Randomized Placebo Controlled Trial of Intravenous N-Acetylcysteine for the Treatment of Acute Ischemic Stroke
Phase: PHASE2
Conditions: Acute Ischemic Stroke
Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

PROTOCOL TITLE: Randomized Placebo Controlled Trial of Intravenous N-Acetylcysteine for 
the Treatment of Acute Ischemic Stroke  
  
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PROTOCOL TITLE:  
Randomized Placebo Controlled Trial of Intravenous N-Acetylcysteine for the Treatment 
of Acute Ischemic Stroke  
  
PRINCIPAL INVESTIGATOR:  
Name: David Tanen, MD  
Department: Emergency Medicine  
Telephone Number: 424-306-5412  
Email Address: dtanen@emedharbor.edu  
  
FDA IND:  
#145,538 
 
VERSION NUMBER:  
1.6 
  
DATE:  
10/24/2023  
   
  
 

PROTOCOL TITLE: Randomized Placebo Controlled Trial of Intravenous N-Acetylcysteine for 
the Treatment of Acute Ischemic Stroke  
  
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Table of Contents  
1)  Protocol Title ................................................................................................................. 3 
2)  HSC Review History ..................................................................................................... 3 
3)  Investigator .................................................................................................................... 3 
4)  Objectives ...................................................................................................................... 3 
5)  Lay Summary ................................................................................................................ 3 
6)  Background .................................................................................................................... 4 
7)  Setting of the Human Research ..................................................................................... 5 
8)  Resources Available to Conduct the Human Research ................................................. 5 
9)  Prior Approvals ............................................................................................................. 6 
10) Study Design ................................................................................................................ 6 
a) Inclusion and Exclusion Criteria ................................................................................ 9 
b)  Local Number of Subjects ......................................................................................... 9 
c)  Study-Wide Number of Subjects ............................................................................. 10 
d)  Study Timelines ....................................................................................................... 10 
e)  Study Endpoints ....................................................................................................... 10 
f)  Procedures Involved in the Human Research .......................................................... 10 
g)  Data and Specimen Banking ................................................................................... 12 
h)  Data Management .................................................................................................... 12 
i)  Confidentiality .......................................................................................................... 12 
j)  Provisions to Monitor the Data to Ensure the Safety of subjects ............................. 12 
k) Withdrawal of Subjects ............................................................................................ 15 
11) Risks to Subjects ........................................................................................................ 15 
12) Potential Benefits to Subjects ..................................................................................... 15 
13) Provisions to Protect the Privacy Interests of Subjects .............................................. 15 
14) Compensation for Research-Related Injury ............................................................... 16 
15)  Economic Burden to Subjects ................................................................................... 16 
16) Consent Process .......................................................................................................... 16 
17) Process to Document Consent in Writing .................................................................. 17 
18) Drugs or Devices ........................................................................................................ 17 
19)  Multi-Site Human Research ...................................................................................... 18 
20)  Community-Based Participatory Research ................................................................ 18 
21)  Sharing of Results with Subjects ............................................................................... 18 
22)  Bibliography .............................................................................................................. 18 
 
  
  
  
 
 

PROTOCOL TITLE: Randomized Placebo Controlled Trial of Intravenous N-Acetylcysteine for 
the Treatment of Acute Ischemic Stroke  
  
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1) Protocol Title  
Randomized Placebo Controlled Trial of Intravenous N-Acetylcysteine for the  
Treatment of Acute Ischemic Stroke   
  
2) HSC Review History  
Version 1.5 dated 6/16/2021: NAC dosing regimen changed to complete the 2-bag 
regimen in 20 hours. Modified regimen will infuse a total 50 mg/kg/hr N-AC over 
4 hours for a total of 200 mg/kg following by 100 mg/kg over 16 hours.  
 
Version 1.6 dated 10/24/2023: Inclusion criteria changed to allow screening and 
enrollment of subjects with at least an NIH Stroke Scale (NIHSS) of 5. Use 
predetermined enrollment caps of 39 subjects 0in each group: moderate (NIHSS = 
5-15), moderate to severe (NIHSS = 16-20) and severe stroke (NIHSS = 21-
42).Population target revised to 117. 
3) Investigator  
David A. Tanen, MD  
 
4) Objectives  
To determine the efficacy of a 20-hour intravenous N-Acetylcysteine 
regimen in patients suffering from acute ischemic stroke.  
  
5) Lay Summary  
Stroke is a major cause of death and long-term disability in the developed world. 
While t-PA (an FDA approved medication that is currently used within the first 4.5 
hours after a stroke) and mechanical thrombectomy (a procedure that is done to try 
and remove the clot using wires placed into the blood vessels in the brain by 
interventional radiologist) have been shown to decrease disability in properly selected 
patients, many patients are left with lifelong symptoms. There are currently limited 
options available for patients who are not candidates for treatment with t-PA and/or 
mechanical thrombectomy. Finding additional or supplemental strategies are urgently 
needed.  
  
N-Acetylcysteine (NAC) is an FDA approved antioxidant and anti-inflammatory 
agent that has been used safely for many years in the treatment of acetaminophen 
(Tylenol) overdose. In studies, the oral form has been shown to improve outcomes in 
acute ischemic stroke and has been shown to decrease the effects of ischemic brain 
injury (stroke) in animal models. In a small human trial, it improved outcomes in 
patients suffering from mild traumatic brain injury (TBI). The intravenous 
formulation has a long safety record for intravenous (IV). It is not FDA approved for 
treating stroke but was reviewed by the FDA and was given an FDA IND for the 
study.   
  

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We propose a prospective randomized, double-blind, placebo-controlled study to 
evaluate the efficacy of administering intravenous N-acetylcysteine to patients with 
acute ischemic stroke. Eligible subjects will receive a commercially available form of 
intravenous NAC (Acetadote®) through an IV for the first 20 hours following their 
enrollment. Patients enrolled who receive t-PA for thrombolysis will have their 
intravenous NAC infusion delayed for 24 hours after the completion of their t-PA 
infusion. Patients undergoing thrombectomy will be excluded from enrollment. 
Subjects will be evaluated by emergency department and/or division of neurology 
physicians at the time of enrollment, during their hospitalization, as well as 30 days 
and 90 days after enrollment. At each visit, subjects will be assessed for functional 
status and quality of life by using well known and tested evaluations: National 
Institutes of Health Stroke Scale (NIHSS), Modified Rankin Scale (MRS), Glasgow 
Outcome Scale (GOS), and Barthel Index (BI).  
  
This study is designed to compare the efficacy of intravenous N-acetylcysteine 
compared to normal treatment in patients with acute ischemic stroke. Secondarily, we 
will also look at whether there was any benefit or harm to the subjects over the time 
course of the study.   
  
6) Background  
Stroke is a leading cause of death and long-term disability in the United States, 
affecting more than 795,000 individuals annually (1). Of these, about 87% are 
ischemic strokes. In properly selected patients, intravenous recombinant tissue 
plasminogen activator (t-PA) has been shown to improve functional outcomes if 
given within 4.5 hours of the onset of stroke symptoms (2, 3). Endovascular 
treatment both via clot retrieval devices and catheter directed t-PA has 
demonstrated benefit in well-selected patients with a large vessel occlusion and 
significant salvable tissue, also known as the penumbra (4-6). For patients who 
are not candidates for treatment with t-PA or mechanical thrombectomy, current 
treatment is centered on supportive care.  
  
N-Acetylcysteine (NAC) is an FDA approved medication that has been used 
successfully for many years in the treatment of acute acetaminophen overdose 
(79). It is generally well tolerated with the exception of rare anaphylactoid type 
reactions to the intravenous formulation (10, 11).   
In mouse studies, N-acetylcysteine (NAC) has led to an increase in glutathione 
levels in the neurons along with a reduced number of microbleeds in ischemic 
models (12). NAC treated rats have been demonstrated to have increased level of 
glutathione in the astrocytes which provides a neuroprotective effect. This 
reduced the number of microbleeds and prevented further thrombosis or infarct 
(12). The efficacy of NAC by scavenging of ROS and increasing mitochondrial 
activities has been shown to reduce noise-induced hearing loss in chinchilla 
models (13). Another study on transient cerebral ischemia rat models defined a 
new pharmacokinetic in which the neuroprotective effects of NAC are mediated 

PROTOCOL TITLE: Randomized Placebo Controlled Trial of Intravenous N-Acetylcysteine for 
the Treatment of Acute Ischemic Stroke  
  
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by the increased protein levels of hypoxia-induced factor 1 (HIF-1), its target 
erythropoietin (EPO) and glucose transporter (GLUT-3) (14).  
Studies have shown consistent, similar results for ischemic brain injury in rat (12, 
15-17). Consistent human studies showing neuroprotective effects which lead to 
reduced symptoms after traumatic brain injury, reduced noise-induced hearing 
loss and as a treatment for Parkinson’s disease (18-20).  
NAC has been shown to stimulate mitochondrial Complex 1 and 4 activities in 
vivo and in vitro in pre-synaptic terminals (17). The antioxidant effect of NAC by 
scavenging of ROS may prevent intracellular damage by inhibiting NF-κB (21, 
22), TNFα (23, 24) and Na+, K+ -ATPase inhibition (25) of the neurons.  
In a human study of NAC for Parkinson’s disease, NAC was found to mitigate the 
effects of ischemic brain injury in animal models (12). The antioxidant effect 
from repletion of intracellular glutathione is thought to preserve mitochondrial 
function and decrease cellular apoptosis (26, 27). A placebo-controlled human 
trial demonstrated that NAC is able to decrease the effects of mild traumatic brain 
injury 7 days after blast injury (18).  
A recent study has shown that sufficient plasma and CSF levels can be achieved 
at well tolerated doses: 7 mg/kg, 35 mg/kg and 50 mg/kg (28).  
A recent randomized placebo-controlled trial demonstrated improvement in 
patients given oral N-acetylcysteine every four hours for a total of 72 hours after 
enrollment in their NIH stroke scale and modified Rankin Score at 90 days. 
Intravenous N-Acetylcysteine given over 20 hours has proven to be equally 
efficacious in the treatment of acetaminophen toxicity and is currently the 
standard of care for that indication. We aim to determine if similarly dosed 
intravenous NAC regimen completed over a 20-hour course will improve NIH 
Stroke Scale at 90 days. of NAC following an acute ischemic stroke. (37)  
   
7) Setting of the Human Research  
This is a prospective randomized placebo-controlled study evaluating the 
efficacy of N-acetylcysteine for the treatment of acute ischemic stroke. It will 
be conducted at Harbor UCLA Medical Center.  
  
8) Resources Available to Conduct the Human Research  
Faculty and residents of the Departments of Emergency Medicine and 
Neurology at Harbor-UCLA will participate in the recruitment, execution, 
and analysis of the trial.  The required number of suitable subjects is 117. 
We will ensure that all persons assisting with the trial are adequately 
informed about the protocol, research method, and their trial-related duties 
and functions.  
  

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Intravenous N-Acetylcysteine will be donated by the manufacturer, 
Cumberland Pharmaceuticals (Acetadote®). Cumberland Pharmaceuticals will 
not have a role in the design, conduct, or analysis of the study.   
  
9) Prior Approvals  
The FDA has reviewed the study and gave an FDA IND (#145,538). 
Approved was also given by the research divisions of Cumberland 
Pharmaceuticals (Cumberland Pharmaceuticals have agreed to donate N-
acetylcysteine for the study).   
  
10)  Study Design  
  
1) 
The treating ED physicians (other than the investigator or 
coinvestigators) will identify potential subjects in the Emergency Department 
at Harbor UCLA via initial evaluation (standard of care) including blood 
draw for a standard CVA panel (CBC, Chemistries, PT, PTT, neuronal 
specific enolase, s100b) and brain imaging. Subjects who present with 
neurological deficits consistent with stroke without hemorrhage less than 24 
hours since symptom onset will be asked to whether they would be interested 
in participation in a research in our study and if so, the treating ED physician 
will contact investigators or study team member. Investigators or study team 
member may access medical record to confirm eligibility before approach 
subject.   
  
If treating physician is member a co-investigator/ study team member, s/he 
will approach subject about participation once deemed to meet eligibility 
criteria. (See inclusion and exclusion criteria below). Informed consent will 
be obtained for all subjects either from the subjects themselves or if they 
do not have capacity, from their legally authorized representative (See 
Section 16 below).  
  
2) 
Each subject will undergo, as part of standard of care, evaluation and 
assessment using the National Institutes of Health Stroke Scale (NIHSS) and 
the Modified Rankin Scale (MRS) which have been similarly used in the 
European Cooperative Acute Stroke Study III, ECASS III (3). The NIHSS is 
a 15-item scale that measures the level of neurologic impairment. The MRS 
is a measure of disability with scores ranging from 0 (no symptoms at all) to 
6 (death). Individuals must have an NIHSS of at least 5 to be eligible for this 
study. This data will be recorded for study purposes using a standard data 
collection sheet.  
  
3) 
Subjects will receive standard of care with the study intervention 
being considered an “add-on” therapy. Thirty minutes after enrollment, 
eligible subjects will be randomized into one of two arms: placebo or NAC. 

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the Treatment of Acute Ischemic Stroke  
  
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Any patient receiving t-PA who enrolls in the study will have their study 
drug infusion delayed by 24 hours after the completion of the t-PA infusion.   
  
The dosing of NAC will be similar to the standard intravenous acetaminophen 
toxicity dosing: 200mg/kg in 1 liter of 5% Dextrose (D5W) infused over 4 
hour, then 100mg/kg in 1000 milliliters D5W infused over 16 hours (29,38).   
 
Prior to receiving NAC, subjects will also receive 12.5 mg diphenhydramine 
(an antihistamine) to further reduce the chance of an allergic reaction.  
  
All subjects will be monitored closely by hospital staff either in the Emergency  
Department or the hospital’s monitored units (Intensive Care Unit or Step Down 
Unit) with vital signs obtained every 15 minutes for the first four hours of the 
infusion, and neurologic symptom checks completed every hour for the 20 hours 
of the study drug infusion in addition to the standard of care for stroke patients. 
The staff will be trained to observe for common side effects of the NAC infusion 
which may include nausea, vomiting, flushing, and pruritus along with the more 
uncommonly seen wheezing and bronchospasm or rarely angioedema and 
hypotension. Investigators will also prospectively ask the subjects every four 
hours up to 48 hours after administering the NAC to report if they are or have 
experienced any nausea, vomiting, flushing, itchiness or experienced wheezing or 
had any trouble breathing. Investigators will also prospectively record vital signs 
and look for evidence of anaphylactoid reactions or other allergic reactions. If any 
of the uncommon or rare drug effects are detected by nursing or by the 
investigators, there will be standing orders to stop the NAC infusion and 
immediately contact the physician caring for the patient. If a mild symptom 
occurs, the staff will be informed to contact the treating physician to assess the 
patient. At the same intervals, subjects will also be queried as to whether they 
have had any new symptoms or problems since the last study assessment to obtain 
data on a broader range of possible adverse and serious adverse events that may 
be unexpected or not typically associated with NAC infusions.   
 
Blood glucose levels will be monitored as part of the standard of care for stroke 
patients admitted to the hospital by the treating physicians. In addition, a finger 
stick glucose will be obtained prior to meals (three times daily) and recorded by 
the investigators. If an abnormal glucose measurement is noted, the treating 
neurology team will be notified. 
  
4) 
Subjects will be contacted by telephone 24 hours post discharge, 3 
days post discharge, and at 7 days to be monitored for adverse events and 
asked whether they have had any new symptoms or problems since the last 
study assessment. This will be an open question that will be recorded 
prospectively for each subject. If the subject reports an adverse event this is 
still present at the time of the phone call and wants to be further evaluated, 
they will be told to return to the emergency department and seen by a 
physician not associated with the investigation. Further the investigator from 

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the Treatment of Acute Ischemic Stroke  
  
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the team will also meet them in the Emergency Department to detail the 
information. All adverse events, whether they are deemed mild or serious, 
will be forwarded immediately to the Medical Monitor who will have 
discretion on whether to halt the study or continue. The Medical Monitor’s 
reports will be forwarded to the Institutional Review Board (IRB). In 
addition, all unanticipated problems pose a risk to subjects or others will be 
reported to the Institutional Review Board (IRB) as required by FDA 
regulations. (There is no sponsor for this study, so no report needs to go to a 
sponsor).   
  
4) Subjects will be instructed to return to the neurology clinic on day 30 
and day 90 for re-evaluation. The same assessment will be performed as 
on day zero: the NIHSS and the MRS as well as the Glasgow Outcome  
Scale (GOS) and Barthel Index (BI). The GOS is a 5-point scale on which  
5 indicates independence and 1 death. The BI assesses the ability to  
perform activities of daily living, on a scale that ranges from 0 (complete 
dependence on help with activities of daily living) to 100 (independence). 
These scores will be recorded on a standard data collection sheet. A 
representative from the neurology department will perform the 
examination, blinded from the previous scoring and treatment. In addition 
to the neurologic evaluation, patients will be queried at this time as to 
whether they experienced any nausea, vomiting, flushing, and itchiness, 
wheezing or difficulty breathing between the time of their discharge and 
the reevaluation.   
  
For convenience, the 30 day follow up will have a tolerance range +/- 3 days 
and the 90 day follow up will permit +/- 10 day window.   
  
These follow-up visits are standard of care. The tests are standard physical 
assessments done by the neurologists, and no specific interventions will be 
made for the study. Our study team will review EMR to obtain 
results/notes.  
  
5) 
Subjects will be instructed to return to the emergency department if 
their condition is worsens or if they develop new neurological symptoms.   
  
6) 
In addition to the clinic data, as standard of care, patients will have 
an MRI of the brain performed during the first 48 hours of their hospital 
admission and a follow-up MRI of the brain at 3 months as part of the 
standard of care for stroke patients. As per standard neurology evaluation, 
a blood test for s100b, neuronal specific enolase level will be obtained by 
the neurology team while the subject is admitted. MRI data will be 
analyzed initially for the type of stroke (either embolic, or thrombotic), 
stroke associated edema, for volumetric changes at three months 
poststroke, and gliosis at three months.   
  

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7) 
Telephone contact will be attempted if a subject is transferred to an 
outside hospital following admission, or if a subject does not show up to 
clinic for re-evaluation as scheduled, and efforts will be made to evaluate 
the patient in the time allotted. We will make a maximum of 3 phone calls 
within a 1 week period.  
  
a) Inclusion and Exclusion Criteria  
  
Inclusion Criteria:   
  
Consecutive subjects between ages 18 years or older evaluated in the emergency 
department at Harbor-UCLA Medical Center with signs and symptoms of acute 
ischemic stroke presenting within 24 hours of symptom onset. Individuals must 
have a NIHSS of at least 5 to be included. All individuals regardless of gender or 
race will be included. For adults who cannot consent for themselves because of 
the severity of their stroke, one of the investigators will offer participation in the 
study to the family member who possesses the authority for medical decision 
making for the patient. There is no financial incentive for either the patient or the 
investigator. It will also be explained that the potential benefit of giving N-
acetylcysteine is unknown and that the patient will receive excellent care 
(standard for their presentation) whether they participate or not and outside of not 
receiving the study drug.  
  
Our patients tend to be economically disadvantaged but since there are no 
financial incentives either for the patient or for the investigators, this bias has 
been minimized. Patients will receive the same care whether they participate in 
the study or decline.  
  
Exclusion Criteria:   
  
-Evidence of hemorrhagic stroke on initial CT scan  
-Need for thrombectomy as determined by the treating neurologist -Known 
allergy to NAC    
-Protected populations, including age < 18, known pregnancy, and 
prisoners  
-Patients who are DNR/DNI at the time of presentation with a short life 
expectancy  
  
b) Local Number of Subjects  
The total number of local subjects will be 117 (39 subjects with moderate stroke = 
NIHSS 5-15; 39 subjects with moderate to severe stroke = NIHSS 16-20; 39 
subjects with severe stroke = NIHSS = 21-42)   
  
This number was derived using a group size analysis based on previous 
work on oral NAC for ischemic stroke (37) and a hypothesis of finding no 

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the Treatment of Acute Ischemic Stroke  
  
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difference (defined as a change in NIHSS < 4) between NIHSS scores at 90 
days. With a power of 0.80 and an alpha 0.05 we would need 47 subjects in 
each group. Assuming a dropout rate of 25% or lost to follow-up, we 
would enroll 59 in each group for a total of 117.   
 
(Group sample sizes of 47 and 47 achieve 81% power to detect a difference 
of 4.0 using a one-sided Mann-Whitney U or Wilcoxon Rank-Sum test 
assuming that the actual data distribution is normal when the significance 
level (alpha) of the test is 0.05 and the standard deviation is 7.4 in both 
groups.) 
 
  
c) Study-Wide Number of Subjects  
This is a single center study at the Harbor-UCLA Medical Center.  
  
d) Study Timelines   
Estimated time to complete enrollment is December 2025.  Review of the 
neurology services revealed that Harbor-UCLA typically sees 20 patients per 
month that would be eligible for the study.   
  
e) Study Endpoints  
The primary study endpoint will be comparison between groups (NAC treated 
group versus treatment) of the NIHSS at 90 days.   
  
Secondary endpoints include changes in the MRS, GOS, BI, and blood tests 
at 30 days and 90 days, as well as MRI data including changes in brain 
volume and gliosis at 90 days.  
  
f) Procedures Involved in the Human Research  
First, subjects will be screened for neurological deficits consistent with 
cerebral vascular accident via history, physical examination and emergent 
evaluation in the Emergency Department which will include a noncontrast 
CT of the brain and an emergent Stroke Code, where our  
Neurology team will immediately consult on the patient at the bedside.  
  
As part of the initial evaluation, the patient will be assessed with the 
National Institutes of Health Stroke Scale (NIHSS) which uses a 15-item 
scoring system to assess the level of neurological impairment. The items 
assessed include: Level of consciousness (LOC) responsiveness, LOC 
questions, LOC commands, best gaze, visual field, facial palsy, best motor 
arm, best motor leg, limb ataxia, sensory function, neglect, dysarthria, best 
language, extinction and inattention, formerly called neglect (31, 32).   
  

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A Modified Rankin Scale (MRS) will also be obtained; The MRS is a 
simple scoring system that runs from 0-6, from perfect health without 
symptoms to death. 1- no significant disability, able to carry out all usual 
activities, despite some symptoms. 2 - slight disability, able to look after 
own affairs without assistance, but unable to carry out all previous 
activities. 3 - moderate disability, requires some help, but able to walk 
unassisted. 4 - moderately severe disability, unable to attend to own bodily 
needs without assistance, and unable to walk unassisted. 5 - severe 
disability, requires constant nursing care and attention, bedridden, 
incontinent.   
  
The neurology consult team in conjunction with the Emergency 
Department will then make an assessment as to whether the patient is 
eligible to receive treatment with t-PA (based on national criteria of the 
American Heart Association and American Stroke Association - 
https://www.stroke.org/-/media/Stroke-Files/Ischemic-StrokeProfessional-
Materials/AIS-Toolkit/AIS-Professional-EducationPresentation-
ucm_485538)  
  
NAC or placebo infusion will be started 30 minutes after the enrollment of 
the study. For subjects who receive t-PA, NAC or placebo infusion will be 
started 24 hours after the conclusion of the t-PA infusion.   
 
Prior to the starting of the study medication, all subjects will receive 12.5 
mg intravenous diphenhydramine to reduce the incidence of allergic 
reactions.  
  
All subjects would then be admitted to the Neurology Service to either an 
Intensive Care Unit bed or a Step-down intensive care unit bed.   
  
Subjects will return to neurology clinic on days 30 and 90 and undergo 
reevaluation by a neurology resident using the same assessments performed 
on day 0. Data will be collected on a standard data collection sheet at each 
visit. In addition, the subjects will undergo the following two assessments:  
  
Glasgow Outcome Scale (GOS, follow-up visits only):  
GOS is a 5-point scale on which 1- death, 2- persistent vegetative state, 3- severe 
disability, 4- moderate disability, and 5- low disability.   
  
Barthel Index (BI, follow-up visits only):   
BI evaluates the ability to perform activities of daily living, on a scale that 
ranges from 0 to 100. Activities assessed include: presence or absence of 
fecal incontinence, presence or absence of urinary incontinence, help 
needed with grooming, with toilet use, with feeding, with transfers, with 
walking, with dressing, with climbing stairs, and with bathing.   
  

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These follow-up visits are standard of care. These tests are standard 
physical assessments done by the neurologists, and no specific 
interventions will be made for the study. Our study team will review EMR 
to obtain results/notes.  
  
  
5. 
Each patient will complete two separate MRI’s of the brain, which 
are both standard of care. The MRI’s are considered standard of care and 
will not be different in acquisition then MRI’s currently obtained for stroke 
patients. We will use software packages available to post-process these 
images for research purposes as outlined in the protocol.   
  
6. 
Patients will have a “stroke panel” of lab tests as mentioned above, 
which are the standard of care at our facility. The total amount of blood 
obtained for the entire duration of the study will be less then 100ml.   
  
7. 
We will also pre-define a per-protocol (excluding Stroke Mimics as 
defined as a negative brain MRI obtained within 2 weeks of the onset of 
symptoms) versus an intent to treat protocol. This would allow for the loss 
of study subjects who might stop the NAC after a negative MRI who are no 
longer thought to have had a Stroke.  
  
g) Data and Specimen Banking  
No specimens will be stored.  
  
Data Collection sheets will be utilized for initial assessment and follow up. See 
attached documents.   
  
h) Data Management   
Data from the patient examinations will be stored in REDCAP database 
after being de-identified. It will be stored until this study completes. The 
data will be shared among the principal investigator and co-investigators. 
Principal investigator will be responsible for receipt or transmission of the 
data.  
  
i) Confidentiality  
Confidentiality will be maintained by use of coded data sheets and an 
enrollment logbook. Data will be stored in a password locked REDCAP 
database. It will be stored till the completion of this study. Only research 
investigators and research associates will have access to this data.  
  
j) Provisions to Monitor the Data to Ensure the Safety of subjects  
  

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Dr Timothy Horezcko is an Emergency Physician and Researcher located 
at the Lundquist Institute at Harbor-UCLA Medical Center who is not 
associated with the study and who will act as a Safety Monitor. Although 
NAC has FDA approval for acetaminophen poisoning, it does not have an 
FDA indication for Acute Ischemic Stroke and Dr Horezcko will review 
the prospectively collected safety data specifically looking for adverse 
events (both non-serious and serious adverse events), and will also analyze 
each subjects’ medical record which includes nursing notes, physician 
notes, ancillary care notes, vital signs, laboratories, clinical studies.   
  
Since this a single hospital trial, Dr Horezcko will the sole Safety Monitor and 
will act as an independent overseer who will access the care of each subject 
and the ongoing compilation of safety data throughout the trial and have the 
authority to modify or stop the trial at his discretion.  
  
Tracking adverse events  
  
All subjects will be monitored closely by hospital staff either in the Emergency  
Department or the hospital’s monitored units (Intensive Care Unit or Step Down 
Unit) with vital signs obtained every 15 minutes, and neurologic symptom checks 
completed every hour. The staff will be trained to observe for common side 
effects of the NAC infusion which may include nausea, vomiting, flushing, and 
pruritus along with the more uncommonly seen wheezing and bronchospasm or 
rarely angioedema and hypotension. Investigators will also prospectively ask the 
subjects every four hours to report if they are or have experienced any nausea, 
vomiting, flushing, itchiness or experienced wheezing or had any trouble 
breathing. Investigators will also prospectively monitor/record vital signs every 
15 minutes for the first 4 hours after the NAC administration and look for 
evidence of anaphylactoid reactions or other allergic reactions. If any of the 
uncommon or rare drug effects are detected by nursing or by the investigators, 
there will be standing orders to stop the NAC infusion and immediately contact 
the physician caring for the patient. If a mild symptom occurs, the staff will be 
informed to contact the treating physician to assess the patient. For serious 
adverse events (defined by the discretion of the treating physician), the NAC will 
be unblinded and the information given to the treating physician and the medical 
monitor. At the same intervals, subjects will also be queried as to whether they 
have had any new symptoms or problems since the last study assessment to obtain 
data on a broader range of possible adverse and serious adverse events that may 
be unexpected or not typically associated with NAC infusions. All adverse events 
will be immediately reported to the Medical Monitor who will have the authority 
to immediately halt the study pending further review by the Lundquist Institute’s 
IRB and the FDA.   
  
In addition, subjects will be contacted by telephone 24 hours post discharge, 3 
days poste discharge, and at 7 days to be monitored for adverse events and asked 
whether they have had any new symptoms or problems since the last study 

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assessment. This will be an open-ended question that will be recorded 
prospectively for each subject. If the subject reports an adverse event this is still 
present at the time of the phone call and wants to be further evaluated, they will 
be asked to return to the emergency department and seen by a physician not 
associated with the investigation. Further the investigator from the team will also 
meet them in the Emergency Department to detail the information. All adverse 
events, whether they are deemed mild or serious, will be forwarded immediately 
to the Medical Monitor who can immediately halt or terminate the study. In 
addition, all adverse events will be reported to the IRB of the Lundquist Institute 
by the investigators (and independently by the Medical Monitor). In a written 
IND safety report, any adverse experience associated with the use of the drug that 
was both serious and unexpected will be immediately reported to the FDA.   
  
Definition of adverse events for this protocol:  
  
Adverse Events  
  
Symptoms that are new or unexpected reported by the subject   
  
Nausea, diaphoresis, chest pain, abdominal pain, paresthesias, 
headache, visual complaints  
  
Cough, pruritis, rash  
  
 
  
Laboratory abnormality  
  
 
  
Minor bleeding from gums, nares  
 
                        Mild Sedation 
  
Serious Adverse Events  
  
Significant adverse events that led to an intervention, including 
withdrawal or dose reduction in the investigation drug or the need for 
concomitant therapy  
  
Wheezing, bronchospasm, angioedema requiring rescue 
medications  
  
Bleeding requiring an intervention   
  
Hemorrhagic conversion of the ischemic CVA  
  

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Worsening neurologic condition as measured by the NIHSS at 4 
hour intervals after enrollment in the study (or sooner as dictated 
by the care of the neurology team)  
  
Laboratory abnormality requiring intervention (e.g. severe 
hyponatremia or hyperkalemia)   
  
Death  
  
  
k) Withdrawal of Subjects  
Subjects will be withdrawn if they leave AMA/elope during their initial 
hospitalization or do not complete their 30 day or 90 day follow up prior to 
completion of the study  
  
11)  Risks to Subjects  
Risk of N-Acetylcysteine:  
Most adverse drug reactions that have been reported are minor and easily 
managed. Serious anaphylactoid reactions are extremely rare (11, 33-36)   
 Common: Nausea, vomiting, flushing, and pruritus,  
 Uncommon: Wheeze and bronchospasm (7.1%)  Rare: 
Angioedema, and hypotension (25-28)   
 
Risks of Diphenhydramine 
 
Most common side effects included drowsiness, dizziness, 
headache, irritability, stomach upset, vision changes (blurred 
vision), decreased coordination or dry mouth/nose/throat 
  
  
12)  Potential Benefits to Subjects  
Improved functional outcomes after a cerebral vascular event.  
  
13)  Provisions to Protect the Privacy Interests of Subjects  
Data confidentiality is maintained as above. Only research investigators will 
have access to this data.  
The enrollment will be performed in the emergency department. We 
will not discuss private medical information in a setting with other 
than a health care provider or in other than a private clinical setting. 
We will make sure situations such as answering sensitive questions by 
telephone while at home or work will not happen in this study.  
We will limit the information being collected to only the minimum 
amount of data necessary to accomplish the research purposes.  
  

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14)  Compensation for Research-Related Injury  
There is no commitment to provide any compensation for research-related 
injury. In the event that subjects are injured as a result of participating in 
this research, emergency care will be available on site. Subjects will, 
however, be responsible for the charges for the emergency and/or inpatient 
care.    
   
15)  Economic Burden to Subjects  
None – subjects will already be present at the hospital for care.   
  
16)  Consent Process  
Consent process will take place in the emergency department, ensuring subject 
privacy away from other on-going activities and personnel. The standard 
operating procedure for informed consent will be followed (SOP: Informed 
Consent Process for Research, HRP-090). Investigators or HIPPA trained 
research associates will seek consent for participation in this study from patients, 
their next of kin, or their legally authorized representative. The study will be 
explained during an approximately 15 minute discussion with the patient or their 
representative. They will be given as much time as they want to decide whether 
to participate in the study. The informed consent process requires that patients, 
their next of kin, or their legally authorized representative must able to 
understand, retain, and repeat the purpose, risks and benefits of the study to the 
consenting physician. Participants will be reminded that participation in the study 
is voluntary and their questions, if any, will be answered. All participants will be 
immediately withdrawn from the study if they appear to be unduly distressed. If 
subject requires some time for the information to be absorbed and appreciated, 
the researcher allow a period of time to elapse between imparting the information 
and requesting a signature on the consent form.   
  
Non-English Speaking Subjects  
Other than English, we expect Spanish speaking population to be participated in 
the study. In such case, consent form written in Spanish will be provided, and we 
will provide oral information using language line or by Spanish speaking 
investigators.  
  
Subjects who are not yet adults (infants, children, teenagers) Only subjects 
over the age of 18 will be included in this study. 
 
Cognitively Impaired Adults & Adults Unable to Consent 
Stroke victims may have cognitive impairment and lack capacity to provided 
informed consent. The study team will assess each patient’s capacity for decision-
making using a post consent survey (Appendix 1: Decision-Making Evaluation 
Form) and decision tree/flow diagram (Appendix 2).  

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Some stroke victims may be able to understand and communicate their 
willingness to participant but unable to physically sign a consent document. In 
these instances, we will seek permission/consent from their legally authorized 
representative for participation and seek the subjects “assent” (verbal) for 
participation as they are deemed able.  
 
If subject is deemed incapable of decision-making or unable to physically sign a 
consent document, consent will be sought from the subject’s the Legally 
Authorized Representative (as per HRP-013 SOP LARs, Children, Guardians). 
This individual will complete the Self-Certification of Surrogate Decision Makers 
form (Appendix 3) for documentation.  
 
Study participation will be discussed with both the patient and the physician of 
record/primary medical providers. Patient capacity to make decisions will be 
determined by the primary medical providers per routine. The study team will 
also determine each patient’s (potential subject’s) decision making capacity for 
participation in the study. Patients without capacity to make decisions and who 
lack a surrogate decision maker will be excluded from the study. Surrogate 
decision makers will be informed about the study in the same way as described 
above and offered to provide consent for the patient to enroll in the study. 
 
If and when a subject regains their capacity for decision-making, consent for 
continued participation in the study will be sought. The standard operating 
procedure for informed consent will be followed (SOP: Informed Consent 
Process for Research, HRP-090).  
 
17)  Process to Document Consent in Writing  
We are following “SOP: Written Documentation of Consent (HRP-091).”  
  
Individuals who are not yet adults, pregnant women, and prisoners will be 
excluded in this study. Other vulnerable subjects, such as students, subjects 
with limited or no treatment options, and socially and economically 
disadvantaged, may be included in this study. This study does not involve 
more than minimal risk to the subject.  
  
18)  Drugs or Devices  
N-Acetylcysteine and placebo. Study drugs will be stored, handled and 
dispensed by an ED pharmacist who is working at the time of study 
enrollment.  
 
Sylvia Youn, Pharm.D., the ED Pharmacist will maintain drug 
accountability logs in compliance with FDA regulations. She will instruct 
other ED pharmacists about the study and the randomization log which will 

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be kept in the pharmacy room in the ED. She will also create study drug 
labels to keep the nurses, physicians and patients blinded to the study 
medication.   
  
19)  Multi-Site Human Research  
N/A  
  
20)  Community-Based Participatory Research  
This is not a community-based participatory research project.  
  
21)  Sharing of Results with Subjects  
There are no results to be shared with the subjects until completion of the 
study. At that time, publication and study results will be available to 
participants at their request.   
  
22) Bibliography  
  
1. 
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart 
Disease and Stroke Statistics—2014 Update: A Report From the American Heart 
Association. Circulation. 2014;129(3):e28-e292.  
2. 
Tissue Plasminogen Activator for Acute Ischemic Stroke. New England Journal of 
Medicine. 1995;333(24):1581-8.  
3. 
Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al. 
Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New 
England Journal of Medicine. 2008;359(13):1317-29.  
4. 
Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. 
Endovascular therapy for ischemic stroke with perfusion-imaging selection. New 
England Journal of Medicine. 2015;372(11):1009-18.  
5. 
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. 
Randomized assessment of rapid endovascular treatment of ischemic stroke. New 
England Journal of Medicine. 2015;372(11):1019-30.  
6. 
Saver JL, Goyal M, Bonafe A, Diener H-C, Levy EI, Pereira VM, et al. 
StentRetriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke. New 
England Journal of Medicine. 2015;372(24):2285-95.  
7. 
Prescott LF, Ballantyne A, Proudfoot AT, Park J, Adriaenssens P. TREATMENT  
OF PARACETAMOL (ACETAMINOPHEN) POISONING WITH 
NACETYLCYSTEINE. The Lancet. 1977;310(8035):432-4.  
8. 
Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral 
Nacetylcysteine in the treatment of acetaminophen overdose. New England Journal 
of Medicine. 1988;319(24):1557-62.  
9. 
Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. 
Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning1979 
1979-11-03 00:00:00. 1097-100 p.  

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Page 19 of 25  
Template Revision: March 16, 2012  
10. Kao LW, Kirk MA, Furbee RB, Mehta NH, Skinner JR, Brizendine EJ. What is the 
rate of adverse events after oral N-acetylcysteine administered by the intravenous 
route to patients with suspected acetaminophen poisoning? Annals of Emergency 
Medicine. 2003;42(6):741-50.  
11. Yip L, Dart RC, Hurlbut KM. Intravenous administration of oral N-acetylcysteine. 
Critical care medicine. 1998;26(1):40-3.  
12. Bueche CZ, Garz C, Kropf S, Bittner D, Li W, Goertler M, et al. NAC changes the 
course of cerebral small vessel disease in SHRSP and reveals new insights for the 
meaning of stases-a randomized controlled study. Experimental & translational 
stroke medicine. 2013;5(1):5.  
13. Kopke RD, Weisskopf PA, Boone JL, Jackson RL, Wester DC, Hoffer ME, et al. 
Reduction of noise-induced hearing loss using L-NAC and salicylate in the 
chinchilla1. Hearing research. 2000;149(1-2):138-46.  
14. Zhang Z, Yan J, Taheri S, Liu KJ, Shi H. Hypoxia-inducible factor 1 contributes to 
N-acetylcysteine’s protection in stroke. Free Radical Biology and Medicine. 
2014;68:8-21.  
15. Cuzzocrea S, Mazzon E, Costantino G, Serraino I, Dugo L, Calabrò G, et al.  
Beneficial effects of n‐acetylcysteine on ischaemic brain injury. British journal of 
pharmacology. 2000;130(6):1219-26.  
16. Sekhon B, Sekhon C, Khan M, Patel SJ, Singh I, Singh AK. N-Acetyl cysteine 
protects against injury in a rat model of focal cerebral ischemia. Brain research. 
2003;971(1):1-8.  
17. Khan M, Sekhon B, Jatana M, Giri S, Gilg AG, Sekhon C, et al. Administration of  
N‐acetylcysteine after focal cerebral ischemia protects brain and reduces 
inflammation in a rat model of experimental stroke. Journal of neuroscience 
research. 2004;76(4):519-27.  
18. Hoffer ME, Balaban C, Slade MD, Tsao JW, Hoffer B. Amelioration of acute 
sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a 
doubleblind, placebo controlled study. PloS one. 2013;8(1):e54163.  
19. Kopke R, Slade MD, Jackson R, Hammill T, Fausti S, Lonsbury-Martin B, et al. 
Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss:  
a randomized clinical trial. Hearing research. 2015;323:40-50.  
20. Martínez-Banaclocha MA. N-acetyl-cysteine in the treatment of Parkinson’s disease. 
What are we waiting for? Medical hypotheses. 2012;79(1):8-12.  
21. Sha D, Chin L-S, Li L. Phosphorylation of parkin by Parkinson disease-linked 
kinase PINK1 activates parkin E3 ligase function and NF-κB signaling. Human 
molecular genetics. 2009;19(2):352-63.  
22. Aoki E, Yano R, Yokoyama H, Kato H, Araki T. Role of nuclear transcription factor 
kappa B (NF-kappaB) for MPTP (1-methyl-4-phenyl-1, 2, 3, 6-
tetrahyropyridine)induced apoptosis in nigral neurons of mice. Experimental and 
molecular pathology. 2009;86(1):57-64.  
23. Cossarizza A, Franceschi C, Monti D, Salvioli S, Bellesia E, Rivabene R, et al. 
Erratum: Protective effect of N-acetylcysteine in tumor necrosis factor-α-induced 

PROTOCOL TITLE: Randomized Placebo Controlled Trial of Intravenous N-Acetylcysteine for 
the Treatment of Acute Ischemic Stroke  
  
Page 20 of 25  
Template Revision: March 16, 2012  
apoptosis in U937 cells: The role of mitochondria (Experimental Cell Research 
(1995) 220: 1 (232-240)). Experimental Cell Research. 1996;222(1):251-3.  
24. Talley AK, Dewhurst S, Perry SW, Dollard SC, Gummuluru S, Fine SM, et al. 
Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection 
by the antioxidant N-acetylcysteine and the genes bcl-2 and crmA. Molecular and 
cellular biology. 1995;15(5):2359-66.  
25. Bagh MB, Maiti AK, Jana S, Banerjee K, Roy A, Chakrabarti S. Quinone and 
oxyradical scavenging properties of N-acetylcysteine prevent dopamine mediated 
inhibition of Na+, K+-ATPase and mitochondrial electron transport chain activity in 
rat brain: implications in the neuroprotective therapy of Parkinson's disease. Free 
radical research. 2008;42(6):574-81.  
26. Martinez-Banaclocha M. Therapeutic potential of N-acetylcysteine in age-related 
mitochondrial neurodegenerative diseases. Medical hypotheses. 2001;56(4):472-7.  
27. Martınez-Banaclocha M, Hernández AI, Mart́ ınez N. N-Acetylcysteine delays age-́ 
associated memory impairment in mice: role in synaptic mitochondria. Brain 
research. 2000;855(1):100-6.  
28. Katz M, Won SJ, Park Y, Orr A, Jones DP, Swanson RA, et al. Cerebrospinal fluid 
concentrations of N-acetylcysteine after oral administration in Parkinson's disease. 
Parkinsonism & related disorders. 2015;21(5):500-3.  
29. Mottram A, Kumar A. Focus on: Acetaminophen toxicity and treatment. ACEP 
News. 2008.  
30. Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, et al. 
Nacetylcysteine and contrast-induced nephropathy in primary angioplasty. New 
England Journal of Medicine. 2006;354(26):2773-82.  
31. Brott T, Adams H, Olinger CP, Marler JR, Barsan WG, Biller J, et al. Measurements 
of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20(7):864-70.  
32. Foundation NS. Clinical Guidelines For Stroke Management. Melbourne 
Australia2010.  
33. Waring WS, Stephen AF, Robinson OD, Dow MA, Pettie JM. Lower incidence of 
anaphylactoid reactions to N-acetylcysteine in patients with high acetaminophen 
concentrations after overdose. Clinical toxicology. 2008;46(6):496-500.  
34. Zyoud Se, Awang R, Sulaiman SAS, Sweileh W, Al-Jabi S. Incidence of adverse 
drug reactions induced by N-acetylcysteine in patients with acetaminophen 
overdose. Human & experimental toxicology. 2010.  
35. Pakravan N, Waring WS, Sharma S, Ludlam C, Megson I, Bateman DN. Risk 
factors and mechanisms of anaphylactoid reactions to acetylcysteine in 
acetaminophen overdose. Clinical toxicology. 2008;46(8):697-702.  
36. Sandilands E, Bateman D. Adverse reactions associated with acetylcysteine. Clinical 
Toxicology. 2009;47(2):81-8.  
37. Sabetghadam M, Mazdeh M, Abolfathi P, et al: Evidence for a beneficial effect of 
oral N-acetylcysteine on functional outcomes and inflammatory biomarkers in 
patients with Acute Ischemic Stroke. Neuropsychiatric Disease and Treatment 
2020;16:1265-1278.   
38. Hoyte C, Dart RC: Transition to two-bag intravenous acetylcysteine for 
acetaminophen overdose: a poison center’s experience Clinical Toxicology 
2019;57:217-218 

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Appendix 1: Lundquist Institute for Biomedical Innovation 
At Harbor-UCLA Medical Center 
 
John F. Wolf, M.D. Human Subjects Committee 
 
DECISION-MAKING EVALUATION FOR CAPACITY TO PROVIDE INFORMED CONSENT 
FOR RESEARCH 
 
Patient Data: 
 
Name: 
 
 
 
 
 
 
 
 
 
 
Date of Birth: 
 
 
 
 
 
 
 
 
 
Directions: 
Make a subjective judgment regarding item 1 below. Ask the patient or proxy/surrogate questions 2 through 5. The 
investigator may select the appropriate language to use in formulating the questions in order to assist the subject’s 
understanding. 
 
Items: 
 
1) Is the individual alert and able to communicate with the examiner?  
 Yes 
 No 
 
2) Ask the individual to name at least two (2) potential risks that may occur as a result of participating in the research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3) Ask the individual to name at least two things that will be expected of him/her in terms of patient cooperation during 
the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4) Ask the individual to explain what he/she would do if he/she decides that they no longer wish to participate in the 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5) Ask the individual to explain what he/she would do if he/she is experiencing distress or discomfort.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 I hereby certify that the above person is alert, able to communicate and able to give acceptable answers to items 2, 3, 
4 and 5 above. 

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 In my judgment, the above person does not appear to be able to give informed consent, based on answers to items 
2, 3, 4 and 5 above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s Signature 
 
 
 
 
 
 
Date/Time 
 
 

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Appendix 2: Flowchart  
 
 
 
 

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Appendix 3: