  Moreover, 
even if amber syringes were available, the emergency medical personnel would almost 
certainly be able to observe the coloration of the test article while administering the 
injection.  Thus, the TSC injections will be prepared and injected by unblinded personnel 
on each ambulance.  All other study personnel will be blinded (see Section 2.9). 
 
Study Objectives 
2.3.1 Primary Efficacy Objective 
The primary efficacy objective is to test the hypothesis that treatment with TSC reduces 
the level of long-term disability of hyperacute stroke subjects.  The study endpoint 
analysis to evaluate this hypothesis will be the difference in distribution of scores 
between TSC and placebo groups on the utility-weighted modified Rankin Scale (UW-
mRS) measure of global disability, assessed 90-days post-stroke. 
2.3.2 Secondary and Exploratory Efficacy Objectives 
A secondary efficacy objectiveis to test the hypothesis that treatment with TSC improves 
the long-term outcome of hyperacute stroke subjects in achieving functional 
independence (mRS 0-2) at 90 days.  
 
Additional secondary efficacy objectives are to test the hypothesis that treatment with 
TSC improves the long-term outcome of patients with final diagnosis of acute cerebral 


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ischemia in reducing the level of long-term disability (assessed with the UW-mRS 
endpoint) and in achieving functional independence (assessed with the mRS 0-2 
endpoint). 
 
Exploratory efficacy objectives are to evaluate for signals of benefit of treatment with 
TSC upon freedom from disability (mRS 0-1) at 90 days, activities of daily living 
(Barthel Index [BI]) at 90 days, neurologic deficit (National Institutes of Health Stroke 
Score [NIHSS]) at 90 days, and quality of life (Stroke Impact Scale [SIS-16] and AMC-
Linear Disability Scale) at 90 days.  
2.3.3 Primary Safety Objective 
The primary safety objective is to test the hypothesis that treatment with TSC is not 
associated with increased occurrence of serious adverse events in hyperacute stroke 
subjects.  The study endpoint analysis to evaluate this hypothesis will be comparison of 
the frequency of SAEs in the TSC and placebo groups.  
2.3.4 Secondary and Exploratory Safety Objectives 
Secondary safety objectives are to test the hypothesis that treatment with TSC is not 
associated with increases in any organ-specific classes of serious adverse events or 
increased mortality.  
 
Study Population 
All suspected stroke subjects transported by Emergency Medical Services (EMS) in the 
participating catchment areas will be screened for study entry.  Subjects in the study will 
be subjects with newly diagnosed stroke as determined by modified Los Angeles 
Prehospital Stroke Screen (mLAPSS) who are ready for transportation to hospital. 
2.4.1 Inclusion Criteria 
1. Age 40-85, inclusive 
2. Last known well time 15-120 minutes before anticipated study drug injection 
3. Suspected stroke identified by the Modified Los Angeles Prehospital Stroke Scale 
(mLAPSS) 
4. Moderate to severe motor deficit, with Los Angeles Motor Scale (LAMS) 2 or higher  
5. No seizure 
2.4.2 Exclusion Criteria 
Subjects are not eligible if they meet any of the following criteria: 
 
1. Coma 
2. Rapidly improving neurologic deficit 
3. History of seizures or epilepsy  


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4. Pre-existing neurologic, psychiatric, or advanced systemic disease that would 
confound the neurological or functional outcome evaluations 
5. SBP < 90 or > 220 
6. Major head trauma in the last 24 hours 
7. Recent stroke within 30 days 
8. Known to be pregnant or lactating 
 
Pregnancy Screening 
Because of the difficulty of performing a pregnancy screening, a Follicle Stimulating 
Hormone (FSH) test or gathering information regarding menstruation history in an 
ambulance environment, emergency medical personnel who are engaged in early 
assessment of a potential female stroke subject will ask the subject, or if the subject is 
unable to respond, those who may be associated with her, whether she is, in fact, 
pregnant.  Subjects for whom the answer is affirmative will be excluded from enrollment 
in the trial. Female subjects younger than 55 and considered of child bearing potential 
will receive a screening for pregnancy at the hospital as part of standard of care.  
 
Women are considered past the age of “child-bearing potential” if they are greater than 
55 years of age, OR if they are at least 50 years of age AND have not menstruated for at 
least 12 months, and have a documented FSH level of greater than 40 mIU/mL, OR they 
are at least 45 years of age AND have not menstruated for at least 18 months, OR  have a 
documented FSH level of greater than 40 mIU/mL. 
 
Details of pregnancies in female participants and female partners of male participants will 
be collected after study drug treatment and until study completion (Day 90 visit or early 
termination). If a pregnancy is reported or discovered, the investigator should inform the 
Sponsor or designee within 24 hours of learning of the pregnancy. Pregnancy itself is not 
considered an AE or SAE, however abnormal pregnancy outcomes (e.g., spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered 
SAEs and should be reported to the sponsor. If a pregnancy is reported, the Sponsor or 
designee will follow up on pregnancy outcome 4 weeks after the projected due date. 
 
Enrollment and Consent 
Subjects are initially enrolled in this study in the ambulance with hours of enrollment 
between 06:00 to 22:00.  Effort will be made to obtain prospective informed consent 
when deemed to be feasible.  If not feasible, subjects will be enrolled under regulations 
for exception from explicit informed consent (EFIC) in emergency research 
circumstances, after public disclosure and community consultation. Written informed 
consent to continue in the study is obtained from subjects or their legally authorized 
representatives as soon as possible after hospital arrival.  Acute stroke is an extremely 
time-urgent medical emergency. The two standard of care therapies for acute ischemic 


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stroke, intravenous tissue plasminogen activator (tPA) and endovascular mechanical 
thrombectomy, both are extremely time-sensitive. 
 
Diffusion has consulted extensively with our clinical investigator team. Based on these 
extensive discussions we have elected to incorporate the requirement for a thoroughly 
documented affirmative agreement process prior to study participation for all subjects to 
the extent that they can communicate, and/or their legally authorized representative, if 
they are on-scene. We believe this process will allow for an effective balance between 
timely treatment delivery and patient informed consent.  
 
Several developments have transpired in the years since the FAST-MAG trial completed 
enrollment in December 2012 that make obtaining prospective informed consent in the 
field within the therapeutic window, as performed in FAST-MAG, no longer ethical to 
pursue.  
 
1. Interval studies have demonstrated an extreme time-dependency for the benefit of 
intravenous tissue plasminogen activator. Every 9-minute delay in IV tPA treatment 
start results in 1 out of 100 treated subjects having a worse outcome (Saver et al, 
2013; Kim et al, 2017).  These studies established unequivocally that IV tPA 
treatment benefit declines very rapidly. As a result, even just the several minutes 
required for a rapid explicit written informed consent process would jeopardize 
subject safety by delaying start of IV tPA. 
 
2. Interval studies have demonstrated that endovascular thrombectomy is an extremely 
beneficial therapy for acute ischemic stroke (Goyal et al, 2016). In addition, studies 
have demonstrated that the time-dependency for the benefit of endovascular 
thrombectomy is even more extreme than that for IV tPA. For endovascular 
mechanical thrombectomy, every 4-minute delay in treatment start results in 1 out of 
100 subjects having a worse outcome (Saver et al, 2016).  As a result, even just the 
several minutes required for a rapid explicit written informed consent process would 
jeopardize subject safety by delaying start of endovascular mechanical 
thrombectomy. 
 
3. The two multicenter clinical trials of prehospital treatment for acute stroke launched 
in the last 5 years have used solely EFIC enrolling, without explicit informed consent: 
the RIGHT 2 trial of glyceryl trinitrate in Great Britain (ISRCTN26986053) and the 
FRONTIER trial of NA-1 in Canada (NCT02315443). These trials demonstrate that 
an international consensus recognizes it is no longer feasible to pursue explicit 
informed consent, rather than EFIC, in prehospital neuroprotective stroke trials, 
because delay of standard therapies jeopardizes subject safety.  
 
As directed by FDA regulations regarding EFIC research, representatives of the 
communities in which the research will be conducted and from which the subjects will be 


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drawn will be consulted before research begins, and all plans for the research, its risks, 
and expected benefits will be publicly disclosed.  These requirements will be performed 
by establishing community advisory committees, extensive public education conferences, 
newspaper advertisements, and mailings. 
 
If a written informed consent process does not take place prior to drug injection, a brief 
thoroughly documented verbal or non-verbal affirmative agreement for study 
participation will be elicited from subjects (to the extent that they can communicate) 
and/or from their legally authorized representatives (LARs – e.g. close family member, 
legal guardian) if they are on scene.  Paramedic training will be focused on all enrollment 
processes in which they will participate. The training will include didactic coverage of 
the regulatory framework of EFIC trials, the distinction between affirmative agreement 
and consent, how to behaviorally assess for affirmative agreement, and the importance of 
communicating key aspects of their affirmative agreement evaluation when they give the 
phone report to the PHAST-TSC central enrolling physician who will be making the final 
decision regarding enrollment in the trial, and authorizing opening of study kit.  In 
addition, all of the central enrolling physicians in the study will also be trained regarding 
these aspects.  If not obtained in the ambulance, once the subject arrives at the hospital a 
full written informed consent process will be performed by a competent consent-provider.  
 
Among enrolled subjects, the following procedures will be utilized to inform, at the 
earliest feasible opportunity, each subject, or if the subject remains incapacitated, a 
legally authorized representative of the subject, or if such a representative is not 
reasonably available, a family member, of the subject’s inclusion in the clinical 
investigation, the details of the investigation, and other information contained in the 
informed consent document. A physician-investigator or study coordinator will interview 
and examine the subject upon arrival in the Emergency Department. During this 
encounter, the physician-investigator and study coordinator will both assess subject 
competency and work with hospital staff and social services to identify and contact a 
legally authorized representative and family members. The physician-investigator and 
study coordinator will continue these efforts throughout the duration of the study. As 
soon as a subject regains competency, or a legally authorized representative or a family 
member has been contacted, the physician-investigator will inform him or her of the 
subject’s inclusion in the clinical investigation, the details of the investigation, and other 
information contained in the informed consent document; and that the subject’s 
participation in the study may be discontinued at any time without penalty or loss of 
benefits to which the subject is otherwise entitled. 
 
 
A physician-investigator or study coordinator will examine the subject at ED arrival, 24 
hrs, 48 hrs, 4 days, 30 days, and 90 days after hospital arrival. If the exam demonstrates 
that the subject’s condition has improved and the subject has regained competency the 
physician-investigator will inform the subject of his or her inclusion in the clinical 
investigation, the details of the investigation, and other information contained in the 


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informed consent document; and that the subject’s participation in the study may be 
discontinued at any time without penalty or loss of benefits to which the subject is 
otherwise entitled. 
 
 
If the subject is entered into the study and dies before the subject’s legally authorized 
representative or family member can be contacted, the physician-investigator and study 
coordinator will continue efforts to identify the subject’s legally authorized representative 
or a family member, working with hospital administration, the coroner’s office, and other 
appropriate personnel.  Once the legally authorized representative or family member is 
identified and contacted, the physician-investigator will discuss with them the essential 
elements of the clinical investigation. 
 
As required by FDA regulations, the investigators will summarize efforts made to contact 
legally authorized representatives in each case and make this information available to the 
local Investigational Review Board (IRB) at the time of continuing review. 
 
Randomization 
This protocol is using the step-forward, pre-encounter method of randomization that has 
been developed for rapid availability of research study agents in emergency trials. Each 
ambulance will be carrying only one study kit at any time, the next kit in its permuted 
random block sequence. Randomization will be 1:1 between active TSC and placebo.  
When that ambulance enrolls a subject, the subject will be assigned to the treatment 
group of the study agent kit the ambulance is carrying at the time. Subjects will be 
considered enrolled in the trial upon study drug injection.  
 
A Schedule of Events is included as an Appendix 8.1 to this protocol. 
 
 
The study design is shown in Table 4. 
 
 


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Table 4.  Study Design 
 
On Ambulance 
Within 2 hours of first stroke symptoms 
• 
Perform mLAPSS 
• 
Determine study eligibility in consultation with PHAST-TSC central enrolling physician 
• 
Explicit informed consent or EFIC enrollment 
• 
Perform GCS; Los Angeles Motor Scale (LAMS); Paramedic Global Impression of Change Score (PGIC) 
• 
Obtain heart rate; blood pressure; body weight estimate 
• 
Administer study drug (TSC or placebo) as IV injection 
 
Emergency Department Arrival 
• 
Informed Consent, if enrolled by EFIC 
• 
SOC demographics; heart rate; blood pressure; body weight; pregnancy screening; labs (hematology, 
chemistry, coagulation); troponin 
• 
SOC brain imaging done within 48 hours of Emergency Department arrival 
• 
Performs mRS; BI; NIHSS   
• 
tPA dose 
• 
Concomitant medications/therapies 
• 
Adverse events 
 
24 Hours 
• 
Obtain Informed Consent if enrolled by EFIC and not obtained at previous visit 
• 
SOC heart rate; blood pressure; labs (hematology, chemistry, coagulation); troponin 
• 
SOC body weight; pregnancy screening if not obtained during previous visit 
• 
Concomitant medications/therapies 
• 
Adverse events 
• 
Performs NIHSS 
 
48 Hours 
• 
Obtain Informed Consent if enrolled by EFIC and not obtained at previous visit 
• 
SOC heart rate; blood pressure; labs (hematology, chemistry, coagulation); troponin 
• 
Concomitant medications/therapies 
• 
Adverse events 
• 
Performs NIHSS 
 
Day 4 (If discharged prior, by phone) 
• 
Obtain Informed Consent if enrolled by EFIC and not obtained at previous visit 
• 
SOC heart rate; blood pressure; labs (hematology, chemistry, coagulation); troponin 
• 
Concomitant medications/therapies 
• 
Adverse events 
• 
Performs mRS; BI; NIHSS 
 
Day of Discharge 
• 
Concomitant medications/therapies 
• 
Adverse events 
• 
Discharge date and destination 
 
 


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Withdrawal of Subjects 
2.8.1 Criteria for Early Withdrawal 
The following events are considered sufficient reason to discontinue a subject from the 
study: 
• Subjects are free to withdraw from the study at any time, for any reason, and without 
prejudice.  
• The subject is non-compliant. 
• The subject experienced an AE that in the investigator’s opinion precludes continued 
participation. 
• The subject incurred a significant protocol violation that constitutes a safety hazard 
or significantly confounds the interpretation of the data from that subject.  
• At the Sponsor’s request. 
• The study is terminated. 
2.8.2 Subjects Lost to Follow-up 
The investigator will attempt to contact any subject that fails to return in order to evaluate 
the reason the subject has not returned and to obtain follow-up safety information.  All 
attempts to contact the subject should be documented, including the use of registered mail 
with return receipt.  
2.8.3 Replacement of Subjects 
Subjects who have received TSC or placebo will not be replaced. 
 
Day 30 (± 6 days) Follow-up (by phone) 
To be performed by a Study Coordinator blinded to subject and subject chart: 
• 
Obtain Informed Consent if enrolled by EFIC and not obtained at previous visit 
• 
Concomitant medications/therapies 
• 
Adverse events 
• 
mRS; BI 
 
Day 90 (± 14 days) Follow-up 
To be performed by a Study Coordinator blinded to subject and subject chart: 
• 
Obtain Informed Consent if enrolled by EFIC and not obtained at previous visit 
• 
Concomitant medications/therapies 
• 
Adverse events 
• 
mRS; BI; NIHSS; LAMS; Stroke Impact Scale (SIS-16) Quality of Life Assessment and AMC-Linear 
Disability Scale (AMC-LDS) 


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2.14.9 CT/MRI 
Image scans of all CTs/MRIs obtained within 48 hours of ED arrival will be obtained for 
independent neuroradiologist review. 
3 
ADVERSE EVENT REPORTING 
 
Definitions  
3.1.1 Adverse Events 
An AE is any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related.  An AE is any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, without any judgment about causality.  This includes 
changes in anatomical, physiological, or metabolic functions as indicated by physical 
examination signs, symptoms, and/or laboratory changes or medical occurrence which 
develops or worsens while enrolled in this study regardless of whether the event is 
considered related to the investigational drug.  Enrolled is defined as a subject that is 
assigned to treatment and is dosed with TSC or placebo.  
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE.  For the purposes of Investigational New Drug (IND) safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE.  The Sponsor or designee will evaluate the 
available evidence and make a judgment about the likelihood that the drug actually 
caused the AE.  
Events occurring before the first TSC dose are to be considered pre-existing conditions 
and should be recorded as medical history.  Unless a worsening occurs, they should not 
be considered AEs.  
Abnormal laboratory values or test results constitute AEs only if they are considered 
clinically significant and are associated with clinical signs or symptoms or require 
therapy.  Clinically significant abnormal laboratory values will be documented in the 
subject’s case report form (CRF).  Neurologic worsening, defined as a  ≥ 4 point 
worsening on the NIH Stroke Scale, will be captured as an AE or SAE per the medical 
opinion of the investigator. 
Events not considered to be AEs are: 
• Hospitalization for treatment which was elective or pre-planned for a pre-existing 
condition that did not worsen 
Events not considered to be SAEs are: 
• Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of serious and not resulting in hospital admission. 


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•
Hospital admissions less than 24 hours in duration.
3.1.2 Serious Adverse Events 
Serious adverse events (SAEs) are AEs that pose a threat to the subject’s life or 
functioning based on the following outcome/actions regardless of whether the event is 
considered related to the investigational drug: 
•
Results in death
•
Is life-threatening
•
Requires in-patient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect
•
Other events, based on medical judgment, which jeopardize the subject and require
medical/surgical intervention to prevent one of the outcomes above.
3.1.3 Unexpected 
Any adverse event where the nature, specificity or frequency of the event is not 
consistent with either: 1) the known or foreseeable risk associated with the procedures 
involved in the research that are described in the protocol or Investigator Brochure; or 2) 
the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor 
profile for the adverse event.  
Refer to Appendices, Section 8.3 for the PHAST-TSC List of Expected Adverse Events. 


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3.1.6 Adverse Event Reporting Requirements 
Each subject will be evaluated for the development of AEs.  It is the responsibility of the 
investigator to document all AEs occurring during this investigation, whether or not the 
AE is considered drug-related.  All AEs will be reported to the Sponsor via the CRF.  
Non-serious AEs will be reported from study drug administration through hospital 
discharge.  SAEs will be reported from study drug administration through study 
completion (Day 90 visit or early termination).  SAEs require expedited review and will 
be reported by the site to the Sponsor or designee by telephone or electronically within 24 
hours of discovery.    The nature of each event, date and time of onset, outcome, 
frequency, intensity, action taken with respect to dosage, whether it was serious or non-
serious, and relationship to treatment should be documented.  Signs and symptoms should 
be grouped into a single diagnosis and reported as a single AE when appropriate.  SAEs 
should be followed by the investigator to resolution, or, if the SAE is not expected to 
resolve, it should be followed until stabilization.   
AEs should be documented in terms of a medical diagnosis(es) when possible.  AEs not 
previously documented at Baseline as pre-existing conditions will be recorded in the 
CRF. 
The following definitions will be utilized when classifying AEs: 
3.1.6.1 Severity 
•
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor 
irritant type causing no loss of time from normal activities.  Symptoms do not 
require therapy or a medical evaluation; signs and symptoms are transient.
•
Moderate: Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities but are usually improved by 
simple therapeutic measures; moderate experiences may cause some interference 
with functioning.
•
Severe: Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating.


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3.1.6.2 Relatedness 
•
Unlikely or Not Related: The adverse event is doubtfully related or clearly not
related to the investigational agent/procedure – i.e. another cause of the event is
most plausible; and\or a clinically plausible temporal sequence is inconsistent
with the onset of the event and the study intervention and/or a causal relationship
is considered biologically implausible.
•
Possibly Related: The adverse event may be related to the investigational
agent/procedure – i.e. an event that follows a reasonable temporal sequence from
administration of the study intervention, follows a known or expected response
pattern to the suspected intervention, but that could readily have been produced
by a number of other factors.
•
Probably Related: The adverse event is likely related to the investigational
agent/procedure – i.e. an event that follows a reasonable temporal sequence from
administration of the study intervention, follows a known or expected response
pattern to the suspected intervention, that is confirmed by improvement on
stopping and is unlikely to be attributed to the known characteristics of the
subject’s clinical state.
•
Definitely related: The adverse event is clearly related to the investigational
agent/procedure – i.e. an event that follows a reasonable temporal sequence from
administration of the study intervention, follows a known or expected response
pattern to the suspected intervention, that is confirmed by improvement on
stopping and that could not be reasonably explained by the known characteristics
of the subject’s clinical state.